Macrocyclic compound as TYK2 inhibitor and pharmaceutical composition thereof

Abstract

Provided in the present application are a macrocyclic compound as a TYK2 inhibitor and a pharmaceutical composition thereof. The compound has a structure as represented by formula I, is a highly selective allosteric TYK2 inhibitor capable of penetrating the blood-brain barrier, and can be used for modulating TYK2-mediated diseases.

Description

Macrocyclic compounds as tyk2 inhibitors and pharmaceutical compositions thereof TECHNICAL FIELD

[0001] The present application provides a novel macrocyclic compound and pharmaceutical compositions and uses thereof, which is a highly selective TYK2 allosteric inhibitor that can cross the blood-brain barrier and can be used to modulate TYK2-mediated related diseases. BACKGROUND

[0002] The JAK kinase family (JAK1, JAK2, JAK3 and TYK2) are non-receptor tyrosine kinases that bind to the intracellular portion of cytokine receptors and are critical in the signaling of a variety of pro-inflammatory cytokines. As a result, small molecule inhibitors of JAK kinases have the potential to be effective therapeutic approaches for a variety of severe inflammatory and autoimmune diseases. Due to the high homology of the ATP active site within the JAK family, achieving high selectivity for a specific JAK family member has been a significant challenge. As a result, while many JAK inhibitors have been developed and shown promising results in treating autoimmune diseases, these JAK inhibitors are largely lacking in specificity and selectivity, and adverse side effects leading to a narrow therapeutic index have been observed in the clinic. Both JAK1 / 2 inhibitor Baricitinib and JAK1 inhibitor Upadacitinib have black box warnings, and there is a risk of serious infections, malignancies and thrombosis. In contrast to JAK1 / 2 / 3, there is substantial evidence that selective targeting of TYK2 can be a target for autoimmune diseases by selectively targeting the signaling of key cytokines (such as IL-23, IL-12 and type I interferons) involved in the pathogenesis of a variety of immune-mediated diseases.

[0003] However, due to the high homology of the catalytic domain (JH1) of the JAK family, achieving such selectivity has been challenging. TYK2 and other JAK family members have a catalytically inactive pseudokinase domain (JH2) adjacent to the JH1 domain, and this is the breakthrough for achieving selectivity. Tyk2 JH2 is very similar to Tyk2 JH1, but there are some unique differences in the binding pocket between the two domains. Tyk2 JH2 only binds ATP very weakly and does not exhibit any catalytic activity. Studies have shown that Tyk2 JH2 plays an important regulatory role in Tyk2 function. By selectively targeting Tyk2 JH2 with high selectivity, it is possible to achieve high selectivity for other JAK family members and the entire kinase family in an allosteric inhibition manner.

[0004] BMS's TYK2 inhibitor Deucravacitinib, which achieves high selectivity against other JAK family members and the entire kinase family in an allosteric inhibition manner, reduces the risk of adverse events such as cardiovascular events or venous thromboembolism, and Deucravacitinib has become the first oral JAK inhibitor on the market without a black box warning.

[0005] Neuroinflammation and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, traumatic brain injury and amyotrophic lateral sclerosis, are chronic major health diseases. The exact mechanism of neuroimmunological dysfunction in the pathogenesis of these diseases is not yet clear. These diseases show dysregulation of neuroimmuno and inflammatory responses, including activation of neurons, glial cells, and damage to neurovascular units associated with excessive release of pro-inflammatory cytokines, chemokines, neurotoxic mediators, infiltration of peripheral immune cells into the brain, and entry of inflammatory cells. TYK2 is a STAT pathway activator against a series of pro-inflammatory cytokines, and inhibition of TYK2 may play an important role in reducing inflammation in the above neurodegenerative diseases, so it is a clinical urgent need to develop a TYK2 allosteric inhibitor that can penetrate the blood-brain barrier for the treatment of neurodegenerative diseases. SUMMARY

[0006] The present application provides a macrocyclic compound represented by Formula I

[0007] or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotopically labeled, isomer or prodrug thereof,

[0008] The present application also relates to a pharmaceutical composition comprising a compound of the present application and a pharmaceutically acceptable carrier, diluent or excipient.

[0009] The present application also relates to a method of treating or preventing a TYK2-mediated disorder, comprising administering to an individual in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present application.

[0010] The present application also relates to the use of a compound described above for the manufacture of a medicament for treating or preventing a TYK2-mediated disorder.

[0011] The above-mentioned compound of the present application is a TYK2 allosteric inhibitor that can penetrate the blood-brain barrier and has high selectivity, and can be used to regulate TYK2-mediated diseases. DETAILED DESCRIPTION

[0012] The present application will be further described in detail by the following examples. Through these descriptions, the characteristics and advantages of the present application will become more apparent.

[0013] The term "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any implementation described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other implementations.

[0014] Furthermore, the features described in the different embodiments of the application described hereinafter can be combined with each other, unless explicitly stated otherwise.

[0015] Definitions

[0016] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Unless mentioned otherwise, all publications, patent applications and publications, patents, published patent applications and publications, and published patent applications referred to herein are incorporated by reference in their entirety. If there is a conflict between the specifications in this document with the specifications in the above and other documents, the specifications in this document control. Where the name of a commercial manufacturer is given, it is intended to refer to the corresponding commercial product or its active ingredients.

[0017] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It should also be noted that, as used in this application, the terms "or" and "and" shall each be interpreted as an "and / or" unless otherwise indicated. Furthermore, the use of the term "including" as well as other forms such as "include", "includes," and "included" is not limiting.

[0018] Definitions of standard chemical terminology can be found in texts such as "Advanced Organic Chemistry 4 th Ed, Vol A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacological techniques within the skill of the art are employed. Unless specific definitions are provided, the nomenclature utilized in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic and medicinal chemistry, and related chemical disciplines are those known to and used by persons of skill in the art. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical formulation, and delivery of a therapeutic agent. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques can be performed, e.g., using kits of manufacturers' instructions, or according to methods known to and described by those of skill in the art, or as described herein. In general, the techniques and procedures described, for example, in the preceding text and examples are standard methods well known to and used by those of skill in the art. Such techniques and procedures can be used to optimize reaction conditions and product recovery.

[0019] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2.

[0020] The term "substituted or unsubstituted" includes both "substituted" and "unsubstituted" cases. "Substituted" means that any one or more hydrogen atoms on a specific atom are substituted by a substituent, provided the valence state of the specific atom is normal and the resulting compound is stable. "Unsubstituted" means that the hydrogen atoms on a specific atom are not substituted by a substituent. For example, "substituted or unsubstituted ethyl" (e.g., in the case of a halogen substituent) includes unsubstituted (-CH2CH3), monosubstituted (e.g., -CH2CH2F), polysubstituted (e.g., -CHFCH2F, -CH2CHF2, etc.), or fully substituted (-CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or impossible to synthesize is introduced. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms on the same atom are substituted.

[0021] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and R has independent options in each case. Furthermore, combinations of substituents and / or their variants are permitted only if such combinations produce a stable compound. The terms "optional" or "optionally" mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition.

[0022] The C used in this article m～n This refers to a portion containing m to n carbon atoms. For example, the "C"... 1～8 "A group refers to a part containing 1-8 carbon atoms, that is, a group containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms... 8 carbon atoms. Therefore, for example, 'C'..." 1～8 "Alkyl" refers to an alkyl group containing 1 to 8 carbon atoms, meaning the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl... octyl, etc. The numerical ranges used in this document, such as "1-8", refer to integers within a given range. For example, "1-8 carbon atoms" means that the group can have 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms.

[0023] The term "alkyl" refers to a saturated aliphatic hydrocarbon group that is optionally substituted, either straight-chain or branched, and is connected to the rest of the molecule by a single bond. As used herein, "alkyl" can have 1 to about 8 carbon atoms, for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms. The "alkyl" examples in this document include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, etc., and longer alkyl groups such as heptyl and octyl. When the group defined in this document, such as "alkyl", appears in a numerical range, for example, "C", is used... 1-8 "Alkyl" refers to an alkyl group that can be composed of 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. For example, "C..." 1-4 "Alkyl" refers to an alkyl group that can be composed of 1, 2, 3, or 4 carbon atoms. The term "alkyl" in this document also includes cases where no numerical range is specified.

[0024] The term "alkenyl" refers to a monovalent hydrocarbon group, optionally substituted straight-chain or optionally substituted branched, having at least one C=C double bond. The alkenyl group has, but is not limited to, 2 to about 8 carbon atoms, such as 2 to about 6 carbon atoms, 2 to about 4 carbon atoms. The double bond in these groups can be in cis or trans conformation and should be understood to include both isomers. Examples of alkenyl groups include, but are not limited to, vinyl (CH=CH2), 1-propenyl (CH2CH=CH2), isopropenyl (C(CH3)=CH2), butenyl, and 1,3-butadienyl. When alkenyl groups as defined herein appear in numerical ranges, for example, "C..." 2-8 "Alkenyl" refers to an alkenyl group that can be composed of 2, 3, 4, 5, 6, 7, or 8 carbon atoms. In this article, alkenyl also includes cases where no numerical range is specified.

[0025] The term "alkynyl" refers to an optionally substituted straight-chain or branched monovalent hydrocarbon group having at least one C≡C triple bond. The alkynyl group has, but is not limited to, 2 to about 8 carbon atoms, for example, 2 to about 6 carbon atoms, or 2 to about 4 carbon atoms. Examples of alkynyl groups described herein include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiynyl. When a numerical range is used for the alkynyl group as defined herein, for example, "C..."2-8 "Alkyne" refers to an alkynyl group that can be composed of 2, 3, 4, 5, 6, 7, or 8 carbon atoms. In this article, alkynyl also includes cases where no numerical range is specified.

[0026] The term "cycloalkyl" refers to a non-aromatic carbon-containing ring, including saturated carbon rings (such as cycloalkyl) or unsaturated carbon rings (such as cycloalkenyl). Carbon rings include monocyclic rings (having one ring), such as monocyclic cycloalkyl; dicyclic rings (having two rings), such as dicyclic cycloalkyl; and polycyclic rings (having more than two rings). The rings can be bridged or spirocyclic. Carbon rings (such as cycloalkyl or cycloalkenyl) can have 3 to 8 carbon atoms, for example, 3 to about 6 cyclic carbon atoms or 3 to about 5 cyclic carbon atoms.

[0027] The term "aryl" refers to an optionally substituted aromatic hydrocarbon group having 6 to about 20, such as 6 to 12 or 6 to 10 cyclic carbon atoms, which can be monocyclic, bicyclic, or more cyclic aryl groups. Bicyclic or more cyclic aryl groups can be a monocyclic aryl group fused with other independent rings, such as alicyclic, heterocyclic, aromatic, or aromatic-heterocyclic rings. Non-limiting examples of monocyclic aryl groups include monocyclic aryl groups with 6 to about 12, 6 to about 10, or 6 to about 8 cyclic carbon atoms, such as phenyl; bicyclic aryl groups, such as naphthyl; and polycyclic aryl groups, such as phenanthryl, anthracene, or azulel.

[0028] The term "heteroaryl" refers to an arbitrarily substituted heteroaryl group comprising about 5 to about 20, such as 5 to 12 or 5 to 10, skeletal cyclic atoms, wherein at least one (e.g., 1-4, 1-3, 1-2) of the cyclic atoms is a heteroatom, which is independently selected from, but not limited to, heteroatoms of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin. Heteroaryl groups include monocyclic heteroaryl groups (having one ring), bicyclic heteroaryl groups (having two rings), or polycyclic heteroaryl groups (having two or more rings). In embodiments where two or more heteroatoms appear in the ring, the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other. Bicyclic or more cyclic heteroaryl groups can be a monocyclic heteroaryl group fused with other independent rings, such as alicyclic, heterocyclic, aromatic, or aromatic-heterocyclic groups (collectively referred to as fused cyclic heteroaryl groups). Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrole, furanyl, thiophene, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiophene, indole, isoindole, etc.

[0029] The term "heterocyclic group" refers to a non-aromatic heterocycle, including saturated or unsaturated heterocycles (containing unsaturated bonds), which do not possess a fully conjugated π-electron system. It can be classified into non-aromatic monocyclic, fused polycyclic, bridged, or spirocyclic systems. One or more (e.g., 1-4, 1-3, 1-2) of the cyclic atoms are heteroatoms, such as oxygen, nitrogen, or sulfur atoms. Heterocycles can include monocyclic (having one ring), bicyclic (having two bridging rings), or polycyclic (having more than two bridging rings); spirocyclic groups also include those with 3 to approximately 20 cyclic atoms, such as 3-approximately 10, 3-approximately 8, 4-approximately 8, 4-approximately 7, 5-approximately 8, or 5-approximately 6. Non-limiting examples of heterocyclic groups include ethylene oxide, cyclothioethylene, cycloazoethylene, acridine, oxobutylcycloyl, thiobutylcycloyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl, dihydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, dihydropyridinyl, tetrahydropyridinyl, dihydropyranyl, tetrahydropyranyl, dihydrothiaranyl, azirheptanyl, oxaheptanyl, thioheptanyl, oxazadiabicyclo[2.2.1]heptyl and azispir[3.3]heptyl, etc.

[0030] The term "halogenated" or "halogen" refers to the substitution of at least one hydrogen atom in an optionally substituted group (such as alkyl, alkenyl, alkynyl, alkoxy, etc.) with a halogen (such as fluorine, chlorine, bromine, iodine, or a combination thereof). In some embodiments, two or more hydrogen atoms are replaced with the same halogen (e.g., difluoromethyl, trifluoromethyl); in other embodiments, two or more hydrogen atoms are replaced with halogens that are not exactly the same (e.g., 1-chloro-1-fluoro-1-iodoethyl).

[0031] The term "alkoxy" refers to an alkyl ether group (O-alkyl), and non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0032] The term "alkyl acyl" refers to a group formed by an alkyl group bonded to -CO-. Non-limiting examples of this term include formyl, acetyl, propionyl, butyryl, etc. For example, the term "C..." 1-6 "alkyl acyl" refers to C 1-6 An alkyl group formed by attaching an alkyl group to a -CO- group. For example, the term "C 1-4 "alkyl acyl" refers to C 1-4 An alkyl group formed by attaching an alkyl group to a -CO- group.

[0033] The term "alkylsulfonyl" refers to a group consisting of an alkyl group bonded to -SO2-. Non-limiting examples of this term include methanesulfonyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl, etc. For example, the term "C..." 1-6 "alkylsulfonyl" refers to C1-6 An alkyl group formed by attaching an alkyl group to -SO2-. For example, the term "C 1-4 "alkylsulfonyl" refers to C 1-4 An alkyl group formed by attaching an alkyl group to -SO2-.

[0034] The term "heteroaryl acyl" refers to a group formed by a heteroaryl group bonded to -CO-. For example, the term "C 5～20 "Heteroarylsulfonyl" refers to C 5～20 A heteroaryl group formed by attaching a heteroaryl group to a -CO- group. "Heteroaryl" and "C" 5～20 The definition of "hybrid aromatics" is as above.

[0035] The terms "monocyclic," "monocyclic group," or "monocyclic ring system" refer to a structure consisting of one ring (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and / or heterocyclic groups). The terms "polycyclic group," "polycyclic group," or "polycyclic ring system" refer to a structure consisting of two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and / or heterocyclic groups), wherein two adjacent rings share one, two, or more ring atoms. For example, the polycyclic ring can be a "fused ring," a "spirocyclic," or a bridged ring structure.

[0036] The term "polycyclic carbide ring" includes bicyclic carbide rings and carbide rings with more than one ring. The term "bicyclic carbide ring" refers to an aromatic or non-aromatic ring containing two rings, where each atom in the ring is carbon, and the two rings share one, two, or more ring atoms. For example, the ring is a "fused ring" or a "spiro ring." Rings connected by non-adjacent atoms are called "bridging" rings, such as C5-C. 12 Bridged carbocyclic rings include, but are not limited to, bicyclo[2.2.2]octyl, bicyclo[1.1.1]pentyl, bicyclo[3.2.1]octyl, and bicyclo[2.1.1]hexyl. Each ring in the bicyclic carbocyclic ring may be substituted with the substituents described above, such as halogens, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, mercapto, imino, amide, phosphate esters, phosphonates, phosphonites, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF3, -CN, etc. The term "C5-C" is used in this context. 12 "Bicyclic carbocyclic ring" refers to a bicyclic carbocyclic ring with 5-12 carbon atoms, excluding carbon atoms on substituents, and may include C5-C6 atoms. 12 Spiroring carbon ring, C5-C 12 Fused carbon rings or C5-C 12 Bridged carbon rings.

[0037] The term "membered ring" refers to the number of skeleton atoms that make up the ring. For example, pyridine is a six-membered ring, and pyrrole is a five-membered ring.

[0038] In this application, each group may have the following definition:

[0039] Hydrogen can be represented as -H, or it can be replaced by isotopes such as deuterium and tritium.

[0040] Halogens can include fluorine, chlorine, bromine, and iodine.

[0041] C 1～8 Alkyl groups may include methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, etc.

[0042] Deuterated C 1～8 Alkyl, tritium C 1～8 Alkyl can represent the C 1～8 One or more, or even all, of the hydrogen atoms on the alkyl group are replaced with isotopes such as deuterium and tritium.

[0043] C 1～8 Alkyl groups can be represented as -OC 1～8 Alkyl group, wherein C 1～8 Alkyl groups include those defined above; for example, C 1～8 Alkoxy groups can include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.

[0044] C 1～8 Haloalkyl can be represented as C 1～8 A group in which any number of hydrogen atoms in an alkyl group are replaced by a halogen, wherein the C atoms are... 1～8 Alkyl groups and halogens include the groups defined above; for example, C 1～8 Halogenated alkyl groups may include -CF3, etc.

[0045] C 3～8 Cycloalkyl groups can be represented as non-aromatic saturated carbocyclic rings, including single-carbon rings (having one ring) and double-carbon rings (having two rings), for example, C 3～8 Cycloalkyl groups may include wait.

[0046] C 3～8 cycloalkyl C 1～8 Alkyl groups can be represented as those containing a C 3～8 C of cycloalkyl 1～8 Alkyl, wherein C3～8 cycloalkyl and C 1～8 Alkyl groups are defined as described above, for example, C 3～8 cycloalkyl C 1～8 Alkyl groups may include cyclopropylmethyl, cyclobutylmethyl, cyclohexylethyl, etc.

[0047] C 3～8 Heterocyclic groups can be represented as C 3～8 A group obtained by replacing any number of ring atoms in a cycloalkyl group with heteroatoms such as O, S, N, P, and Si, wherein the C... 3～8 Cycloalkyl groups include those defined above. For example, C 3～8 Heterocyclic groups may include ethylene oxide, cyclothioethylene, cycloazoethylene, acridine, oxobutylcycloyl, thiobutylcycloyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl, dihydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, dihydropyridinyl, tetrahydropyridinyl, dihydropyranyl, tetrahydropyranyl, dihydrothiaranyl, azirheptanyl, oxaheptanyl, thioheptanyl, oxazabicyclo[2.2.1]heptyl, azispir[3.3]heptyl, etc.

[0048] C 6～20 The aryl group may include monocyclic aryl, bicyclic aryl, or more cyclic aryl groups, for example, it may include phenyl, biphenyl, naphthyl, phenanthryl, anthracene, azulel, etc.

[0049] C 5～20 Heteroaryl groups can represent unsaturated groups containing any number of heteroatoms such as O, S, N, P, and Si as ring atoms. For example, C 5～20 Heteroaryl groups may include pyrrole, furanyl, thiophene, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiophene, indole, isoindole, etc.

[0050] A hydroxyl group can be represented as -OH.

[0051] A thiol group can be represented as -SH.

[0052] The carboxyl group can be represented as -COOH.

[0053] The ester group can be represented as -COOR', and R' can be C. 1～8 Alkyl, such as C 1～8 Alkyl-substituted ester groups can be represented as -COOC 1～8 Alkyl group, wherein C 1～8 Alkyl groups are as defined above.

[0054] The acyl group can be represented as -COR', and R' can be C. 1～8Alkyl, such as C 1～8 Alkyl-substituted acyl groups can be represented as -COC 1～8 Alkyl group, wherein C 1～8 Alkyl groups are as defined above.

[0055] The amino group can be represented as -NH2, -NHR', or -N(R')2, where R' can be C. 1～8 Alkyl, such as C 1～8 Alkyl-substituted amino groups can be represented as -NHC 1～8 Alkyl or -N(C) 1～8 Alkyl)2, wherein C 1～8 Alkyl groups are as defined above.

[0056] The amide group can be represented as -CO amino, where the amino group is as defined above.

[0057] The sulfonyl group can be represented as -S(O)2R', where R' can be C 1～8 Alkyl, such as C 1～8 Alkyl-substituted sulfonyl groups can be represented as -S(O)2C 1～8 Alkyl group, wherein C 1～8 Alkyl groups are as defined above.

[0058] A cyano group can be represented as -CN.

[0059] Oxidation can be represented as (=O).

[0060] Thio can be represented as (=S).

[0061] In the aforementioned definitions, when the number of carbon atoms changes, the definitions only change according to the change in the number of carbon atoms and do not affect the definitions of the types of functional groups; for example, "C 1～5 "alkyl" may include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, etc., as mentioned above. 1～8 The definition of "alkyl" includes all groups with 1-5 carbon atoms.

[0062] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0063] The term "pharmaceutical composition" refers to a bioactive compound optionally mixed with at least one pharmaceutically acceptable chemical component or reagent, which is a "carrier" that facilitates the introduction of the compound into cells or tissues, including but not limited to stabilizers, diluents, suspending agents, thickeners and / or excipients.

[0064] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological potency of the specified compound's free acid and free base and has no adverse effects in biological or other respects. Unless otherwise specified, the term "salt" in this disclosure may refer to metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with basic or acidic amino acids, etc. Non-limiting examples of metal salts include, but are not limited to, alkali metal salts, such as sodium salts, potassium salts, etc.; alkaline earth metal salts, such as calcium salts, magnesium salts, barium salts, etc.; aluminum salts, etc. Non-limiting examples of salts formed with organic bases include, but are not limited to, salts formed with trimethylamine, triethylamine, pyridine, methylpyridine, 2,6-dimethylpyridine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, etc. Non-limiting examples of salts formed with inorganic acids include, but are not limited to, salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Non-limiting examples of salts formed with organic acids include, but are not limited to, salts formed with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Non-limiting examples of salts formed with basic amino acids include, but are not limited to, salts formed with arginine, lysine, and ornithine. Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid and glutamic acid.

[0065] Pharmaceutically acceptable salts can be synthesized from parent compounds containing an acid radical or a base using conventional chemical methods. Generally, such salts are prepared by reacting these compounds, in their free acid or base form, with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture of both. Non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred.

[0066] The term "solvent" refers to a physical aggregate formed by a compound of this disclosure with one or more solvent molecules, the physical aggregate including varying degrees of ions and covalent bonds, such as hydrogen bonds. It has been demonstrated that the solvate can be separated, for example, when one or more solvent molecules are mixed in the crystal lattice. "Solvent" comprises both a solvent phase and a separable solvate portion. Numerous examples of solvates exist, including ethanol solvates, methanol solvates, etc. "Hydrate" is a solvate that uses water (H₂O) molecules as a solvent. One or more compounds of this disclosure can be prepared as solvates at will. The preparation of solvates is well known. For example, the preparation of a solvate of the antifungal drug fluconazole, i.e., using ethyl acetate and water, is described in M. Caira et al., J. Pharmaceutical Sci., 93(3), 601-611 (2004). Similar preparation methods for solvates and hydrates are also described in ECvan Tonder et al., AAPS PharmSciTech., 5(1), article 12 (2004); and ALBingham et al., Chem. Commun., 603-604 (2001). A typical, non-limiting preparation process involves dissolving the invented compound in a desired amount of an ideal solvent (organic solvent, water, or a mixture thereof) at a temperature above room temperature, cooling, allowing crystals to crystallize, and then separating and picking out the crystals using standard methods. The presence of the solvent (water) that forms the solvate (hydrate) during crystallization can be confirmed by IR spectroscopy.

[0067] The term "active metabolite" refers to an active derivative of a compound that is formed during its metabolism.

[0068] The term "polymorph" refers to the compounds of this disclosure that exist in different lattice forms.

[0069] The term "isotope-labeled" refers to compounds of this disclosure that are labeled with isotopes. For example, the isotopes in the compounds of this disclosure may include various isotopes of elements such as H, C, N, O, P, F, and S, such as... 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 S.

[0070] The term "pharmaceuticalally acceptable prodrug" or "prodrug" refers to any pharmaceutically acceptable salt, ester, salt of ester, or other derivative of the compounds disclosed herein, which, upon administration to a receptor, can directly or indirectly provide the disclosed compound or its pharmaceutically active metabolites or residues. Particularly preferred derivatives or prodrugs are those compounds that, when administered to a patient, can improve the bioavailability of the compounds of this application (e.g., make orally administered compounds more readily absorbed into the bloodstream), or those compounds that facilitate the delivery of the parent compound to a biological organ or site of action (e.g., the brain or lymphatic system). Prodrugs can be prepared by modifying functional groups present in the compound in a manner that allows them to decompose into the parent compound, either through conventional procedures or in vivo. Various forms of prodrugs are well known in the art. See also the discussion of prodrugs in T. Higuchi and V. Stella's Pro-drugs as Novel Delivery Systems (1987), Vol. 14 of the ACSSymposium Series, Bioreversible Carriers in Drug Design (1987), Edward B. Roche, ed., American Pharmaceutical Association, and Pergamon Press. Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985; and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, pp. 309-396; Bundgaard, H. "Design and Application of Prodrugs" in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, pp. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38. These references are incorporated herein by reference.

[0071] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule. The compounds disclosed herein contain asymmetric or chiral centers, double bonds, and other structures; therefore, the compounds disclosed herein may include various isomer forms such as optical isomers, geometric isomers, tautomers, and transisomers. These isomers, their single isomers, racemates, etc., are all included within the scope of this disclosure. For example, optical isomers can be prepared by chiral resolution, chiral synthesis, or chiral reagents or other conventional techniques to produce optically active (R)- and (S)- isomers, as well as D- and L isomers. For example, they can be converted to diastereomers by reacting with suitable optically active substances (e.g., chiral alcohols or Mosher's chloride), and then separated and converted (e.g., hydrolyzed) to the corresponding single isomers. Furthermore, separation can also be achieved by chromatographic column chromatography.

[0072] The “pharmaceutical compositions” described herein may be prepared in a manner well known in the pharmaceutical field and may be administered or applied via a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. They may be administered topically (e.g., transdermal, skin, eye, and mucous membrane delivery, including intranasal, vaginal, and rectal delivery), pulmonaryly (e.g., by inhalation or blowing of powders or aerosols, including via nebulizers; intratracheal, intranasal), or orally or parenterally. Parenterally administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenterally administration may be in the form of a single large dose or via, for example, a continuous infusion pump. The pharmaceutical compositions described herein include, but are not limited to, the following forms: tablets, pills, powders, lozenges, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or soluble in liquid solvents); ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders containing, for example, up to 10% by weight of an active compound.

[0073] The pharmaceutical compositions described herein can be formulated in unit dosage forms, each containing approximately 0.1–1000 mg, typically approximately 5–1000 mg of active ingredient, and more typically approximately 100–500 mg of active ingredient. The term “unit dosage form” refers to a physically isolated single-dose unit suitable for use in human patients and other mammals, each unit containing a predetermined amount of active substance, calculated to produce the desired therapeutic effect, when mixed with a suitable drug carrier.

[0074] The term "individual" refers to an individual suffering from a disease, symptom, or condition, including both mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, and pigs; domesticated animals, such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs.

[0075] The term "treatment" and other similar synonyms include relieving, reducing, or improving symptoms of a disease or condition; preventing other symptoms; improving or preventing the underlying metabolic causes of symptoms; inhibiting a disease or condition, such as preventing its progression; alleviating a disease or condition; improving a disease or condition; relieving symptoms caused by a disease or condition; or stopping the symptoms of a disease or condition. Furthermore, the term may also include a preventative purpose. The term also includes achieving therapeutic and / or preventative effects. A therapeutic effect refers to the cure or improvement of the underlying disease being treated. Additionally, the cure or improvement of one or more physiological symptoms associated with the underlying disease is also a therapeutic effect; for example, an improvement is observed in a patient even though they may still be affected by the underlying disease. In terms of preventative effects, the composition or compound may be administered to a patient at risk of developing a specific disease, or to a patient exhibiting one or more physiological symptoms of a disease, even if no disease diagnosis has been made.

[0076] The terms "dosage to achieve the necessary therapeutic effect" or "therapeutic effective dose" refer to the amount of at least one drug or compound, when administered, sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent. The result may be a reduction and / or relief of signs, symptoms, or causes, or any other desired change in the biological system. Effective doses suitable for any individual case can be determined using techniques such as dose escalation testing. The actual amount of compound, pharmaceutical composition, or drug administered is usually determined by the physician based on relevant circumstances, including the condition being treated, the chosen route of administration, the actual compound administered, the individual patient's age, weight, and response, and the severity of the patient's symptoms.

[0077] The proportion or concentration of the disclosed compound in a pharmaceutical composition may not be fixed and depends on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), route of administration, etc. For example, the disclosed compound may be provided in a physiologically buffered aqueous solution containing about 0.1 to 10% w / v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg / kg to about 1 g / kg body weight / day. In some embodiments, the dosage range is from about 0.01 mg / kg to about 100 mg / kg body weight / day. The dosage is likely to depend on variables such as the type and severity of the disease or condition, the general health status of the specific patient, the relative biological potency of the selected compound, the excipient formulation, and the route of administration.

[0078] The term "administration" refers to a method capable of delivering a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral administration, duodenal administration, parenteral administration (including intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), topical application, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein, such as those discussed in Goodman and Gilman, *The Pharmacological Basis of Therapeutics*, current ed.; Pergamon; and Remington's, *Pharmaceutical Sciences* (current edition), Mack Publishing Co., Easton, Pa.

[0079] To make the objectives, technical solutions, and advantages of the present invention clearer, the technical solutions of exemplary embodiments of the present invention will be further described below.

[0080] compound

[0081] This application provides macrocyclic compounds represented by Formula I.

[0082] Or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope label, isomer, or prodrug.

[0083] in,

[0084] W 1 and W 2 Each is independently selected from N or CH;

[0085] X 1 and X 2 Each is independently selected from -NH-, -O-, -S-, or -CH2-;

[0086] R1 is selected from any alternative, R. 10 C 1-6 Alkyl, optionally substituted with R 10 C 1-6 alkoxy or R 11 R 12 N-; R 11 and R 12 Each is independently selected from hydrogen or optionally substituted with R. 10 C 1-6 Alkyl; R 10 Each is independently selected from protium, deuterium, tritium, or halogens;

[0087] R2 is selected from R 21O-, R 21 S-, R 21 C(O)-, R 21 S(O)-、R 21 S(O)2- or R 22 R 23 N-,

[0088] R 21 Selected from hydrogen, with optional substitution of R 20 C 1-6 Alkyl, optionally substituted with R 20 C 3-8 Cycloalkyl, optionally substituted with R 20 C 6-10 Aryl or optionally substituted with R 20 5-6 aryl heteroaryl groups;

[0089] R 22 and R 23 Each is independently hydrogen, with optional substitution having R 20 C 1-6 Alkyl, optionally substituted with R 20 C 3-8 Cycloalkyl or optionally substituted with R 20 C 6-10 aryl; or, R 22 and R 23 Together with the nitrogen atoms they are attached to, they form 3-8 membered heterocycles;

[0090] R 20 Each is independently selected from protium, deuterium, tritium, halogen, cyano, or hydroxyl; R 40 Selected from any alternatives R 10 C 1-6 Alkyl or optionally substituted with R 10 C 1-6 alkoxy; or, R 21 R4 and the atoms they are attached to form optional substitutions with R. 40 5-8 membered heterocycles;

[0091] R3 is selected from any alternative R. 30 C 1-6 Alkyl, optionally substituted with R 30 C 1-6 Alkoxy, optionally substituted with R 30 C 3-8 Cycloalkyl, optionally substituted with R 30 C 6-10 Aryl or optionally substituted with R 30 5-6 nucleotide heteroaryl groups; R 30 Each is independently selected from protium, deuterium, tritium, halogen, cyano or hydroxyl;

[0092] R4 is selected from hydrogen, and can be optionally substituted with R. 10 C 1-6 Alkyl or optionally substituted with R 10 C 1-6 alkoxy groups; or, R2 and R4 together with the atoms they are attached to form optional substitutions with R. 40 5-8 membered heterocycles;

[0093] Ring A is selected from C 6-10 aryl or heteroaryl;

[0094] R5 is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, and optionally substituted with R 50 C 1-6 Alkyl, optionally substituted with R 50 C 1-6 Alkoxy, optionally substituted with R 50 C 3-8 Cycloalkyl, optionally substituted with R 50 C 6-10 Aryl or optionally substituted with R 50 5-6 nucleotide heteroaryl groups; R 50 Each is independently selected from protium, deuterium, tritium, halogen, cyano or hydroxyl;

[0095] R6 is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, and optionally substituted with R 60 C 1-6 Alkyl, optionally substituted with R 60 C 1-6 Alkoxy, optionally substituted with R 60 C 3-8 Cycloalkyl, optionally substituted with R 60 C 6-10 Aryl or optionally substituted with R 60 5-6 nucleotide heteroaryl groups; R 60 Each is independently selected from protium, deuterium, tritium, halogen, cyano or hydroxyl;

[0096] L is a set of p interconnected L 1 The connection A ring and containing W 2 The connecting base of the six-membered ring, two adjacent L 1 Connected by a single bond, the two L's at both ends 1 Through single bonds with A rings and W-containing rings respectively 2 Connect the six-membered rings; p is an integer from 1 to 8, L 1 Each is independently selected from -C(R7)2- and -NR 8 -、-O-、-S-、-C(O)-、-S(O)- or -S(O)2-;

[0097] R7 Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl or C 1-3 Haloalkoxy; or, two R 7 Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl;

[0098] R 8 Each is independently selected from hydrogen and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 alkyl carbonyl, C 1-3 Alkoxycarbonyl, phenyl C 1-3 alkyl carbonyl or phenyl C 1-3 alkoxycarbonyl;

[0099] m is an integer from 1 to 4.

[0100] For compounds of Formula I in this application, ring A can be a monocyclic structure, such as selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, pyrrole ring, pyrazole ring, imidazole ring, oxazole ring, thiazole ring, etc., or it can be a fused ring structure, such as benzopyridine ring, etc.

[0101] In one implementation, ring A can be selected from one of the following structural formulas: “a” indicates that this end connects to X. 1 connect.

[0102] In one embodiment, the macrocyclic compound has the structural formula II.

[0103] Among them, W 3 It can be N or CH;

[0104] R 1 R 2 R 3 R 4 R 5 R 6 W 1 W 2 X 1 X 2 L and n are defined as before.

[0105] Ring A in Formula I and W-containing compounds in Formula II 3 A six-membered ring can have m R elements. 5 m can be an integer from 0 to 4, such as 1 or 2. R5 can be independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, or optionally substituted with R.50 C 1-6 Alkyl, optionally substituted with R 50 C 1-6 Alkoxy, optionally substituted with R 50 C 3-8 Cycloalkyl, optionally substituted with R 50 C 6-10 Aryl or optionally substituted with R 50 5-6 nucleotide heteroaryl groups; R 50 Each of the elements is independently selected from protium, deuterium, tritium, halogen, cyano, or hydroxyl. Preferably, R5 is hydrogen.

[0106] In one embodiment of the compounds of formula I and formula II, R3 can be C 1-3 Alkyl or deuterated C 1-3 Alkyl, preferably methyl or deuterated methyl, such as trideuterated methyl.

[0107] In one embodiment of the compounds of formula I and formula II, R1 can be C 1-3 Alkyl groups (e.g., methyl, ethyl, propyl, or isopropyl) or deuterated C 1-3 Alkyl groups (e.g., deuterated methyl, deuterated ethyl, deuterated propyl, or deuterated isopropyl, etc.); preferably, R1 can be methyl, ethyl, deuterated methyl, or deuterated ethyl, such as trideuterated methyl or trideuterated ethyl, thereby forming ketone compounds. In one embodiment of compounds of formula I and formula II, R1 can be C 1-3 Alkyl groups (e.g., methoxy, ethoxy, propoxy, or isopropoxy) or deuterated C 1-3 Alkoxy groups, for example, can be deuterated methoxy, deuterated ethoxy, deuterated propoxy, or deuterated isopropoxy, etc. Preferably, R1 can be a methoxy or ethoxy group, or a deuterated methoxy group such as trideuterated methoxy, thereby forming an ester compound. In one embodiment of the compounds of formula I and formula II, R1 can be C... 1-3 Alkylamino (e.g., methylamino, ethylamino, propylamino, or isopropylamino, etc.) or deuterated C 1-3 Alkylamino groups, such as methylamino or deuterated methylamino groups, such as trideuterated methylamino, can be used to form amide compounds.

[0108] In one embodiment of the compounds of Formula I and Formula II, R6 may be hydrogen.

[0109] In one embodiment of the compounds of formula I and formula II, R2 can be R 21 O-, where R 21 It can be C 1-3 Alkyl groups (e.g., methyl, ethyl, propyl, or isopropyl) or deuterated C 1-3Alkyl group (e.g., deuterated methyl, deuterated ethyl, deuterated propyl, or deuterated isopropyl, etc.), preferably methyl or deuterated methyl, such as trideuterated methyl. In one embodiment of compounds of formula I and formula II, R2 is R 21 O-, where R 21 R4 and the atoms they are attached to form C-substituted compounds. 1-3 Alkyl groups containing oxygen-containing 5-6-membered heterocycles, such as oxygen-containing 6-membered heterocycles, thereby forming polycyclic fused structures containing triazoles.

[0110] In one embodiment of the compounds of formula I and formula II, R2 can be R 22 R 23 N-, where R 22 and R 23 Each can be independently of C 1-3 Alkyl or deuterated C 1-3 Alkyl group, preferably methyl or deuterated methyl, such as trideuterated methyl. Or, R 23 C 1-3 Alkyl or deuterated C 1-3 Alkyl group, preferably methyl or deuterated methyl, such as trideuterated methyl, R 22 R4 and the atoms they are attached to form C-substituted compounds. 1-3 The alkyl nitrogen-containing 5-6 membered heterocycle, preferably a nitrogen-containing 6 membered heterocycle substituted with a methyl group, thereby forming a polycyclic fused structure containing a triazole.

[0111] In one embodiment of the compounds of Formula I and Formula II, R4 may be hydrogen.

[0112] In one embodiment of the compounds of formula I and formula II, X 1 and X 2 All are -NH-.

[0113] In one embodiment of the compounds of formula I and formula II, W 1 and W 2 Each is independently selected from N or CH. Preferably, W 2 It is CH, and at this time it contains W. 2 The six-membered ring is a benzene ring. Or, W 2 Let N be the number of elements, then W is included. 2 The six-membered ring is a pyridine ring. Preferably, W 1 It is CH, and at this time it contains W. 1 The six-membered ring is a pyridine ring. Or, W 1 Let N be the number of elements, then W is included. 2 The six-membered ring is a pyridazine ring.

[0114] In one embodiment of the compound of formula II, W 3It is CH, and at this time it contains W. 3 The six-membered ring is a benzene ring. In one embodiment of the compound of formula II, W 3 Let N be the number of elements, then W is included. 3 The six-membered ring is a pyridine ring.

[0115] In one embodiment of the compounds of Formula I and Formula II, L represents p interconnected L... 1 The connection A ring and containing W 2 The connecting base of the six-membered ring, two adjacent L 1 Connected by a single bond, the two L's at both ends 1 Through single bonds with A rings and W-containing rings respectively 2 Connect the six-membered rings; p is an integer from 1 to 8, L 1 Each is independently selected from -C(R7)2- and -NR 8 -、-O-、-S-、-C(O)-、-S(O)- or -S(O)2-.

[0116] In one embodiment of the compounds of Formula I and Formula II, p is 3, 4, 5, or 6; preferably, p is 4 or 5. When p is an integer greater than or equal to 2, two adjacent L 1 Not all are -O-, -S-, -C(O)-, -S(O)-, or -S(O)2-. When p is an integer greater than or equal to 2, two adjacent L... 1 One of the L 1 It can be -NR 8 - The other can be -C(O)-, -S(O)-, or -S(O)2-, thus forming an amide bond, a sulfinamide bond, or a sulfonamide bond.

[0117] In one embodiment of the compounds of formula I and formula II, p L 1 Only one of them is -NR 8 -, -O-, -S-, -C(O)-, -S(O)- or -S(O)2-, preferably -O-; the rest L 1 For -C(R7)2-, R 7 Each is independently selected from hydrogen or C. 1-3 Alkyl group, preferably hydrogen.

[0118] In one embodiment of the compounds of Formula I and Formula II, L is selected from one of the following structures:

[0119] Preferably, L is selected from one of the following structures:

[0120] in Indicates L and W 2The position of the six-membered ring connection ---- indicates that L is connected to ring A or contains W. 3 The position where the six-element ring is connected.

[0121] The macrocyclic compound in this application can be one of the following compounds:

[0122] Pharmaceutical Compositions and Applications

[0123] This application relates to a pharmaceutical composition comprising the compound described above or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope label, isomer, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0124] As demonstrated in this application, the compound of this application possesses excellent TYK2 inhibitory activity, particularly acting on the TYK2 JH2 pseudokinase domain. It is a highly selective TYK2 allosteric inhibitor that can cross the blood-brain barrier and can be used to regulate TYK2-mediated diseases. Therefore, this application also relates to the above-mentioned compound or its pharmaceutically acceptable salts, hydrates, solvates, active metabolites, polymorphs, isotope labels, isomers, or prodrugs, as well as the use of pharmaceutical compositions in the preparation of drugs for treating tyrosine kinase-mediated diseases.

[0125] In one embodiment, the tyrosine kinase is selected from TYK2 kinase. In one embodiment, the diseases mediated by the tyrosine kinase include inflammatory autoimmune diseases, tumors, and neurodegenerative diseases. Inflammatory autoimmune diseases mainly include atopic dermatitis, hidradenitis suppurativa, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, lupus erythematosus, and brain autoimmune diseases of the central nervous system; tumors mainly include leukemia, lymphoma, myeloma, and brain tumors; neurodegenerative diseases mainly include brain atrophy, Alzheimer's disease, Parkinson's syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, and multiple sclerosis.

[0126] This application also relates to a method of treating a tyrosine kinase-mediated disease, comprising administering a therapeutically effective amount of the aforementioned compound of this application or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope label, isomer, or prodrug, or pharmaceutical composition thereof, to a patient in need of administration.

[0127] The compounds described herein can be prepared by the following methods. The methods and examples below are for illustrative purposes. These processes and examples should not be construed as limiting the invention in any way. The compounds described herein can also be synthesized using standard synthetic techniques known to those skilled in the art, or in combination with methods known in the art.

[0128] The chemical reactions in the embodiments of the present invention are carried out in a suitable solvent, which must be suitable for the chemical changes of the present invention and the reagents and materials required therefor. To obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

[0129] A crucial consideration in planning any synthetic route in this art is selecting suitable protecting groups for reactive functional groups (such as the amino groups in this invention). For trained practitioners, Greene and Wuts's (Protective Groups in Organic Synthesis, Wiley and Sons, 1991) is an authority in this field. All references cited in this invention are incorporated herein by reference in their entirety.

[0130] The reactions described herein can be monitored using any suitable method known in the art. For example, they can be monitored using broad-spectrum methods such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) Infrared spectroscopy, spectrophotometry (e.g., UV-Vis), mass spectrometry, or monitoring of product formation by chromatography such as high performance liquid chromatography (HPLC) or thin-layer chromatography.

[0131] The compounds of general formula I of this invention can be prepared by those skilled in the art of organic synthesis using standard methods in the art through the following process:

[0132] Compound 1, which is substituted by a dihalogen, undergoes a coupling or substitution reaction with compound 2 to generate compound 3. Compound 3 then undergoes cyclization to generate compound I.

[0133] The invention is illustrated in more detail by way of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily recognize that various non-critical parameters can be changed or modified to obtain substantially the same results. The compounds in the following examples were found to be TYK2 allosteric inhibitors according to one or more of the determinations described herein.

[0134] Example 1: 1-(5) 6 -Methoxy-5 5 -(2-Methyl-2H-1,2,3-triazol-4-yl)-8-oxa-2,4-diaza-1(2,6),3(2,4)-dipyridin-5(1,3)-benzocyclononane-3 5 -yl)prop-1-one

[0135] Synthesis route:

[0136] Step A: Ethyl 6-(bis(tert-butoxycarbonyl)amino)pyridinecarboxylate:

[0137] Ethyl 6-aminopyridinecarboxylate (25.0 g, 150.5 mmol, 1.0 eq) was added to a 1 L round-bottom flask and dissolved in 250 mL of dichloromethane. Then, di-tert-butyl dicarbonate (98.6 g, 451.8 mmol, 3.0 eq) and 4-dimethylaminopyridine (9.2 g, 75.3 mmol, 0.5 eq) were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. After the raw material was completely converted by LC-MS, 200 mL of water was added to the mixture and it was extracted three times with (300 mL) dichloromethane. The organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, filtered to remove inorganic salts, concentrated to dryness, and the concentrated residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain ethyl 6-(bis(tert-butoxycarbonyl)amino)pyridinecarboxylate (51.9 g, yield = 94%) as a white solid.

[0138] LC-MS: (M+1) + m / z = 367.2;

[0139] Step B: (6-(hydroxymethyl)pyridin-2-yl)tert-butyl carbamate:

[0140] In a 1L round-bottom flask, ethyl 6-(bis(tert-butyloxycarbonyl)amino)pyridinecarboxylate (46.0 g, 125.6 mmol, 1.0 eq) was added and dissolved in 500 mL of anhydrous tetrahydrofuran. The reaction mixture was cooled to below 5°C in an ice-water bath, and lithium aluminum hydride (9.5 g, 250.0 mmol, 2.0 eq) was added in portions. After the addition was complete, the reaction mixture was slowly brought to room temperature and stirred for 2 h. After the starting material was completely converted by LC-MS, 10 mL of water was added to quench the reaction mixture. Then, 10 mL of 15% sodium hydroxide solution was added, and the mixture was stirred for 20 minutes to precipitate the aluminum salt, followed by the addition of 50 mL of water. The mixture was filtered, and the filter cake was washed 3-5 times with ethyl acetate. The filtrate was extracted three times with ethyl acetate (300 mL), the organic phases were combined, the organic phase was washed with saturated brine and dried with anhydrous sodium sulfate, the inorganic salts were removed by filtration, the organic phase was concentrated to dryness, and the residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain tert-butyl 6-(hydroxymethyl)pyridin-2-yl)carbamate (11.4 g, yield = 41%), which was a white solid.

[0141] LC-MS: (M+1) + m / z = 225.1;

[0142] Step C: (6-(bromomethyl)pyridin-2-yl)tert-butyl carbamate:

[0143] In a 250 mL round-bottom flask, tert-butyl (6.0 g, 26.8 mmol, 1.0 eq) and triphenylphosphine (14.0 g, 53.4 mmol, 2.0 eq) were added and dissolved in 100 mL of dichloromethane. The reaction solution was cooled to below 5 °C in an ice-water bath, and carbon tetrabromide (17.8 g, 53.7 mmol, 2.0 eq) was slowly added dropwise under nitrogen protection. After the addition was complete, the reaction solution was slowly brought to room temperature and the mixture was stirred for 4 hours. After the raw material was completely converted by LC-MS, 100 mL of water was added to the mixture and it was extracted three times with 200 mL of dichloromethane. The organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, filtered to remove inorganic salts, concentrated to dryness, and the residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 5:1 to 1:1) to obtain tert-butyl (6-(bromomethyl)pyridin-2-yl)carbamate (4.8 g, yield = 63%) as a yellow solid.

[0144] LC-MS: (M+1) + m / z = 287.0 & 289.1;

[0145] Step D: 2-Bromo-4-(2-hydroxyethyl)phenol

[0146] In a 2L three-necked flask, 50.0 g (362.1 mmol, 1.0 eq) of 4-hydroxyphenylethanol was added, followed by 500 mL of water and 200 mL of acetone to dissolve it. The reaction solution was cooled to below 15°C in an ice-water bath, and potassium peroxide monosulfonate (178 g, 289.7 mmol, 0.8 eq) was added in portions. Then, a pre-prepared 50 wt% sodium bromide aqueous solution (37.3 g, 362.1 mmol, 1.0 eq) was slowly added, maintaining the temperature below 20°C. After the addition was complete, the reaction was stirred in an ice-water bath for 1–2 hours, and LC-MS was used to monitor the reaction until completion. After the reaction was complete, sodium thiosulfate (28.6 g, 181.0 mmol, 0.5 eq) was slowly added in portions in an ice-water bath to quench the reaction. The reaction solution was then poured into a single-necked flask, and acetone was distilled under reduced pressure at below 45°C. As the amount of acetone decreased, the product precipitated as a white solid. After filtration, the filter cake was washed with water 2-3 times and then dried under vacuum to obtain 2-bromo-4-(2-hydroxyethyl)phenol (50.7g, yield = 65%).

[0147] LC-MS: (M-17) + m / z = 199.0 & 201.0;

[0148] Step E: 2-Bromo-4-(2-hydroxyethyl)-6-nitrophenol

[0149] In a 1.0 L three-necked flask, 45.5 g (210.7 mmol, 1.0 eq) of 2-bromo-4-(2-hydroxyethyl)phenol was dissolved in 350 mL of acetic acid. An ice-water bath was set up, and the reaction mixture was cooled to below 5 °C. Concentrated nitric acid (24.5 g, 252.8 mmol, 1.2 eq) was added dropwise. After the addition was complete, the reaction mixture was slowly brought to room temperature and stirred for 4–5 hours. LC-MS was used to monitor complete conversion of the starting materials. Then, a saturated sodium carbonate aqueous solution was added dropwise to the mixture under ice-water bath to adjust the pH to 8–9. After adjustment, the sample was extracted three times with 500 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, and the inorganic salts were removed by filtration. The organic phase was concentrated to dryness, and the concentrated residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1 to 3:1) to obtain 2-bromo-4-(2-hydroxyethyl)-6-nitrophenol (40.9 g, yield = 74%), which was a pale yellow solid.

[0150] LC-MS: (M-17) + m / z = 244.0 & 245.9;

[0151] Step F: 2-(3-bromo-4-methoxy-5-nitrophenyl)ethane-1-ol

[0152] In a 1.0 L round-bottom flask, 2-bromo-4-(2-hydroxyethyl)-6-nitrophenol (40.9 g, 156.7 mmol, 1.0 eq) and iodomethane (26.7 g, 188.0 mmol, 1.2 eq) were dissolved in 500 mL of DMF, and potassium carbonate (43.3 g, 313.3 mmol, 2.0 eq) was added under nitrogen protection. The reaction mixture was heated and stirred at 60 °C for 2 hours. After the LCMS monitoring showed complete conversion of the raw material, 500 mL of water was added to the mixture and it was extracted three times with 500 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, and the inorganic salts were removed by filtration. The organic phase was concentrated to dryness, and the concentrated residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to obtain 2-(3-bromo-4-methoxy-5-nitrophenyl)ethane-1-ol (28.2 g, yield = 65%) as a yellow solid.

[0153] LC-MS: (M-17) + m / z = 258.0 & 260.0.

[0154] Step G: 2-(4-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)-5-nitrophenyl)ethane-1-ol:

[0155] In a 1.0 L round-bottom flask, 2-(3-bromo-4-methoxy-5-nitrophenyl)ethane-1-ol (16.0 g, 58.2 mmol, 1.0 eq) and (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (8.9 g, 70.1 mmol, 1.2 eq) were dissolved in 1,4-dioxane (200 mL) and water (40 mL). Cesium carbonate (37.9 g, 116.3 mmol, 2.0 eq) and Pd(dppf)Cl2 (4.2 g, 5.8 mmol, 0.1 eq) were then added sequentially. After evacuating to nitrogen three times, the mixture was heated at 100 °C for 2 hours under nitrogen protection. After complete conversion of the starting materials was monitored by LC-MS, the reaction mixture was filtered. Ethyl acetate (200 mL) was added for extraction three times. The organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, and the inorganic salts were removed by filtration. The organic phase was concentrated to dryness, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 3:1 to 1:1) to obtain 2-(4-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)-5-nitrophenyl)ethane-1-ol (8.4 g, yield = 52%), as a yellow solid.

[0156] LC-MS: (M+1) + m / z = 279.1

[0157] Step H: (6-((4-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)-5-nitrophenylethoxy)methyl)pyridin-2-yl)tert-butyl carbamate:

[0158] In a 250 mL round-bottom flask, 2-(4-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)-5-nitrophenyl)ethane-1-ol (3.0 g, 10.8 mmol, 1.0 eq) and (6-(bromomethyl)pyridin-2-yl)carbamate tert-butyl ester (3.7 g, 12.9 mmol, 1.2 eq) were dissolved in anhydrous tetrahydrofuran (100 mL). 60% sodium hydride (1.3 g, 32.5 mmol, 3.0 eq) was slowly added under an ice-water bath, and the reaction mixture was stirred under an ice-water bath for 2 hours. After the raw material was completely converted by LC-MS, the reaction solution was quenched with ice water (50 mL) and extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, filtered to remove inorganic salts, concentrated to dryness, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1) to obtain tert-butyl 6-((4-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)-5-nitrophenylethoxy)methyl)pyridin-2-yl)carbamate (1.5 g, yield = 29%), as a yellow solid.

[0159] LC-MS: (M+1) + m / z = 485.4;

[0160] Step I: (6-((3-amino-4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)phenethoxy)methyl)pyridin-2-yl)tert-butyl carbamate:

[0161] In a 50 mL round-bottom flask, tert-butyl (6-((4-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)-5-nitrophenylethoxy)methyl)pyridin-2-yl)carbamate (1.5 g, 3.1 mmol, 1.0 eq) was dissolved in ethanol (5 mL) and water (2 mL). Ammonium chloride (829 mg, 15.5 mmol, 5.0 eq) and zinc powder (1.0 g, 15.5 mmol, 5.0 eq) were then added to the reaction mixture. The mixture was heated and stirred in an oil bath at 60 °C for 12 hours. After complete conversion of the starting materials was monitored by LC-MS, the reaction mixture was filtered. After vacuum concentration of the filtrate, the residue was purified by preparative chromatography (mobile phase A: pure water; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 60 mL / min) to obtain tert-butyl 6-((3-amino-4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (910 mg, yield = 65%) as a white solid.

[0162] LC-MS: (M+1)+ m / z = 455.3;

[0163] Step J: 1-(4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-6-chloropyridin-3-yl)prop-1-one:

[0164] In a 50 mL Shrek tube, 600 mg (1.3 mmol, 1.0 eq) of tert-butyl (6-((3-amino-4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)phenethoxy)methyl)pyridin-2-yl)carbamate was dissolved in 5 mL of ethanol. Then, 322 mg (1.6 mmol, 5.0 eq) of 1-(4,6-dichloropyridin-3-yl)prop-1-one and 5 drops of concentrated hydrochloric acid were added to the reaction solution as a catalyst. The reaction solution was heated and stirred in a 90 °C oil bath for 12 hours. After the raw material conversion was completed by LCMS, the reaction solution was concentrated under vacuum, and the residue was purified by preparative chromatography (mobile phase A: pure water; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 60 mL / min) to obtain 1-(4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-6-chloropyridin-3-yl)prop-1-one (277 mg, yield = 40%) as a white solid.

[0165] LC-MS: (M+1) + m / z = 522.3;

[0166] Step K: 1-(5) 6 -Methoxy-5 5 -(2-Methyl-2H-1,2,3-triazol-4-yl)-8-oxa-2,4-diaza-1(2,6),3(2,4)-dipyridin-5(1,3)-benzocyclononane-3 5 -yl)prop-1-one:

[0167] In a 50 mL Shrek tube, 1-(4-((5-(2-(((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-6-chloropyridin-3-yl)prop-1-one (277 mg, 0.5 mmol, 1.0 eq) was dissolved in dioxane (5 mL), followed by the addition of cesium carbonate (346 mg, 1.0 mmol, 1.0 eq), XantPhos (62.0 mg, 0.1 mmol, 0.2 eq), and Pd-G4 (102 mg, 0.1 mmol, 0.2 eq). The mixture was purged with nitrogen three times and then heated in an oil bath at 100 °C for 2 hours. After complete conversion of the starting material was monitored by LC-MS, the reaction solution was concentrated under vacuum. The residue was purified by preparative chromatography (mobile phase A: water (0.1% NH4HCO3); mobile phase B: acetonitrile; gradient: 20%-70% B, 60 min; flow rate: 60 mL / min) to obtain 1-(5 6 -Methoxy-5 5 -(2-Methyl-2H-1,2,3-triazol-4-yl)-8-oxa-2,4-diaza-1(2,6),3(2,4)-dipyridin-5(1,3)-benzocyclononane-3 5 1-propyl-1-one (95.0 mg, yield = 40%) is a white solid.

[0168] LC-MS: (M+1) + m / z = 486.4;

[0169] 1 H-NMR(400MHz,DMSO-d6)δ11.59(s,1H),10.07(s,1H),8.86(s,1H),8.74(s ,1H),8.14(s,1H),7.70-7.59(m,2H),7.50(d,J=1.9Hz,1H),7.05(d,J=8.3H z,1H),6.88(d,J=7.3Hz,1H),4.44(s,2H),4.24(s,3H),3.81-3.72(m,2H),3 .63(s,3H),3.11(q,J=7.2Hz,2H),2.93-2.85(m,2H),1.14(t,J=7.2Hz,3H).

[0170] The following examples demonstrate preparations made according to the experimental routes and methods described in the examples:

[0171] Bioactivity and pharmacokinetic experiments

[0172] 1. Enzymatic activities (IC50) of compounds TYK2-JH2 and JAK1-JH2 50 ) Detection experiment

[0173] Control compound 1 (Deucravacitinib), control compound 2, and the test compound were diluted from the 10 mmol / L stock solution to 0.2 mmol / L. Specifically, 1.2 μL of each compound was added to 58.8 μL of DMSO, followed by a 3-fold dilution to obtain 10 concentrations. 50 nmol of the test compound was transferred to a 384 plate using an Echo transducer, with two replicates per compound. The plates were centrifuged at 1000 rpm for 1 minute, with a final DMSO concentration of 0.5%. 5 μL of TYK2 or JAK1 was added to the 384 plate, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 10 minutes. 5 μL of TYK2 JH2 probe1 or JAK1 JH2 probe1 was added to the 384 plate, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 60 minutes. The FP 520 / 48 signal was read using a BMG high-throughput microplate reader.

[0174] Experimental data for TYK2-JH2 and JAK1-JH2 were analyzed using GraphPad Prism 8 software. The negative control (0.5% DMSO well) was set to 0% inhibition rate, and the positive control (well with the highest concentration of the control compound) was set to 100% inhibition rate. After calculating the inhibition rate, the IC50 values ​​for the control compound and the test compound were obtained using the software's nonlinear fitting formula. 50 Value (half-maximal inhibitory concentration);

[0175] Average value of positive control wells

[0176] Average value of negative control wells

[0177] Specific IC 50 The test results are shown in Table 1 below:

[0178] Table 1: IC50 of the compounds in the examples 50 Test results

[0179] As can be seen from the data in the table, the compounds in the embodiments of the present invention all have good enzymatic inhibitory activity against TYK2-JH2, and some of the compounds have IC50 activity.50 Even at <5 nM, compared to the control compounds, the compounds of the present invention exhibit good selectivity for JAK1, and most compounds show IC50 for JAK1-JH2. 50 >1000nM, thus it can be seen that the compound of the present invention is a potent and highly selective TYK2 (tyrosine kinase 2) allosteric inhibitor.

[0180] Deucravacitinib has the following structural formula:

[0181] Comparative compound 2 has the following structural formula:

[0182] 1. Pharmacokinetic studies

[0183] Male Balb / c mice or beagles were divided into groups of three. Mice were administered compound 1 (2 mg / kg) intravenously or orally via a single gavage (10 mg / kg), while beagles were administered compound 1 (1 mg / kg) intravenously or orally via a single gavage (5 mg / kg). Animals were fasted overnight before the experiment, from 10 hours before administration to 4 hours after administration. Blood samples were collected at 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after intravenous administration, and at the same time after oral administration. After anesthesia with isoflurane, 0.3 mL of whole blood was collected from the animals and placed in heparin-anticoagulated tubes. The samples were centrifuged at 4000 rpm for 5 min at 4°C. Plasma was transferred to centrifuge tubes and stored at -80°C until analysis. Plasma samples were extracted using protein precipitation, and the extracts were analyzed by LC / MS / MS. Pharmacokinetic results are shown in Tables 2 and 3 below:

[0184] Table 2: Pharmacokinetic parameters of the compound from Example 1 in mouse and beagle dog plasma after intravenous administration

[0185] Table 3: Pharmacokinetic parameters of the compound from Example 1 in mouse and beagle dog plasma after oral administration

[0186] As can be seen from the data in the table, the compound of Example 1 of the present invention has good absorption and bioavailability in mice and beagle dogs after oral administration, with a bioavailability of 44% in mice and 46.6% in beagle dogs.

[0187] 2. Blood-brain distribution experiment

[0188] Male Balb / c mice were divided into groups of three and administered the test compound via a single intravenous injection. Animals were fasted overnight before the experiment, from 10 hours before administration to 4 hours after administration. Each mouse was sacrificed 0.5 hours after administration, and blood and brain tissue were collected. Samples were centrifuged at 4000 rpm for 5 min at 4°C. Plasma was transferred to centrifuge tubes and stored at -80°C until analysis. Protein precipitation was used to extract the plasma samples, and the extracts were analyzed by LC / MS / MS. Data showed that the compound of this embodiment could cross the blood-brain barrier.

[0189] Table 4. Blood-brain ratio of the compound in the examples after IV administration to mice 0.5 h.

[0190] 3. Protein binding assay

[0191] Plasma protein binding assay:

[0192] Thaw the frozen plasma. After complete thawing, centrifuge at 3000g for 5 minutes to remove suspended solids and precipitates. Measure the pH value and adjust the plasma pH to 7.0-8.0 with sodium hydroxide or phosphoric acid. Plasma with a pH between 7.0 and 8.0 can be used for experiments.

[0193] The dialysis membrane was soaked in ultrapure water for 60 minutes, then in 20% ethanol for 20 minutes, rinsed three times with pure water, and finally soaked in isotonic phosphate buffer for later use. The prepared membrane was then loaded into the dialysis apparatus and installed according to the manufacturer's instructions.

[0194] Take 747 μL of blank plasma, add 3 μL of test sample or warfarin working solution (500 μM), mix well to obtain a plasma sample with a final concentration of 2 μM. Take 50 μL of each genus of test sample and warfarin plasma sample into a sample plate, and immediately add 50 μL of buffer; then add 500 μL of stop solution (50 ng / mL tolbutamide) to obtain T0 samples, store at 2-8℃, and wait for further processing with other dialysis samples.

[0195] Add 150 μL of blank dialysate to the receiving side of the dialysis membrane and 150 μL of plasma sample to the donor side, in duplicate. Seal the dialysis apparatus after adding the samples and incubate it in a 37°C, 100 rpm incubator for 5 hours to achieve dialysis equilibration. Place the remaining plasma sample in the incubator and incubate for 5 hours to determine the stability of the test sample in plasma, in duplicate.

[0196] Take 50 μL of dialysis fluid after dialysis equilibration, add blank plasma, and then add 500 μL of stop solution to obtain the T5 receiver-side sample; take 50 μL of dialysis equilibration plasma, add 50 μL of buffer solution, and then add 500 μL of stop solution to obtain the T5 donor-side sample; take 50 μL of plasma sample for stability testing after incubation for 5 hours, add 50 μL of buffer solution, and then add 500 μL of stop solution to obtain the T5 stability sample.

[0197] All samples (T0, T5 hours, and stability samples) were vortexed at 1000 rpm for 10 minutes, then centrifuged at 4000 rpm for 15 minutes. 100 μL of the supernatant was transferred to a new 96-well plate, 100 μL of pure water was added, and the mixture was thoroughly mixed. The samples were then analyzed by HPLC-MS / MS.

[0198] All data calculations were performed using Microsoft Excel software. The protein binding rate of the test sample in plasma was calculated using the following formula:

[0199] Free rate (%) = (Area ratio receiver side / Area ratio donor side) × 100

[0200] Binding rate (%) = 100 - Free rate

[0201] Recovery rate (%) = (Area ratio receiver side + Area ratio donor side) / (Area ratio T0) × 100

[0202] Residual rate (%) = Area ratio 5hr / Area ratio 0hr × 100

[0203] Where: Area ratio is the ratio of the sample peak area to the internal standard peak area.

[0204] Brain tissue protein binding assay:

[0205] The frozen brain tissue was thawed at room temperature, then weighed according to a brain tissue weight (mg) to buffer volume (µL) ratio of 1:4, and homogenized together with the buffer. The dialysis membrane was immersed in ultrapure water for 60 minutes, then in 20% ethanol for 20 minutes, rinsed three times with pure water, and finally immersed in isotonic phosphate buffer for later use. The prepared membrane was loaded into the dialysis apparatus and installed according to the manufacturer's instructions.

[0206] Take 747 μL of homogenized blank brain tissue, add 3 μL of test sample or warfarin working solution (500 μM), mix well to obtain a brain tissue sample with a final concentration of 2 μM. Take 50 μL of each genus of test sample and warfarin brain tissue sample into a sample plate, and immediately add 50 μL of buffer solution; then add 500 μL of stop solution (50 ng / mL tolbutamide) to obtain T0 samples, store at 2-8℃, and wait for further processing with other dialysis samples.

[0207] Add 150 μL of blank dialysate to the receiving side of the dialysis membrane and 150 μL of brain tissue sample to the donor side, in duplicate. Seal the dialysis apparatus after adding the samples and incubate it in a 37°C, 100 rpm incubator for 5 hours to achieve dialysis equilibrium. Place the remaining brain tissue sample in the incubator and incubate for 5 hours to determine the stability of the test sample in brain tissue, in duplicate.

[0208] Take 50 μL of dialysis equilibration dialysate, add blank brain tissue, and then add 500 μL of stop solution to obtain the T5 receiver-side sample; take 50 μL of dialysis equilibration brain tissue, add 50 μL of buffer solution, and then add 500 μL of stop solution to obtain the T5 donor-side sample; take 50 μL of brain tissue sample used for stability testing after 5 hours of incubation, add 50 μL of buffer solution, and then add 500 μL of stop solution to obtain the T5 stability sample.

[0209] All samples (T0, T5 hours, and stability samples) were vortexed at 1000 rpm for 10 minutes, then centrifuged at 4000 rpm for 15 minutes. 100 μL of the supernatant was transferred to a new 96-well plate, 100 μL of pure water was added, and the mixture was thoroughly mixed. The samples were then analyzed by HPLC-MS / MS.

[0210] All data calculations were performed using Microsoft Excel software. The protein binding rate of the test sample in brain tissue was calculated using the following formula:

[0211] Free homogenate ratio (%) = (Area ratio receiver side / Area ratio donor side) × 100

[0212] Brain tissue free rate (%) = 1 / 5 / [(1 / (free homogenate rate / 100) - 1) + 1 / 5] × 100

[0213] Brain tissue binding rate (%) = 100 - Brain tissue free rate (%)

[0214] Recovery rate (%) = (Area ratio receiver side + Area ratio donor side) / (Area ratio T0) × 100

[0215] Residual rate (%) = Area ratio 5hr / Area ratio 0hr × 100

[0216] Where: Area ratio is the ratio of the sample peak area to the internal standard peak area.

[0217] The test results are shown in Table 5 below:

[0218] Table 5. Protein binding rates of the compounds in the examples to plasma and brain tissue in different species.

[0219] As can be seen from the data in the table, the compound of Example 1 of this invention has a high protein binding rate, which can reduce the rate of drug clearance in tissues, thereby prolonging the duration of action; drugs bound to proteins are less likely to be metabolized, thus maintaining a more stable concentration in vivo; drugs with high binding rates generally have lower competition in vivo, thereby reducing the risk of adverse interactions with other drugs. In summary, a high protein binding rate of a drug helps improve its efficacy and safety.

[0220] The present application has been described above with reference to preferred embodiments; however, these embodiments are merely exemplary and illustrative. Various substitutions and modifications can be made to the present application based on these embodiments, all of which fall within the protection scope of the present application.

Claims

Macrocycles of the formula I or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotopically-labeled, isomer, or prodrug thereof, wherein, W 1 and W 2 are each independently selected from N or CH; X 1 and X 2 are each independently selected from -NH-, -O-, -S- or -CH2-; R1is selected from C1-6alkyl, C1-6alkoxy, or R 10 N-; each R 1-6 and R 10 are independently selected from hydrogen or C1-6alkyl optionally substituted with R 1-6 N-; each R 11 is independently selected from hydrogen or C1-6alkyl optionally substituted with R 12 N-; each R 11 is independently selected from hydrogen or C1-6alkyl optionally substituted with R 12 N-; each R 10 is independently selected from hydrogen or C1-6alkyl optionally substituted with R 1-6 N-; each R 10 is independently selected from hydrogen, deuterium, tritium, or halogen; R2is selected from R 21 O-, R 21 S-, R 21 C(O)-, R 21 S(O)-, R 21 S(O)2-, or R 22 R 23 N-, R 21 selected from hydrogen, C 20 1-6 alkyl optionally substituted with R 1-6 1-6 alkoxy optionally substituted with R 20 1-6 cycloalkyl optionally substituted with R 3-8 1-6 haloalkyl optionally substituted with R 20 1-6 haloalkoxy optionally substituted with R 6-10 1-6 heteroaryl optionally substituted with R 20 1-6 hydroxy optionally substituted with R R 22 and R 23 are each independently hydrogen, C 20 1-6 alkyl optionally substituted with R 1-6 1-6 alkoxy, C 20 3-8 cycloalkyl optionally substituted with R 3-8 1-6 alkoxy, or C 20 6 aryl optionally substituted with R 6-10 1-6 alkoxy; or, R 22 and R 23 together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclic ring; R 20 each independently selected from protium, deuterium, tritium, halogen, cyano or hydroxyl; R 40 is selected from C 10 1-6alkyl optionally substituted with R 1-6 ; or C 10 1-6alkoxy optionally substituted with R 1-6 ; R3is selected from C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkyl optionally substituted with R 30 C1-6alkoxy, C3-6cycloalkyl optionally substituted with R 1-6 C1-6alkyl, C3-6cycloalkyl optionally substituted with R 30 C1-6alkoxy, C3-6cycloalkyl optionally substituted with R 1-6 C1-6alkyl, C3-6cycloalkyl optionally substituted with R 30 C1-6alkoxy, C3-6cycloalkyl optionally substituted with R 3-8 C1-6alkyl, C3-6cycloalkyl optionally substituted with R 30 C1-6alkoxy, C3-6cycloalkyl optionally substituted with R 6-10 C1-6alkyl, C3-6cycloalkyl optionally substituted with R 30 C1-6alkoxy, C3-6cycloalkyl optionally substituted with R 30 each independently selected from protium, deuterium, tritium, halogen, cyano or hydroxyl; R4is selected from hydrogen, optionally substituted C1-6alkyl or optionally substituted C1-6alkoxy; or, R2and R4together with the atoms to which they are attached form a 5-8 membered heterocyclic ring optionally substituted with R 10 1-6 10 1-6 40 R4is selected from hydrogen, optionally substituted C1-6alkyl or optionally substituted C1-6alkoxy; or, R2and R4together with the atoms to which they are attached form a 5-8 membered heterocyclic ring optionally substituted with R​​​​ Ring A is selected from heteroaryl or C 6-10 aryl; R5are each independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, optionally substituted C 50 alkyl, optionally substituted C 1-6 alkyl, optionally substituted C 50 alkyl, optionally substituted C 1-6 alkyl, optionally substituted C 50 alkyl, optionally substituted C 3-8 alkyl, optionally substituted C 50 alkyl, optionally substituted C 6-10 alkyl, optionally substituted C 50 alkyl, optionally substituted C 50 are each independently selected from protium, deuterium, tritium, halogen, cyano or hydroxyl; R6is each independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, optionally substituted C 60 alkyl, optionally substituted C 1-6 alkyl, optionally substituted C 60 alkyl, optionally substituted C 1-6 alkyl, optionally substituted C 60 alkyl, optionally substituted C 3-8 alkyl, optionally substituted C 60 alkyl, optionally substituted C 6-10 alkyl, optionally substituted C 60 alkyl, optionally substituted C 60 is each independently selected from protium, deuterium, tritium, halogen, cyano or hydroxyl; L is p number of mutually connected L 1 linking A ring and W 2 containing six-membered ring, two adjacent L 1 are connected by a single bond, the L 1 at both ends are connected to the A ring and W 2 containing six-membered ring by a single bond, respectively; p is an integer from 1 to 8, L 1 are each independently selected from -C(R7)2-, -NR 8 -, -O-, -S-, -C(O)-, -S(O)- or -S(O)2-; R 7 are each independently selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl or C 1-3 haloalkoxy; or, two R 7 form, together with the carbon atom to which they are attached, a C 3-6 cycloalkyl; R 8 each independently selected from hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkylcarbonyl, C 1-3 alkoxycarbonyl, phenylC 1-3 alkylcarbonyl or phenylC 1-3 alkoxycarbonyl; m is an integer from 0 to 4. The macrocycle of claim 1, wherein, The macrocyclic compound has a structural formula of Formula II wherein W 3 is N or CH; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , W 1 , W 2 , X 1 , X 2 , L and n are as defined in claim 1. The macrocycle of claim 1 or 2, wherein, R3is C 1-3 alkyl or deuterated C 1-3 alkyl, preferably, methyl or deuterated methyl, e.g., trideuteromethyl. The macrocycle of claim 1 or 2, wherein, R1is C 1-3 alkyl or deuterated C 1-3 alkyl, preferably, methyl, ethyl, deuterated methyl or deuterated ethyl, such as trideuterated methyl or trideuterated ethyl; or, R1is C 1-3 alkylamino or deuterated C 1-3 alkylamino, such as methylamino or deuterated methylamino, such as trideuterated methylamino; or, R1is C 1-3 alkoxy or deuterated C 1-3 alkoxy, such as methoxy or deuterated methoxy, such as trideuterated methoxy. The macrocycle of claim 1 or 2, wherein, R5and R6are hydrogen. The macrocycle of claim 1 or 2, wherein, R2is R 21 O-, wherein R 21 is C 1-3 alkyl or deuterated C 1-3 alkyl, preferably, methyl or deuterated methyl, e.g., trideuterated methyl. The macrocycle of claim 1 or 2, wherein, R2is R 21 O-, wherein R 21 and R4together with the atoms to which they are attached form an optionally substituted oxygen-containing 5-6 membered heterocyclic ring, for example an oxygen-containing 6 membered heterocyclic ring. 1-3 alkyl, for example an oxygen-containing 6 membered heterocyclic ring. The macrocycle of claim 1 or 2, wherein, R2is R 22 R 23 N- wherein R 23 is C 1-3 alkyl or deuterated C 1-3 alkyl, preferably, methyl or deuterated methyl, e.g. trideuteromethyl; R 22 and R4together with the atoms to which they are attached form a nitrogen containing 5-6 membered heterocyclic ring, optionally substituted with C 1-3 alkyl, preferably a nitrogen containing 6 membered heterocyclic ring substituted with methyl. The macrocycle of claim 1 or 2, wherein, X 1 and X 2 are each -NH-. The macrocycle of claim 1 or 2, wherein, p is 3, 4, 5, or 6; preferably, p is 4 or 5. The macrocycle of claim 1 or 2, wherein, p L 1 only one of which is -NR 8 -, -O-, -S-, -C(O)-, -S(O)- or -S(O)2-, preferably -O-; the remaining L 1 -C(R7)2-, R 7 each independently selected from hydrogen, or C 1-3 alkyl, preferably hydrogen. The macrocycle of claim 1 or 2, wherein, L is selected from one of the following structures: Preferably, L is selected from one of the following structures: wherein represents the position of L attached to the six-membered ring containing W 2 ​ represents the position of L attached to the six-membered ring of ring A or W 3 containing ring A or W. The macrocycle of claim 1, wherein, Ring A is selected from one of the following structural formulae: "a" means connected to X through this end 1 Connection. The macrocycle of claim 1 or 2, wherein, The compound is one of the following compounds: A pharmaceutical composition comprising a compound of any one of claims 1 to 14 and a pharmaceutically acceptable carrier, diluent, or excipient. A method of treating or preventing a TYK2-mediated disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 14 or a pharmaceutical composition of claim 15. The method of claim 16, wherein the disorder is selected from the group consisting of inflammatory autoimmune diseases, tumors, neurodegenerative diseases, and the like, wherein the inflammatory autoimmune diseases are mainly atopic dermatitis, hidradenitis suppurativa, psoriasis, psoriatic arthritis, Crohn’s disease, ulcerative colitis, lupus erythematosus, central nervous system autoimmune diseases, and the like, wherein the tumors are mainly leukemias, lymphomas, myelomas, brain tumors, and the like, wherein the neurodegenerative diseases are mainly brain atrophy, senile dementia, Parkinson’s syndrome, Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and the like. Use of a compound of any one of claims 1 to 14 in the manufacture of a medicament for treating or preventing a TYK2-mediated disorder. A method of treating or preventing a TYK2-mediated disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 14 or a pharmaceutical composition of claim 15.

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