TYK2 inhibitor compounds containing alkoxy groups and amide groups

Abstract

The present application belongs to the field of medicinal chemistry, provides a TYK2 inhibitor compound containing an alkoxy group and an amide group and a preparation method thereof, and relates to its use in preparing a drug for treating TYK2-related diseases. #imgabs0#

Description

[0001] Citation of Related Applications

[0002] This application claims the priority and benefits of Chinese Patent Application No. 202010412342.X filed with the State Intellectual Property Office of the People's Republic of China on May 15, 2020, the entire contents of which are hereby incorporated by reference into the text in their entirety. Technical Field

[0003] The present application belongs to the field of medicinal chemistry, provides a TYK2 inhibitor compound containing an alkoxy group and an amide group and a preparation method thereof, and relates to the use of the compound in the preparation of a drug for treating TYK2-related diseases. Background of the Invention

[0004] 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 crucial in the regulatory signal transduction cascade downstream of IL-12, IL-23 and type I interferon receptors. TYK2 mediates receptor-induced phosphorylation of members of the STAT transcription factor family, which is an essential signal for the transcription of dimerization of STAT proteins and STAT-dependent proinflammatory genes. TYK2-deficient mice resist experimental models of colitis, psoriasis and multiple sclerosis, thereby demonstrating the importance of TYK2-mediated signal transduction in autoimmunity and related disorders. In humans, individuals expressing inactive variants of TYK2 are protected from multiple sclerosis and possible other autoimmune disorders.

[0005] In view of the conditions that may 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 IFNα and methods of using these compounds may provide substantial therapeutic benefit to numerous patients in need thereof. Summary of the invention

[0006] In one aspect, the present application provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in,

[0009] Every R 1 are independently selected from C 1-8 Alkyl or C 3-10 Cycloalkyl;

[0010] m is selected from 1, 2, 3 or 4;

[0011] Every R 2are independently selected from hydrogen, halogen, amino, hydroxyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-8 Alkyl or C 3-10 Cycloalkyl, the C 6-10 Aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclic group, C 1-8 Alkyl or C 3-10 The cycloalkyl group is optionally substituted with one or more R a replace;

[0012] n is selected from 1, 2 or 3;

[0013] Every R a are independently selected from halogen, hydroxyl, cyano, amino, C 1-8 Alkyl, C 1-8 Alkoxy or C substituted by one or more halogen 1-8 alkyl;

[0014] L is selected from -C(O)- or a bond;

[0015] R 3 is selected from 5-10 membered heteroaryl, C 3-10 Cycloalkyl or C 6-10 Aryl, wherein the 5-10 membered heteroaryl, C 3-10 Cycloalkyl or C 6-10 The aryl group is optionally substituted with one or more R b replace;

[0016] Every R b are independently selected from halogen, hydroxyl, cyano, amino, C 1-8 Alkyl, C 1-8 Alkoxy, (C 1-8 Alkyl)2P(O)-, C 1-8 Alkyl-C(O)-, C 1-8 Alkyl-SO2- or C substituted by one or more halogen or hydroxyl groups 1-8 alkyl.

[0017] In some embodiments, each of the above R 1 are independently selected from C 1-6 Alkyl or C 3-6 In some embodiments, each of the above R 1 are independently selected from C 1-4 Alkyl or C 3-6 Cycloalkyl.

[0018] In some embodiments, each of the above R 1 are independently selected from C 1-8 In some embodiments, each of the above R 1are independently selected from C 1-6 In some embodiments, each of the above R 1 are independently selected from C 1-4 In some embodiments, each of the above R 1 are independently selected from methyl, isopropyl or tert-butyl.

[0019] In some embodiments, each of the above R 1 There is at least one R 1 In some embodiments, when m is selected from 2, 3 or 4, each of the above R 1 There are at least two R 1 It is methyl.

[0020] 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.

[0021] In some embodiments, each R 2 are independently selected from hydrogen, C 6-10 Aryl, 5-6 membered heteroaryl, C 1-6 Alkyl or C 3-6 Cycloalkyl, the C 6-10 Aryl, 5-6 membered heteroaryl, C 1-6 Alkyl or C 3-6 Cycloalkyl C 6-10 Aryl, 5-6 membered heteroaryl, C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with one or more R a In some embodiments, each R 2 are independently selected from hydrogen, phenyl, 5-6 membered heteroaryl, C 1-3 Alkyl or C 3-6 Cycloalkyl, the phenyl, 5-6 membered heteroaryl, C 1-3 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with one or more R a replace.

[0022] In some embodiments, each R 2 are independently selected from hydrogen or 5-10 membered heteroaryl, the 5-10 membered heteroaryl is optionally substituted by one or more R a In some embodiments, each R 2 are independently selected from hydrogen or 5-6 membered heteroaryl, the 5-6 membered heteroaryl is optionally substituted by one or more R a In some embodiments, each R 2are independently selected from hydrogen, triazolyl, pyridyl or pyrimidinyl, wherein the triazolyl, pyridyl or pyrimidinyl is optionally substituted by one or more R a In some embodiments, each R 2 are independently selected from hydrogen, 1,2,4-triazolyl, pyridyl or pyrimidinyl, wherein the 1,2,4-triazolyl, pyridyl or pyrimidinyl is optionally substituted by one or more R a In some embodiments, each R 2 are independently selected from hydrogen, Said Optionally one or more R a replace.

[0023] In some embodiments, n is selected from 1 or 2. In some embodiments, n is selected from 1.

[0024] In some embodiments, each R a are independently selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C substituted by one or more halogen 1-6 In some embodiments, each R a are independently selected from halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 1-3 Alkoxy or C substituted by one or more halogen 1-3 alkyl.

[0025] In some embodiments, each R a are independently selected from C 1-8 In some embodiments, each R a are independently selected from C 1-6 In some embodiments, each R a are independently selected from C 1-3 In some embodiments, each R a are each independently selected from methyl.

[0026] In some embodiments, each R 2 are independently selected from hydrogen,

[0027] In some embodiments, L is -C(O)-. In some embodiments, L is a bond.

[0028] In some embodiments, R 3 is selected from 5-6 membered heteroaryl, C 3-6 Cycloalkyl or C 6-10Aryl, wherein the 5-6 membered heteroaryl, C 3-6 Cycloalkyl or C 6-10 The aryl group is optionally substituted with one or more R b In some embodiments, R 3 is selected from 5-6 membered heteroaryl, C 3-6 Cycloalkyl or phenyl, wherein the 5-6 membered heteroaryl, C 3-6 Cycloalkyl or phenyl is optionally substituted with one or more R b replace.

[0029] In some embodiments, R 3 is selected from 5-10 membered heteroaryl or C 3-10 Cycloalkyl, wherein the 5-10 membered heteroaryl or C 3-10 The cycloalkyl group is optionally substituted with one or more R b In some embodiments, R 3 is selected from 5-6 membered heteroaryl or C 3-6 Cycloalkyl, wherein the 5-6 membered heteroaryl or C 3-6 The cycloalkyl group is optionally substituted with one or more R b In some embodiments, R 3 is selected from pyridyl, cyclopropyl or pyrimidinyl, wherein the pyridyl, cyclopropyl or pyrimidinyl is optionally substituted by one or more R b In some embodiments, R 3 Selected from It is stated Optionally one or more R b replace.

[0030] In some embodiments, each R b are independently selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 Alkyl)2P(O)-, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-SO2- or C substituted by one or more halogen or hydroxyl groups 1-6 In some embodiments, each R b are independently selected from halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 1-3 Alkoxy, (C 1-3 Alkyl)2P(O)-, C 1-3 Alkyl-C(O)-, C 1-3 Alkyl-SO2- or C substituted by one or more halogen or hydroxyl groups 1-3 In some embodiments, each Rb are independently selected from fluorine, chlorine, bromine, cyano, C 1-3 Alkyl, (C 1-3 alkyl)2P(O)- or C substituted by one or more hydroxyl groups 1-3 alkyl.

[0031] In some embodiments, each R b are independently selected from halogen, (C 1-8 alkyl)2P(O)- or C substituted by one or more hydroxyl groups 1-8 In some embodiments, each R b are independently selected from halogen, (C 1-6 alkyl)2P(O)- or C substituted by one or more hydroxyl groups 1-6 In some embodiments, each R b are independently selected from halogen, (C 1-3 alkyl)2P(O)- or C substituted by one or more hydroxyl groups 1-3 In some embodiments, each R b Each is independently selected from fluorine, chlorine, (CH3CH2)2P(O)- or hydroxymethyl.

[0032] In some embodiments, R 3 Selected from

[0033] In some embodiments, the structural fragment Selected from Further selected from Further selection Further selected from

[0034] In some embodiments, the structural fragment Selected from Further selected from

[0035] On the other hand, the present application provides a compound of formula II, a compound of formula III, a compound of formula IV or a pharmaceutically acceptable salt thereof:

[0036]

[0037] Among them, L, R 1 , R 2 and R 3The same as defined for compounds of formula I.

[0038] In some embodiments, the structural fragments of the compound of formula II, the compound of formula III, and the compound of formula IV As defined above.

[0039] In some embodiments, the structural fragment Can be selected from the above structural fragments defined and covered by The group.

[0040] In some embodiments, the present application comprises the above-defined variables and embodiments thereof, and any combination thereof.

[0041] In another aspect, the present application provides the following compound or a pharmaceutically acceptable salt thereof:

[0042]

[0043] On the other hand, the present application also provides a pharmaceutical composition, which comprises the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable excipient.

[0044] On the other hand, the present application also provides a method for treating or preventing various diseases related to TYK2, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human being, in need of such treatment.

[0045] On the other hand, the present application also provides the use of the above-mentioned compound or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of drugs for treating or preventing various TYK2-related diseases.

[0046] On the other hand, the present application also provides the use of the above-mentioned compound or its pharmaceutically acceptable salt, or its pharmaceutical composition in the treatment or prevention of various TYK2-related diseases.

[0047] On the other hand, the present application also provides the above-mentioned compound of the present application, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating or preventing various TYK2-related diseases.

[0048] In some embodiments, the TYK2-associated diseases are selected from autoimmune diseases.

[0049] definition

[0050] Unless otherwise specified, the following terms used in this application have the following meanings. A particular term should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a trade name appears in this article, it is intended to refer to the corresponding commodity or its active ingredient.

[0051] When a covalent bond in certain structural units or groups in the present application is not connected to a specific atom, it means that the covalent bond can be connected to any atom in the structural unit or group as long as it does not violate the valence bond connection rules.

[0052] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo will not occur on an aromatic group.

[0053] The term "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be appreciated by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and / or cannot be synthesized will be introduced.

[0054] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. For example, C 1-3 It means that the group may have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0055] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 2 R's, each R has an independent choice.

[0056] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a covalent bond.

[0057] When one of the variables is selected from a covalent bond, it means that the two groups it connects are directly connected. For example, when L' in A-L'-Z represents a covalent bond, it means that the structure is actually AZ.

[0058] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0059] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0060] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight chain or branched. For example, the term "C 1-6 The term "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, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above. For another example, the term "C 1-3 The term "alkyl" refers to an alkyl group containing 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, and isopropyl).

[0061] The term "alkoxy" refers to an -O-alkyl group.

[0062] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 10-membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, bicyclo[1.1.1]pent-1-yl, and the like. For example, C 3-4 Cycloalkyl groups include cyclopropyl and cyclobutyl.

[0063] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetrahydronaphthalene, etc.

[0064] The term "heteroaryl" refers to a monocyclic or fused polycyclic 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 heteroaryls 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 heteroaryls include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.

[0065] The term "treatment" means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0066] (i) inhibiting a disease or disease state, i.e. arresting its development;

[0067] (ii) ameliorating a disease or condition, even if causing regression of the disease or condition.

[0068] The term "prevention" means administering the compounds or formulations described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0069] The term "therapeutically effective amount" means an amount of the compound of the present application that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of the 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 based on their own knowledge and the present disclosure.

[0070] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0071] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0072] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0073] The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients 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, etc.

[0074] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be construed in an open and non-exclusive sense, ie, "including but not limited to".

[0075] The compounds and intermediates of the present application can also exist in different tautomeric forms, and all such forms are included in 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 prototransfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. The specific example of a proton tautomer is an imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by the reorganization of some bonding electrons.

[0076] The present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by atoms 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 the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 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 et al.

[0077] Certain isotope-labeled compounds of the present application (e.g. 3H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. 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 Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0078] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution may provide certain therapeutic advantages arising from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium, and all such forms of compounds are included within the scope of the present application.

[0079] The compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present application containing asymmetric carbon atoms can be separated in optically pure form or racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral raw materials or chiral reagents.

[0080] The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0081] Typical routes of administration of the compounds of the present application or their pharmaceutically acceptable salts or their pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0082] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0083] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be prepared by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

[0084] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

[0085] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0086] The therapeutic dose of the compounds of the present application may be determined, for example, based on the specific use of the treatment, the method of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compounds 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 route of administration. For example, the compounds of the present application may be provided by a physiologically buffered aqueous solution containing about 0.1 to 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg body weight / day. In certain embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg body weight / day. The dosage is likely to depend on such variables as the type and degree of development of the disease or condition, the general health status of the specific patient, the relative biological efficacy of the selected compound, the excipient formulation, and its route of administration. The effective dose can be obtained by extrapolation of a dose-response curve derived from an in vitro or animal model test system.

[0087] The compounds of the present application can 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 combining them with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0088] The chemical reactions of the specific embodiments of the present application are carried out in a suitable solvent, which must be suitable for the chemical changes of the present application and the reagents and materials required. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.

[0089] An important consideration in the planning of synthetic routes in this field is to select a suitable protecting group for a reactive functional group (such as an amino group in this application). For example, reference may be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0090] In some embodiments, the compounds of the present application can be prepared by those skilled in the art of organic synthesis with reference to the following routes:

[0091]

[0092] Among them, R 1 , R 2 , R 3 The definitions of , m, n, and L are as described above.

[0093] This application uses the following abbreviations:

[0094] DIPEA represents diisopropylethylamine; Xantphos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; Pd(dba)2 represents bis(dibenzylideneacetonepalladium); DMF represents N,N-dimethylformamide; Pd(dppf)2Cl2·CH2Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex; DMSO represents dimethyl sulfoxide.

[0095] For the sake of clarity, the present application is further described with examples, but the examples do not limit the scope of the present application. All reagents used in the present application are commercially available and can be used without further purification. DETAILED DESCRIPTION

[0096] Intermediates:

[0097]

[0098] Preparation of (6-aminopyridin-3-yl)diethylphosphine oxide:

[0099] Dissolve 2-amino-5-iodopyridine (1.0 g), diethylphosphine oxide (0.95 g), palladium acetate (0.2 g), Xantphos (0.5 g) and potassium carbonate (1.9 g) in 5 mL of dioxane, protect with nitrogen, and heat to 130 ° C for 5 h. The reaction solution is concentrated to obtain the compound (6-aminopyridin-3-yl) diethylphosphine oxide (1.5 g). ESI-MS: m / z = 199.0 [M + H] + .

[0100] Embodiment 1:

[0101]

[0102] (1) Preparation method of compound A:

[0103] Dissolve 4,6-dichloropyridazine-3-carboxylic acid lithium salt (50g) in 500mL dichloromethane, place at 0℃, add catalytic amount of DMF, slowly add oxalyl chloride (96g) to the above solution, move to room temperature after the addition, continue to stir and react for 2h, and the reaction is complete. Concentrate. Dissolve deuterated methylamine (18.6g) and DIPEA (162g) in 200mL dichloromethane, place at -25℃, stir to dissolve, dissolve the above concentrate in 300mL dichloromethane and slowly add to the above solution, continue to stir for 2h after the addition. Add 750mL water to quench the reaction, extract twice with dichloromethane (2×500mL), combine the organic phases, wash with saturated sodium chloride aqueous solution, dry with anhydrous Na2SO4, filter, and concentrate the filtrate to obtain compound A (52g). ESI-MS: m / z=209.2[M+H] + .

[0104] (2) Preparation method of compound B:

[0105] Compound A (15 g) was dissolved in 250 mL of tetrahydrofuran, placed at 0°C, and 250 mL of ammonia water was slowly added dropwise to the above solution. After the addition was complete, the mixture was stirred at room temperature for 5 h. The tetrahydrofuran was removed by concentration under reduced pressure, stirred in an ice bath, filtered, and dried under vacuum at 45°C to obtain compound B (11 g). ESI-MS: m / z = 189.96 [M+H] + .

[0106] (3) Preparation method of compound C:

[0107] Dissolve 2,3-dimethoxybenzoic acid (455 mg) in 15 mL of dichloromethane, place at 0°C, add a catalytic amount of DMF, slowly drop oxalyl chloride (952.5 mg) into the above solution, move to room temperature after the addition is complete, continue stirring and react for 2 hours, the reaction is complete and ready for use. Dissolve compound B (472.5 mg) in 30 mL of N-methylpyrrolidone, place at -25°C, add sodium hydride (480 mg) in batches and stir to dissolve, slowly drop the prepared 2,3-dimethoxybenzoyl chloride solution into the solution of compound B, continue stirring for 2 hours after the addition is complete. Concentrate under reduced pressure to remove dichloromethane, add 150 mL of water, solid precipitates, filter, and vacuum dry at 45°C to obtain compound C (500 mg). ESI-MS: m / z=354.03[M+H] + .

[0108] (4) Preparation method of compound 1:

[0109] Compound C (400 mg), cyclopropylcarboxamide (192 mg), Pd(dba)2 (101 mg), Xantphos (127 mg) and cesium carbonate (1.47 g) were added to 100 mL of 1,4-dioxane, replaced with nitrogen three times, heated to 100°C and reacted for 5 h. Filtered and concentrated, the concentrate was purified by preparative liquid phase to obtain compound 1 (40 mg). 1 H 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]+.

[0110] Referring to the preparation process of compound 1 in Example 1, in step (4), cyclopropylcarboxamide was replaced with different intermediates 1-A to prepare the following compounds:

[0111]

[0112]

[0113]

[0114] Embodiment 9:

[0115]

[0116] (1) Preparation method of compound D:

[0117] Referring to the preparation method of compound C in Example 1, the raw material 2,3-dimethoxybenzoic acid was replaced with 2,4-dimethoxybenzoic acid to obtain compound D. ESI-MS: m / z=354.02 [M+H] + .

[0118] (2) Preparation method of compound 9:

[0119] Referring to the preparation method of compound 1 in Example 1, the raw material compound C was replaced with compound D to obtain compound 9. ESI-MS: m / z=403.11 [M+H] + .

[0120] Referring to the preparation process of Example 9, in step (1), 2,4-dimethoxybenzoic acid was replaced with a different intermediate 1-B to prepare the following compounds:

[0121]

[0122]

[0123] Embodiment 16:

[0124]

[0125] (1) Preparation method of compound E:

[0126] Add methyl 2-methoxy-4-bromobenzoate (10 g), bipyraclostrobin (15.5 g), Pd(dppf)2Cl2·CH2Cl2 (1.65 g) and potassium acetate (12 g) to 400 mL of 1,4-dioxane, replace with nitrogen three times, heat to 115°C and react for 2 h. Filter to obtain a 1,4-dioxane solution of compound E (400 mL, 0.1 mol / L). ESI-MS: m / z=292.92[M+H]+.

[0127] (2) Preparation method of compound F:

[0128] A 1,4-dioxane solution of compound E (125 mL, 0.1 mol / L), 2-bromopyridine (2.23 g), Pd(dppf)2Cl2·CH2Cl2 (0.51 g) and potassium phosphate (8.0 g) were added to a reaction vessel, replaced with nitrogen three times, heated to 110°C and reacted for 4 h. Filtered and concentrated under reduced pressure to obtain compound F. ESI-MS: m / z=244.2[M+H]+.

[0129] (3) Preparation method of compound G:

[0130] Compound F was added to methanol (40 mL) and NaOH aqueous solution (20 mL, 1 mol / L) and refluxed for 5 h. Concentrated under reduced pressure, water was added, pH was adjusted to 6, solid precipitated, filtered, and vacuum dried at 45 °C to obtain compound G (1.2 g). ESI-MS: m / z = 230.0 [M+H] + .

[0131] (4) Preparation method of compound H:

[0132] Referring to the preparation method of compound C in Example 1, the raw material 2,3-dimethoxybenzoic acid was replaced with compound G to obtain compound H. ESI-MS: m / z=401.03 [M+H] + .

[0133] (5) Preparation method of compound 16:

[0134] Referring to the preparation method of Example 1, the raw material compound C was replaced with compound H to obtain compound 16. ESI-MS: m / z=450.16 [M+H] + .

[0135] Embodiment 17:

[0136]

[0137] (1) Preparation method of compound I:

[0138] Referring to the preparation method of compound F in Example 16, the raw material 2-bromopyridine was replaced with 2-bromopyrimidine to obtain compound I. ESI-MS: m / z=245.2 [M+H] + .

[0139] (2) Preparation method of compound J:

[0140] Referring to the preparation method of compound G in Example 16, compound F was replaced with compound I to obtain compound J. ESI-MS: m / z=231.2 [M+H] + .

[0141] (3) Preparation method of compound K:

[0142] Referring to the preparation method of compound C in Example 1, the raw material 2,3-dimethoxybenzoic acid was replaced with compound J to obtain compound K. ESI-MS: m / z=402.1[M+H] + .

[0143] (4) Preparation method of compound 17:

[0144] Referring to the preparation method of Example 1, the raw material compound C was replaced with compound K to obtain compound 17. ESI-MS: m / z=451.13 [M+H] + .

[0145] Embodiment 18:

[0146]

[0147] (1) Preparation method of compound L:

[0148] Referring to the preparation method of compound F in Example 16, the raw material 2-bromopyridine was replaced with 3-bromo-1-methyl-1H-1,2,4-triazole to obtain compound L. ESI-MS: m / z=248.2 [M+H] + .

[0149] (2) Preparation method of compound M:

[0150] Referring to the preparation method of compound G in Example 16, compound F was replaced with compound L to obtain compound M. ESI-MS: m / z=234.2 [M+H] + .

[0151] (3) Preparation method of compound N:

[0152] Referring to the preparation method of compound C in Example 1, the raw material 2,3-dimethoxybenzoic acid was replaced with compound M to obtain compound N. ESI-MS: m / z=405.09 [M+H] + .

[0153] (4) Preparation method of compound 18:

[0154] Referring to the preparation method of Example 1, the raw material compound C was replaced with compound N to obtain compound 18. ESI-MS: m / z=454.13 [M+H] + .

[0155] Embodiment 19:

[0156]

[0157] (1) Preparation method of compound P:

[0158] Referring to the preparation method of compound F in Example 16, the raw material 2-bromopyridine was replaced with 3-bromo-1-methyl-1H-1,2,4-triazole, and compound E was replaced with compound O to obtain compound P. ESI-MS: m / z=248.02 [M+H] + .

[0159] (2) Preparation method of compound Q:

[0160] Referring to the preparation method of compound G in Example 16, compound F was replaced with compound P to obtain compound Q. ESI-MS: m / z=234.01 [M+H] + .

[0161] (3) Preparation method of compound R:

[0162] Referring to the preparation method of compound C in Example 1, the raw material 2,3-dimethoxybenzoic acid was replaced with compound Q to obtain compound R. ESI-MS: m / z=405.0 [M+H] + .

[0163] (4) Preparation method of compound 19:

[0164] Referring to the preparation method of Example 1, the raw material compound C was replaced with compound R to obtain compound 19. ESI-MS: m / z=454.1 [M+H] + .

[0165] Experimental Example 1 TYK2 JH2 Thermal Stability Determination

[0166] 0.52mg / mL TYK2 JH2 protein stock solution was diluted to 50ng / μL with phosphate buffer (PBS), and 5000x protein dye (Orange dye) (manufacturer Sigma; item number S5692) was diluted to 20x with DMSO. 16μL of TYK2 JH2 protein dilution was added to each well, and then the DMSO-dissolved example compound was added to the well using a nanoliter pipette to make the final concentration of the compound 10μM and 1μM, respectively, for a total of 2 concentrations. At the same time, a blank control well (without enzyme) and a negative control well (with enzyme, with solvent DMSO) were set up, and 2 duplicate wells were set up. Finally, 4μL of Orange dye protein dye was added to each well and centrifuged to mix. Roche Light Cycler 480 fluorescence quantitative PCR instrument was used for detection, and the operating system was: 20℃15s; 30℃~90℃0.02℃ / s; 20℃15s. The melting temperature (Tm) was obtained by analysis using Light Cycler Thermal Shift Analysis software.

[0167] The compounds of the present application have a melting temperature (Tm) greater than 40°C, preferably greater than 45°C, more preferably greater than 55°C, and further preferably greater than 60°C, when the final concentration is 1 μM. The melting temperature (Tm) is greater than 40°C, preferably greater than 45°C, more preferably greater than 50°C, and further preferably greater than 55°C, when the final concentration is 1 μM.

[0168] Experimental Example 2 Jurkat Detection of STAT3 Phosphorylation

[0169] STAT3 phosphorylation detection kit (Y705), Cisbio, catalog number 62AT3PEG. Take 20 μL of Jurakt cells in logarithmic growth, count, take the required number of cells (mL), centrifuge at 1300 rpm for 3 min, add phenol red-free 1640 basal medium (Gibco, catalog number 11835-030) to adjust the cell density to about 1.7*10E7 cells / mL. The cells were plated at the above cell density (384-well small volume white plate), 8 μL / well; the samples were added using a nanoliter pipette, and the compounds were incubated for 1.5 h; IFN-α (manufacturer Sino Biological, catalog number 13833-HNAY) was diluted to 75 ng / mL (final concentration 25 ng / mL) with phenol red-free 1640 complete medium; then 4 μL IFN-α (3X) was added to each well according to the plate distribution, the blank group was inoculated with cells, no compounds, no IFN-α; the control group was inoculated with cells, no compounds, and IFN-α; incubated at 37°C for 20 min. Immediately add 4 μL of lysis buffer (4X) with added blocking solution, and incubate with shaking at room temperature for 40 min. Add 4 μL of pre-mixed antibodies (vol / vol) prepared in detection buffer, cover the plate, centrifuge to mix evenly, and incubate at room temperature overnight. The PE Envision multi-function plate reader detects the 665nm / 620nm signal value, and the IC is calculated by four-parameter fitting. 50 The experimental results are shown in Table 1.

[0170] Table 1

[0171]

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: in, Every R 1 are independently selected from C 1-4 alkyl; m is selected from 1, 2, 3 or 4; Every R 2 are independently selected from hydrogen, C 6-10 Aryl, or 5-6 membered heteroaryl, the C 6-10 Aryl or 5-6 membered heteroaryl is optionally substituted by one or more R a replace; n is selected from 1, 2 or 3; Every R a are independently selected from halogen, hydroxyl, cyano, amino, or C 1-3 alkyl; L is selected from -C(O)- or a bond; R 3 is selected from 5-6 membered heteroaryl, C 3-6 Cycloalkyl or C 6-10 Aryl, wherein the 5-6 membered heteroaryl, C 3-6 Cycloalkyl or C 6-10 The aryl group is optionally substituted with one or more R b replace; Every R b are independently selected from halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, (C 1-3 alkyl) 2 P(O)- or C substituted by one or more halogen or hydroxyl groups 1-3 alkyl.

2. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein Every R 1 are independently selected from methyl, isopropyl or tert-butyl.

3. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein each R 1 There is at least one R 1 It is methyl.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, when m is selected from 2, 3 or 4, each of the above R 1 There are at least two R 1 It is methyl.

5. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein m is selected from 1, 2 or 3.

6. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 5, wherein m is selected from 1 or 2.

7. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 5, wherein m is selected from 1 or 3.

8. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 5, wherein m is selected from 2 or 3.

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 8, wherein m is selected from 2.

10. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, Every R 2 are independently selected from hydrogen or 5-6 membered heteroaryl, the 5-6 membered heteroaryl is optionally substituted by one or more R a replace.

11. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 10, wherein each R 2 are independently selected from hydrogen, triazolyl, pyridyl or pyrimidinyl, wherein the triazolyl, pyridyl or pyrimidinyl is optionally substituted by one or more R a replace.

12. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R 2 are independently selected from hydrogen, 1,2,4-triazolyl, pyridyl or pyrimidinyl, wherein the 1,2,4-triazolyl, pyridyl or pyrimidinyl is optionally substituted by one or more R a replace.

13. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R 2 are independently selected from hydrogen, Said Optionally one or more R a replace.

14. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R 2 are independently selected from hydrogen, 15. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein n is selected from 1 or 2.

16. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 15, wherein n is selected from 1.

17. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R a are independently selected from C 1-3 alkyl.

18. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 17, wherein each R a are each independently selected from methyl.

19. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, R 3 is selected from 5-6 membered heteroaryl, C 3-6 Cycloalkyl or phenyl, wherein the 5-6 membered heteroaryl, C 3-6 Cycloalkyl or phenyl is optionally substituted with one or more R b replace.

20. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 19, wherein R 3 is selected from 5-6 membered heteroaryl or C 3-6 Cycloalkyl, wherein the 5-6 membered heteroaryl or C 3-6 The cycloalkyl group is optionally substituted with one or more R b replace.

21. A compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 20, wherein R 3 is selected from pyridyl, cyclopropyl or pyrimidinyl, wherein the pyridyl, cyclopropyl or pyrimidinyl is optionally substituted by one or more R b replace.

22. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein R 3 Selected from It is stated Optionally one or more R b replace.

23. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein R 3 Selected from 24. A compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1, Every R b are independently selected from fluorine, chlorine, bromine, cyano, C 1-3 Alkyl, (C 1-3 alkyl) 2 P(O)- or C substituted with one or more hydroxyl groups 1-3 alkyl.

25. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein each R b are independently selected from halogen, (C 1-3 alkyl) 2 P(O)- or C substituted with one or more hydroxyl groups 1-3 alkyl.

26. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 25, wherein each R b are independently selected from fluorine, chlorine, (CH 3 CH 2 ) 2 P(O)- or hydroxymethyl.

27. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structural fragment Selected from 28. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structural fragment Selected from 29. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structural fragment Selected from 30. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structural fragment Selected from 31. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the structural fragment Selected from 32. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the structural fragment Selected from 33. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from a compound of formula II, a compound of formula III, a compound of formula IV or a pharmaceutically acceptable salt thereof:

34. The following compound or a pharmaceutically acceptable salt thereof:

35. A pharmaceutical composition comprising the compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof.

36. Use of the compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 35, in the preparation of drugs for treating or preventing various TYK2-related diseases.

37. The method of claim 36, wherein the various diseases associated with TYK2 are selected from autoimmune diseases.

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