CN113666877A - Alkoxy and amido containing TYK2 inhibitor compound - Google Patents

Alkoxy and amido containing TYK2 inhibitor compound Download PDF

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CN113666877A
CN113666877A CN202110530272.2A CN202110530272A CN113666877A CN 113666877 A CN113666877 A CN 113666877A CN 202110530272 A CN202110530272 A CN 202110530272A CN 113666877 A CN113666877 A CN 113666877A
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alkyl
independently selected
compound
cycloalkyl
membered heteroaryl
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刘飞
孟庆义
冯涛涛
郑新涛
徐宏江
施伟
贺香依
王斌
李阳
常厦云
马雪琴
邹筱芳
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Abstract

This application is in the field of pharmaceutical chemistryThe utility model provides an alkoxy and amido containing TYK2 inhibitor compound, a preparation method thereof and application thereof in preparing medicaments for treating TYK2 related diseases.

Description

Alkoxy and amido containing TYK2 inhibitor compound
Reference to related applications
The priority and benefit of the present application, filed on the year 2020, month 05 and 15 with the national intellectual property office of the people's republic of china patent application No. 202010412342.X, the entire contents of which are hereby incorporated by reference in their entirety.
Technical Field
The application belongs to the field of pharmaceutical chemistry, provides an alkoxy and amido containing TYK2 inhibitor compound and a preparation method thereof, and relates to application of the compound in preparation of medicines for treating TYK2 related diseases.
Background
Tyrosine kinase 2(TYK2) is a member of the Janus kinase (JAK) family of non-receptor tyrosine kinases and has been shown in both mice and humans to be critical in regulating signal transduction cascades downstream of IL-12, IL-23 and type I interferon receptors. TYK2 mediates receptor-induced phosphorylation of members of the STAT transcription factor family, an essential signal for causing dimerization of STAT proteins and transcription of STAT-dependent pro-inflammatory genes. TYK2 lacks experimental models of mice resistant to colitis, psoriasis and multiple sclerosis, thus demonstrating the importance of TYK 2-mediated signaling in autoimmunity and related disorders. In humans, individuals expressing an inactive variant of TYK2 are protected from multiple sclerosis and possibly other autoimmune disorders.
In view of the conditions that can benefit from treatment involving modulation of cytokines and/or interferons, TYK2 inhibitor compounds capable of modulating cytokines and/or interferons such as IL-12, IL-23, and/or IFN α and methods of using these compounds can provide substantial therapeutic benefit to a wide variety of patients in need thereof.
Disclosure of Invention
In one aspect, the present application provides a compound of formula I:
Figure BDA0003067384170000011
wherein the content of the first and second substances,
each R1Are each independently selected from C1-8Alkyl or C3-10A cycloalkyl group;
m is selected from 1,2,3 or 4;
each R2Each independently selected from hydrogen, halogen, amino, hydroxy, C6-10Aryl, 5-10 membered heteroaryl, C1-8Alkyl or C3-10Cycloalkyl radical, said C6-10Aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl, C1-8Alkyl or C3-10Cycloalkyl is optionally substituted by one or more RaSubstitution;
n is selected from 1,2 or 3;
each RaEach independently selected from halogen, hydroxy, cyano, amino, C1-8Alkyl radical, C1-8Alkoxy orC substituted by one or more halogens1-8An alkyl group;
l is selected from-C (O) -or a bond;
R3selected from 5-10 membered heteroaryl, C3-10Cycloalkyl or C6-10Aryl, wherein the 5-10 membered heteroaryl, C3-10Cycloalkyl or C6-10Aryl is optionally substituted with one or more RbSubstitution;
each RbEach independently selected from halogen, hydroxy, cyano, amino, C1-8Alkyl radical, C1-8Alkoxy group, (C)1-8Alkyl radical)2P(O)-、C1-8alkyl-C (O) -, C1-8alkyl-SO2Or C substituted by one or more halogens or hydroxy groups1-8An alkyl group.
In some embodiments, each of the above R1Are each independently selected from C1-6Alkyl or C3-6A cycloalkyl group. In some embodiments, each of the above R1Are each independently selected from C1-4Alkyl or C3-6A cycloalkyl group.
In some embodiments, each of the above R1Are each independently selected from C1-8An alkyl group. In some embodiments, each of the above R1Are each independently selected from C1-6An alkyl group. In some embodiments, each of the above R1Are each independently selected from C1-4An alkyl group. In some embodiments, each of the above R1Each independently selected from methyl, isopropyl or tert-butyl.
In some embodiments, each of the above R1In (2), at least one R1Is methyl. In some embodiments, when m is selected from 2,3 or 4, each R as described above1In (2), at least two R1Is methyl.
In some embodiments, m is selected from 1,2, or 3. In some embodiments, m is selected from 1 or 2. In some embodiments, m is selected from 1 or 3. In some embodiments, m is selected from 2 or 3. In some embodiments, m is selected from 2.
In some embodiments, each R is2Each independently selected from hydrogen and C6-10Aryl, 5-6 membered heteroaryl, C1-6Alkyl or C3-6Cycloalkyl radical, said C6-10Aryl, 5-6 membered heteroaryl, C1-6Alkyl or C3-6Cycloalkyl radical C6-10Aryl, 5-6 membered heteroaryl, C1-6Alkyl or C3-6Cycloalkyl is optionally substituted by one or more RaAnd (4) substitution. In some embodiments, each R is2Each independently selected from hydrogen, phenyl, 5-6 membered heteroaryl, C1-3Alkyl or C3-6Cycloalkyl, said phenyl, 5-6 membered heteroaryl, C1-3Alkyl or C3-6Cycloalkyl is optionally substituted by one or more RaAnd (4) substitution.
In some embodiments, each R is2Each independently selected from hydrogen or 5-10 membered heteroaryl, said 5-10 membered heteroaryl optionally substituted with one or more RaAnd (4) substitution. In some embodiments, each R is2Each independently selected from hydrogen or 5-6 membered heteroaryl, said 5-6 membered heteroaryl optionally substituted with one or more RaAnd (4) substitution. In some embodiments, each R is2Each independently selected from hydrogen, triazolyl, pyridyl or pyrimidinyl, said triazolyl, pyridyl or pyrimidinyl being optionally substituted with one or more RaAnd (4) substitution. In some embodiments, each R is2Each independently selected from hydrogen, 1,2, 4-triazolyl, pyridyl or pyrimidinyl, said 1,2, 4-triazolyl, pyridyl or pyrimidinyl being optionally substituted with one or more RaAnd (4) substitution. In some embodiments, each R is2Each independently selected from hydrogen,
Figure BDA0003067384170000021
The above-mentioned
Figure BDA0003067384170000022
Figure BDA0003067384170000023
Optionally substituted by one or more RaAnd (4) substitution.
In some embodiments, n is selected from 1 or 2. In some embodiments, n is selected from 1.
In some embodiments, each R isaEach independently selected from halogen, hydroxy, cyano, amino, C1-6Alkyl radical, C1-6Alkoxy or C substituted by one or more halogens1-6An alkyl group. In some embodiments, each R isaEach independently selected from halogen, hydroxy, cyano, amino, C1-3Alkyl radical, C1-3Alkoxy or C substituted by one or more halogens1-3An alkyl group.
In some embodiments, each R isaAre each independently selected from C1-8An alkyl group. In some embodiments, each R isaAre each independently selected from C1-6An alkyl group. In some embodiments, each R isaAre each independently selected from C1-3An alkyl group. In some embodiments, each R isaEach independently selected from methyl.
In some embodiments, each R is2Each independently selected from hydrogen,
Figure BDA0003067384170000024
In some embodiments, L is-C (O) -. In some embodiments, L is a bond.
In some embodiments, R3Selected from 5-6 membered heteroaryl, C3-6Cycloalkyl or C6-10Aryl, wherein the 5-6 membered heteroaryl, C3-6Cycloalkyl or C6-10Aryl is optionally substituted with one or more RbAnd (4) substitution. In some embodiments, R3Selected from 5-6 membered heteroaryl, C3-6Cycloalkyl or phenyl, wherein said 5-6 membered heteroaryl, C3-6Cycloalkyl or phenyl optionally substituted by one or more RbAnd (4) substitution.
In some embodiments, R3Selected from 5-10 membered heteroaryl or C3-10Cycloalkyl, wherein said 5-10 membered heteroaryl or C3-10Cycloalkyl is optionally substituted by one or more RbAnd (4) substitution. In some embodiments, R3Selected from 5-6 membered heteroaryl or C3-6A cycloalkyl group,wherein the 5-6 membered heteroaryl or C3-6Cycloalkyl is optionally substituted by one or more RbAnd (4) substitution. In some embodiments, R3Selected from pyridyl, cyclopropyl or pyrimidinyl, wherein said pyridyl, cyclopropyl or pyrimidinyl is optionally substituted with one or more RbAnd (4) substitution. In some embodiments, R3Is selected from
Figure BDA0003067384170000031
Figure BDA0003067384170000032
Wherein said
Figure BDA0003067384170000033
Optionally substituted by one or more RbAnd (4) substitution.
In some embodiments, each R isbEach independently selected from halogen, hydroxy, cyano, amino, C1-6Alkyl radical, C1-6Alkoxy group, (C)1-6Alkyl radical)2P(O)-、C1-6alkyl-C (O) -, C1-6alkyl-SO2Or C substituted by one or more halogens or hydroxy groups1-6An alkyl group. In some embodiments, each R isbEach independently selected from halogen, hydroxy, cyano, amino, C1-3Alkyl radical, C1-3Alkoxy group, (C)1-3Alkyl radical)2P(O)-、C1-3alkyl-C (O) -, C1-3alkyl-SO2Or C substituted by one or more halogens or hydroxy groups1-3An alkyl group. In some embodiments, each R isbEach independently selected from fluorine, chlorine, bromine, cyano, C1-3Alkyl, (C)1-3Alkyl radical)2P (O) -or C substituted by one or more hydroxy groups1-3An alkyl group.
In some embodiments, each R isbAre respectively and independently selected from halogen, (C)1-8Alkyl radical)2P (O) -or C substituted by one or more hydroxy groups1-8An alkyl group. In some embodiments, each R isbAre respectively and independently selected from halogen, (C)1-6Alkyl radical)2P(O)-Or C substituted by one or more hydroxy groups1-6An alkyl group. In some embodiments, each R isbAre respectively and independently selected from halogen, (C)1-3Alkyl radical)2P (O) -or C substituted by one or more hydroxy groups1-3An alkyl group. In some embodiments, each R isbEach independently selected from fluorine, Chlorine and (CH)3CH2)2P (O) -or hydroxymethyl.
In some embodiments, R3Is selected from
Figure BDA0003067384170000034
Figure BDA0003067384170000035
In some embodiments, a structural fragment
Figure BDA0003067384170000036
Is selected from
Figure BDA0003067384170000037
Figure BDA0003067384170000038
Is further selected from
Figure BDA0003067384170000039
Figure BDA00030673841700000310
Is further selected from
Figure BDA00030673841700000311
Figure BDA0003067384170000041
Is still further selected from
Figure BDA0003067384170000042
Figure BDA0003067384170000043
In some embodiments, a structural fragment
Figure BDA0003067384170000044
Is selected from
Figure BDA0003067384170000045
Is further selected from
Figure BDA0003067384170000046
Figure BDA0003067384170000047
In another aspect, the present application provides a compound of formula II, formula III, formula IV, or a pharmaceutically acceptable salt thereof:
Figure BDA0003067384170000048
wherein, L, R1、R2And R3Are as defined for compounds of formula I.
In some embodiments, the structural fragments in the compounds of formula II, III, IV
Figure BDA0003067384170000049
As defined above.
In some embodiments, a structural fragment
Figure BDA00030673841700000410
May be selected from the structural fragments mentioned above
Figure BDA0003067384170000051
Is defined and covered by
Figure BDA0003067384170000052
A group of (1).
In some embodiments, the present application encompasses the variables defined above and embodiments thereof, as well as any combination thereof.
In yet another aspect, the present application provides the following compounds, or pharmaceutically acceptable salts thereof:
Figure BDA0003067384170000053
in another aspect, the present application also provides a pharmaceutical composition comprising a compound of the present application, or a pharmaceutically acceptable salt thereof, as described above. In some embodiments, the pharmaceutical compositions of the present application further comprise a pharmaceutically acceptable excipient.
In another aspect, the present application also provides a method for treating or preventing various disorders associated with TYK2, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound described above, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
In another aspect, the present application also provides a use of the above compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating or preventing various diseases related to TYK 2.
In another aspect, the present application also provides the use of the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment or prevention of various diseases associated with TYK 2.
In another aspect, the present application also provides a compound of the present application, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating or preventing various diseases associated with TYK 2.
In some embodiments, the TYK 2-related disorders are selected from autoimmune diseases.
Definition of
The following terms used in the present application have the following meanings, unless otherwise specified. A particular term should not be considered as ambiguous or unclear without special definition, but rather construed according to ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.
When a covalent bond in some structural unit or group is not attached to a particular atom in this application, it is meant that the covalent bond can be attached to any atom in the structural unit or group, as long as the valence bond attachment rules are not violated.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., ═ O), meaning that two hydrogen atoms are substituted, oxo does not occur on the aryl.
The terms "optionally" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl is "optionally" substituted with halo, meaning that ethyl may be unsubstituted (CH)2CH3) Monosubstituted (e.g. CH)2CH2F) Polysubstituted (e.g. CHFCH)2F、CH2CHF2Etc.) or completely substituted (CF)2CF3). It will be appreciated by those skilled in the art that any group containing one or more substituents will not incorporate any substitution or substitution pattern which is sterically impossible and/or cannot be synthesized.
Herein Cm-nIt is the moiety that has an integer number of carbon atoms in the given range. E.g. "C1-6By "is meant that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. E.g. C1-3Meaning that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms.
When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 2R, then there are separate options for each R.
When the number of one linking group is 0, e.g. - (CH)2)0-, indicates that the linking group is a covalent bond.
When one of the variables is selected from a covalent bond, it means that the two groups to which it is attached are directly linked, for example, in A-L '-Z where L' represents a covalent bond, it means that the structure is actually A-Z.
When a substituent's bond is cross-linked to two atoms on a ring, such substituent may be bonded to any atom on the ring. For example, a structural unit
Figure BDA0003067384170000061
Meaning that it may be substituted at any position on the cyclohexyl or cyclohexadiene.
The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.
The term "alkyl" refers to a group of formula CnH2n+1A hydrocarbon group of (1). The alkyl group may be linear or branched. For example, the term "C1-6Alkyl "means an alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio groups have the same definitions as above. Also for example, the term "C1-3Alkyl "refers to alkyl groups containing 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, and isopropyl).
The term "alkoxy" refers to-O-alkyl.
The term "cycloalkyl" refers to a carbon ring that is fully saturated and may exist as a single ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1 ] n]Heptyl), bicyclo [2.2.2]Octyl, adamantyl, bicyclo [1.1.1]Pent-1-yl, and the like. E.g. C3-4Cycloalkyl groups include cyclopropyl and cyclobutyl.
The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated pi-electron system. For example, the aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3, 4-tetrahydronaphthalene, and the like.
The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryl groups have a single 5 to 8 membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like.
The term "treating" means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i) inhibiting the disease or disease state, i.e., arresting its development;
(ii) alleviating the disease or condition, i.e., causing regression of the disease or condition.
The term "preventing" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes: prevention of a disease or condition occurs in a mammal, particularly when such mammal is susceptible to the disease condition, but has not yet been diagnosed as having the disease condition.
The term "therapeutically effective amount" means an amount of a compound of the present application that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art with their own knowledge and this disclosure.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As the pharmaceutically acceptable salt, for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like can be mentioned.
The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
The term "pharmaceutically acceptable adjuvants" refers to those adjuvants which do not have a significant irritating effect on the organism and do not impair the biological activity and properties of the active compound. Suitable adjuvants are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
The words "comprise" or "comprise" and variations thereof such as "comprises" or "comprising," are to be understood in an open, non-exclusive sense, i.e., "including but not limited to.
The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is an imidazole moiety, wherein the proton can migrate between two ring nitrogens. Valence tautomers include interconversion by recombination of some of the bonding electrons.
The present application also includes isotopically-labeled compounds of the present application, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as respectively2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I and36cl, and the like.
Certain isotopically-labelled compounds of the present application (e.g. with3H and14c-labeled ones) can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e. by tritiation)3H) And carbon-14 (i.e.14C) Isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as15O、13N、11C and18f can be used in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
In addition, heavier isotopes are used (such as deuterium (i.e., deuterium)2H) Substitution may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and thus may be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is substituted with at least one deuterium, all such forms of the compounds being encompassed within the scope of the present application.
The compounds of the present application may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present application containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.
The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.
Typical routes of administration of a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical compositions of the present application can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.
In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These adjuvants enable the compounds of the present application to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions and the like, for oral administration to a patient.
Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: the active compounds are mixed with solid adjuvants, optionally the mixture obtained is milled, if desired with further suitable adjuvants, and the mixture is then processed to granules, to give tablets or dragee cores. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
The pharmaceutical compositions may also be adapted for parenteral administration, as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
Therapeutic dosages of the compounds of the present application may be determined, for example, by: the particular use of the treatment, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compound of the present application in the pharmaceutical composition may not be fixed, depending on a variety of factors including dosage, chemical properties (e.g., hydrophobicity), and the route of administration. For example, the compounds of the present application can be provided for parenteral administration by a physiological buffered aqueous solution containing about 0.1-10% w/v of the compound. Some typical dosage ranges are from about 1. mu.g/kg to about 1g/kg body weight/day. In certain embodiments, the dosage range is from about 0.01mg/kg to about 100mg/kg body weight/day. The dosage will likely depend on such variables as the type and extent of progression of the disease or disorder, the general health status of the particular patient, the relative biological efficacy of the selected compound, the excipient formulation and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present application.
The chemical reactions of the embodiments herein are carried out in a suitable solvent that is compatible with the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes based on the existing embodiments.
An important consideration in the art of synthetic route planning is the selection of suitable protecting Groups for reactive functional Groups (e.g., amino Groups as used herein), for example, see Greene's Protective Groups in Organic Synthesis (4th Ed.) Hoboken, New Jersey: John Wiley & Sons, Inc.
In some embodiments, the compounds of the present application may be prepared by one skilled in the art of organic synthesis by reference to the following routes:
Figure BDA0003067384170000091
wherein R is1、R2、R3M, n, L are as defined above.
The following abbreviations are used in this application:
DIPEA for diisopropylethylamine; xanthphos stands for 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene; pd (dba)2Represents bis-dibenzylideneacetone palladium; DMF represents N, N-dimethylformamide; pd (dppf)2Cl2·CH2Cl2Represents [1,1' -bis (diphenylphosphino) ferrocene]A palladium dichloride dichloromethane complex; DMSO stands for dimethylsulfoxide.
For clarity, the present application is further illustrated by examples, which do not limit the scope of the present application. All reagents used herein were commercially available and used without further purification.
Detailed Description
Intermediate:
Figure BDA0003067384170000092
preparation of (6-aminopyridin-3-yl) oxydiethylphosphine:
2-amino-5-iodopyridine (1.0g), diethyloxyphosphorus (0.95g), palladium acetate (0.2g), Xantphos (0.5g) and potassium carbonate (1.9g) were dissolved in this order in 5mL dioxane, protected with nitrogen, and heated to 130 ℃ for 5 h. The reaction mixture was concentrated to give a compound (6-aminopyridin-3-yl) oxydiethylphosphine (1.5 g). ESI-MS: 199.0[ M + H ] M/z]+。
Example 1:
Figure BDA0003067384170000101
(1) the preparation method of the compound A comprises the following steps:
dissolving 4, 6-dichloropyridazine-3-carboxylic acid lithium salt (50g) in 500mL dichloromethane, placing at 0 ℃, adding a catalytic amount of DMF, slowly dropwise adding oxalyl chloride (96g) into the solution, moving to room temperature after the dropwise adding is finished, and continuously stirring for reacting for 2h until the reaction is complete. And (5) concentrating. Dissolving deuterated methylamine (18.6g) and DIPEA (162g) in 200mL dichloromethane, placing at-25 ℃, stirring to dissolve, dissolving the concentrate in 300mL dichloromethane, slowly dropwise adding the concentrate into the solution, and continuing stirring for 2h after the dropwise addition is finished. The reaction was quenched by addition of 750mL of water, extracted twice with dichloromethane (2X 500mL), the organic phases combined, washed with saturated aqueous sodium chloride, anhydrous Na2SO4Drying, filtration and concentration of the filtrate gave compound a (52 g). ESI-MS: M/z 209.2[ M + H ]]+。
(2) The preparation method of the compound B comprises the following steps:
compound A (15g) was dissolved in 250mL of tetrahydrofuran, the solution was brought to 0 ℃ and 250mL of aqueous ammonia was slowly added dropwise to the solution, after which stirring was continued at room temperature for 5 h. The mixture was concentrated under reduced pressure to remove tetrahydrofuran, stirred in an ice bath, filtered under suction, and dried under vacuum at 45 ℃ to give Compound B (11 g). ESI-MS: M/z 189.96[ M + H ]]+。
(3) The preparation method of the compound C comprises the following steps:
dissolving 2, 3-dimethoxybenzoic acid (455mg) in 15mL of dichloromethane, placing at 0 ℃, adding a catalytic amount of DMF, slowly dropwise adding oxalyl chloride (952.5mg) into the solution, moving to room temperature after the dropwise addition is finished, and continuously stirring for reacting for 2 hours until the reaction is complete for later use. Dissolving compound B (472.5mg) in 30mL of N-methylpyrrolidone, standing at-25 ℃, adding sodium hydride (480mg) in batches, stirring to dissolve the solution, slowly dropwise adding the prepared 2, 3-dimethoxybenzoyl chloride solution into the compound B solution, and continuing stirring for 2 hours after the dropwise addition is finished. The dichloromethane was removed by concentration under reduced pressure, 150mL of water was added, the solid precipitated, filtered off with suction and dried in vacuo at 45 ℃ to give Compound C (500 mg). ESI-MS: M/z 354.03[ M + H ]]+。
(4) A method for preparing compound 1:
compound C (400mg), cyclopropylcarboxamide (192mg, Ltd.), Pd (dba)2(101mg), Xantphos (127mg) and cesium carbonate (1.47g) were added to 100mL of 1, 4-dioxane, replaced with nitrogen three times, and heated to 100 ℃ for reaction for 5 h. Filtration, concentration and purification of the concentrate via preparative liquid phase gave compound 1(40 mg).1H NMR(DMSO-d6,500MHz,δppm):0.89-0.90(m,4H),2.08-2.16(m,1H),3.87(s,3H),3.88(s,3H),7.23(t,1H),7.32(d,1H),7.39(d,1H),9.26(s,1H),9.71(s,1H),11.55(s,1H),12.83(s,1H).ESI-MS:m/z＝403.12[M+H]+。
Referring to the procedure for the preparation of compound 1 in example 1, the following compound was prepared in step (4) replacing cyclopropylcarboxamide with the different intermediate 1-a:
Figure BDA0003067384170000102
Figure BDA0003067384170000111
Figure BDA0003067384170000121
example 9:
Figure BDA0003067384170000122
(1) the preparation method of the compound D comprises the following steps:
referring to the preparation method of compound C in example 1,2, 3-dimethoxybenzoic acid, which is a raw material, was changed to 2, 4-dimethoxybenzoic acid to obtain compound D. ESI-MS: M/z 354.02[ M + H ]]+。
(2) A method for preparing compound 9:
referring to the preparation method of compound 1 in example 1, the starting compound C was changed to compound D to give compound 9. ESI-MS: M/z 403.11[ M + H ]]+。
Referring to the preparation of example 9, substituting different intermediate 1-B for 2, 4-dimethoxybenzoic acid in step (1), the following compound was prepared:
Figure BDA0003067384170000123
Figure BDA0003067384170000131
example 16:
Figure BDA0003067384170000132
(1) preparation of compound E:
methyl 2-methoxy-4-bromobenzoate (10g), pinacol diboron (15.5g), Pd (dppf)2Cl2·CH2Cl2(1.65g) and potassium acetate (12g) were added to 400mL of 1, 4-dioxane, and the mixture was replaced with nitrogen three times, heated to 115 ℃ and reacted for 2 hours. Filtration gave a solution of Compound E in 1, 4-dioxane (400mL,0.1 mol/L). ESI-MS: M/z 292.92[ M + H ]]+。
(2) The preparation method of the compound F comprises the following steps:
mixing a solution of compound E in 1, 4-dioxane (125mL,0.1mol/L), 2-bromopyridine (2.23g), Pd (dppf)2Cl2·CH2Cl2(0.51g) and potassium phosphate (8.0g) were added to the reaction vessel, purged with nitrogen three times, and heated to 110 ℃ for 4 hours. Filtering, and concentrating under reduced pressure to obtain compound F. ESI-MS: 244.2[ M + H ] M/z]+。
(3) A process for the preparation of compound G:
compound F was reacted with methanol (40mL) and aqueous NaOH (20mL,1mol/L) under reflux for 5 h. Concentrating under reduced pressure, adding water, adjusting pH to 6, precipitating solid, vacuum filtering, and vacuum drying at 45 deg.C to obtain compound G (1.2G). ESI-MS: M/z 230.0[ M + H ]]+。
(4) The preparation method of the compound H comprises the following steps:
referring to the preparation method of compound C in example 1, the starting material 2, 3-dimethoxybenzoic acid was changed to compound G to give compound H. ESI-MS: M/z 401.03[ M + H ]]+。
(5) A method of preparing compound 16:
referring to the preparation method of example 1, the starting compound C was changed to compound H to give compound 16. ESI-MS: M/z 450.16[ M + H ]]+。
Example 17:
Figure BDA0003067384170000141
(1) a process for the preparation of compound I:
referring to the procedure for the preparation of compound F in example 16, the starting material, 2-bromopyridine, was replaced with 2-bromopyrimidine to give compound I. ESI-MS: M/z 245.2[ M + H ]]+。
(2) Preparation of compound J:
referring to the preparation of compound G in example 16, compound F therein was changed to compound I to give compound J. ESI-MS: M/z 231.2[ M + H ]]+。
(3) The preparation method of the compound K comprises the following steps:
referring to the preparation method of compound C in example 1, the starting material 2, 3-dimethoxybenzoic acid was changed to compound J to obtain compound K. ESI-MS: M/z 402.1[ M + H ]]+。
(4) A method of preparing compound 17:
referring to the preparation method of example 1, the starting compound C was changed to compound K to give compound 17. ESI-MS: M/z 451.13[ M + H ]]+。
Example 18:
Figure BDA0003067384170000151
(1) a process for the preparation of compound L:
preparation of Compound F in reference example 16The method comprises the step of replacing the raw material 2-bromopyridine with 3-bromo-1-methyl-1H-1, 2, 4-triazole to obtain a compound L. ESI-MS: M/z 248.2[ M + H ]]+。
(2) Preparation of compound M:
referring to the preparation of compound G in example 16, compound F therein was replaced with compound L to give compound M. ESI-MS: M/z 234.2[ M + H ]]+。
(3) The preparation method of the compound N comprises the following steps:
referring to the preparation method of compound C in example 1, the starting material 2, 3-dimethoxybenzoic acid was changed to compound M to give compound N. ESI-MS: M/z 405.09[ M + H ]]+。
(4) A method of preparing compound 18:
referring to the preparation method of example 1, the starting compound C was changed to compound N to give compound 18. ESI-MS: M/z 454.13[ M + H ]]+。
Example 19:
Figure BDA0003067384170000152
(1) the preparation method of the compound P comprises the following steps:
referring to the preparation of compound F in example 16, the starting material, 2-bromopyridine, was replaced with 3-bromo-1-methyl-1H-1, 2, 4-triazole, and compound E was replaced with compound O to give compound P. ESI-MS: M/z 248.02[ M + H ]]+。
(2) A method for preparing compound Q:
referring to the preparation method of compound G in example 16, compound F therein was changed to compound P to give compound Q. ESI-MS: M/z 234.01[ M + H ]]+。
(3) A process for the preparation of compound R:
referring to the preparation method of compound C in example 1, the starting material 2, 3-dimethoxybenzoic acid was changed to compound Q to give compound R. ESI-MS: M/z 405.0[ M + H ]]+。
(4) A method of preparing compound 19:
referring to the preparation method of example 1, the starting compound C was changed to compound R to give compound 19. ESI-MS: M/z 454.1[ M + H ]]+。
Experimental example 1TYK2 JH2 thermal stability assay
0.52mg/mL of TYK2 JH2 protein stock solution was diluted to 50 ng/. mu.L in Phosphate Buffered Saline (PBS), while 5000 Xprotein dye (Orange dye) (Sigma; cat # S5692) was diluted to 20 Xin DMSO, 16. mu.L of TYK2 JH2 protein diluent was added to each well, then DMSO-dissolved example compounds were added to the wells using a nanoliter loading apparatus to give final concentrations of 10. mu.M and 1. mu.M, respectively, for 2 concentrations, while blank control wells (containing no enzyme) and negative control wells (containing enzyme, in DMSO vehicle) were set for 2 replicate wells, and finally 4. mu.L of Orange dye was added to each well and mixed by centrifugation. The Roche LightCycler480 fluorescent quantitative PCR instrument is used for detection, and the operation system is as follows: 15s at 20 ℃; 0.02 ℃/s at the temperature of 30-90 ℃; 20 ℃ for 15 s. The melting temperature (Tm) was determined by Analysis using the LightCycler Thermal Shift Analysis software.
A compound of the application, wherein the melting temperature (Tm) is more than 40 ℃ under the condition of 10 mu M of final concentration; preferably greater than 45 ℃; more preferably greater than 55 ℃; further preferably greater than 60 deg.c. Under the condition of a final concentration of 1 mu M, the melting temperature (Tm) is more than 40 ℃; preferably greater than 45 ℃; more preferably greater than 50 ℃; further preferably greater than 55 deg.c.
Experimental example 2Jurkat detection STAT3 phosphorylation method
STAT3 phosphorylation assay kit (Y705), manufacturer Cisbio, cat # 62AT3 PEG. The number of Jurakt cells growing in the logarithmic phase was counted at 20. mu.L, the number of cells (mL) was counted, the cells were centrifuged at 1300rpm for 3min, and phenol red-free 1640 basic medium (Gibco, Cat. 11835-. Cells were plated at the above cell density (384 well low volume white plate) at 8. mu.L/well; loading by a nano-lift loading instrument, and incubating the compound for 1.5 h; IFN- α (manufactured by Casino Proteus, Cat. 13833-HNAY) was diluted to 75ng/mL (final concentration 25ng/mL) in phenol-free red 1640 complete medium; subsequently 4 μ LIFN- α (3X) was added per well according to plate distribution, and the blank was inoculated with cells without compound and without IFN- α;control group, inoculated cells, no compound, added IFN-alpha; incubate at 37 ℃ for 20 min. mu.L of blocking solution plus lysate (4X) was added immediately and incubated with shaking at room temperature for 40 min. Add 4. mu.L of pre-mixed antibody (vol/vol) in assay buffer, cover plate, centrifuge to mix well, and incubate overnight at room temperature. The PE Envision multifunctional plate reading instrument detects 665nm/620nm signal values, and four-parameter fitting calculation IC50. The results are shown in Table 1.
TABLE 1
Figure BDA0003067384170000161

Claims (10)

1. A compound of formula I:
Figure FDA0003067384160000011
wherein the content of the first and second substances,
each R1Are each independently selected from C1-8Alkyl or C3-10A cycloalkyl group;
m is selected from 1,2,3 or 4;
each R2Each independently selected from hydrogen, halogen, amino, hydroxy, C6-10Aryl, 5-10 membered heteroaryl, C1-8Alkyl or C3-10Cycloalkyl radical, said C6-10Aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl, C1-8Alkyl or C3-10Cycloalkyl is optionally substituted by one or more RaSubstitution;
n is selected from 1,2 or 3;
each RaEach independently selected from halogen, hydroxy, cyano, amino, C1-8Alkyl radical, C1-8Alkoxy or C substituted by one or more halogens1-8An alkyl group;
l is selected from-C (O) -or a bond;
R3selected from 5-10 membered heteroaryl, C3-10Cycloalkyl or C6-10An aryl group, a heteroaryl group,wherein said 5-10 membered heteroaryl, C3-10Cycloalkyl or C6-10Aryl is optionally substituted with one or more RbSubstitution;
each RbEach independently selected from halogen, hydroxy, cyano, amino, C1-8Alkyl radical, C1-8Alkoxy group, (C)1-8Alkyl radical)2P(O)-、C1-8alkyl-C (O) -, C1-8alkyl-SO2Or C substituted by one or more halogens or hydroxy groups1-8An alkyl group.
2. A compound of formula I according to claim 1, wherein each R is1Are each independently selected from C1-6Alkyl or C3-6A cycloalkyl group;
or, each R1Are each independently selected from C1-4Alkyl or C3-6A cycloalkyl group;
or, each R1Are each independently selected from C1-8An alkyl group;
or, each R1Are each independently selected from C1-6An alkyl group;
or, each R1Are each independently selected from C1-4An alkyl group;
or, each R1Each independently selected from methyl, isopropyl or tert-butyl;
or, each R1In (2), at least one R1Is methyl;
or, when m is selected from 2,3 or 4, each of the above R1In (2), at least two R1Is methyl;
optionally, m is selected from 1,2 or 3;
alternatively, m is selected from 1 or 2;
alternatively, m is selected from 1 or 3;
alternatively, m is selected from 2 or 3;
alternatively, m is selected from 2.
3. A compound of formula I as claimed in claims 1-2, or a pharmaceutically acceptable salt thereof, each R2Each independently selected from hydrogen and C6-10Aryl, 5-6 membered heteroaryl, C1-6Alkyl or C3-6Cycloalkyl radical, said C6-10Aryl, 5-6 membered heteroaryl, C1-6Alkyl or C3-6Cycloalkyl radical C6-10Aryl, 5-6 membered heteroaryl, C1-6Alkyl or C3-6Cycloalkyl is optionally substituted by one or more RaSubstitution;
or, each R2Each independently selected from hydrogen, phenyl, 5-6 membered heteroaryl, C1-3Alkyl or C3-6Cycloalkyl, said phenyl, 5-6 membered heteroaryl, C1-3Alkyl or C3-6Cycloalkyl is optionally substituted by one or more RaSubstitution;
or, each R2Each independently selected from hydrogen or 5-10 membered heteroaryl, said 5-10 membered heteroaryl optionally substituted with one or more RaSubstitution;
or, each R2Each independently selected from hydrogen or 5-6 membered heteroaryl, said 5-6 membered heteroaryl optionally substituted with one or more RaSubstitution;
or, each R2Each independently selected from hydrogen, triazolyl, pyridyl or pyrimidinyl, said triazolyl, pyridyl or pyrimidinyl being optionally substituted with one or more RaSubstitution;
or, each R2Each independently selected from hydrogen, 1,2, 4-triazolyl, pyridyl or pyrimidinyl, said 1,2, 4-triazolyl, pyridyl or pyrimidinyl being optionally substituted with one or more RaSubstitution;
or, each R2Each independently selected from hydrogen,
Figure FDA0003067384160000021
The above-mentioned
Figure FDA0003067384160000022
Figure FDA0003067384160000023
Optionally substituted by one or more RaSubstitution;
or, each R2Each independently selected from hydrogen,
Figure FDA0003067384160000024
Optionally, n is selected from 1 or 2;
alternatively, n is selected from 1;
optionally, each RaEach independently selected from halogen, hydroxy, cyano, amino, C1-6Alkyl radical, C1-6Alkoxy or C substituted by one or more halogens1-6An alkyl group;
or, each RaEach independently selected from halogen, hydroxy, cyano, amino, C1-3Alkyl radical, C1-3Alkoxy or C substituted by one or more halogens1-3An alkyl group;
or, each RaAre each independently selected from C1-8An alkyl group;
or, each RaAre each independently selected from C1-6An alkyl group;
or, each RaAre each independently selected from C1-3An alkyl group;
or, each RaEach independently selected from methyl.
4. A compound of formula I as claimed in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, R3Selected from 5-6 membered heteroaryl, C3-6Cycloalkyl or C6-10Aryl, wherein the 5-6 membered heteroaryl, C3-6Cycloalkyl or C6-10Aryl is optionally substituted with one or more RbSubstitution;
or, R3Selected from 5-6 membered heteroaryl, C3-6Cycloalkyl or phenyl, wherein said 5-6 membered heteroaryl, C3-6Cycloalkyl or phenyl optionally substituted by one or more RbSubstitution;
or, R3Selected from 5-10 membered heteroaryl or C3-10Cycloalkyl, wherein said 5-10 membered heteroaryl or C3-10Cycloalkyl is optionally substituted by one or more RbSubstitution;
or, R3Selected from 5-6 membered heteroaryl or C3-6Cycloalkyl, wherein said 5-6 membered heteroaryl or C3-6Cycloalkyl is optionally substituted by one or more RbSubstitution;
or, R3Selected from pyridyl, cyclopropyl or pyrimidinyl, wherein said pyridyl, cyclopropyl or pyrimidinyl is optionally substituted with one or more RbSubstitution;
or, R3Is selected from
Figure FDA0003067384160000025
Wherein said
Figure FDA0003067384160000026
Figure FDA0003067384160000031
Optionally substituted by one or more RbSubstitution;
or, R3Is selected from
Figure FDA0003067384160000032
5. A compound of formula I as claimed in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, each RbEach independently selected from halogen, hydroxy, cyano, amino, C1-6Alkyl radical, C1-6Alkoxy group, (C)1-6Alkyl radical)2P(O)-、C1-6alkyl-C (O) -, C1-6alkyl-SO2Or C substituted by one or more halogens or hydroxy groups1-6An alkyl group;
or, each RbEach independently selected from halogen, hydroxy, cyano, amino, C1-3Alkyl radical, C1-3Alkoxy group, (C)1-3Alkyl radical)2P(O)-、C1-3alkyl-C (O) -, C1-3alkyl-SO2Or C substituted by one or more halogens or hydroxy groups1-3An alkyl group;
or, each RbEach independently selected from fluorine, chlorine, bromine, cyano, C1-3Alkyl, (C)1-3Alkyl radical)2P (O) -or C substituted by one or more hydroxy groups1-3An alkyl group;
or, each RbAre respectively and independently selected from halogen, (C)1-8Alkyl radical)2P (O) -or C substituted by one or more hydroxy groups1-8An alkyl group;
or, each RbAre respectively and independently selected from halogen, (C)1-6Alkyl radical)2P (O) -or C substituted by one or more hydroxy groups1-6An alkyl group;
or, each RbAre respectively and independently selected from halogen, (C)1-3Alkyl radical)2P (O) -or C substituted by one or more hydroxy groups1-3An alkyl group;
or, each RbEach independently selected from fluorine, Chlorine and (CH)3CH2)2P (O) -or hydroxymethyl.
6. A compound of formula I according to any one of claims 1 to 5 or a pharmaceutically acceptable salt, structural fragment thereof
Figure FDA0003067384160000033
Is selected from
Figure FDA0003067384160000034
Or, a structural fragment
Figure FDA0003067384160000035
Is selected from
Figure FDA0003067384160000036
Figure FDA0003067384160000037
Or, a structural fragment
Figure FDA0003067384160000038
Is selected from
Figure FDA0003067384160000039
Figure FDA0003067384160000041
Or, a structural fragment
Figure FDA0003067384160000042
Is selected from
Figure FDA0003067384160000043
Figure FDA0003067384160000044
Optionally, a structural fragment
Figure FDA0003067384160000045
Is selected from
Figure FDA0003067384160000046
Or, a structural fragment
Figure FDA0003067384160000047
Is selected from
Figure FDA0003067384160000048
Figure FDA0003067384160000049
7. A compound of formula I according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, selected from a compound of formula II, a compound of formula III, a compound of formula IV, or a pharmaceutically acceptable salt thereof:
Figure FDA00030673841600000410
8. the following compounds or pharmaceutically acceptable salts thereof:
Figure FDA0003067384160000051
9. a pharmaceutical composition comprising a compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof.
10. Use of a compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 9, in the manufacture of a medicament for the treatment or prevention of various disorders associated with TYK 2;
optionally, wherein the TYK 2-related disorders are selected from autoimmune diseases.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023076161A1 (en) 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Tyk2 degraders and uses thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023076161A1 (en) 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Tyk2 degraders and uses thereof

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