TYK2 inhibitor compounds containing amide groups and linked rings

Abstract

The present application belongs to the field of medicinal chemistry, provides an amide- and linked-ring-containing TYK2 inhibitor compound and a preparation method thereof, and relates to the use of the compound in the preparation of drugs for treating TYK2-related diseases.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This disclosure claims the benefits and priority of Chinese invention patent application No. 202110165848.X filed with the State Intellectual Property Office of the People's Republic of China on February 6, 2021, the entire contents of which are hereby incorporated by reference in their entirety. Technical Field

[0003] The present application belongs to the field of medicinal chemistry, provides an amide- and linked-ring-containing TYK2 inhibitor compound and a preparation method thereof, and relates to the use of the compound in the preparation of a drug for treating or preventing 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] Cy 1 With Cy 2 are independently selected from C 6-10 Aryl or 5-10 membered heteroaryl;

[0010] Every R 1 or R 2 are independently selected from halogen, hydroxyl, amino, cyano, C1-8 Alkyl, C 3-10 Cycloalkyl or 5-10 membered heterocycloalkyl, the C 1-8 Alkyl, C 3-10 Cycloalkyl or 5-10 membered heterocycloalkyl is optionally substituted with one or more halogen, deuterium, hydroxyl or cyano;

[0011] m is selected from 0, 1, 2, 3, 4 or 5;

[0012] n is selected from 0, 1, 2, 3, 4 or 5;

[0013] L is selected from -C(O)- or a bond;

[0014] R 3 is selected from 5-10 membered heteroaryl, C 3-10 Cycloalkyl, C 6-10 aryl or 3-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl, C 3-10 Cycloalkyl, C 6-10 Aryl or 3-10 membered heterocycloalkyl is optionally substituted with one or more R a replace;

[0015] Every R 4 are each independently selected from halogen;

[0016] p is selected from 0, 1, 2 or 3;

[0017] R a Selected from halogen, cyano, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, amino, C 1-8 Alkyl NH-, (C 1-8 Alkyl)2N-, C 3-10 CycloalkylNH- or C substituted by one or more halogen 1-8 alkyl.

[0018] In some embodiments, the Cy 1 With Cy 2 Each is independently selected from phenyl or 5-10 membered heteroaryl.

[0019] In some embodiments, the Cy 1 With Cy 2 are independently selected from phenyl, 5-membered heteroaryl or 6-membered heteroaryl. 1 With Cy 2 Each is independently selected from phenyl or 5-membered heteroaryl.

[0020] In some embodiments, the Cy 1 With Cy 2 They are each independently selected from a phenyl group, a 5-membered heteroaryl group containing a nitrogen atom, or a 6-membered heteroaryl group containing a nitrogen atom.

[0021] In some embodiments, the Cy 1 With Cy 2 They are independently selected from phenyl, 5-membered heteroaryl or 6-membered heteroaryl, and the ring atoms of the 5-membered heteroaryl or 6-membered heteroaryl consist of nitrogen atoms and carbon atoms.

[0022] In some embodiments, the Cy 1 With Cy 2 Each is independently selected from phenyl, pyridyl, triazolyl or tetrazolyl.

[0023] In some embodiments, the Cy 1 It is phenyl.

[0024] In some embodiments, the Cy 2 is selected from pyridyl, triazolyl or tetrazolyl.

[0025] In some embodiments, each R 1 or R 2 are independently selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl or 5-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-6 The cycloalkyl or 5-6 membered heterocycloalkyl is optionally substituted with one or more halogen, deuterium, hydroxyl or cyano.

[0026] In some embodiments, each R 1 or R 2 are independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl or 5-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 3-6 The cycloalkyl or 5-6 membered heterocycloalkyl is optionally substituted with one or more halogen, deuterium, hydroxyl or cyano.

[0027] In some embodiments, each R 1 are independently selected from halogen, hydroxyl or cyano.

[0028] In some embodiments, each R 2 are independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl or 5-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 3-6The cycloalkyl or 5-6 membered heterocycloalkyl is optionally substituted with one or more halogen or deuterium.

[0029] In some embodiments, each R 2 are independently selected from C 1-4 Alkyl or C 3-6 Cycloalkyl, the C 1-4 The alkyl group is optionally substituted with one or more halogens or deuterium.

[0030] In some embodiments, each R 2 Each is independently selected from methyl, ethyl, isopropyl, 2-methylpropyl or cyclopropyl.

[0031] In some embodiments, said m is selected from 0, 1, 2 or 3. In some embodiments, said m is selected from 0, 1 or 2. In some embodiments, said m is 0.

[0032] In some embodiments, n is selected from 0, 1, 2, or 3. In some embodiments, n is selected from 0, 1, or 2. In some embodiments, n is 1.

[0033] In some embodiments, m is 0 and n is 1.

[0034] In some embodiments, said L is -CO-.

[0035] In some embodiments, the R 3 is selected from 6-10 membered heteroaryl, C 3-6 cycloalkyl, phenyl or 3-6 membered heterocycloalkyl, wherein the 6-10 membered heteroaryl, C 3-6 Cycloalkyl, phenyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more R a replace.

[0036] In some embodiments, the R 3 is selected from 6-membered heteroaryl, cyclopropyl, cyclobutyl or cyclohexyl, wherein the 6-membered heteroaryl, cyclopropyl, cyclobutyl or cyclohexyl is optionally substituted by one or more R a replace.

[0037] In some embodiments, the R 3 is selected from pyridyl or cyclopropyl, the pyridyl or cyclopropyl being optionally substituted by one or more R a replace.

[0038] In some embodiments, the R 3 Selected from optionally one or more R a In some embodiments, R 3 In some embodiments, each R4 are independently selected from fluorine, chlorine, bromine or iodine.

[0039] In some embodiments, the R 4 For fluorine.

[0040] In some embodiments, said p is selected from 0, 1 or 2. In some embodiments, said p is selected from 0 or 1.

[0041] In some embodiments, said p is 0.

[0042] In some embodiments, the R 4 is fluorine, and p is 1.

[0043] In some embodiments, the R a Selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl or C substituted by one or more halogen 1-6 alkyl.

[0044] In some embodiments, the R a Selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyloxy, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl or substituted by one or more fluorine 1-3 alkyl.

[0045] In some embodiments, the R a Selected from fluorine, chlorine, bromine, cyano, C 1-3 Alkyl, C 1-3 Alkoxy or 1, 2 or 3 fluorine-substituted C 1-3 alkyl.

[0046] In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from

[0047] In some embodiments, the structural unit Selected from

[0048] In some embodiments, the structural unit Selected from

[0049] In some embodiments, the structural unit Selected from

[0050] In some embodiments, the structural unit Selected from

[0051] In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from

[0052] In some embodiments, the structural unit Selected from

[0053] In some embodiments, the structural unit for wherein X is selected from hydrogen or fluorine; or a structural unit Selected from

[0054] In some embodiments, the structural unit Selected from

[0055] 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

[0056] Wherein, X is selected from hydrogen or fluorine, Y is selected from N or CH; Cy 1 , Cy 2 , R 1 , R 2 The definitions of , m, and n are as described above.

[0057] In some embodiments, the structural unit The definition of is as mentioned above.

[0058] In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from

[0059] In some embodiments, the present application comprises the above-defined variables and embodiments thereof, and any combination thereof.

[0060] On the other hand, the present application provides the following compound or a pharmaceutically acceptable salt thereof:

[0061]

[0062] 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.

[0063] On the other hand, the present application also provides a method for treating or preventing various diseases related to TYK2, comprising administering a therapeutically or preventively 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] In some embodiments, the TYK2-associated diseases are selected from inflammatory or autoimmune diseases.

[0068] The compounds of the present application have good in vitro enzyme or cell activity, metabolic stability such as liver microsome metabolic stability, as well as pharmacokinetic properties and in vivo pharmacodynamic properties.

[0069] definition

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a covalent bond.

[0077] When the number of a substituent is 0, such as -(R 1 )0, indicating no substitution, e.g. express

[0078] 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.

[0079] 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.

[0080] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0081] 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).

[0082] The term "alkoxy" refers to an -O-alkyl group.

[0083] The term "cycloalkoxy" refers to an -O-cycloalkyl group.

[0084] 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.

[0085] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged (including cyclic) or spirocyclic ring. Unless otherwise indicated, the heterocycle 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, oxirane, thioethane, and cyclonitroethane. Non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxadiazolyl, and thiadinyl. Examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl. Examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl. Examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Preferably, the monocyclic heterocycloalkyl has 5 or 6 ring atoms.

[0086] 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.

[0087] 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.

[0088] 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, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which fall within the scope of the present application. Additional asymmetric carbon atoms may exist in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present application.

[0089] Unless otherwise specified, the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Represents a straight solid bond and straight dashed key

[0090] Unless otherwise specified, when a compound contains a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each atom on the double bond is connected to two different substituents (in a double bond containing a nitrogen atom, a lone pair of electrons on the nitrogen atom is regarded as a substituent connected to it), if a wavy line is used between the atom on the double bond and its substituent in the compound, If they are connected, it means the (Z) isomer, (E) isomer or a mixture of the two isomers of the compound.

[0091] 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:

[0092] (i) inhibiting a disease or disease state, i.e. arresting its development;

[0093] (ii) ameliorating a disease or condition, even if causing regression of the disease or condition.

[0094] 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.

[0095] The term "therapeutically or prophylactically effective amount" means an amount of the present invention compound 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 present invention compound 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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".

[0101] 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.

[0102] 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.

[0103] Certain isotope-labeled compounds of the present application (e.g. 3 H 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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] An important consideration in synthetic route planning in the art is to select a suitable protecting group for a reactive functional group (such as the amino group in the present application). For example, reference may be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0116] 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:

[0117]

[0118] Among them, Cy 1 , Cy 2 , R 1 , R 2 , m, n, L, R 3 , R 4 Or p is defined as before.

[0119] This application uses the following abbreviations:

[0120] DIPEA stands for diisopropylethylamine; Xantphos stands for 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene; Pd(dba)2 stands for bis(dibenzylideneacetonepalladium); DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EDCI stands for 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; and HOBT stands for 1-hydroxybenzotriazole.

[0121] 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

[0122] Example 1: Compound 1-f

[0123]

[0124] 1) Preparation method of compound 1-a:

[0125] Dissolve 4,6-dichloropyridazine-3-carboxylic acid lithium salt (50g) in dichloromethane (500mL), add catalytic amount of DMF at 0℃, slowly add oxalyl chloride (96g) to the above solution, continue stirring and reacting for 2h at room temperature, and concentrate the reaction solution after the reaction is complete. Dissolve deuterated methylamine hydrochloride (18.6g) and DIPEA (162g) in dichloromethane (200mL) at -25℃, dissolve the above concentrated reaction solution in dichloromethane (300mL), and slowly add it to the above dichloromethane solution containing deuterated methylamine and DIPEA, and continue stirring for 2h after the addition is complete. Water (750 mL) was added to quench the reaction, and the mixture was extracted twice with dichloromethane (2×500 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain compound 1-a (52 g). ESI-MS: m / z=209.2 [M+H] + .

[0126] 2) Preparation method of compound 1-b:

[0127] Compound 1-a (12 g), 2-methoxy-3-aminobenzoic acid hydrochloride (11.7 g) and zinc acetate (31.6 g) were dissolved in isopropanol (200 mL), stirred at 50°C for 8 h, the reaction solution was concentrated, purified water was added, stirred at room temperature overnight, filtered, and dried under vacuum at 50°C to obtain compound 1-b (10.7 g). ESI-MS: m / z=340.09 [M+H] + .

[0128] 3) Preparation of compound 1-c:

[0129] Compound 1-b (2.0 g), cyclopropylcarboxamide (0.5 g), palladium acetate (0.2 g), Xantphos (0.6 g) and cesium carbonate (3.8 g) were dissolved in dioxane (3 mL) in sequence, heated to 130 ° C under nitrogen protection, and reacted for 5 h. The reaction solution was concentrated and purified by column chromatography to obtain compound 1-c (1.3 g). ESI-MS: m / z = 389.16 [M+H] + .

[0130] 4) Preparation method of compound 1-d:

[0131] Compound 1-c (2 g), ammonium chloride (0.54 g), 1EDCI (1.48 g), HOBt (1.04 g), triethylamine (1.56 g) and DMF (30 mL) were added to a reaction bottle and stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated, water (50 mL) was added and slurried for 2 hours, filtered, and dried to obtain compound 1-d (1.8 g). ESI-MS: m / z=388.15 [M+H] + .

[0132] 5) Preparation of compound 1-f:

[0133] Compound 1-d (200 mg), compound 1-e (200 mg), Pd2(dba)3 (90 mg), Xantphos (60 mg) and cesium carbonate (420 mg) were dissolved in dioxane (3 mL) in sequence, and heated to 105°C for 5 h under nitrogen protection. The reaction solution was concentrated and purified to obtain compound 1-f (130 mg). ESI-MS: m / z=571.14 [M+H] + .

[0134] 1 H NMR(500MHz,DMSO-d6)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).

[0135] Example 2: Compound 2-f

[0136]

[0137] 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 obtain compound 2-f. ESI-MS: m / z=545.36[M+H] + .

[0138] Example 3: Compound 3-f

[0139]

[0140] Referring to the preparation method of compound 1-f in Example 1, in step 5), compound 1-e is replaced with compound 3-e to obtain compound 3-f.

[0141] ESI-MS: m / z = 559.36 [M+H] + .

[0142] Experimental Example 1 TYK2 JH2 Thermal Stability Determination

[0143] 0.52mg / mL TYK2 JH2 protein stock solution was diluted to 50ng / μL with phosphate buffer (PBS), and 5000x protein dye (Orange dye) was diluted to 20x with DMSO. First, 16μL of TYK2 JH2 protein dilution was added to each well, and then different compounds dissolved in DMSO were added to the wells using a nanoliter pipette to make the final concentration of the compound 10μM and 1μM, with a total of 2 concentrations. At the same time, blank control wells (without enzyme) and negative control wells (with enzyme, 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 LightCycler480 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 using LightCycler Thermal Shift Analysis software.

[0144] The compounds of the present application have a melting temperature (Tm) greater than 40°C, preferably greater than 45°C, and more preferably greater than 55°C, when the final concentration is 10 μM; and a melting temperature (Tm) greater than 40°C, preferably greater than 45°C, and more preferably greater than 50°C, when the final concentration is 1 μM.

[0145] Experimental Example 2 Jurkat method for detecting STAT3 phosphorylation

[0146] Take Jurkat cells in logarithmic phase, take 20 μL to count, take the required number of cells (mL), centrifuge at 1300rpm for 3min, add phenol red-free 1640 basal medium to adjust the cell density, and adjust the cell density to about 1.7*10E7 cells / mL. Cells are plated (384-well small volume white plate) according to the above cell density, 8 μL / well; add samples with nanoliter pipette, incubate with compounds for 1.5h; dilute IFN-α to 75ng / mL (final concentration 25ng / ml) with phenol red-free 1640 basal medium; then add 4 μL IFN-α (3X) to each well according to the plate distribution, the blank group is inoculated with cells, no compounds, no IFN-α; the control group is inoculated with cells, no compounds, and IFN-α; incubate at 37℃ for 30min. Immediately add 4 μL lysis solution (4X) with blocking solution, and shake at room temperature for lysis for 40min. 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. PE Envision multi-function plate reader detects 665nm / 620nm signal values, and four-parameter fitting calculates IC 50 .

[0147] The experimental results are shown in Table 1.

[0148] Table 1

[0149] Example <![CDATA[IC 50 (nM)]]> 1-f 4.8

[0150] Experimental Example 3 Evaluation of in vitro liver microstructure stability

[0151] The final 300μL incubation system contains 30μL liver microsomes (protein concentration: 5mg / mL), 30μL NADPH+MgCl2, 3μL test compound (prepared in acetonitrile), and 237μL PBS buffer (pH7.4). The proportion of organic solvent (acetonitrile) is 1%. Two portions of 0.30mL are made for each species. Prepare a total volume of 270μL of substrate and enzyme mixed solution in each tube, pre-incubate with NADPH at 37℃ for 5min, add 30μL NADPH+MgCl2 and mix, take out 50μL at 0, 10, 30, and 60min, and terminate the reaction with 300μL of ice acetonitrile containing internal standard.

[0152] 50 μL of the incubated sample was added with 300 μL of acetonitrile containing internal standard (20 ng / mL) for precipitation, vortexed for 10 min, and centrifuged (13000 rpm, 20°C) for 10 min. 70 μL of the supernatant was taken, 70 μL of ultrapure water was added for dilution and mixing, and 0.5 μL was injected for analysis. The experimental results are shown in Table 2.

[0153] Table 2

[0154]

[0155] Experimental Example 4: Pharmacokinetic evaluation in mice

[0156] ICR mice weighing 20-24 g were randomly divided into groups after acclimation for 3-5 days, with 9 mice in each group, and the experimental compound was gavaged at a dose of 30 mg / kg.

[0157] The test animals (ICR mice) were fasted for 12 h before administration and given food 4 h after administration. They were allowed to drink water freely before, during and after the experiment.

[0158] After intragastric administration, blood samples were collected from each mouse at 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, and 10 h for 3 to 4 time points, with 3 mice at each time point. About 0.1 mL of blood was collected from the eye sockets, anticoagulated with EDTA-K2, and centrifuged at 4 ° C, 4000 rpm, and 10 min to separate plasma. After all plasma was collected, it was immediately stored at -20 ° C for testing.

[0159] Pipette 20 μL of the plasma sample to be tested and the standard sample, add 400 μL of acetonitrile solution containing the internal standard (20 ng / mL), shake and mix for 10 min, centrifuge at 13000 rpm for 10 min, take 50 μL of the supernatant, add 100 μL of ultrapure water to dilute, mix, and take 0.5 μL for LC / MS / MS determination, and record the chromatogram.

[0160] The oral exposure of the compound of the present invention was evaluated by a pharmacokinetic experiment in mice. The experimental results are shown in Table 3.

[0161] Table 3

[0162] PK parameters Compound 1-f IG 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

1. A compound of formula I or a pharmaceutically acceptable salt thereof: in, Cy 1 is phenyl; Cy 2 is selected from a 5-membered heteroaryl group containing a nitrogen atom; Every R 1 or R 2 are independently selected from C 1-6 Alkyl or C 3-6 Cycloalkyl; m is selected from 0, 1 or 2; n is selected from 0, 1 or 2; L is selected from -C(O)-; R 3 Selected from C 3-6 Cycloalkyl; Every R 4 are each independently selected from halogen; p is selected from 0 or 1.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, Cy 2 A 5-membered heteroaryl group containing a nitrogen atom, wherein the ring atoms of the 5-membered heteroaryl group consist of a nitrogen atom and a carbon atom.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the Cy 2 Selected from triazolyl or tetrazolyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, Every R 2 are independently selected from C 1-4 Alkyl or C 3-6 Cycloalkyl.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 1 or R 2 Each is independently selected from methyl, ethyl, isopropyl, 2-methylpropyl or cyclopropyl.

6. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein m is 0.

7. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein n is 1. 8 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein m is 0 and n is 1.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 4 are each independently selected from fluorine. 10 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein p is 0.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, R 4 is fluorine, and p is 1.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from 13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from 14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from 15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from 16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from 17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from 18. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from 19. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from 20. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from 21. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from 22. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from 23. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from 24. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from a compound of formula I-1 or a pharmaceutically acceptable salt thereof, in, X is selected from hydrogen or fluorine.

25. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from a compound of formula I-2 or a pharmaceutically acceptable salt thereof, in, X is selected from hydrogen or fluorine, and Y is selected from N or CH.

26. The compound according to claim 25 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from 27. The compound according to claim 25 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from 28. The following compound or a pharmaceutically acceptable salt thereof:

29. A pharmaceutical composition comprising the compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof.

30. Use of the compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 29, in the preparation of drugs for treating or preventing various TYK2-related diseases.

31. The use according to claim 30, wherein the various diseases associated with TYK2 are selected from autoimmune diseases.

Images