WO2018028557A1 - Tricyclic compound and use thereof - Google Patents

Abstract

The present invention relates to a series of tricyclic compounds and the use thereof as receptor agonists of 1-phosphate sphingosine 1 subtype (S1P1), and in particular to the compounds shown in formula (I), and tautomers or pharmaceutically acceptable salts thereof.

Description

Tricyclic compounds and their applications

The present application claims priority to Chinese Patent Application No. CN201610650168.6 filed on Apr. 08.

Technical field

The present invention relates to a series of tricyclic compounds and their use as receptor agonists of the sphingosine 1-phosphate 1 subtype (S1P1), in particular, the compounds of the formula (Ι), their tautomers or A pharmaceutically acceptable salt.

Background technique

Sphingosine-1-phosphate (S1P) is a pleiotropic lipid mediator with a broad spectrum of physiological activities including cell proliferation, survival, lymphocyte trafficking, cytoskeletal organization and morphogenesis. Sphingosine is catalyzed by enzyme ceramide and released from ceramide. Sphingosine is phosphorylated by sphingosine kinase to produce sphingosine-1-phosphate (S1P) and interacts with the sphingosine 1 -phosphate receptor (S1PR) to produce physiological activity.

Sphingosine 1-phosphate receptor 1 (S1PR1), also known as endothelial cell differentiation gene 1 (EDG1), is a G-protein coupled receptor belonging to the endothelial cell differentiation gene (EDG) receptor family. A protein encoded by the S1PR1 gene. The sphingosine 1-phosphate receptor (S1PR) includes five subtypes (S1PR1-5) in which sphingosine 1-phosphate receptor 1 (S1PR1) is abundantly distributed on endothelial cell membranes. Like other G-protein coupled receptors, S1PR1 detects its ligand from the outside of the cell and activates intracellular signaling pathways to cause cellular responses.

Sphingosine-1-phosphate (S1P) is very important in humans and it mainly regulates the vascular system and immune system. Small molecule S1P1 agonists and inhibitors mimic the binding mechanism of sphingosine-1-phosphate (S1P) to receptors and have been shown to have important physiological roles in their signaling systems. Activation of sphingosine-1-phosphate receptor 1 (S1PR1) disrupts lymphocyte trafficking, isolating lymphocytes from lymph nodes and other secondary lymphoid organs, resulting in rapidly reversible lymphopenia. Clinical studies have shown that lymphocyte isolation reduces inflammation or autoimmune disease responses and is critical for immune regulation.

Currently, in vivo pharmacodynamic studies of sphingosine 1 -phosphate receptor 1 (S1PR1) agonists are used to treat or prevent autoimmune diseases. The discovery and application of novel sphingosine 1 -phosphate receptor 1 (S1PR1) agonists has broad prospects.

WO2015066515A1 discloses Ozanimod, which has the following structure:

Summary of the invention

The present invention provides a compound of the formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof,

among them,

X is independently selected from CH or N;

Ring A is selected from a 5- to 9-membered heteroaryl group;

Ring B is selected from phenyl or 5- to 9-membered heteroaryl;

R _{1 is} selected from H or is selected from C _{1 1-6} alkyl, C _1-6 heteroalkyl optionally substituted by 1, 2 or 3 R;

R _{2 is} selected from H or is selected from: C _1-6 alkyl optionally substituted by 1, 2 or 3 R;

Or R ₁ and R _{2 are} bonded to form a 3 to 6 membered ring optionally substituted by 1, 2 or 3 R;

R _{3 is} selected from H, F, Cl, Br, I, CN, NH ₂ or from a C _1-6 alkyl group optionally substituted by 1, 2 or 3 R;

R _{4 is} selected from H or is selected from C _{1 1-6} alkyl, C _1-6 heteroalkyl optionally substituted by 1, 2 or 3 R;

R is selected from H, F, Cl, Br, I, OH, CN, NH ₂ , COOH, or selected from C _{1 1-6} alkyl, C _1-6 optionally substituted by 1, 2 or 3 R' Alkoxy, C _1-6 alkylamino, C _3-6 cycloalkyl;

R' is selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , Me, Et, CF ₃ , CHF ₂ , CH ₂ F, NHCH ₃ , N(CH ₃ ) ₂ ;

The "hetero" of the C _1-6 heteroalkyl group and the 5- to 9-membered heteroaryl group are each independently selected from -C(=O)NH-, -NH-, -S(=O) ₂ NH-, - S(=O)NH-, -O-, -S-, N, =O, =S, -C(=O)O-, -C(=O)-, -S(=O)-,- S(=O) ₂ -, -NHC(=O)NH-;

In either case, the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.

In some embodiments of the invention, the above R is selected from the group consisting of H, F, Cl, Br, I, OH, CN, NH ₂ , COOH, or selected from the group consisting of 1, 2 or 3 R' substitutions: C _{1- 3} alkyl, C _1-3 alkoxy, C _1-3 alkylamino, C _3-6 cycloalkyl, R' is as defined in the invention.

In some aspects of the invention, the above R is selected from the group consisting of: H, F, Cl, Br, I, OH, CN, NH ₂ , COOH, Me, Et,

In some embodiments of the invention, the above R _{1 is} selected from H or is selected from C _{1 1-6} alkyl, C _1-6 alkoxy, C _1-6 alkane optionally substituted by 1, 2 or 3 R Thio group, C _1-6 alkylamino group, N,N'-di(C _1-2 alkyl)amino group, C _1-6 alkyl-S(=O)-, C _1-6 alkyl-S (= O) ₂ -, C _1-3 alkyl-NH-C _1-3 alkyl-, C _1-3 alkyl-S(=O)-C _1-3 alkyl-, C _1-3 alkyl- S(=O) ₂ -C _1-3 alkyl-, C _1-6 alkyl-C(=O)-, C _1-3 alkyl-NHC(=O)-C _1-3 alkyl-, R is as defined by the present invention.

R如本发明所定义。In some embodiments of the invention, the above R _{1 is} selected from the group consisting of: 1, 2 or 3, R:

R is as defined by the present invention.

In some aspects of the invention, the above R _{1 is} selected from the group consisting of

In some aspects of the invention, the above R _{2 is} selected from the group consisting of: H, Me, Et,

In some embodiments of the invention, R ₁ and R ₂ are appended together to form a piperazinyl, azetidinyl group, optionally substituted by 1, 2 or 3 R, as defined in the invention.

选自：

In some aspects of the invention, the above R ₁ and R _{2 are} linked, and the structural unit

From:

In some embodiments of the invention, the above R _{3 is} selected from the group consisting of H, F, Cl, Br, I, OH, CN, NH ₂ .

In some embodiments of the invention, the above R _{4 is} selected from H or is selected from methoxy, isopropyl, isopropyloxy optionally substituted by 1, 2 or 3 R, as defined in the present invention .

In some aspects of the invention, the above R _{4 is} selected from the group consisting of

In some embodiments of the invention, the ring A is selected from the group consisting of: 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3, 4-thiadiazolyl, thiazolyl, thienyl, oxazolyl.

In some aspects of the invention, the ring A is selected from the group consisting of:

In some embodiments of the invention, the ring B is selected from the group consisting of a phenyl group or a 5-membered heteroaryl group.

In some embodiments of the invention, the ring B is selected from the group consisting of phenyl, thiazolyl, oxazolyl, and thienyl.

In some aspects of the invention, the ring B is selected from the group consisting of:

选自:

变量R₃、R₄如本发明所定义。In some aspects of the invention, the structural unit

From:

The variables R ₃ , R _{4 are} as defined by the present invention.

选自:

变量R₃、R₄如本发明所定义。In some aspects of the invention, the structural unit

From:

The variables R ₃ , R _{4 are} as defined by the present invention.

选自：

本发明的一些方案中，上述R选自H、F、Cl、Br、I、OH、CN、NH₂、COOH，或选自任选被1、2或3个R’取代的：C_1-3烷基、C_1-3烷氧基、C_1-3烷氨基、C_3-6环烷基，其他变量如上述定义。In some aspects of the invention, the structural unit

From:

In some embodiments of the invention, the above R is selected from the group consisting of H, F, Cl, Br, I, OH, CN, NH ₂ , COOH, or selected from the group consisting of 1, 2 or 3 R' substitutions: C _{1- 3} alkyl, C _1-3 alkoxy, C _1-3 alkylamino, C _3-6 cycloalkyl, and other variables are as defined above.

其他变量如上述定义。In some aspects of the invention, the above R is selected from the group consisting of: H, F, Cl, Br, I, OH, CN, NH ₂ , COOH, Me, Et,

Other variables are defined as above.

In some embodiments of the invention, the above R _{1 is} selected from H or is selected from C _{1 1-6} alkyl, C _1-6 alkoxy, C _1-6 alkane optionally substituted by 1, 2 or 3 R Thio group, C _1-6 alkylamino group, N,N'-di(C _1-2 alkyl)amino group, C _1-6 alkyl-S(=O)-, C _1-6 alkyl-S (= O) ₂ -, C _1-3 alkyl-NH-C _1-3 alkyl-, C _1-3 alkyl-S(=O)-C _1-3 alkyl-, C _1-3 alkyl- S(=O) ₂ -C _1-3 alkyl-, C _1-6 alkyl-C(=O)-, C _1-3 alkyl-NHC(=O)-C _1-3 alkyl-, Other variables are defined as above.

其他变量如上述定义。 In some embodiments of the invention, the above R _{1 is} selected from the group consisting of: 1, 2 or 3, R:

Other variables are defined as above.

其他变量如上述定义。In some aspects of the invention, the above R _{1 is} selected from the group consisting of

Other variables are defined as above.

其他变量如上述定义。In some aspects of the invention, the above R _{2 is} selected from the group consisting of: H, Me, Et,

Other variables are defined as above.

In some embodiments of the invention, R ₁ and R ₂ described above are joined together to form a piperazinyl, azetidinyl group optionally substituted by 1, 2 or 3 R, and other variables are as defined above.

选自：

其他变量如上述定义。In some aspects of the invention, the above R ₁ and R _{2 are} linked, and the structural unit

From:

Other variables are defined as above.

In some aspects of the invention, the above R _{3 is} selected from the group consisting of H, F, Cl, Br, I, OH, CN, NH ₂ , and other variables are as defined above.

In some embodiments of the invention, the above R _{4 is} selected from H or is selected from the group consisting of: 1, 2 or 3, R: methoxy, isopropyl, isopropyloxy, and other variables are as defined above.

其他变量如上述定义。In some aspects of the invention, the above R _{4 is} selected from the group consisting of

Other variables are defined as above.

In some embodiments of the invention, the ring A is selected from the group consisting of: 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3, 4-thiadiazolyl, thiazolyl, thienyl, oxazolyl, and other variables are as defined above.

其他变量如上述定义。In some aspects of the invention, the ring A is selected from the group consisting of:

Other variables are defined as above.

In some embodiments of the invention, the ring B is selected from the group consisting of: phenyl or 5-membered heteroaryl, and other variables are as defined above.

In some embodiments of the invention, the ring B is selected from the group consisting of phenyl, thiazolyl, oxazolyl, thienyl, and other variables are as defined above.

其他变量如上述定义。 In some aspects of the invention, the ring B is selected from the group consisting of:

Other variables are defined as above.

选自:

其他变量如上述定义。In some aspects of the invention, the structural unit

From:

Other variables are defined as above.

选自:

其他变量如上述定义。In some aspects of the invention, the structural unit

From:

Other variables are defined as above.

选自：

其他变量如上述定义。In some aspects of the invention, the structural unit

From:

Other variables are defined as above.

Still other aspects of the invention are arbitrarily combined from the above variables.

In some embodiments of the invention, the above compound, a tautomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

among them,

m, n are each independently selected from: 1 or 2;

D _{1 is} independently selected from: S or O;

T ₁ , T ₂ , T ₃ are each independently selected from: N or CH;

R, R ₁ , R ₃ and R _{4 are} as defined above.

The invention also provides a compound, a tautomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

The present invention also provides the use of the above compound, a tautomer thereof or a pharmaceutically acceptable salt thereof for the preparation of a medicament as a sphingosine 1-sulphate 1 subtype (S1P1) receptor agonist.

In some embodiments of the invention, the use of the above compound, its tautomer or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of inflammatory bowel disease.

Technical effect:

The present invention synthesizes a compound of formula (I) and its tautomers, and obtains a novel class of S1P1 receptor agonists for the treatment of inflammatory bowel disease. At the same time, the compound of the present invention has better activity, better pharmacokinetics, and good drug-forming properties.

Definition and description

Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered undefined or unclear without a particular definition, but should be understood in the ordinary sense. When a trade name appears in this document, it is intended to refer to its corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base. When a relatively acidic functional group is contained in the compound of the present invention, a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When a relatively basic functional group is contained in the compound of the present invention, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine, etc.) And salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functional groups which can be converted to any base or acid addition salt.

Preferably, the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound. The parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.

As used herein, "pharmaceutically acceptable salts" are derivatives of the compounds of the invention wherein the salt is formed by salting with an acid or with a base. The parent compound is modified. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturaldehyde, propionic acid, salicylic acid, stearic acid, acrylic acid, succinic acid, sulfamic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin, Tartaric acid and p-toluenesulfonic acid.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid. Generally, a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.

In addition to the form of the salt, the compounds provided herein also exist in the form of prodrugs. Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention. Furthermore, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.

Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.

The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.

Unless otherwise indicated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of one another.

Unless otherwise indicated, the term "cis-trans isomer" or "geometric isomer" is caused by the inability to freely rotate a single bond due to a double bond or a ring-forming carbon atom.

Unless otherwise indicated, the term "diastereomer" refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirrored relationship.

Unless otherwise indicated, "(D)" or "(+)" means dextrorotatory, "(L)" or "(-)" means left-handed, "(DL)" or "(±)" means racemic.

和楔形虚线键

表示一个立体中心的绝对构型，用直形实线键

和直形虚线键

表示立体中心的相对构型，用波浪线

表示楔形实线键

或楔形虚线键

或用波浪线

表示直形实线键

和直形虚线键

Wedge solid key unless otherwise stated

And wedge-shaped dashed keys

Represents the absolute configuration of a solid center with straight solid keys

And straight dashed keys

Indicates the relative configuration of the stereocenter, using wavy lines

Indicates a wedge solid key

Or wedge-shaped dotted key

Or with wavy lines

Represents a straight solid key

And straight dashed keys

The compounds of the invention may be present in particular. Unless otherwise indicated, the terms "tautomer" or "tautomeric form" mean that the different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. If tautomers are possible (as in solution), the chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton transfer, such as keto-enol isomerization and imine-enes. Amine isomerization. The valence tautomer includes the mutual transformation of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

Unless otherwise indicated, the terms "enriched in one isomer", "isomer enriched", "enriched in one enantiomer" or "enantiomeric enriched" refer to one of the isomers or pairs The content of the oligo is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or greater than or equal to 99.9%.

Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomeric excess (ee value) is 80%. .

The optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer. Alternatively, when a molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art. The diastereomers are resolved and the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate). The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, radiolabeled compounds can be used, such as tritium ⁽³ H), iodine -125 ⁽¹²⁵ I) or ^C-14 (14 C). For another example, hydrogen can be replaced by heavy hydrogen to form a deuterated drug. The bond composed of barium and carbon is stronger than the bond composed of common hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have reduced side effects and increased drug stability. Improve the efficacy and prolong the biological half-life of the drug. Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention. The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts.

The term "excipient" generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.

The term "effective amount" or "therapeutically effective amount" with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect. For oral dosage forms in the present invention, an "effective amount" of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.

The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating a target disorder, disease or condition.

"Optional" or "optionally" means that the subsequently described event or condition may, but is not necessarily, to occur, and that the description includes instances in which the event or condition occurs and instances in which the event or condition does not occur.

The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of. When the substituent is oxygen (ie, =0), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on the aromatic group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.

When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with at most two R, and each case has an independent option. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

When the number of one linking group is 0, such as -(CRR) ₀ -, it indicates that the linking group is a single bond.

When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.

表示取代基R可在环己基或者环己二烯上的任意一个位置发生取代。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，

中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成

也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成

所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A. When a substituent can be attached to more than one atom on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit.

It is indicated that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene. When the listed substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group. When the listed linking group does not indicate its direction of attachment, its connection direction is arbitrary, for example,

The medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B.

It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right.

Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

Unless otherwise specified, the term "hetero" denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O). ), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, =O, =S, -C (= O) O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) ₂ -, and optionally substituted -C(=O)N (H)-, -N(H)-, -C(=NH)-, -S(=O) ₂ N(H)- or -S(=O)N(H)-.

Unless otherwise specified, "ring" means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring" means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms. Thus, "5- to 7-membered ring" includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term "5- to 7-membered heterocycloalkyl ring" includes pyridyl and piperidinyl, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, each of which "ring" independently conforms to the above definition.

Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring. The nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein). The heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites. The nitrogen atom in the heterocycle is optionally quaternized. A preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one. The term "aromatic heterocyclic group" or "heteroaryl" as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein). The nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed one. Bridged rings are also included in the definition of heterocycles. A bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms. Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.

Examples of heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, furyl, furazyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indole Azyl, decenyl, indanyl, mesoindolyl, fluorenyl, 3H-indenyl, isobenzofuranyl, isodecyl, isoindoline, isoquinoline Base, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, hydroxymethyl, pyrimidinyl, Phenyridinyl, phenanthroline, phenazine, phenothiazine, benzoxanthyl, phenoloxazinyl, pyridazinyl, piperazinyl, piperidinyl, piperidinone, 4-piperidinyl , piperonyl, pteridinyl, fluorenyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, Pyridyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolyl, 4H-quinazinyl, quinoxalinyl, quinine Base, tetrahydrofuranyl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thioxyl, thiazolyl, isothiazolylthiophenyl, thienooxazolyl, thieno Thiazolyl, thienoimidazolyl, thienyl, triazinyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl 4H-1,2,4-triazolyl and xanthene. Also included are fused ring and spiro compounds.

Unless otherwise specified, the term "hydrocarbyl" or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic. The hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C ₁ -C ₁₂ represents 1 to 12 carbons) , C _{1-12 is} selected from C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ and C ₁₂ ; C _{3-12 is} selected from C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ and C ₁₂ .). "Hydrocarbyl" includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members. An aromatic hydrocarbon group such as benzene, naphthalene or the like. In some embodiments, the term "hydrocarbyl" means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl). A homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl. The unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.

Unless otherwise specified, the term "heterohydrocarbyl" or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom. In some embodiments, the term "heteroalkyl" by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom. In a typical embodiment, the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized. The hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy). By customary expression, those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively. Examples include, but are not limited to, -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ , -CH ₂ -S -CH ₂ -CH ₃ , -CH ₂ -CH ₂ , -S(O)-CH ₃ , -CH ₂ -CH ₂ -S(O) ₂ -CH ₃ , -CH=CH-O-CH ₃ ,- CH ₂ -CH=N-OCH ₃ and -CH=CH-N(CH ₃ )-CH ₃ . Up to two heteroatoms may be consecutive, for example, -CH ₂ -NH-OCH _3.

Unless otherwise specified, the term "cycloalkyl", "heterocycloalkyl" or its subordinate concept (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl) A heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized "hydrocarbyl group" or "heterohydrocarbyl group", respectively. Further, in the case of a heterohydrocarbyl group or a heterocycloalkyl group (such as a heteroalkyl group or a heterocycloalkyl group), a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule. Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.

Unless otherwise specified, the term "alkyl" is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH ₂ F) or polysubstituted (eg, -CF ₃ ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of the alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.

Unless otherwise specified, "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent. Examples of the alkenyl group include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a butadienyl group, a pentadienyl group, a hexadienyl group and the like.

Unless otherwise specified, "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent. Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and the like.

Unless otherwise specified, a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent. Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.

Unless otherwise specified, a cycloalkenyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more unsaturated carbon-carbon double bonds at any position of the ring, and may be monosubstituted or polysubstituted, It can be one price, two price or multiple price. Examples of such cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.

Unless otherwise specified, a cycloalkynyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more carbon-carbon triple bonds at any position of the ring, which may be monosubstituted or polysubstituted, and may be one Price, price or price.

Unless otherwise specified, the term "halo" or "halogen", by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom. Further, the term "haloalkyl" is intended to include both monohaloalkyl and polyhaloalkyl. For example, the term "halo(C ₁ -C ₄ )alkyl" is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait. Unless otherwise specified, examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

The above-described alkyl groups having the specified number of carbon atoms, "alkoxy" represents attached through an oxygen bridge, unless otherwise specified, C _1-6 alkoxy groups include _{C 1, C 2, C 3} , C 4, C 5 , and C ₆ alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.

Unless otherwise specified, the term "aryl" denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), they are fused together or covalently linked. The term "heteroaryl" refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl or heteroaryl groups include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isomerism Azyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, indolyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl, 1 -naphthyl, 2-naphthyl, 4-biphenylyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, fluorenyl, 2-benzimidazolyl, 5-indenyl, 1-isoquinolinyl, 5-isoquinolinyl, 2-quina Porphyrin, 5-quinoxalinyl, 3-quinolyl and 6-quinolinyl. The substituents of any of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

Unless otherwise specified, aryl groups, when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above. Thus, the term "aralkyl" is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen. Those alkyl groups substituted by an atom, such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.

The term "leaving group" refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.

The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and the like. The term "hydroxy protecting group" refers to a protecting group suitable for use in preventing hydroxy side reactions. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and Diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and the like.

The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.

The solvent used in the present invention is commercially available. The present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyloxycarbonyl, an amine protecting group; BOC for t-butoxycarbonyl is an amine protecting group; HOAc for acetic acid; NaCNBH ₃ for sodium cyanoborohydride ; rt stands for room temperature; O/N stands for overnight; THF stands for tetrahydrofuran; Boc ₂ O stands for di-tert-butyl dicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl ₂ stands for chloride Sulfone; CS ₂ represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI stands for N-fluoro-N-(phenylsulfonyl)benzenesulfonamide; NCS stands for 1-chloropyrrolidine-2,5-dione; n-Bu ₄ NF stands for fluorine Tetrabutylammonium; iPrOH represents 2-propanol; mp mp Representative; Representative LDA lithium diisopropylamide; CDCl ₃ deuterated chloroform Representative; Methonal representative of methanol.

软件命名，市售化合物采用供应商目录名称。Compound by hand or

Software naming, commercially available compounds using the supplier catalog name.

Detailed ways

The invention is described in detail below by the examples, but is not intended to limit the invention. The present invention has been described in detail herein, the embodiments of the present invention are disclosed herein, and various modifications and changes may be made to the embodiments of the present invention without departing from the spirit and scope of the invention. It will be obvious.

Example 1

first step

Compound 1-1 (5.00 g, 23.6 mmol), N-bromosuccinimide (4.64 g, 26.0 mmol), azobisisobutyronitrile (389 mg, 2.37 mmol) was dissolved in carbon tetrachloride (100 mL) ). The reaction solution was replaced with nitrogen three times, warmed to 90 ° C and stirred for 3 hours. The reaction mixture was cooled to room EtOAc. EtOAc m. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was separated and purified by silica gel column chromatography (3:1 petroleum ether/ethyl acetate, Rf = 0.5) to give compound 1-2 (6.20 g, yellow solid).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.85 (d, J = 8.0Hz, 1H), 7.74 (d, J = 8.0Hz, 1H), 7.40 (t, J = 8.0Hz, 1H), 5.55 (d , J = 6.8 Hz, 1H), 3.44 - 3.35 (dd, J = 6.8, 27.6 Hz, 1H), 3.20 (d, J = 27.6 Hz, 1H). MS-ESI calcd for [M+H] ⁺ 289, 291, 293

Second step

Triethylamine (4.33 g, 42.7 mmol) was added dropwise to a solution of Compound 1-2 (6.20 g, 21.3 mmol) THF. The reaction solution It was replaced with nitrogen three times and stirred at 10 ° C for 15 hours. The reaction mixture was concentrated with EtOAc EtOAc m. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by silica gel column chromatography (jjjjjjjj

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.69 (d, J = 6.0Hz, 1H), 7.47 (d, J = 8.0Hz, 1H), 7.38 (d, J = 7.2Hz, 1H), 7.09-7.20 (m, 1H), 6.00 (d, J = 6.0 Hz, 1H). MS-ESI calcd for [M ⁺ H] + 209,211, 209, 211 found.

third step

Trimethylsilyldiazomethane (2M, 14.8 mL, 29.7 mmol) was added dropwise to a solution of Compound 1-3 (3.10 g, 14.8 mmol), palladium acetate (322 mg, 1.44 mmol) in toluene (60 mL). ). The reaction solution was replaced with nitrogen three times, heated to 10 ° C and stirred for 15 hours. The reaction mixture was concentrated with EtOAc EtOAc m. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by silica gel column chromatography (jjjjjjjjj

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.61 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 2.88 (t) , J = 4.4 Hz, 1H), 2.51 (t, J = 4.4 Hz, 1H), 1.01 (t, J = 4.8 Hz, 1H), 0.11 (s, 9H). MS-ESI calcd for [M ⁺ H] + 295,297, 295,297 found.

the fourth step

A solution of tetrabutylammonium fluoride (1 M, 13 mL) in tetrahydrofuran was added dropwise to a solution of Compound 1-4 (3.20 g, 10.8 mmol) THF. The reaction solution was replaced with nitrogen three times, and stirred at 10 ° C for 15 hours. The reaction mixture was concentrated with EtOAc EtOAc m. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by silica gel column chromatography (EtOAc (EtOAc)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.63 (d, J = 7.6Hz, 1H), 7.57 (d, J = 7.6Hz, 1H), 7.17 (t, J = 7.6Hz, 1H), 3.11-2.96 (m, 1H), 2.56-2.53 (m, 1H), 1.69-1.64 (m, 1H), 1.38-1.34 (m, 1H). MS-ESI calcd for [M+H] &^lt;

the fifth step

Compound 1-5 (1.30 g, 5.83 mmol), tetrakistriphenylphosphine palladium (336 mg, 0.291 mmol), zinc cyanide (1.37 g, 11.6 mmol) were dissolved in N-methylpyrrolidone (20 mL). The reaction solution was replaced with nitrogen three times and stirred at 100 ° C for 15 hours. The reaction was cooled to room temperature, diluted with EtOAc (EtOAc) (EtOAc) The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was separated and purified using silica gel column chromatography (EtOAc (EtOAc) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 3.24-3.21 (m, 1H), 2.72-2.67 (m, 1H), 1.81-1.70 (m, 1H), 1.45-1.40 (m, 1H). MS-ESI calcd for [M+H] ⁺ 170, found 170.

Step 6

Compound 1-6 (300 mg, 1.77 mmol), 2-[tert-butyl(dimethyl)silyl]oxyethylamine (620 mg, 3.54 mmol), sodium borohydride (334 mg, 8.85 mmol) Ethanol (10 mL). The reaction solution was replaced with nitrogen three times and stirred at 80 ° C for 36 hours. The reaction was cooled to room temperature, diluted with dichloromethane (20 mL) andEtOAc. The aqueous phase was extracted with dichloromethane (30 mL EtOAc). The crude product was purified by silica gel column chromatography (EtOAc (EtOAc)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.46 (d, J = 7.6Hz, 1H), 7.41 (d, J = 7.6Hz, 1H), 7.20 (t, J = 7.6Hz, 1H), 4.66 (d , J=6.0 Hz, 1H), 3.89-3.76 (m, 2H), 3.10-3.04 (m, 1H), 2.93-2.83 (m, 1H), 2.76-2.71 (m, 1H), 2.17-2.11 (m , 1H), 1.17-1.04 (m, 1H), 0.89 (s, 9H), 0.36-0.32 (m, 1H), 0.07 (s, 6H). MS-ESI calcd for [M+H] ⁺ 329.

Seventh step

To a solution of compound 1-7 (100 mg, 0.34 mmol) in EtOAc (2 mL), EtOAc (EtOAc:EtOAc: The reaction solution was replaced with nitrogen three times and stirred at 60 ° C for 15 hours. The reaction mixture was concentrated with EtOAc EtOAc m. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by silica gel column chromatography ( EtOAc (EtOAc)

^{1 H NMR (400MHz, DMSO-} d 6) δ9.52 (s, 1H), 7.24 (d, J = 7.2Hz, 1H), 7.16-7.08 (m, 2H), 5.77-5.62 (m, 3H), 4.52-4.47 (m, 1H), 3.74-3.70 (m, 2H), 2.78-2.75 (m, 2H), 1.96-1.92 (m, 1H), 0.85 (s, 9H), 0.05 (s, 6H). MS-ESI calcd for [M+H] ⁺ 372. Eighth step

3-cyano-4-isopropoxybenzoic acid (42.5 mg, 0.207 mmol), 1-hydroxybenzotriazole (56.0 mg, 0.414 mmol), 1-ethyl-3-(3-dimethyl Aminopropyl)carbodiimide hydrochloride (79.5 mg, 0.414 mmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL). The reaction solution was replaced with nitrogen three times. After stirring at 10 ° C for one hour, a solution of compound 1-8 (75.0 mg, 0.207 mmol) in anhydrous N, N-dimethylformamide (1 mL) was added. After the reaction mixture was further stirred for 1 hour, the temperature was raised to 90 ° C and stirred for 13 hours. The reaction mixture was concentrated with EtOAc EtOAc m. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by high performance liquid chromatography to give Compound 1-9 (1 mg).

^{1 H NMR (400MHz, Methonal-} d 4) δ8.48 (d, J = 2.0Hz, 1H), 8.45 (dd, J = 2.4,8.8Hz, 1H), 7.98 (d, J = 7.6Hz, 1H) , 7.53 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 5.01-4.94 (m, 1H), 4.75 (d, J=6.4 Hz, 1H), 3.81 (t, J=5.6 Hz, 2H), 3.27-3.20 (m, 1H), 3.19-3.12 (m, 1H), 3.03-2.95 (m, 1H), 2.20-2.12 (m, 1H), 1.48 (d, J = 6.0 Hz, 6H), 1.16-1.10 (m, 1H), 0.49 - 0.43 (m, 1H). MS-ESI calcd for [M+H] ⁺ 417.

Step 9

SFC separation method:

Column: C2 250mm × 30mm, 10um;

Mobile phase: A: carbon dioxide; B: 40% isopropanol (containing 0.05% diethylamine);

Flow rate: 80 mL/min;

Column temperature: 40 ° C.

Compound 1-10 isomer 1 (6 mg, yield: 15%), retention time: 5.736 min. ¹ H NMR (400 MHz, Methonal-d ₄ ): δ 8.45-8.41 (m, 2H), 8.01 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.42 (d, J=9.2 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 4.97-4.86 (m, 2H), 3.68-3.64 (m, 2H), 3.27-3.26 (m, 1H), 2.87-2.84 (m, 1H), 2.73-2.70 (m, 1H), 2.10-2.08 (m, 1H), 1.45 (d, J = 6.0 Hz, 1H), 1.34-1.31 (m, 1H), 0.08-0.05 (m) , 1H). MS-ESI calcd for [M+H] ⁺ 417.

Compound 1-10 isomer 2 (54 mg, yield: 27%), retention time: 6.791 min. ^{1 HNMR (400MHz, Methonal-d} 4): δ8.46-8.41 (m, 2H), 7.98 (d, J = 7.6Hz, 1H), 7.52 (d, J = 7.6Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 4.98 - 4.91 (m, 1H), 4.79 (d, J = 6.0 Hz, 1H), 3.83 - 3.80 (m, 2H), 3.25-3.18(m,2H), 3.04-3.01(m,1H), 2.18-2.15(m,1H), 1.45(d,J=6.0Hz,6H),1.16-1.11(m,1H),0.50- 0.47 (m, 1H). MS-ESI calcd for [M+H] ⁺ 417.

Compound 1-10 isomer 3 (8 mg, yield: 20%), retention time: 7.948 min. ^{1 HNMR (400MHz, Methonal-d} 4): δ8.44-8.43 (m, 2H), 8.02 (d, J = 7.6Hz, 1H), 7.59 (d, J = 7.6Hz, 1H), 7.42 (d, J=9.2 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 4.97-4.91 (m, 1H), 4.20 (s, 1H), 3.69-3.65 (m, 2H), 3.28-3.27 (m) , 1H), 2.88-2.85 (m, 1H), 2.73-2.70 (m, 1H), 2.11-2.09 (m, 1H), 1.46 (d, J = 6.0 Hz, 6H), 1.36-1.34 (m, 1H) ), 0.10-0.07 (m, 1H). MS-ESI calcd for [M+H] ⁺ 417.

Compound 1-10 isomer 4 (44 mg, yield: 18%), retention time: 8.456 min. ¹ H NMR (400 MHz, Methonal-d ₄ ): δ 8.47-8.42 (m, 2H), 8.06 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.46-7.41 ( m, 2H), 5.02-4.92 (m, 2H), 3.88-3.85 (m, 2H), 3.38-3.34 (m, 2H), 3.25-3.22 (m, 1H), 2.26-2.20 (m, 1H), 1.45 (d, J = 6.0 Hz, 6H), 1.28-1.23 (m, 1H), 0.65-0.64 (m, 1H). MS-ESI calcd for [M+H] ⁺ 417.

Example 2

first step

Compound 2-1 (3.00 g, 17.7 mmol) was dissolved in ethanol (40 mL), and sodium borohydride (1.30 g, 35.5 mmol) was added portionwise at 20 ° C and stirred for 2 hours. The reaction mixture was concentrated with EtOAc EtOAc m. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by silica gel column chromatography (EtOAc:EtOAc:

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.53 - 7.42 (m, 2H), 7.25 (d, J = 6.8 Hz, 1H), 5.62 (d, J = 6.8 Hz, 1H), 2.73-2.66 (m, 1H), 2.25-2.16 (m, 1H), 1.18-1.13 (m, 1H), 0.66-0.60 (m, 1H). MS-ESI calcd for [M+H] ⁺ 172.

Second step

Compound 2-2 (2.80 g, 16.4 mmol) was dissolved in ethanol (50 mL), and then hydroxylamine hydrochloride (3.40 g, 49.1 mmol), triethyl Amine (6.60 g, 65.4 mmol). The resulting solution was heated to 60 ° C and stirred for 15 hours. The reaction mixture was cooled to EtOAc EtOAc (EtOAc)EtOAc. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by silica gel column chromatography (jjjjjjjjj

^{1 H NMR (400MHz, Methonal-} d 4) δ7.28-7.21 (m, 2H), 7.15 (d, J = 7.6Hz, 1H), 5.49 (d, J = 6.0Hz, 1H), 2.73-2.67 ( m, 1H), 2.04-1.92 (m, 1H), 0.98-0.92 (m, 1H), 0.59-0.50 (m, 1H). MS-ESI calcd for [M+H] ⁺ 205.

third step

3-cyano-4-isopropylbenzoic acid (2.00 g, 9.76 mmol), 1-hydroxybenzotriazole (2.70 g, 19.6 mmol), 1-ethyl-3-(3-dimethylamino) Propyl) carbodiimide hydrochloride (3.80 g, 19.6 mmol) was dissolved in anhydrous N,N-dimethylformamide (25 mL). The reaction solution was replaced with nitrogen three times. After stirring at 20 ° C for one hour, a solution of compound 2-3 (2.00 g, 938 mmol) in anhydrous N, N-dimethylformamide (5 mL) was added. After the reaction mixture was further stirred for 1 hour, the temperature was raised to 90 ° C and stirred for 13 hours. The reaction mixture was concentrated with EtOAc EtOAc m. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by silica gel column chromatography (EtOAc (EtOAc)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.48-8.40 (m, 1H), 8.39-8.32 (m, 1H), 8.02-7.99 (m, 1H), 7.67-7.62 (m, 1H), 7.38-7.30 (m, 1H), 7.13 (d, J = 6.4 Hz, 1H), 5.68 (d, J = 6.4 Hz, 1H), 4.86 - 4.76 (m, 1H), 3.28-3.20 (m, 1H), 2.22 2.13 (m, 1H), 1.48 (d, J = 6.0 Hz, 6H), 1.19-1.14 (m, 1H), 0.64-0.56 (m, 1H). MS-ESI calcd [M+H] ⁺ 372.

the fourth step

Compound 2-4 (3.30 g, 8.84 mmol) was dissolved in anhydrous dichloromethane (30 mL) and EtOAc (EtOAc) The reaction solution was stirred for 2 hours. Water (5 mL) was added to the reaction mixture and stirred for 5 minutes, and a large amount of white solid was formed. The compound was filtered and the filter cake was washed with dichloromethane (10 mL x 3). The filtrate was concentrated under reduced pressure. EtOAc (EtOAc:EtOAc)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.45 (d, J = 2.0Hz, 1H), 8.36 (dd, J = 2.0,8.8Hz, 1H), 8.31 (d, J = 7.2Hz, 1H), 7.81 (d, J = 7.2 Hz, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 4.86 - 4.77 (m, 1H), 3.79 - 3.75 (m, 1H), 2.64-2.60 (m, 1H), 1.82-1.78 (m, 1H), 1.49 (d, J = 6.0 Hz, 6H), 1.45-1.40 (m, 1H). MS-ESI calcd [M+H] ⁺ 372.

the fifth step

Compound 2-5 (50.0 mg, 134 mmol), 2-amino-N,N-dimethylacetamide (37.0 mg, 269 mmol), tetraisopropyl titanate (76.0 The mixture was dissolved in anhydrous tetrahydrofuran (2 mL). The reaction solution was lowered to 20 ° C, sodium borohydride (10.0 mg, 269 mmol) and methanol (1 mL) were added, and the mixture was stirred for 2 hr. The solution was poured into water (5 mL) and stirred for 5 min. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by high performance liquid chromatography (hydrochloric acid) to give compound 2-6 (17.0 mg).

¹ H NMR (400 MHz, Methonal-d ₄ ) δ 8.52-8.41 (m, 2H), 8.17 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.56-7.43 ( m, 2H), 5.31 (d, J = 6.8 Hz, 1H), 5.06-5.03 (m, 1H), 5.01-4.96 (m, 1H), 4.44 (s, 2H), 3.48 (br s, 1H), 3.15 (s, 3H), 3.07 (s, 3H), 1.48 (d, J = 6.0 Hz, 6H), 1.45-1.40 (m, 1H), 0.88-0.85 (m, 1H). MS-ESI calcd for [M+H] ⁺ 495.

Example 3

The reaction procedure was similar to the fifth step of Example 2 to give Compound 3-2 (4.0 mg).

^{1 H NMR (400MHz, Methonal-} d 4) δ8.47-8.35 (m, 2H), 8.02-7.92 (m, 1H), 7.46-7.38 (m, 2H), 7.34-7.28 (m, 1H), 4.98 -4.77 (m, 2H), 4.56 (s, 1H), 3.71 (t, J = 6.0 Hz, 1H), 3.67-3.62 (m, 1H), 3.11-3.05 (m, 1H), 3.01-2.87 (m , 4H), 2.75-2.58 (m, 5H), 2.25-2.10 (m, 1H), 1.43 (d, J = 6.0 Hz, 6H), 1.36-1.28 (m, 1H), 1.18-1.13 (m, 1H) ). MS-ESI calcd [M+H] ⁺ 486.

Example 4

first step

The reaction procedure was similar to the fifth step of Example 2, and the residue was purified by silica gel column chromatography (3:1 petroleum ether / ethyl acetate, Rf = 0.2) to give compound 4-2 (57.0 mg). 37%.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.37 (d, J = 2.0Hz, 1H), 8.28 (dd, J = 2.0,8.8Hz, 1H), 7.90 (d, J = 7.6Hz, 1H), 7.34 (br d, J=6.8 Hz, 1H), 7.24-7.20 (m, 1H), 7.05 (d, J = 8.8 Hz, 1H), 5.04-4.91 (m, 1H), 4.77-4.67 (m, 1H) , 4.62 (d, J = 6.0 Hz, 1H), 3.28-3.19 (m, 1H), 3.21-3.10 (m, 1H), 3.02-2.98 (m, 1H), 2.54 (t, J = 6.0 Hz, 2H) ), 2.08-1.99 (m, 1H), 1.41 (d, J = 6.0 Hz, 7H), 1.19 (d, J = 6.0 Hz, 6H), 1.09-1.04 (m, 1H), 0.30-0.20 (m, 1H). MS-ESI calcd for [M+H] ⁺ 487.

Second step

Compound 4-2 (57.0 mg, 0.117 mmol) was dissolved in methanol (1 mL), water (1 mL). The reaction solution was stirred at 20 ° C for 3 hours. The reaction solution was adjusted to pH = 7 with dilute hydrochloric acid and ethyl acetate (20 mL). The aqueous phase was extracted with EtOAc (EtOAc)EtOAc. The residue was purified by high performance liquid chromatography (hydrochloric acid) to afford product 4-3 (8.0 mg): 14%.

^{1 H NMR (400MHz, Methonal-} d 4) δ8.52-8.40 (m, 2H), 8.16 (d, J = 8.0Hz, 1H), 7.71 (d, J = 8.0Hz, 1H), 7.53-7.44 ( m, 2H), 5.31 (d, J = 6.4 Hz, 1H), 5.02-4.96 (m, 1H), 3.80-3.71 (m, 1H), 3.63-3.58 (m, 1H), 3.52-3.47 (m, 1H), 2.98-2.86 (m, 2H), 2.43 - 2.33 (m, 1H), 1.48 (d, J = 6.0 Hz, 6H), 1.39-1.28 (m, 1H), 0.88-0.82 (m, 1H) . MS-ESI calcd for [M+H] ⁺ 445.

Example 5

The reaction procedure was similar to the fifth step of Example 2, and the residue was purified by high-performance liquid chromatography (hydrochloric acid) to give Compound 5-2 (2.0 mg), yield: 2%.

¹ H NMR (400 MHz, Methonal-d ₄ ) δ 8.52-8.43 (m, 2H), 8.29-8.16 (m, 1H), 7.56-7.46 (m, 3H), 5.59-5.50 (m, 1H), 5.39 -5.30 (m, 1H), 4.75-4.65 (m, 2H), 3.97-3.70 (m, 1H), 3.58-3.42 (m, 1H), 2.43 - 2.38 (m, 1H), 2.34 - 2.15 (m, 1H), 1.48 (d, J = 6.0 Hz, 6H), 1.40-1.32 (m, 1H), 0.96-0.88 (m, 1H), 0.79-0.72 (m, 1H). MS-ESI calcd [M+H] ⁺ 495.

Example 6

The reaction procedure was similar to the fifth step of Example 2. The residue was purified by high-performance liquid chromatography (hydrochloric acid) to afford compound 6-2 (18.0 mg).

¹ H NMR (400 MHz, Methonal-d ₄ ) δ 8.44 - 8.33 (m, 2H), 8.10 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.51 - 7.41 ( m, 2H), 5.32-5.28 (m, 1H), 5.01-4.93 (m, 1H), 3.83-3.81 (m, 2H), 3.76-3.65 (m, 2H), 3.48 (s, 3H), 3.47- 3.39 (m, 1H), 2.38-2.25 (m, 1H), 1.47 (d, J = 6.0 Hz, 6H), 1.44-1.33 (m, 1H), 0.96-0.83 (m, 1H). MS-ESI calcd for [M+H] ⁺ 431.

Example 7

first step

The reaction procedure was similar to the fifth step of Example 2, and the residue was purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, Rf=0.2) to afford compound 7-2 (66.0 mg, pale yellow solid) , Yield: 55%.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.37 (d, J = 2.0Hz, 1H), 8.28 (dd, J = 2.0,8.8Hz, 1H), 7.90 (d, J = 7.6Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 4.76 - 4.71 (m, 1H), 4.66 - 4.61 (m, 1H), 4.33-4.26 (m, 1H), 4.10-4.00 (m, 1H), 3.83-3.70 (m, 1H), 3.18-3.04 (m, 2H), 2.95-2.80 (m, 1H), 2.08- 1.98 (m, 1H), 1.41 (d, J = 6.0 Hz, 6H), 1.38 (d, J = 2.8 Hz, 3H), 1.31 (d, J = 2.8 Hz, 3H), 1.08-1.02 (m, 1H) ), 0.34-0.24 (m, 1H). MS-ESI calcd for [M+H] ⁺ 487.

Second step

Compound 7-2 (75.8 mg, 0.135 mmol) was dissolved in dichloromethane (2 mL), and a solution of dioxane hydrochloride (4M, 2mL) was added dropwise. The reaction solution was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified and purified,363363363363363363363363363363363363

¹ H NMR (400 MHz, Methonal-d ₄ ) δ 8.44 - 8.33 (m, 2H), 8.10 (d, J = 7.78 Hz, 1H), 7.79 - 7.72 (m, 1H), 7.51 - 7.40 (m, 2H) ), 5.32-5.24 (m, 1H), 5.01-4.93 (m, 1H), 4.20-4.07 (m, 1H), 3.79-3.66 (m, 1H), 3.68-3.53 (m, 2H), 3.47-3.37 (m, 2H), 2.34 - 2.25 (m, 1H), 1.47 (d, J = 6.0 Hz, 6H), 1.44-1.33 (m, 1H), 0.96 - 0.83 (m, 1H). MS-ESI calcd for [M+H] ⁺ 447.

Example 8

first step

The reaction procedure was similar to the fifth step of Example 2. The residue was purified by silica gel column chromatography (2:1 petroleum ether / ethyl acetate, Rf = 0.2) Compound 8-2 (44.0 mg, white solid) was obtained.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.36 (d, J = 2.0Hz, 1H), 8.27 (dd, J = 2.0,8.8Hz, 1H), 7.88 (d, J = 7.6Hz, 1H), 7.49 -7.40 (m, 1H), 7.28-7.18 (m, 2H), 7.05 (d, J = 8.8 Hz, 1H), 6.38-6.43 (m, 2H), 4.75 - 4.68 (m, 1H), 4.63 (d , J = 6.0 Hz, 1H), 4.05 (d, J = 13.2 Hz, 1H), 3.88 (d, J = 13.2 Hz, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.14 - 3.03 (m, 1H), 2.01-1.89 (m, 1H), 1.41 (d, J = 6.0 Hz, 6H), 1.04-0.98 (m, 1H), 0.33-0.28 (m, 1H). MS-ESI calcd for [M ⁺ H] + 523, found 523.

Second step

Compound 8-2 (44.0 mg, 69.0 umol) was dissolved in anhydrous dichloromethane (2 mL), and triethylamine (20.9 mg, 0.207 mmol) and 2-methoxyethylsulfonyl chloride ( 21.9 mg, 0.138 mmol). The reaction solution was stirred at 20 ° C for 3 hours. The reaction was diluted with dichloromethane (10 mL) andEtOAc. The aqueous phase was extracted with dichloromethane (10 mL×3). The residue was purified by preparative EtOAc EtOAc (EtOAc)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.41 (d, J = 2.0Hz, 1H), 8.32 (dd, J = 2.0,8.8Hz, 1H), 7.97 (d, J = 7.6Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.47 (dd , J = 2.0, 8.8 Hz, 1H), 6.29 (d, J = 2.0 Hz, 1H), 5.95 (d, J = 6.4 Hz, 1H), 4.82-4.75 (m, 1H), 4.68 (d, J = 17.6 Hz, 1H), 4.13 (d, J = 17.6 Hz, 1H), 3.94-3.82 (m, 2H), 3.78 (s, 3H), 3.61 (s, 3H), 3.41 (s, 3H), 3.40- 3.30 (m, 2H), 3.20-3.10 (m, 1H), 1.98-1.90 (m, 1H), 1.47 (d, J = 6.0 Hz, 6H), 0.99-0.92 (m, 1H), 0.50-0.40 ( m, 1H). MS-ESI calcd. [M+H] ⁺

third step

The compound 8-3 (10.0 mg, 15.5 umol) was dissolved in anhydrous dichloromethane (1 mL), and trifluoroacetic acid (17.6 mg, 0.155 mmol) was added dropwise to the reaction mixture, and the mixture was stirred at 20 ° C for 15 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified mjjjjjj

^{1 H NMR (400MHz, Methonal-} d 4) δ8.49-8.40 (m, 2H), 8.00 (d, J = 7.6Hz, 1H), 7.51 (d, J = 7.6Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 5.32 (d, J = 6.4 Hz, 1H), 5.00 - 4.93 (m, 1H), 3.94 - 3.87 (m, 2H), 3.58-3.50 (m, 2H), 3.43 (s, 3H), 3.29-3.20 (m, 1H), 2.26-2.18 (m, 1H), 1.48 (d, J = 6.0 Hz, 6H), 1.22-1.16 ( m, 1H), 0.52-0.47 (m, 1H). MS-ESI calcd [M+H] ⁺ 495.

Example 9

The reaction procedure was similar to the fifth step of Example 2, and the residue was purified by high-performance liquid chromatography (hydrochloric acid) to afford Compound 9-2 (6.0 mg).

¹ H NMR (400 MHz, Methonal-d ₄ ) δ 8.53 - 8.45 (m, 2H), 8.19 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.53 - 7.44 ( m, 2H), 5.39 (d, J = 6.4 Hz, 1H), 5.03-4.96 (m, 1H), 4.00-3.86 (m, 2H), 3.85-3.69 (m, 2H), 3.66-3.58 (m, 1H), 3.20 (s, 3H), 2.46-2.37 (m, 1H), 1.48 (d, J = 6.0 Hz, 6H), 1.37-1.32 (m, 1H), 0.88-0.84 (m, 1H). MS-ESI calcd [M+H] ⁺ 495.

Example 10

first step

The reaction was carried out in a similar manner to the second step of Example 8 and the residue was purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, Rf=0.2) to give compound 10-2 (78.0 mg, white solid). Yield: 79%.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.34 (d, J = 2.0Hz, 1H), 8.26 (dd, J = 2.0,8.8Hz, 1H), 7.93 (d, J = 8.8Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 6.4 Hz, 1H), 6.44 - 6.38 (m, 1H), 6.34 (d, J = 2.0 Hz, 1H), 4.75 - 4.68 (m, 1H), 4.04 (s, 2H), 3.74 (s, 3H), 3.65 (s, 3H), 3.43 ( s, 2H), 3.40 (s, 3H), 3.12-3.00 (m, 1H), 1.85-1.77 (m, 1H), 1.40 (d, J = 6.0 Hz, 6H), 0.71 - 0.63 (m, 1H) , 0.18-0.12 (m, 1H). MS-ESI calcd for [M+H] ⁺ 495.

Second step

The reaction procedure was similar to the third step of Example 8, and the residue was purified by high-performance liquid chromatography (hydrochloric acid) to give Compound 10-3 (21.0 mg).

¹ H NMR (400 MHz, Methonal-d ₄ ) δ 8.52-8.40 (m, 2H), 8.04-7.98 (m, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.37-7.32 (m, 2H) ), 5.87 (d, J = 6.4 Hz, 1H), 4.99 - 4.92 (m, 1H), 4.04 (s, 2H), 3.46 (s, 3H), 3.29 - 3.22 (m, 1H), 2.24 - 2.18 ( m, 1H), 1.48 (d, J = 6.0 Hz, 6H), 1.19-1.12 (m, 1H), 0.56-0.50 (m, 1H). MS-ESI calcd [M+Na] ⁺ 467.

Example 11

first step

The reaction procedure was similar to the fifth step of Example 2, and the residue was purified by silica gel column chromatography (1:1 petroleum ether / ethyl acetate, Rf = 0.2) to afford compound 11-2 (40.0 mg, pale yellow oil ), yield: 29%.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.37 (d, J = 2.0Hz, 1H), 8.28 (dd, J = 2.0,9.2Hz, 1H), 7.92 (d, J = 7.6Hz, 1H), 7.26 -7.20 (m, 2H), 7.06 (d, J = 9.2 Hz, 1H), 4.99-4.90 (m, 1H), 4.78-4.64 (m, 2H), 3.20-3.14 (m, 1H), 3.06-2.97 (m, 1H), 2.92-2.85 (m, 1H), 2.43-2.33 (m, 2H), 2.10-2.03 (m, 1H), 1.96-1.85 (m, 3H), 1.41 (d, J = 6.0 Hz) , 6H), 1.17 (d, J = 6.0 Hz, 6H), 0.38-0.30 (m, 1H). MS-ESI calcd [M+H] ⁺ 501.

Second step

The reaction procedure was similar to the second step of Example 4, and the residue was purified by high-performance liquid chromatography (hydrochloric acid) to give Compound 11-3 (7.0 mg), yield: 19%.

¹ H NMR (400 MHz, Methonal-d ₄ ) δ 8.50 (d, J = 2.4 Hz, 1H), 8.46 (dd, J = 2.4, 9.2 Hz, 1H), 8.18 (d, J = 7.6 Hz, 1H) , 7.68 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 5.30 (d, J = 6.4 Hz, 1H), 5.01 -4.97(m,1H),3.59-3.39(m,3H), 2.60(t,J=6.8Hz,2H), 2.39-2.30(m,1H),2.22-2.04(m,2H), 1.48(d , J = 6.0 Hz, 6H), 1.45-1.39 (m, 1H), 0.84-0.80 (m, 1H). MS-ESI calcd [M+H] ⁺ 459.

Example 12

first step

Compound 12-1 (100 mg, 0.501 mmol), compound 12-2 (143 mg, 0.501 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (36.0 mg, 50.1 umol) Cesium carbonate (326 mg, 1.00 mmol) was dissolved in dioxane (2 mL), water (0.2 mL). The reaction solution was replaced with nitrogen three times, warmed to 80 ° C and stirred for 15 hours. The reaction solution was cooled to room temperature, then evaporated, evaporated, evaporated, evaporated The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by preparative EtOAc EtOAc (EtOAc:EtOAc:

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (d, J = 2.4 Hz, 1H), 8.1 (dd, J = 2.4, 8.8 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 4.76 -4.65 (m, 1H), 1.40 (d, J = 6.0 Hz, 6H). MS-ESI calcd for [M+H] ⁺ 324, 326

Second step

Compound 12-3 (110 mg, 0.339 mmol), compound 12-4 (92.0 mg, 0.339 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (24.0 mg, 33.9 umol) Cesium carbonate (221 mg, 0.678 mmol) was dissolved in dioxane (3 mL), water (0.3 mL). The reaction solution was replaced with nitrogen three times, warmed to 80 ° C and stirred for 15 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure and the residue dissolved in dichloromethane (20 mL), and washed with water (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by preparative EtOAc EtOAc (EtOAc:EtOAc:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.45 (dd, J = 1.2,8.0Hz, 1H), 8.22 (d, J = 2.0Hz, 1H), 8.11 (dd, J = 2.4,8.8Hz, 1H) , 7.70 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 4.77 - 4.68 (m, 1H), 3.96 - 3.90 ( m, 1H), 2.56-2.49 (m, 1H), 1.73-1.68 (m, 1H), 1.41 (d, J = 6.0 Hz, 6H), 1.38-1.30 (m, 1H). MS-ESI calcd [M+H] ⁺ 388.

third step

Compound compound 12-5 (75.0 mg, 193 mmol), 2-aminoethanol ((23.0 mg, 0.387 mmol), tetraisopropyl titanate (110 mg, 0.387 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL). The mixture was replaced with nitrogen three times, warmed to 50 ° C and stirred for 13 hours. The reaction mixture was dropped to 20 ° C, sodium borohydride (14.7 mg, 0.387 mmol) and methanol (1 mL) were added, and the solution was stirred for 2 hours. The solution was poured into water ( 5mL), stirring for 5 minutes, the suspension was filtered, and the filtrate was extracted with ethyl acetate (10 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by high-performance liquid chromatography (hydrochloric acid system) Compound Compound 12-6 (27.0 mg), yield 29%.

¹ H NMR (400 MHz, Methonal-d ₄ ) δ 8.41 (d, J = 2.4 Hz, 1H), 8.38-8.32 (m, 2H), 7.66 (d, J = 7.6 Hz, 1H), 7.51-7.45 ( m,1H), 7.41 (d, J = 8.8 Hz, 1H), 5.31 (d, J = 6.8 Hz, 1H), 4.98-4.90 (m, 1H), 3.99-3.95 (m, 2H), 3.76-3.66 (m, 1H), 3.64-3.52 (m, 1H), 3.55-3.44 (m, 1H), 2.37-2.26 (m, 1H), 1.47 (d, J = 6.0 Hz, 6H), 1.43-1.37 (m , 1H), 0.89-0.84 (m, 1H). MS-ESI calcd for [M+H] ⁺ 433.

Example 13

first step

Compound 13-1 (1.00 g, 4.48 mmol), bis-colonol borate (1.30 g, 5.12 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride ( 327 mg, 0.447 mmol), potassium acetate (879 mg, 8.96 mmol) was dissolved in dioxane (20 mL). The reaction solution was replaced with nitrogen three times, warmed to 80 ° C and stirred for 15 hours. The reaction mixture was cooled to room EtOAc. EtOAc m. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by silica gel column chromatography (EtOAc (EtOAc)

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (dd, J = 0.8, 7.6 Hz, 1H), 7.50 (dd, J = 0.8, 7.6 Hz, 1H), 7.6 (t, J = 7.6 Hz, 1H) , 3.26-3.20 (m, 1H), 2.29-2.22 (m, 1H), 1.49-1.39 (m, 1H), 1.18 (s, 12H), 1.12-1.05 (m, 1H). MS-ESI calcd [M+H] ⁺ 271.

Second step

The compound 3-bromo-5-chloro-1,2,4 thiadiazole (103 mg, 0.518 mmol), compound 13-2 (140 mg, 0.518 mmol), 1,1'-bis(diphenylphosphino) Ferrocene palladium dichloride (37.9 mg, 51.8 umol), cesium carbonate (337 mg, 1.0 mmol) was dissolved in dioxane (2 mL), water (0.2 mL). The reaction solution was replaced with nitrogen three times, warmed to 80 ° C and stirred for 15 hours. The reaction solution was cooled to room temperature, then evaporated, evaporated, evaporated, evaporated The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by preparative EtOAc (EtOAc:EtOAc:EtOAc

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.09 (dd, J = 0.8,7.6Hz, 1H), 7.77 (dd, J = 0.8,7.6Hz, 1H), 7.45-7.38 (t, J = 7.6Hz, 1H), 3.42-3.35 (m, 1H), 2.62-2.57 (m, 1H), 1.82-1.77 (m, 1H), 1.39-1.34 (m, 1H). MS-ESI calcd for [M+H] ⁺ 303, 303, 303, 309.

third step

Compound 13-3 (100 mg, 0.325 mmol), compound 13-4 (93.0 mg, 0.325 mmol), 1,1'-bis(diphenylphosphino) Ferrocene palladium dichloride (23.0 mg, 32.5 umol), cesium carbonate (212 mg, 0.651 mmol) dissolved in dioxane (2 mL), water (0.2 mL). The reaction solution was replaced with nitrogen three times, warmed to 80 ° C and stirred for 15 hours. The reaction solution was cooled to room temperature, then evaporated, evaporated, evaporated, evaporated The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by preparative EtOAc (EtOAc:EtOAc:EtOAc

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.55 (d, J = 2.0Hz, 1H), 8.47 (dd, J = 2.0,8.8Hz, 1H), 8.19-8.12 (m, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 4.74 - 4.64 (m, 1H), 3.55 - 3.45 (m, 1H), 2.68-2.56 (m, 1H), 1.89-1.74 (m, 2H), 1.40 (d, J = 6.0 Hz, 6H). MS-ESI calcd [M+H] ⁺ 388.

the fourth step

Compound 13-5 (65.0 mg, 167 mmol), 2-aminoethanol (20.0 mg, 0.335 mmol), tetraisopropyl titanate (95.0 mg, 0.335 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL). Replace three times, warm to 50 ° C and stir for 13 hours. The reaction solution was lowered to 20 ° C, sodium borohydride (13.0 mg, 0.335 mmol) and methanol (1 mL) were added, and the mixture was stirred for 2 hr. The solution was poured into water (5 mL) and stirred for 5 min. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by high-performance liquid chromatography (hydrochloric acid) to give compound 13-6 (16.0 mg).

^{1 H NMR (400MHz, Methonal-} d 4) δ8.57 (dd, J = 2.0,8.8Hz, 1H), 8.52 (d, J = 2.0Hz, 1H), 8.15 (d, J = 7.6Hz, 1H) , 7.78 (d, J = 7.6 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 5.36 (d, J = 6.8 Hz, 1H), 4.98 -4.92 (m, 1H), 4.02-3.96 (m, 2H), 3.63-3.47 (m, 2H), 3.31-3.25 (m, 1H), 2.48-2.38 (m, 1H), 1.56-1.50 (m, 1H), 1.46 (d, J = 6.0 Hz, 6H), 1.02-0.96 (m, 1H). MS-ESI calcd for [M+H] ⁺ 433.

Example 14

first step

Compound 14-1 (60.0 mg, 0.222 mmol), compound 14-2 (72.0 mg, 0.222 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (16.2 mg, 22.2 Umol), cesium carbonate (145 mg, 0.444 mmol) was dissolved in dioxane (1 mL), water (0.1 mL). The reaction solution was replaced with nitrogen three times, warmed to 80 ° C and stirred for 15 hours. The reaction solution was cooled to room temperature, then evaporated, evaporated, evaporated, evaporated The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by preparative EtOAc (EtOAc:EtOAc:EtOAc The yield was 64%.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.19 (dd, J = 2.4,8.8Hz, 1H), 8.11 (d, J = 2.4Hz, 1H), 7.95 (d, J = 7.6Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 4.76 - 4.66 (m, 1H), 3.66 - 3.60 (m, 1H), 2.61-2.52 (m, 1H), 1.79-1.72 (m, 1H), 1.41 (d, J = 6.0 Hz, 6H), 1.38-1.34 (m, 1H). MS-ESI calcd [M+H] ⁺ 388.

Second step

The reaction procedure was similar to the fourth step of Example 13, and the residue was purified by high-performance liquid chromatography (hydrochloric acid) to afford compound 14-4 (8.0 mg).

¹ H NMR (400 MHz, Methonal-d ₄ ) δ 8.34 - 8.28 (m, 2H), 7.98 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 5.35 (d, J = 6.0 Hz, 1H), 4.99 - 4.92 (m, 1H), 4.01-3.95 (m, 2H), 3.62-3.47(m,2H), 3.38-3.30(m,1H),2.43-2.35(m,1H), 1.47(d,J=6.0Hz,6H),1.36-1.30(m,1H),0.98- 0.94 (m, 1H). MS-ESI calcd for [M+H] ⁺ 433.

Example 15

first step

The reaction procedure was similar to the second step of Example 14 to afford compound 15-3 (95.0 mg, pale yellow solid).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (d, J = 2.4 Hz, 1H), 8.08 (dd, J = 2.4, 8.8 Hz, 1H), 8.02 (s, 1H), 7.62-7.58 (m, 2H), 7.32 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 4.74 - 4.62 (m, 1H), 3.10 - 3.05 (m, 1H), 2.57-2.47 (m , 1H), 1.74-1.68 (m, 1H), 1.45-1.40 (m, 1H), 1.39 (d, J = 6.0 Hz, 6H). MS-ESI calcd [M+H] ⁺ 387.

Second step

The reaction procedure was similar to the fourth step of Example 13, and the residue was purified by high-performance liquid chromatography (hydrochloric acid) to give Compound 15-4 (10.0 mg).

^{1 H NMR (400MHz, Methonal-} d 4) δ8.25-8.17 (m, 2H), 8.15 (s, 1H), 7.63-7.58 (m, 2H), 7.40 (t, J = 7.6Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 5.30 (d, J = 6.8 Hz, 1H), 4.87 - 4.82 (m, 1H), 4.01-3.92 (m, 2H), 3.60 - 3.44 (m, 2H) , 2.99-2.90 (m, 1H), 2.39-2.27 (m, 1H), 1.45 (d, J = 6.0 Hz, 6H), 1.34-1.26 (m, 1H), 1.01 - 0.96 (m, 1H). MS-ESI calcd for [M+H] ⁺ 422.

Example 16

first step

The reaction procedure was similar to the second step of Example 14 to afford compound 16-3 (130 mg, pale yellow solid).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.84 (d, J = 2.4Hz, 1H), 7.77 (dd, J = 2.4,8.8Hz, 1H), 7.70 (d, J = 8.0Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 4.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 4.0 Hz, 1H), 7.03 (d) , J=8.8Hz, 1H), 4.76-4.66(m,1H), 3.26-3.22(m,1H), 2.65-2.53(m,1H),1.83-1.77(m,1H),1.54-1.50(m , 1H), 1.46 (d, J = 6.0 Hz, 6H). MS-ESI calculated [M+H] ⁺ 386. Found 386.

Second step

The reaction procedure was similar to the fourth step of Example 13, and the residue was purified by high-performance liquid chromatography (hydrochloric acid) to afford Compound 16-4 (30.0 mg).

¹ H NMR (400 MHz, Methonal-d ₄ ) δ 7.96-7.90 (m, 2H), 7.60 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.49 - 7.45 ( m,1H), 7.45-7.41 (m, 1H), 7.40-7.34 (m, 1H), 7.26 (d, J = 8.4 Hz, 1H), 5.28 (d, J = 6.4 Hz, 1H), 4.87-4.77 (m, 1H), 3.99-3.93 (m, 2H), 3.60-3.44 (m, 2H), 3.01-2.95 (m, 1H), 2.36-2.26 (m, 1H), 1.48-1.42 (m, 1H) , 1.44 (d, J = 6.0 Hz, 6H), 0.99-0.94 (m, 1H). MS-ESI calcd for [M+H] ⁺ 431.

Example 17

first step

The reaction procedure was similar to the second step of Example 14 to give compound 17-3 (100 mg, pale yellow solid).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.24-8.20 (m, 1H), 8.22-8.16 (m, 1H), 7.79 (dd, J = 1.2, 8.0 Hz, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.50 (s, 1H), 7.38 (d, J = 9.2 Hz, 1H), 7.02 (d, J = 9.2 Hz, 1H), 4.74 - 4.65 (m, 1H), 3.18-3.14 (m , 1H), 2.57-2.48 (m, 1H), 1.78-1.72 (m, 1H), 1.42-1.38 (m, 1H), 1.39 (d, J = 6.0 Hz, 6H). MS-ESI calcd [M+H] ⁺ 372.

Second step

The reaction procedure was similar to the fourth step of Example 13, and the residue was purified by high-performance liquid chromatography (hydrochloric acid) to afford compound 17-4 (52.0 mg).

^{1 H NMR (400MHz, Methonal-} d 4) δ8.33-8.27 (m, 2H), 7.83 (d, J = 76Hz, 1H), 7.72 (s, 1H), 7.59 (d, J = 7.6Hz, 1H ), 7.48-7.42 (m, 1H), 7.39 (d, J = 9.2 Hz, 1H), 5.31 (d, J = 6.4 Hz, 1H), 4.92-4.86 (m, 1H), 4.01-3.95 (m, 2H), 3.62-3.46 (m, 2H), 3.11-3.02 (m, 1H), 2.39-2.30 (m, 1H), 1.52-1.47 (m, 1H), 1.46 (d, J = 6.0 Hz, 6H) , 0.99-0.92 (m, 1H). MS-ESI calcd for [M+H] ⁺ 416.

Example 18

The reaction procedure was similar to the eighth step of Example 1 to give Compound 18-2 (3.0 mg).

^{1 H NMR (400MHz, Methonal-} d 4) δ8.57 (s, 1H), 8.13 (d, J = 7.6Hz, 1H), 7.73 (d, J = 7.6Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 5.32 (d, J = 6.4 Hz, 1H), 4.00-3.94 (m, 2H), 3.61-3.42 (m, 4H), 2.38-2.31 (m, 1H), 1.50 (d, J) = 7.2 Hz, 6H), 1.43-1.38 (m, 1H), 0.89-0.85 (m, 1H). MS-ESI calcd for [M+H] ⁺ 383.

Example 19

The reaction procedure was similar to the eighth step of Example 1 to give Compound 19-2 (1.2 mg).

^{1 H NMR (400MHz, Methonal-} d 4) δ8.20-8.14 (m, 3H), 7.70 (d, J = 7.6Hz, 1H), 7.50 (t, J = 7.6Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 5.32 (d, J=6.4 Hz, 1H), 3.99-3.94 (m, 3H), 3.62-3.52 (m, 1H), 3.55-3.43 (m, 2H), 2.39-2.28 (m, 1H), 1.45-1.28 (m, 3H), 0.89-0.85 (m, 1H), 0.69-0.65 (m, 2H), 0.44-0.40 (m, 2H). MS-ESI calculated [M+H] ⁺ 404. Found 404.

Example 20

The reaction procedure was similar to the eighth step of Example 1 to give Compound 20-2 (3.3 mg).

¹ H NMR (400 MHz, Methonal-d ₄ ) δ 8.39 (d, J = 8.8 Hz, 2H), 8.16 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.52-7.46 (m, 1H), 5.23 (d, J = 6.8 Hz, 1H), 3.98-3.92 (m, 2H), 3.54-3.48 (m, 1H), 2.38-2.27 (m, 1H), 2.08-2.02 (m, 1H), 1.42-1.36 (m, 1H), 0.94-0.88 (m, 1H), 0.83-0.78 (m, 1H). MS-ESI calcd for [M ⁺ H] + 418, found 418.

Example 21

The reaction procedure was similar to the eighth step of Example 1 to give Compound 21-2 (2.4 mg), yield: 2%.

^{1 H NMR (400MHz, Methonal-} d 4) δ8.24 (d, J = 2.0Hz, 1H), 8.15 (dt, J = 2.0,8.8Hz, 2H), 7.71 (d, J = 8.0Hz, 1H) , 7.51 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 5.32 (d, J = 6.0 Hz, 1H), 4.96 - 4.92 (m, 1H), 4.00 - 3.95 ( m, 2H), 3.62-3.54 (m, 1H), 3.45-3.43 (m, 2H), 2.38-2.30 (m, 1H), 1.44 (d, J = 6.0 Hz, 6H), 1.42-1.36 (m, 1H), 0.90-0.85 (m, 1H). MS-ESI calcd for [M ⁺ H] + 426, found 426.

Example 22

The reaction procedure was similar to the eighth step of Example 1 to give Compound 22-2 (1.4 mg).

¹ H NMR (400 MHz, Methonal-d ₄ ) δ 8.41 (d, J = 2.0 Hz, 1H), 8.24 - 8.14 (m, 2H), 7.70 (d, J = 7.6 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.31 (d, J=9.2 Hz, 1H), 5.32 (d, J=6.0 Hz, 1H), 4.96-4.92 (m, 1H), 4.00-3.95 (m, 2H), 3.62-3.54(m,1H), 3.52-3.46(m,2H), 2.38-2.30(m,1H), 1.44(d,J=6.0Hz,6H),1.40-1.36(m,1H),0.90- 0.86 (m, 1H). MS-ESI calcd for [M+H] ⁺ 470, 472.

Experimental example 1

Test Methods:

I. Cell processing

1. Thaw the PathHunter cell line according to standard procedures;

2. The cells were seeded in 20 microliter 384 well microplates and incubated at 37 °C for the appropriate time.

Agonist

1. For agonist assays, cells are incubated with the sample to be tested to induce a reaction;

2. The test solution to be tested is diluted 5 times into the buffer;

3.5 microliters of a 5-fold dilution was added to the cells and incubated at 37 degrees for 90-180 minutes. The solvent concentration was 1%.

3. Signal detection

1. Add 12.5 μl or 15 μl of 50% by volume of PathHunter detection reagent in a single time, then incubate for 1 hour at room temperature to generate a detection letter. number;

2. The microplate was read using a PerkinElmer EnvisionTM instrument for chemiluminescent signal detection.

4. Data analysis

1. Perform compound activity analysis using the CBIS data analysis kit;

2. Calculation formula:

% Activity = 100% x (Average Test Sample RLU - Average Solvent RLU) / (Average Maximum Control Ligand - Average Solvent RLU) The experimental results are shown in Table 1:

Table 1: S1P1 receptor agonistic activity test results

Note: “+”>100nM; 100nM≧“++”>10nM; “+++”≦10nM

Conclusion: The compounds of the invention have significant and unexpected S1P1 receptor agonistic activity.

Experimental Example 2: Evaluation of Compound Pharmacokinetics

Objective: To test the pharmacokinetics of compounds in SD rats

Experimental Materials:

Sprague Dawley rats (male, 200-300 g, 7-9 weeks old, Shanghai Slack)

Experimental operation:

The rodent pharmacological characteristics of the compound after intravenous injection and oral administration were tested by a standard protocol. In the experiment, the candidate compound was formulated into a clear solution, and the rats were administered a single intravenous injection and oral administration. The intravenous and oral vehicles are a certain proportion of aqueous hydroxypropyl β-cyclodextrin or physiological saline solution. Collect whole blood samples within 24 hours, centrifuge at 3000g for 15 minutes, separate the supernatant to obtain plasma samples, add 4 times volume of acetonitrile solution containing internal standard to precipitate protein, centrifuge to remove the supernatant, add equal volume of water and centrifuge to remove the supernatant. The LC-MS/MS analysis method was used to quantitatively analyze the plasma concentration, and the pharmacokinetic parameters such as peak concentration, peak time, clearance rate, half-life, area under the curve of the drug, and bioavailability were calculated.

The experimental results are shown in Table 2:

Table 2: Pharmacokinetic test results

Conclusion: The compound of the present invention can significantly increase the single or partial index of rat pharmacokinetics compared with Ozanimod.

Claims (24)

a compound of the formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof,

among them, X is independently selected from CH or N; Ring A is selected from a 5- to 9-membered heteroaryl group; Ring B is selected from phenyl or 5- to 9-membered heteroaryl; R _{1 is} selected from H or is selected from C _{1 1-6} alkyl, C _1-6 heteroalkyl optionally substituted by 1, 2 or 3 R; R _{2 is} selected from H or is selected from: C _1-6 alkyl optionally substituted by 1, 2 or 3 R; Or R ₁ and R _{2 are} bonded to form a 3 to 6 membered ring optionally substituted by 1, 2 or 3 R; R _{3 is} selected from H, F, Cl, Br, I, CN, NH ₂ or from a C _1-6 alkyl group optionally substituted by 1, 2 or 3 R; R _{4 is} selected from H or is selected from C _{1 1-6} alkyl, C _1-6 heteroalkyl optionally substituted by 1, 2 or 3 R; R is selected from H, F, Cl, Br, I, OH, CN, NH ₂ , COOH, or selected from C _{1 1-6} alkyl, C _1-6 optionally substituted by 1, 2 or 3 R' Alkoxy, C _1-6 alkylamino, C _3-6 cycloalkyl; R' is selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , Me, Et, CF ₃ , CHF ₂ , CH ₂ F, NHCH ₃ , N(CH ₃ ) ₂ ; The "hetero" of the C _1-6 heteroalkyl group and the 5- to 9-membered heteroaryl group are each independently selected from -C(=O)NH-, -NH-, -S(=O) ₂ NH-, - S(=O)NH-, -O-, -S-, N, =O, =S, -C(=O)O-, -C(=O)-, -S(=O)-,- S(=O) ₂ -, -NHC(=O)NH-; In either case, the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, F, Cl, Br, I, OH, CN, NH ₂ , COOH, or selected from 1, 2 or 3 Substituted by R': C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylamino, C _3-6 cycloalkyl. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, F, Cl, Br, I, OH, CN, NH ₂ , COOH, Me, Et,

The compound according to any one of claims 1 to 3, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R _{1 is} selected from H or is selected from the group consisting of 1, 2 or 3 R :C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, N,N'-di(C _1-2 alkyl)amino, C _{1- 6} alkyl-S(=O)-, C _1-6 alkyl-S(=O) ₂ -, C _1-3 alkyl-NH-C _1-3 alkyl-, C _1-3 alkyl- S(=O)-C _1-3 alkyl-, C _1-3 alkyl-S(=O) ₂ -C _1-3 alkyl-, C _1-6 alkyl-C(=O)-, C _1-3 alkyl-NHC(=O)-C _1-3 alkyl-. The compound according to claim 4, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R _{1 is} selected from the group consisting of: 1, 2 or 3, R:

The compound according to claim 5, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R _{1 is} selected from the group consisting of:

The compound according to any one of claims 1 to 3, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R _{2 is} selected from the group consisting of H, Me, Et,

The compound according to any one of claims 1 to 3, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R ₁ and R _{2 are} bonded together to form one, optionally 2, 3 or 3 R Substituted: piperazinyl, azetidinyl. The compound according to claim 8, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R ₁ and R _{2 are} bonded, and the structural unit

From:

The compound according to any one of claims 1 to 3, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R _{3 is} selected from the group consisting of H, F, Cl, Br, I, OH, CN, NH ₂ . The compound according to any one of claims 1 to 3, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R _{4 is} selected from H or is selected from the group consisting of 1, 2 or 3 R : methoxy, isopropyl, isopropyloxy. The compound according to claim 11, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R _{4 is} selected from the group consisting of:

The compound according to any one of claims 1 to 3, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of 1,2,4-oxadiazolyl, 1,3,4 -oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, oxazolyl. The compound according to claim 13, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of:

The compound according to any one of claims 1 to 3, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein the ring B is selected from the group consisting of a phenyl group or a 5-membered heteroaryl group. The compound according to claim 15, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein the ring B is selected from the group consisting of a phenyl group, a thiazolyl group, an oxazolyl group, and a thienyl group. The compound according to claim 16, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of:

The compound according to any one of claims 1 to 3 or 17, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structural unit

From:

The compound according to claim 18, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein the structural unit

From:

The compound according to claims 1 to 3, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein the structural unit

From:

A compound according to claims 1 to 12, a tautomer thereof or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

among them, m, n are each independently selected from: 1 or 2; D _{1 is} independently selected from: S or O; T ₁ , T ₂ , T ₃ are each independently selected from: N or CH; R, R ₁ , R ₃ and R _{4 are} as defined in claims 1 to 7, 10 to 12 or 15 to 19. a compound of the formula, a tautomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

The compound according to any one of claims 1 to 22, a tautomer thereof, or a pharmaceutically acceptable salt thereof, for use in the preparation of a sphingosine 1 sphingosine 1 subtype (S1P1) receptor agonist Applications. The use according to claim 23, wherein the compound, its tautomer or a pharmaceutically acceptable salt thereof is used for the preparation of a medicament for treating inflammatory bowel disease.