CN114907326A - Amido and bicyclic inhibitors of TYK2 - Google Patents

Amido and bicyclic inhibitors of TYK2 Download PDF

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CN114907326A
CN114907326A CN202210092555.8A CN202210092555A CN114907326A CN 114907326 A CN114907326 A CN 114907326A CN 202210092555 A CN202210092555 A CN 202210092555A CN 114907326 A CN114907326 A CN 114907326A
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optionally
cycloalkyl
compound
membered heteroaryl
structural unit
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刘飞
刘彦龙
邢磊
杨玲
胡中元
蔡正贵
聂全登
王斌
王善春
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Abstract

The application belongs to the field of medicinal chemistry, provides an amido group and bicycling TYK2 inhibitor compound and a preparation method thereof, and relates to application of the compound in preparing medicaments for treating TYK2 related diseases.

Description

Amido and bicyclic TYK2 inhibitor compounds
Cross Reference to Related Applications
The present disclosure claims the benefit and priority of chinese patent application No. 202110165848, filed on the intellectual property office of the people's republic of china at 2021, month 06, the entire contents of which are hereby incorporated by reference in their entirety.
Technical Field
The application belongs to the field of medicinal chemistry, provides an amido group and bicycling TYK2 inhibitor compound and a preparation method thereof, and relates to application of the compound in preparing a medicament for treating or preventing 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 application provides a compound of formula I, or a pharmaceutically acceptable salt thereof:
Figure BDA0003489744900000011
wherein,
Cy 1 and Cy 2 Are each independently selected from C 6-10 Aryl or 5-10 membered heteroaryl;
each R 1 Or R 2 Each independently selected from halogen, hydroxy, amino, cyano, C 1-8 Alkyl radical, C 3-10 Cycloalkyl or 5-to 10-membered heterocycloalkyl, said C 1-8 Alkyl radical, C 3-10 Cycloalkyl or 5-10 membered heterocycloalkyl optionally substituted with one or more halogen, deuterium, hydroxy or cyano;
m is selected from 0, 1,2,3,4 or 5;
n is selected from 0, 1,2,3,4 or 5;
l is selected from-C (O) -or a bond;
R 3 selected from 5-10 membered heteroaryl, C 3-10 Cycloalkyl radical, C 6-10 Aryl or 3-10 membered heterocycloalkyl, wherein said 5-10 membered heteroaryl, C 3-10 Cycloalkyl radical, C 6-10 Aryl or 3-10 membered heterocycloalkyl optionally substituted with one or more R a Substitution;
each R 4 Each independently selected from halogen;
p is selected from 0, 1,2 or 3;
R a selected from halogen, cyano, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 3-10 Cycloalkyl oxy, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, amino, C 1-8 Alkyl NH-, (C) 1-8 Alkyl radical) 2 N-、C 3-10 Cycloalkyl NH-or C substituted by one or more halogens 1-8 An alkyl group.
In some embodiments, the Cy is a divalent cation 1 And Cy 2 Each independently selected from phenyl or 5-10 membered heteroaryl.
In some embodiments, the Cy is a divalent cation 1 And Cy 2 Each independently selected from phenyl, 5-membered heteroaryl or 6-membered heteroaryl. In thatIn some embodiments, the Cy is 1 And Cy 2 Each independently selected from phenyl or 5-membered heteroaryl.
In some embodiments, the Cy is a divalent cation 1 And Cy 2 Each independently selected from phenyl, a nitrogen atom-containing 5-membered heteroaryl group, or a nitrogen atom-containing 6-membered heteroaryl group.
In some embodiments, the Cy is a divalent cation 1 And Cy 2 Each independently selected from phenyl, 5-membered heteroaryl or 6-membered heteroaryl, the ring atoms of which consist of a nitrogen atom and a carbon atom.
In some embodiments, the Cy is 1 And Cy 2 Each independently selected from phenyl, pyridyl, triazolyl or tetrazolyl.
In some embodiments, the Cy is 1 Is phenyl.
In some embodiments, the Cy is a divalent cation 2 Selected from pyridyl, triazolyl or tetrazolyl.
In some embodiments, each R is 1 Or R 2 Each independently selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or 5-6 membered heterocycloalkyl, said C 1-6 Alkyl radical, C 3-6 Cycloalkyl or 5-6 membered heterocycloalkyl is optionally substituted with one or more halogen, deuterium, hydroxy or cyano.
In some embodiments, each R is 1 Or R 2 Are each independently selected from C 1-4 Alkyl radical, C 3-6 Cycloalkyl or 5-6 membered heterocycloalkyl, said C 1-4 Alkyl radical, C 3-6 Cycloalkyl or 5-6 membered heterocycloalkyl is optionally substituted with one or more halogen, deuterium, hydroxy or cyano groups.
In some embodiments, each R is 1 Each independently selected from halogen, hydroxy or cyano.
In some embodiments, each R is 2 Are each independently selected from C 1-4 Alkyl radical, C 3-6 Cycloalkyl or 5-6 membered heterocycloalkyl, said C 1-4 Alkyl radical, C 3-6 Cycloalkyl or 5-6 membered heterocycloalkyl optionally substituted by oneOr multiple halogen or deuterium substitutions.
In some embodiments, each R is 2 Are each independently selected from C 1-4 Alkyl or C 3-6 Cycloalkyl radical, said C 1-4 Alkyl is optionally substituted with one or more halogen or deuterium.
In some embodiments, each R is 2 Each independently selected from methyl, ethyl, isopropyl, 2-methylpropyl or cyclopropyl.
In some embodiments, said m is selected from 0, 1,2 or 3. In some embodiments, m is selected from 0, 1 or 2. In some embodiments, m is 0.
In some embodiments, the n is selected from 0, 1,2, or 3. In some embodiments, the n is selected from 0, 1 or 2. In some embodiments, said n is 1.
In some embodiments, m is 0 and n is 1.
In some embodiments, the L is-CO-.
In some embodiments, the R is 3 Selected from 6-10 membered heteroaryl, C 3-6 Cycloalkyl, phenyl or 3-6 membered heterocycloalkyl wherein said 6-10 membered heteroaryl, C 3-6 Cycloalkyl, phenyl or 3-6 membered heterocycloalkyl optionally substituted with one or more R a And (4) substitution.
In some embodiments, the R is 3 Selected from 6-membered heteroaryl, cyclopropyl, cyclobutyl or cyclohexyl, wherein said 6-membered heteroaryl, cyclopropyl, cyclobutyl or cyclohexyl is optionally substituted by one or more R a And (4) substitution.
In some embodiments, the R is 3 Selected from pyridyl or cyclopropyl optionally substituted by one or more R a And (4) substitution.
In some embodiments, the R is 3 Selected from optionally substituted by one or more R a A substituted cyclopropyl group. In some embodiments, R 3 Selected from cyclopropyl. In some embodiments, each R is 4 Each independently selected from fluorine, chlorine, bromine or iodine.
In some casesIn embodiments, the R 4 Is fluorine.
In some embodiments, p is selected from 0, 1 or 2. In some embodiments, p is selected from 0 or 1.
In some embodiments, p is 0.
In some embodiments, the R is 4 Is fluorine and p is 1.
In some embodiments, the R is a Selected from halogen, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl oxy, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl or C substituted with one or more halogens 1-6 An alkyl group.
In some embodiments, the R is a Selected from halogen, cyano, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 3-6 Cycloalkyl oxy, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl or C substituted by one or more fluoro 1-3 An alkyl group.
In some embodiments, the R is a Selected from fluorine, chlorine, bromine, cyano, C 1-3 Alkyl radical, C 1-3 Alkoxy or C substituted by 1,2 or 3 fluorine 1-3 An alkyl group.
In some embodiments, a building block
Figure BDA0003489744900000031
Is selected from
Figure BDA0003489744900000032
In some embodiments, a building block
Figure BDA0003489744900000033
Is selected from
Figure BDA0003489744900000034
In some embodiments, a building block
Figure BDA0003489744900000035
Is selected from
Figure BDA0003489744900000036
In some embodiments, a building block
Figure BDA0003489744900000037
Is selected from
Figure BDA0003489744900000038
Figure BDA0003489744900000039
In some embodiments, a building block
Figure BDA00034897449000000310
Is selected from
Figure BDA00034897449000000311
Figure BDA00034897449000000312
In some embodiments, a building block
Figure BDA00034897449000000313
Is selected from
Figure BDA00034897449000000314
In some embodiments, a building block
Figure BDA0003489744900000041
Is selected from
Figure BDA0003489744900000042
In some embodiments, a building block
Figure BDA0003489744900000043
Is selected from
Figure BDA0003489744900000044
In some embodiments, a building block
Figure BDA0003489744900000045
Is selected from
Figure BDA0003489744900000046
In some embodiments, a building block
Figure BDA0003489744900000047
Is selected from
Figure BDA0003489744900000048
In some embodiments, a building block
Figure BDA0003489744900000049
Is selected from
Figure BDA00034897449000000410
Figure BDA00034897449000000411
In some embodiments, a building block
Figure BDA00034897449000000412
Is selected from
Figure BDA00034897449000000413
In some embodiments, a building block
Figure BDA00034897449000000414
Is selected from
Figure BDA00034897449000000415
In some embodiments, a building block
Figure BDA0003489744900000051
Is selected from
Figure BDA0003489744900000052
In some embodiments, a building block
Figure BDA0003489744900000053
Is composed of
Figure BDA0003489744900000054
Wherein X is selected from hydrogen or fluorine; or a structural unit
Figure BDA0003489744900000055
Is selected from
Figure BDA0003489744900000056
In some embodiments, a building block
Figure BDA0003489744900000057
Is selected from
Figure BDA0003489744900000058
In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from a compound of formula I-1 or a compound of formula I-2 or a pharmaceutically acceptable salt thereof
Figure BDA0003489744900000059
Wherein X is selected from hydrogen or fluorine, and Y is selected from N or CH; cy is a Cy-is 1 、Cy 2 、R 1 、R 2 M, n are as defined above.
In some embodiments, a building block
Figure BDA00034897449000000510
As defined above.
In some embodiments, a building block
Figure BDA00034897449000000511
Is selected from
Figure BDA00034897449000000512
In some embodiments, a building block
Figure BDA0003489744900000061
Is selected from
Figure BDA0003489744900000062
In some embodiments, the present application encompasses the variables defined above and embodiments thereof, as well as any combination thereof.
In another aspect, the present application provides the following compounds, or pharmaceutically acceptable salts thereof:
Figure BDA0003489744900000063
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 diseases associated with TYK2, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically or prophylactically 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 compounds of the present application or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in 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 inflammatory or autoimmune diseases.
The compounds of the present application possess good in vitro enzymatic or cellular activity, metabolic stability such as hepatic microsomal metabolic stability, as well as pharmacokinetic and in vivo pharmacodynamic properties.
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, the oxo does not occur on the aryl group.
The terms "optional" 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) 2 CH 3 ) Monosubstituted (e.g. CH) 2 CH 2 F) Polysubstituted (e.g. CHFCH) 2 F、CH 2 CHF 2 Etc.) or completely substituted (CF 2 CF 3 ). 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 C m-n Is the partEach having an integer number of carbon atoms in the given range. E.g. "C 1-6 By "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. C 1-3 Meaning 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 the number of one substituent is 0, for example- (R) 1 ) 0 Represents unsubstituted, for example
Figure BDA0003489744900000071
To represent
Figure BDA0003489744900000072
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 BDA0003489744900000073
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 C n H 2n+1 A hydrocarbon group of (1). The alkyl group may be linear or branched. For example, the term "C 1-6 Alkyl "refers to an alkyl group containing 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 "C 1-3 Alkyl "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 "cycloalkoxy" refers to-O-cycloalkyl.
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. C 3-4 Cycloalkyl groups include cyclopropyl and cyclobutyl.
The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and may exist as a single ring, a bridged ring (including fused rings), or a spiro ring. Unless otherwise indicated, the heterocyclic ring is typically a 3 to 7 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. Examples of 3-membered heterocycloalkyl include, but are not limited to, oxiranyl, thietanyl, cycloazenyl, non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thiabutinyl, examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, examples of tetrahydropyrazolyl, 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thialkyl, 1, 4-dioxanyl, thiomorpholinyl, 1, 3-dithianyl, 1, 4-dithianyl, and examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, thiepanyl. Monocyclic heterocycloalkyl groups having 5 or 6 ring atoms are preferred.
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 compounds of the present application may exist in specific geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present application.
Using solid wedge keys, unless otherwise indicated
Figure BDA0003489744900000081
And wedge dotted bond
Figure BDA0003489744900000082
Showing the absolute configuration of a solid centre, by means of straight solid keys
Figure BDA0003489744900000083
And straight dotted bond
Figure BDA0003489744900000084
Showing the relative configuration of the centres of solids, by wavy lines
Figure BDA0003489744900000085
Representing solid-line keys of wedge shape
Figure BDA0003489744900000086
Or wedge dotted bond
Figure BDA0003489744900000087
Or by wavy lines
Figure BDA0003489744900000088
Indicating straight solid-line keys
Figure BDA0003489744900000089
And straight dotted bond
Figure BDA00034897449000000810
Unless otherwise indicated, when a double bond structure such as a carbon-carbon double bond, a carbon-nitrogen double bond and a nitrogen-nitrogen double bond is present in a compound and each atom on the double bond has two different substituents attached thereto (in a double bond containing a nitrogen atom, one lone pair of electrons on the nitrogen atom is considered as one substituent to which it is attached), if a wavy line is used between the atom on the double bond and its substituent in the compound
Figure BDA00034897449000000811
The term "linked" means either the (Z) -isomer, the (E) -isomer, or a mixture of both isomers of the compound.
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 or prophylactically effective amount" means an amount of a compound of the present application that (i) treats or prevents a particular disease, condition, or disorder, (ii) reduces, 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 excipients are well known to those skilled in the art, for example carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
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 respectively 2 H、 3 H、 11 C、 13 C、 14 C、 13 N、 15 N、 15 O、 17 O、 18 O、 31 P、 32 P、 35 S、 18 F、 123 I、 125 I and 36 cl, and the like.
Certain isotopically-labelled compounds of the present application (e.g. with 3 H and 14 c-labeled ones) can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e. by tritiation) 3 H) And carbon-14 (i.e. 14 C) Isotope pairs for their ease of preparationAnd detectability is particularly preferred. Positron emitting isotopes, such as 15 O、 13 N、 11 C and 18 f 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) 2 H) 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 by 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 of body weight per 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 herein 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 a synthesis procedure or a reaction scheme 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 BDA0003489744900000111
wherein, Cy 1 、Cy 2 、R 1 、R 2 、m、n、L、R 3 、R 4 Or p is 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) 2 Represents bis-dibenzylideneacetone palladium; DMF represents N, N-dimethylformamide; DMSO represents dimethyl sulfoxide; EDCI represents 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride; HOBT represents 1-hydroxybenzotriazole.
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
Example 1 Compounds 1-f
Figure BDA0003489744900000112
1) A method for preparing compound 1-a:
dissolving 4, 6-dichloropyridazine-3-carboxylic acid lithium salt (50g) in dichloromethane (500mL), adding a catalytic amount of DMF (N-dimethylformamide) at 0 ℃, slowly dropwise adding oxalyl chloride (96g) into the solution, after dropwise adding, continuously stirring for reacting for 2 hours at room temperature, and completely reacting and concentrating the reaction solution. Deuterated methylamine hydrochloride (18.6g) and DIPEA (162g) are dissolved in dichloromethane (200mL) at-25 ℃, the concentrated reaction solution is dissolved in dichloromethane (300mL), the solution is slowly added dropwise to the deuterated methylamine and DIPEA-containing dichloromethane solution, and stirring is continued for 2h after the dropwise addition is finished. The reaction was quenched by addition of water (750mL), extracted twice with dichloromethane (2X 500mL), the organic phases combined, washed with saturated aqueous sodium chloride, anhydrous Na 2 SO 4 Drying, filtration and concentration of the filtrate gave compound 1-a (52 g). ESI-MS: M/z 209.2[ M + H ]] + 。
2) A method for preparing compound 1-b:
dissolving the compound 1-a (12g), 2-methoxy-3-aminobenzoate (11.7g) and zinc acetate (31.6g) in isopropanol (200mL), stirring at 50 ℃ for 8h, concentrating the reaction solution, adding purified water, stirring at room temperature overnight, filtering, and vacuum-drying at 50 ℃ to obtain the compound 1-b (10.7 g). ESI-MS, M/z 340.09[ M + H ]] + 。
3) Preparation of Compounds 1-c:
compound 1-b (2.0g), cyclopropylcarboxamide (0.5g), palladium acetate (0.2g), Xantphos (0.6g) and cesium carbonate (3.8g) were dissolved in this order in dioxane (3mL) and heated under nitrogen protectionReact for 5h to 130 ℃. The reaction solution was concentrated and purified by column chromatography to give compound 1-c (1.3 g). ESI-MS, M/z 389.16[ M + H ]] + 。
4) A process for preparing compounds 1-d:
compound 1-c (2g), ammonium chloride (0.54g), 1EDCI (1.48g), HOBt (1.04g), triethylamine (1.56g) and DMF (30mL) were added to a reaction flask, stirred at room temperature for 5 hours, after completion of the reaction, the reaction mixture was concentrated, added with water (50mL), slurried for 2 hours, filtered and dried to give compound 1-d (1.8 g). ESI-MS: M/z 388.15[ M + H ]] + 。
5) Preparation of Compounds 1-f:
compound 1-d (200mg), compound 1-e (200mg), Pd 2 (dba) 3 (90mg), Xantphos (60mg) and cesium carbonate (420mg) were dissolved in this order in dioxane (3mL) and heated to 105 ℃ for 5h under nitrogen protection. The reaction mixture was concentrated, purified and isolated to give compound 1-f (130 mg). ESI-MS: M/z 571.14[ M + H ]] + 。
1 H NMR(500MHz,DMSO-d 6 )δ11.36(s,1H),11.00(s,1H),10.52(s,1H),9.16(s,1H),8.61(s,1H),8.18(s,1H),8.01–7.90(m,2H),7.87–7.77(m,2H),7.60(dd,J＝7.9,1.7Hz,1H),7.45–7.22(m,2H),3.86–3.72(m,4H),2.09(m,1H),1.19–1.00(m,4H),0.83(dq,J＝5.5,3.3Hz,4H).
Example 2 Compound 2-f
Figure BDA0003489744900000121
Referring to the preparation method of compound 1-f in example 1, in step 5), compound 1-e is replaced with compound 2-e to give compound 2-f. ESI-MS: M/z 545.36[ M + H ]] + .
Example 3 Compound 3-f
Figure BDA0003489744900000122
Referring to the preparation method of compound 1-f in example 1, in step 5), compound 1-e was changed to compound 3-e to give compound 3-f.
ESI-MS:m/z＝559.36[M+H] + .
Experimental example 1 TYK2 JH2 thermal stability assay
0.52mg/mL of TYK2 JH2 protein stock was diluted to 50 ng/. mu.L in Phosphate Buffered Saline (PBS) while 5000 Xof protein dye (Orange dye) was diluted to 20 Xin DMSO, 16. mu.L of TYK2 JH2 protein diluent was added to each well, then DMSO-dissolved different compounds were added to the wells using a nanoliter loader to give final concentrations of 10. mu.M and 1. mu.M for 2 concentrations, a blank control well (no enzyme) and a negative control well (enzyme-containing, DMSO-solubilized) were set to 2 duplicate wells, and finally 4. mu.L of Orange dye protein was added to each well and mixed by centrifugation. Detecting by a Roche LightCycler480 fluorescent quantitative PCR instrument, wherein the operation system is 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 ℃; 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 deg.c.
Experimental example 2 Jurkat detection method for STAT3 phosphorylation
The log phase growth of Jurkat cells, 20 u L counting, the required number of cells (mL), 1300rpm centrifugal 3min, adding phenol red 1640 culture medium to adjust the cell density, the adjustment of cell density is about 1.7 x 10E 7/mL. The 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-alpha was diluted to 75ng/mL (final concentration 25ng/mL) in phenol red-free 1640 basal medium; then 4. mu.L IFN-. alpha. (3X) was added per well according to plate distribution, and the blank was inoculated with cells without compound and without IFN-. alpha.; control group, inoculated cells, no compound, added IFN-alpha; incubate at 37 ℃ for 30 min. mu.L of blocking buffer-added lysate (4X) was added immediately and lysed 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, incubate at room temperatureAnd (4) at night. Detecting 665nm/620nm signal values by using a PE Envision multifunctional plate reading instrument, and calculating IC (integrated Circuit) by four-parameter fitting 50 。
The results are shown in Table 1.
TABLE 1
Examples IC 50 (nM)
1-f 4.8
Experimental example 3 evaluation of in vitro hepatic microsomal stability
mu.L of the final incubation system contained 30. mu.L of liver microsomes (protein concentration: 5mg/mL), 30. mu.L of NADPH + MgCl 2 mu.L of test compound (in acetonitrile), 237. mu.L of PBS buffer (pH 7.4). Wherein the proportion of the organic solvent (acetonitrile) is 1%. Each species was made in 2 portions of 0.30 mL. Each tube is prepared with a substrate and enzyme mixing solution with a total volume of 270 mu L, and NADPH is added with 30 mu L NADPH + MgCl after pre-incubation for 5min at 37 DEG C 2 After mixing, 50. mu.L of the mixture was removed at 0, 10, 30 and 60min and quenched with 300. mu.L of glacial acetonitrile containing an internal standard.
mu.L of incubated sample was added to 300. mu.L of glacial acetonitrile containing internal standard (20ng/mL) for precipitation, vortexed for 10min, and centrifuged (13000rpm, 20 ℃) for 10 min. And sucking 70 mu L of supernatant, adding 70 mu L of ultrapure water for dilution and mixing uniformly, and injecting 0.5 mu L of sample for analysis. The results are shown in Table 2.
TABLE 2
Figure BDA0003489744900000131
Experimental example 4 evaluation of pharmacokinetics in mice
ICR mice with the weight of 20-24 g are randomly grouped after being adapted for 3-5 days, 9 mice in each group are subjected to intragastric administration of experimental compounds according to the dose of 30 mg/kg.
The test animals (ICR mice) were fasted for 12h before administration and food for 4h after administration, and water was freely available before and after the experiment and during the experiment.
After the gavage, 3-4 time points are collected for 0.25(15min), 0.5(30min), 1,2, 4,6, 8 and 10h for each mouse, 3 mice at each time point are collected, blood is collected from the orbit by about 0.1mL, EDTA-K2 is anticoagulated, and the blood is transferred to 4 ℃ within 30min, 4000rpm and centrifuged for 10min to separate the blood plasma. All plasma was collected and immediately stored at-20 ℃ for testing.
Sucking 20 mu L of plasma sample to be detected and the standard curve sample, adding 400 mu L of acetonitrile solution containing an internal standard (20ng/mL), oscillating and uniformly mixing for 10min, centrifuging at 13000rpm for 10min, taking 50 mu L of supernatant, adding 100 mu L of ultrapure water for dilution, uniformly mixing, sucking 0.5 mu L of liquid for LC/MS/MS measurement, and recording a chromatogram.
Oral exposure of the compounds of the invention was assessed by in vivo pharmacokinetic experiments in mice. The results are shown in Table 3.
TABLE 3
PK parameters Compound 1-fIG 30mg/kg
AUC(0-10h)(ng*h/mL) 59730
AUC(0-∞)(ng*h/mL) 171069
MRT(0-t)(h) 5.21
t1/2(h) 14.7
Tmax(h) 4.00
Cmax(ng/mL) 7096
。

Claims (10)

1. A compound of formula I:
Figure FDA0003489744890000011
wherein,
Cy 1 and Cy 2 Are each independently selected from C 6-10 Aryl or 5-10 membered heteroaryl;
each R 1 Or R 2 Each independently selected from halogen, hydroxy, amino, cyano, C 1-8 Alkyl radical, C 3-10 Cycloalkyl or 5-to 10-membered heterocycloalkyl, said C 1-8 Alkyl radical, C 3-10 Cycloalkyl or 5-10 membered heterocycloalkyl optionally substituted with one or more halogen, deuterium, hydroxy or cyano;
m is selected from 0, 1,2,3,4 or 5;
n is selected from 0, 1,2,3,4 or 5;
l is selected from-C (O) -or a bond;
R 3 selected from 5-10 membered heteroaryl, C 3-10 Cycloalkyl radical, C 6-10 Aryl or 3-10 membered heterocycloalkyl wherein said 5-10 membered heteroaryl, C 3-10 Cycloalkyl radical, C 6-10 Aryl or 3-10 membered heterocycloalkyl optionally substituted with one or more R a Substitution;
each R 4 Each independently selected from halogen;
p is selected from 0, 1,2 or 3;
R a selected from halogen, cyano, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 3-10 Cycloalkyl oxy, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, amino, C 1-8 Alkyl NH-, (C) 1-8 Alkyl radical) 2 N-、C 3-10 Cycloalkyl NH-or C substituted by one or more halogens 1-8 An alkyl group.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, the Cy being 1 And Cy 2 Each independently selected from phenyl or 5-10 membered heteroaryl;
alternatively, the Cy 1 And Cy 2 Each independently selected from phenyl, 5-membered heteroaryl or 6-membered heteroaryl;
alternatively, the Cy 1 And Cy 2 Each independently selected from phenyl or 5-membered heteroaryl;
optionally, the Cy 1 And Cy 2 Each independently selected from phenyl, a nitrogen atom-containing 5-membered heteroaryl group, or a nitrogen atom-containing 6-membered heteroaryl group;
or, the Cy is 1 And Cy 2 Each independently selected from phenyl, 5-membered heteroaryl or 6-membered heteroaryl, the ring atoms of which are composed of nitrogen and carbon atoms;
alternatively, the Cy 1 And Cy 2 Each independently selected from phenyl, pyridyl, triazolyl or tetrazolyl;
optionally, the Cy 1 Is phenyl;
optionally, the Cy 2 Selected from pyridyl, triazolyl or tetrazolyl.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, each R 1 Or R 2 Each independently selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or 5-6 membered heterocycloalkyl, said C 1-6 Alkyl radical, C 3-6 Cycloalkyl or 5-6 membered heterocycloalkyl optionally substituted with one or more halogen, deuterium, hydroxy or cyano groups;
or, each R 1 Or R 2 Are each independently selected from C 1-4 Alkyl radical, C 3-6 Cycloalkyl or 5-6 membered heterocycloalkyl, said C 1-4 Alkyl radical, C 3-6 Cycloalkyl or 5-6 membered heterocycloalkyl optionally substituted with one or more halogen, deuterium, hydroxy or cyano;
optionally, each R 1 Each independently selected from halogen, hydroxy or cyano;
optionally, each R 2 Are each independently selected from C 1-4 Alkyl radical, C 3-6 Cycloalkyl or 5-6 membered heterocycloalkyl, said C 1-4 Alkyl radical, C 3-6 Cycloalkyl or 5-6 membered heterocycloalkyl optionally substituted with one or more halogen or deuterium;
or, each R 2 Are each independently selected from C 1-4 Alkyl or C 3-6 Cycloalkyl radical, said C 1-4 Alkyl optionally substituted with one or more halogen or deuterium;
or, each R 2 Each independently selected from methyl, ethyl, isopropyl, 2-methylpropyl or cyclopropyl.
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, m is selected from 0, 1,2 or 3; alternatively, m is selected from 0, 1 or 2; alternatively, m is 0;
optionally, n is selected from 0, 1,2 or 3; alternatively, n is selected from 0, 1 or 2; alternatively, n is 1;
optionally, m is 0 and n is 1.
5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein L is-CO-;
optionally, R 3 Selected from 6-10 membered heteroaryl, C 3-6 Cycloalkyl, phenyl or 3-6 membered heterocycloalkyl wherein said 6-10 membered heteroaryl, C 3-6 Cycloalkyl, phenyl or 3-6 membered heterocycloalkyl optionally substituted with one or more R a Substitution;
optionally, said R 3 Selected from 6-membered heteroaryl, cyclopropyl, cyclobutyl or cyclohexyl, wherein said 6-membered heteroaryl, cyclopropyl, cyclobutyl or cyclohexyl is optionally substituted by one or more R a Substitution;
optionally, said R 3 Selected from pyridyl or cyclopropyl optionally substituted by one or more R a Substitution;
optionally, said R 3 Selected from optionally substituted by one or more R a A substituted cyclopropyl group;
optionally, said R 3 Selected from cyclopropyl;
optionally, R a Selected from halogen, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl oxy, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl or C substituted with one or more halogens 1-6 An alkyl group;
optionally, R a Selected from halogen, cyano, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 3-6 Cycloalkyl oxy, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl or C substituted by one or more fluoro 1-3 An alkyl group;
optionally, R a Selected from fluorine, chlorine, bromine, cyano, C 1-3 Alkyl radical, C 1-3 Alkoxy or C substituted by 1,2 or 3 fluorine 1-3 An alkyl group.
6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, each R 4 Each independently selected from fluorine, chlorine, bromine or iodine;
or, said R 4 Is fluorine;
optionally, said p is selected from 0, 1 or 2;
alternatively, p is selected from 0 or 1;
alternatively, p is 0;
optionally, R 4 Is fluorine and p is 1;
optionally, a structural unit
Figure FDA0003489744890000021
Is selected from
Figure FDA0003489744890000022
Or, a structural unit
Figure FDA0003489744890000023
Is selected from
Figure FDA0003489744890000024
Or, a structural unit
Figure FDA0003489744890000025
Is selected from
Figure FDA0003489744890000026
Or, a structural unit
Figure FDA0003489744890000031
Is selected from
Figure FDA0003489744890000032
Or, a structural unit
Figure FDA0003489744890000033
Is selected from
Figure FDA0003489744890000034
Figure FDA0003489744890000035
Optionally, a structural unit
Figure FDA0003489744890000036
Is selected from
Figure FDA0003489744890000037
Or, a structural unit
Figure FDA0003489744890000038
Is selected from
Figure FDA0003489744890000039
Or, a structural unit
Figure FDA00034897448900000310
Is selected from
Figure FDA00034897448900000311
Or, a structural unit
Figure FDA00034897448900000312
Is selected from
Figure FDA00034897448900000313
Or, a structural unit
Figure FDA00034897448900000314
Is selected from
Figure FDA00034897448900000315
Or, a structural unit
Figure FDA0003489744890000041
Is selected from
Figure FDA0003489744890000042
Figure FDA0003489744890000043
Or, a structural unit
Figure FDA0003489744890000044
Is selected from
Figure FDA0003489744890000045
Or, a structural unit
Figure FDA0003489744890000046
Is selected from
Figure FDA0003489744890000047
Figure FDA0003489744890000048
Optionally, a structural unit
Figure FDA0003489744890000049
Is selected from
Figure FDA00034897448900000410
Or, a structural unit
Figure FDA00034897448900000411
Is composed of
Figure FDA00034897448900000412
Wherein X is selected from hydrogen or fluorine;
or, a structural unit
Figure FDA00034897448900000413
Is selected from
Figure FDA00034897448900000414
Optionally, a structural unit
Figure FDA00034897448900000415
Is selected from
Figure FDA00034897448900000416
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula I-1 or a compound of formula I-2, or a pharmaceutically acceptable salt thereof
Figure FDA0003489744890000051
Wherein X is selected from hydrogen or fluorine, and Y is selected from N or CH.
8. The following compounds or pharmaceutically acceptable salts thereof:
Figure FDA0003489744890000052
Figure FDA0003489744890000061
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 (2)

* 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
WO2024131935A1 (en) * 2022-12-24 2024-06-27 津药生物科技（天津）有限公司 Novel aromatic ring derivative containing amide substitution and use thereof

Cited By (2)

* 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
WO2024131935A1 (en) * 2022-12-24 2024-06-27 津药生物科技（天津）有限公司 Novel aromatic ring derivative containing amide substitution and use thereof

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