Alkyl carboxylic acid compounds and their use

Abstract

The present invention relates to a series of alkyl carboxylic acid compounds and uses thereof, and more particularly to the compound represented by formula (II) and pharma- ceutically acceptable salts thereof: [Formula 1] JPEG2024518991000086.jpg58169

Description

Detailed Description of the Invention

[0001] This application claims the following priority: CN2021105302756, with a filing date of May 14, 2021; CN202111463413X, with a filing date of December 2, 2021.

[0002] [Technical Field] The present invention relates to a series of alkyl carboxylic acid compounds and their uses, specifically to the compounds represented by formula (II) and their pharmaceutically acceptable salts.

[0003] [Background Art] Soluble guanylate cyclase (sGC) is a receptor enzyme for nitric oxide (NO), a second messenger, and is widely present in several cell types such as muscle, epithelial, neuron, and endothelial cells. sGC is a heterodimer in which an α1 or α2 subunit is bound to a β1 subunit containing a heme-deficient molecular family, and is an important signaling enzyme in the NO-sGC-cGMP signaling pathway. Under physiological conditions, NO binds to the heme-deficient molecular family of sGC and, when activated, catalyzes the conversion of guanosine-5'-triphosphate (GTP) to cyclic guanosine monophosphate (cGMP).

[0004] cGMP is an important secondary messenger molecule that activates a series of downstream cascade reactions by activating various downstream effector molecules such as phosphodiesterase (PDE), cyclic nucleotide-dependent ion channel (CNG), and protein kinase (PKG), and plays important physiological functions in the gastrointestinal system, blood circulation system, and nervous system, such as promoting vasodilation and smooth muscle relaxation, inhibiting platelet aggregation, vascular remodeling, cell apoptosis and inflammation, and participating in neurotransmission. Therefore, sGC stimulants can be used as potential treatments for cardiovascular diseases (heart failure, pulmonary hypertension, angina pectoris, myocardial infarction) and fibrotic diseases (renal fibrosis, systemic sclerosis). Under the above pathological conditions, due to long-term oxidative stress, the heme-deficient molecular family of sGC is oxidized (from the ferrous state to the ferric state), and the sGC enzyme cannot be activated by NO, which may promote the deterioration of the disease. Furthermore, it causes diseases such as endothelial dysfunction, atherosclerosis, hypertension, stable or unstable angina pectoris, thrombosis, myocardial infarction, stroke, or exacerbation of erectile dysfunction. Therefore, by activating oxidized sGC to generate cGMP, the treatment and / or prevention of such diseases becomes possible.

[0005] sGC activators are independent of NO and also independent of the heme-deficient molecular family, and can directly activate the sGC-cGMP signaling pathway. This may bring benefits to many diseases caused particularly by defects in NO pathway signaling after oxidative stress.

[0006] In response to the current unmet market and clinical needs for such soluble guanylate cyclase stimulants, the present invention provides a new class of compounds. Such compounds function as activators of soluble guanylate cyclase, have excellent in vitro stimulating activity against soluble guanylate cyclase, and have good pharmacokinetic properties. Ru In response to the current unmet market and clinical needs for such soluble guanylate cyclase stimulants, the present invention provides a new class of compounds. Such compounds function as activators of soluble guanylate cyclase, have excellent in vitro stimulating activity against soluble guanylate cyclase, and have good pharmacokinetic properties. Ru In response to the current unmet market and clinical needs for such soluble guanylate cyclase stimulants, the present invention provides a new class of compounds. Such compounds function as activators of soluble guanylate cyclase, have excellent in vitro stimulating activity against soluble guanylate cyclase, and have good pharmacokinetic properties. Ru In response to the current unmet market and clinical needs for such soluble guanylate cyclase stimulants, the present invention provides a new class of compounds. Such compounds function as activators of soluble guanylate cyclase, have excellent in vitro stimulating activity against soluble guanylate cyclase, and have good pharmacokinetic properties.

[0007] [Summary of the Invention] The present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof.

[0008]

Chemical formula

[0009] However, R1 is selected from R2,

[0010]

Chemical formula

[0011] R2 is selected from cyclopentyl, C 4-6 bicycloalkyl and 4- to 5-membered heterocycloalkyl, and the cyclopentyl, C 4-6 bicycloalkyl and 4- to 5-membered heterocycloalkyl are each independently optionally substituted with 1, 2 or 3 R a groups, R3 is selected from C 3-6 cycloalkyl and 4- to 5-membered heterocycloalkyl, and the C 3-6 cycloalkyl and 4- to 5-membered heterocycloalkyl are each independently optionally substituted with 1, 2 or 3 R b groups, L is selected from -O-, -OCH2-, -CH(R c )- and -C(R d R e )-, R a and R b are each independently selected from halogen, CN, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are each independently optionally substituted with 1, 2 or 3 R f groups, R c and R d and R e are each independently selected from halogen and C1-3 selected from alkyl, R f is selected from halogen and C 1-3 alkoxy, R4 is selected from halogen and C 1-3 alkyl, T1 is selected from CH and N, and the "hetero" in said "heterocycloalkyl" represents 1, 2 or 3 heteroatoms or heteroatomic groups each independently selected from O, NH, S and N.

[0012] In some embodiments of the present invention, the above R a and R b are each independently selected from F and methoxy, and the other variables are as defined in the present invention. In some embodiments of the present invention, the above R c , R d and R e are each independently selected from F and methyl, and the other variables are as defined in the present invention.

[0013] In some embodiments of the present invention, the above R f is selected from F, and the other variables are as defined in the present invention. In some embodiments of the present invention, the above R2 is

[0014]

Chemical formula

[0015]

Chemical formula

[0016] In some embodiments of the present invention, the above R2 is

[0017] [Chemical formula] selected from, and other variables are as defined in the present invention.

[0018] In some embodiments of the present invention, the above R3 is

[0019] [Chemical formula] selected from, and the

[0020] [Chemical formula] is optionally substituted by 1, 2 or 3 R b and other variables are as defined in the present invention.

[0021] In some embodiments of the present invention, the above R3 is

[0022] [Chemical formula] selected from, and other variables are as defined in the present invention.

[0023] In some embodiments of the present invention, the above L is selected from -O-, -OCH2- and -C(CH3)2-, and other variables are as defined in the present invention. In some embodiments of the present invention, the above R1 is

[0024] [Chemical formula] selected from, and other variables are as defined in the present invention.

[0025] In some embodiments of the present invention, the above R4 is selected from F, Cl and methyl, and other variables are as defined in the present invention. The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0026]

Chemical formula

[0027] However, R1 is selected from R2,

[0028]

Chemical formula

[0029] R2 is selected from cyclopentyl, C 4-6 bicycloalkyl and 4- to 5-membered heterocycloalkyl, and the cyclopentyl, C 4-6 bicycloalkyl and 4- to 5-membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R a , R3 is selected from C 3-6 cycloalkyl and 4- to 5-membered heterocycloalkyl, and the C 3-6 cycloalkyl and 4- to 5-membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R b , L is selected from -O-, -OCH2-, -CH(R c )- and -C(R d R e )-, R a and R b are each independently selected from halogen, CN, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 F, R c , R d and R e are each independently selected from halogen and C 1-3 alkyl, T1 is selected from CH and N, The "hetero" in the "heterocycloalkyl" contains 1, 2 or 3 atoms or atomic groups selected from O, S, N and NH.

[0030] In some embodiments of the present invention, the above R a and R b are each independently selected from F, and the other variables are as defined in the present invention. In some embodiments of the present invention, the above R c , R d and R e are each independently selected from F and methyl, and the other variables are as defined in the present invention.

[0031] In some embodiments of the present invention, the above R2 is

[0032]

Chemical formula

[0033]

Chemical formula

[0034] In some embodiments of the present invention, the above R2 is

[0035]

Chemical formula

[0036] In some embodiments of the present invention, the above R3 is

[0037]

Chemical formula

[0038]

Chemical formula

[0039] In some embodiments of the present invention, the above R3 is

[0040]

Chemical formula

[0041] In some embodiments of the present invention, the above L is selected from -O-, -OCH2- and -C(CH3)2-, and the other variables are as defined in the present invention. In some embodiments of the present invention, the above R1 is

[0042]

Chemical formula

[0043] Some further embodiments of the present invention are formed by any combination of the above variables. The present invention further provides a compound represented by formula (II-1) or a pharmaceutically acceptable salt thereof.

[0044]

Chemical formula

[0045] provided that R1, R4 and T1 are as defined in the present invention. The present invention further provides the following compound or a pharmaceutically acceptable salt thereof.

[0046] [Chemical formula] JPEG0007701475000021.jpg124169

[0047] In some embodiments of the present invention, the above-mentioned compound is selected from the following formulas.

[0048] [Chemical formula] JPEG0007701475000023.jpg122170

[0049] In some embodiments of the present invention, the above-mentioned compound is selected from the following formulas.

[0050] [Chemical formula] JPEG0007701475000025.jpg185170

[0051] The present invention further provides the use of the above-mentioned compound or its pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition, in the preparation of a medicament for treating diseases related to soluble guanylate cyclase activators. Ru In some embodiments of the present invention, the disease related to the soluble guanylate cyclase activator is chronic kidney disease.

[0052] The present invention further provides the use of the above-mentioned compound or its pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition, in the preparation of a medicament for treating chronic kidney disease.

[0053] Definition and Explanation ​Unless otherwise specified, the following terms and phrases used in this specification shall have the following meanings. Specific terms and phrases, when not otherwise defined, should not be considered uncertain or unclear, but should be understood according to their ordinary meanings. When a trade name appears in this specification, it is intended to refer to the corresponding trade name or its active ingredient.

[0054] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are within the scope of sound medical judgment, suitable for use in contact with human and animal tissues, have relatively low toxicity, irritation, allergic reaction or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0055] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present application prepared from a relatively non-toxic acid or base with the specific substituents disclosed in the present application. When the compound of the present application contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound with a sufficient amount of a base in a pure solution or a suitable inert solvent. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound with a sufficient amount of an acid in a pure solution or a suitable inert solvent. Some specific compounds of the present invention contain both basic and acidic functional groups and can therefore be converted into either a base addition salt or an acid addition salt.

[0056] The pharmaceutically acceptable salts of the present invention, the term "pharmaceutically acceptable salts" refers to salts of the compounds of the present application prepared from acids or bases that are relatively non-toxic compared to the compounds having the specific substituents appearing in the present application. When the compounds of the present application contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Some specific compounds of the present invention contain both basic and acidic functional groups and can therefore be converted into either base addition salts or acid addition salts.

[0057] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compounds containing acid groups or bases by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or free base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.

[0058] The compounds of the present invention can exist in the form of specific geometric isomers or stereoisomers. All such compounds contemplated by the present invention include cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as mixtures rich in enantiomers or diastereomers, all of which are within the scope of the present invention. Other asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

[0059] Unless otherwise specified, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other. Unless otherwise specified, the term "diastereomer" refers to stereoisomers in which the molecules have two or more chiral centers and the molecules are in a non-mirror image relationship.

[0060] Unless otherwise specified, “(+)” means dextrorotatory, “(-)” means levorotatory, and “(±)” means racemic. Unless otherwise specified, the wedge solid line bond (

[0061] [Chem.] ) and the wedge dashed line bond (

[0062] [Chem.] ) are used to represent the absolute configuration of a single stereocenter, the straight solid line bond (

[0063] [Chem.] ) and the straight dashed line bond (

[0064] [Chem.] ) are used to represent the relative configuration of a stereocenter, the wavy line (

[0065] [Chem.] ) is used to represent the wedge solid line bond (

[0066] [Chem.] ) or the wedge dashed line bond (

[0067] [Chem.] ) or the wavy line (

[0068] [Chem.] ) is used to represent the straight solid line bond (

[0069] [Chemistry] ) and a straight dotted line bond (

[0070] [Chemistry] ) represents.

[0071] Unless otherwise specified, when a group has one or more bondable sites, any one or more sites of the group can be bonded to other groups by chemical bonds. The chemical bond by which the site is bonded to another group is a straight solid line bond (

[0072] [Chemistry] ), a straight dashed line bond (

[0073] [Chemistry] ), or a wavy line (

[0074] [Chemistry] ). For example, the straight solid line bond of -OCH3 represents that it is bonded to another group through the oxygen atom in the group,

[0075] [Chemistry] The straight dashed line bond of represents that it is bonded to another group through both ends of the nitrogen atom in the group,

[0076] [Chemistry] The wavy line of represents that it is bonded to another group through the carbon atoms at the 1st and 2nd positions of the phenyl group.

[0077] Unless otherwise specified, "C 1-3The term "alkyl" is used to represent a straight-chain or branched-chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The said C 1-3 alkyl includes C 1-2 and C 2-3 alkyl and the like, which may be monovalent (e.g., methyl), divalent (e.g., methylene), and polyvalent (e.g., methine). Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0078] Unless otherwise specified, the number of atoms in a ring is generally defined as the number of ring members. For example, "5- to 7-membered ring" refers to a "ring" around which 5 to 7 atoms are arranged. 1-3 Unless otherwise specified, the term "C 1-3 alkoxy" means an alkyl group containing 1 to 3 carbon atoms bonded to the remainder of the molecule through one oxygen atom. The said C 1-2 alkoxy includes C 2-3 and C 1-3 alkoxy, C3 alkoxy, and C2 alkoxy. Examples of C

[0079] alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy or isopropoxy), and the like. Unless otherwise specified, C n-n+m or C n to C n+m includes any one specific form of n to n + m carbons. For example, C 1-12 includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 and C 11 and C 12 and also includes any one range of n to n + m. For example, C 1-12 includes C 1-3 and C 1-6 and C 1-9 and C 3-6 and C 3-9 and C 3-12 and C 6-9 and C 6-12 and C9-12 including the like. Similarly, "n-membered to (n+m)-membered" represents that the number of atoms in the ring is from n to (n+m). For example, a 3- to 12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any one range among n to (n+m). For example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, and a 6- to 10-membered ring, etc.

[0080] Unless otherwise specified, "C" 3-6 "cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic ring system. The C 3-6 cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc., and it may be monovalent, divalent or polyvalent. Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0081] Unless otherwise specified, "C" 3-5 "cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic ring system. The C 3-5 cycloalkyl includes C 3-4 and C 4-5 cycloalkyl, etc., and it may be monovalent, divalent or polyvalent. Examples of C 3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.

[0082] Unless otherwise specified, "C" 4-6 "bicycloalkyl" means a saturated cyclic hydrocarbon group consisting of 4 to 6 carbon atoms, which is a bicyclic ring system including a spiro ring, a fused ring and a bridged ring. The C 4-6 bicycloalkyl includes C 4-5 and C 5-6 bicycloalkyl, etc., and it may be monovalent, divalent or polyvalent. C 4-6Examples of bicycloalkyl include,

[0083] [Chemical Formula] and the like, but are not limited thereto.

[0084] Unless otherwise specified, the term "4- to 5-membered heterocycloalkyl" means, by itself or in combination with other terms, a saturated cyclic group consisting of 4 to 5 ring atoms each, 1, 2, 3, or 4 of which ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, where the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring systems include spiro rings, fused rings, and bridged rings. Also, with respect to said "4- to 6-membered heterocycloalkyl", the heteroatom can occupy the position where it is bonded to the rest of the molecule and the heterocycloalkyl. Said 4- to 5-membered heterocycloalkyl includes 4-membered, 5-membered, and 6-membered heterocycloalkyl. Examples of 4- to 5-membered heterocycloalkyl include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), and the like, but are not limited thereto.

[0085] Unless otherwise specified, the term "halo" or "halogen" means, by itself or as part of another substituent, a fluorine, chlorine, bromine, or iodine atom. The compounds of the present invention can exist in specific forms. Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can rapidly interconvert. If tautomers are possible (e.g., in solution), the chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via the movement of protons, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by the recombination of some bonding electrons. Among them, a specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0086] Unless otherwise specified, the terms "enriched in one isomer", "enriched in isomers", "enriched in one enantiomer", or "enriched in enantiomers" mean that the content of one of the isomers or enantiomers is less than 100%, and the content of this 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, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

[0087] Unless otherwise specified, the term "isomer excess" or "enantiomer excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, when the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80%.

[0088] The optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or by chiral reagents or other conventional techniques. To obtain one enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomers are resolved by conventional methods known in the art and recovered to obtain the pure enantiomer. Also, the separation of enantiomers and diastereomers is usually carried out using chromatography with a chiral stationary phase and optionally in combination with a chemical derivatization method (e.g., generating a carbamate from an amine).

[0089] The compounds of the present invention may contain an unnatural proportion of atomic isotopes in one or more of the atoms that make up the compound. For example, the compound can be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), C-14 ( 14 C), etc. Or for example, hydrogen can be replaced with deuterium to form a deuterated drug, and the bond formed between deuterium and carbon is stronger than the bond formed between normal hydrogen and carbon. Compared with the non-deuterated drug, the deuterated drug has advantages such as reducing toxic side effects, enhancing drug stability, enhancing efficacy, and extending the biological half-life of the drug. The conversion of the isotope composition of the compounds of the present invention is included within the scope of the present invention regardless of whether it is radioactive or not.

[0090] The terms "optionally" or "optionally with" refer to the fact that the matters or situations described thereafter may occur but do not necessarily have to occur, and the description includes both the cases where the matters or situations occur and the cases where the matters or situations do not occur.

[0091] The term "substituted" means that any one or more hydrogen atoms at a particular atom are substituted with a substituent, and the substituent may include deuterium and variants of hydrogen as long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are substituted. Keto group substitution does not occur in aromatic groups. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents are arbitrary as long as they are chemically feasible.

[0092] If any of the variables (e.g., R) appears one or more times in the composition or structure of the compound, its definition is independent in each case. Therefore, for example, when one group is substituted with 0 to 2 Rs, the above group is optionally substituted with 2 or fewer Rs, and in each case, R has independent options. Also, combinations of substituents and / or their variants are only permitted if such combinations result in a stable compound.

[0093] When the number of linking groups is 0, for example, -(CRR)0- means that the linking group is a single bond. When the substituent is empty, it means that the substituent does not exist. For example, when X in A-X is empty, the structure actually means A. When it is not indicated through which atom the listed substituent is bonded to the substituted group, such a substituent can be bonded through any of its atoms. For example, pyridinyl as a substituent may be bonded to the substituted group through any carbon atom of the pyridine ring.

[0094] Unless otherwise specified, when a group has one or more bondable sites, any one or more sites of the group can be bonded to other groups by chemical bonds. When the bonding mode of the chemical bond is delocalized and there is an H atom at the bondable site, when bonding with the chemical bond, the number of H atoms at the site decreases to a group with a corresponding valence according to the number of the bonded chemical bonds. The chemical bond by which the site is bonded to another group is a straight solid line bond (

[0095]

Chem.

[0096]

Chem.

[0097]

Chem.

[0098]

Chem.

[0099]

Chem.

[0100] The compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution forms well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0101] The structure of the compounds of the present invention can be confirmed by conventional methods well-known to those skilled in the art. When the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by the conventional technical means of those skilled in the art. For example, in single crystal X-ray diffraction (SXRD), the diffraction intensity data of the cultured single crystal is collected with a Bruker D8 venture diffractometer, the light source is CuKα radiation, the scanning method is φ / ω scanning, and after collecting the relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, whereby the absolute configuration can be confirmed.

[0102] The solvents used in the present invention can be obtained from commercially available products. The following abbreviations are used in the present invention: aq represents water; eq represents equivalent; M represents mol / L; DMSO represents dimethyl sulfoxide; EtOH represents ethanol; CBz represents benzyloxycarbonyl, which is an amine protecting group; Boc represents tert-butoxycarbonyl, which is an amine protecting group; r.t. represents room temperature; Boc2O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; IPAm represents isopropylamine.

[0103] Compounds are named according to the ordinary naming principles in the art or using ChemDraw® software. Commercially available compounds are named in the supplier's catalog. [Advantages of the Invention] The compounds of the present invention have significant in vitro stimulating activity against guanylate cyclase, and have excellent pharmacokinetic properties and good hepatocyte stability.

Modes for Carrying Out the Invention

[0104] Hereinafter, the present invention will be described in detail by way of examples, which do not limit the present invention in any adverse way. Although the present invention has been described in detail in this specification, its specific embodiments are also disclosed. It is obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0105] Example 1

[0106]

Chem.

[0107] Synthesis route:

[0108]

Chem.

[0109] Step 1: Synthesis of compound WX001_2 Under room temperature and nitrogen gas protection, tert-butyl diethylphosphonoacetate (5.14 g, 20.38 mmol) was dissolved in tetrahydrofuran (30 mL), the reaction system was cooled to 0 °C, potassium tert-butoxide (2.52 g, 22.48 mmol) was added, and after stirring for 30 minutes, WX001_1 (2 g, 20.38 mmol) was slowly added dropwise. After the addition was complete, the reaction system was returned to room temperature and stirred for 12 hours. After the reaction was completed, water (50 mL) was added for dilution, and the mixture was extracted with ethyl acetate (60 mL × 3). The organic phases were combined. The organic phase was washed successively with saturated brine (60 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1, volume ratio) to obtain compound WX001_2. 1 H NMR (400 MHz, DMSO_d6) δ: 6.75 (dd, J=8.0, 15.5 Hz, 1H), 5.75-5.65 (m, 1H), 2.62 -2.52 (m, 1H), 1.83-1.72 (m, 2H), 1.65-1.53 (m, 4H), 1.42 (s, 9H), 1.36-1.28 (m, 2H).

[0110] Step 2: Synthesis of compound WX001_4 Under room temperature and nitrogen gas protection, 2,2-bis(diphenylphosphino)-1,1-binaphthyl (18.24 mg, 29.29 μmol) and chloro(1,5-cyclooctadiene)rhodium(I) (dimer) (62.80 mg, 127.37 μmol) were dissolved in tetrahydrofuran (10 mL), and the reaction system was stirred at room temperature for 15 minutes. Compound WX001_3 (1.42 g, 5.60 mmol) was dissolved in isopropanol (5 mL) and tetrahydrofuran (10 mL), and compound WX001_2 (1.00 g, 5.09 mmol), potassium hydroxide (343.00 mg, 6.11 mmol) and 1,5-cyclooctadiene (55.11 mg, 509.46 μmol) were added sequentially. The reaction system was heated to 60 °C, the prepared catalyst was added, and the reaction system was stirred at 60 °C for 9 hours. After the reaction was completed, it was cooled to room temperature, diluted by adding water (150 mL), extracted with ethyl acetate (150 mL × 3), and the organic phases were combined. The organic phase was washed successively with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1, volume ratio) to obtain compound WX001_4. 1 H NMR (400 MHz, CDCl3) δ: 7.12 (d, J = 8.1 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 6.52 (dd, J = 2.0, 8.3 Hz, 1H), 3.98 (s, 2H), 2.73 - 2.61 (m, 2H), 2.45 - 2.35 (m, 1H), 1.97 - 1.78 (m, 2H), 1.70 - 1.61 (m, 1H), 1.59 - 1.49 (m, 2H), 1.45 - 1.35 (m, 2H), 1.28 - 1.25 (m, 9H), 1.08 - 0.96 (m, 1H), 0.91 - 0.82 (m, 1H).

[0111] Step 3: Synthesis of compound WX001_7 Under room temperature and nitrogen gas protection atmosphere, diisopropylamine (31.52 g, 311.45 mmol, 44.02 mL) was added to a dried reaction flask, and tetrahydrofuran (350 mL) was added and dissolved. The reaction system was cooled to -70 °C, and an n-hexane solution of n-butyllithium (130.00 mL, 324.99 mmol, 2.5 M) was added. After the reaction system was stirred at -70 °C for 30 minutes, the temperature was raised to -40 °C and stirred for 30 minutes. The reaction system was cooled to -70 °C, and WX001_6 (50 g, 270.83 mmol) dissolved in tetrahydrofuran (120 mL) was added. The reaction system was stirred at -70 °C for 1 hour, and trifluoroacetone (45.52 g, 406.24 mmol) dissolved in tetrahydrofuran (150 mL) was added. The reaction system was stirred at -70 °C for 2 hours. After the reaction was completed, the reaction system was warmed to 0 °C, 120 mL of 5N dilute hydrochloric acid was added to the reaction system to quench the reaction system, and the reaction system was stirred at room temperature for 30 minutes, then concentrated under reduced pressure to remove most of the organic solvent. Ethyl acetate (300 mL) was added for dilution, the liquid was separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (200 mL × 3), and the organic phases were combined. The organic phase was washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain compound WX001_7.

[0112] Step 4: Synthesis of compound WX001_8 Under room temperature and a nitrogen gas protection atmosphere, WX001_7 (80.35 g, 270.84 mmol) was dissolved in pyridine (160 mL). At room temperature, phosphorus oxychloride (49.83 g, 325.01 mmol) was added to the reaction system, and the reaction system was stirred at 110 °C for 12 hours. After the reaction was completed, the reaction system was cooled to room temperature, the reaction system was poured into 200 mL of water to quench the reaction system, 6N dilute hydrochloric acid was added to adjust the pH to about 3, dichloromethane (400 mL) was added for dilution, the liquid was separated, the organic phase was collected, the aqueous phase was extracted with dichloromethane (300 mL × 3), and the organic phases were combined. The organic phase was washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 9 / 1, volume ratio) to obtain a mixture of compounds WX001_8 and WX001_9. The obtained mixture was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 9 / 1, volume ratio) to obtain compound WX001_8.

[0113] Step 5: Synthesis of compound WX001_9 Under room temperature and nitrogen gas protection atmosphere, diisopropylamine (7.99 g, 78.95 mmol) was added to a dried reaction flask, tetrahydrofuran (50 mL) was added and dissolved, and the reaction system was replaced with nitrogen gas three times. The reaction system was cooled to -60 °C, and an n-hexane solution of n-butyllithium (71.77 mmol, 28.71 mL, 2.5 M) was slowly added. The reaction system was heated to -40 °C and stirred at -40 °C for 30 minutes, then cooled to -65 °C. WX001_8 (10 g, 35.89 mmol) dissolved in tetrahydrofuran (50 mL) was added, and the reaction system was stirred at -65 °C for 1.5 hours. After the reaction was completed, a solution of acetic acid (8.62 g, 143.55 mmol) in tetrahydrofuran (40 mL) was added to the reaction system to quench the reaction system, and it was stirred at room temperature for 2 hours. Water (80 mL) and ethyl acetate (80 mL) were added for dilution, the liquid was separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (80 mL × 3), and the organic phases were combined. The organic phase was washed with saturated brine (80 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 9 / 1, volume ratio) to obtain compound WX001_9, and the crude product was directly put into the next step.

[0114] Step 6: Synthesis of compound WX001_10 Under room temperature and argon gas protection atmosphere, Pt / C (0.57 g, purity: 5%) was added to a dried hydrogenation flask, methanol (60 mL) was added to moisten it, WX001_9 (5.7 g, 20.46 mmol) was added, and the reaction system was stirred at 50 °C under a hydrogen gas atmosphere of 50 psi for 12 hours. After the reaction was completed, the reaction system was filtered through diatomaceous earth, the cake was washed with methanol (60 mL × 5), the filtrates were combined, and concentrated under reduced pressure to obtain a residue. Compound WX001_10 was obtained.

[0115] Step 7: Synthesis of compound WX001_11 Under room temperature and a nitrogen gas protection atmosphere, WX001_10 (5.8 g, 20.66 mmol) was dissolved in methanol (60 mL), sodium methoxide (3.35 g, 61.99 mmol) was added to the reaction system, and the reaction system was stirred at 80 °C for 12 hours. Sodium methoxide (1.12 g, 20.66 mmol) was added, and after the reaction system was continuously stirred at 80 °C for 12 hours, the temperature was raised to 90 °C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure to remove most of the organic solvent, water (60 mL) was added for dilution, extracted with tert-butyl methyl ether (70 mL), the organic phase was discarded, the aqueous phase was adjusted to pH 2-3 with 3N dilute hydrochloric acid, extracted with ethyl acetate (80 mL × 3), and the organic phases were combined. The combined organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. Compound WX001_11 was obtained.

[0116] Step 8: Synthesis of Compound WX001_5 Under room temperature and a nitrogen gas protection atmosphere, quinine (3.51 g, 10.83 mmol) was dissolved in ethanol (36 mL), the temperature of the reaction system was raised to 80 °C, and WX001_11 (3.85 g, 14.44 mmol) dissolved in ethanol (19 mL) was added dropwise one by one, and the reaction system was stirred at 80 °C for 10 minutes. A white solid was precipitated. The reaction system was slowly cooled to 0 °C, stirred at 0 °C for 1 hour, filtered, the cake was washed with 5 mL of water, and the solid was collected. The solid was dissolved in methanol (157 mL) and water (20 mL), the temperature of the reaction system was raised to 100 °C and stirred for 30 minutes, the reaction system was slowly cooled to room temperature, a white solid was precipitated, filtered, the cake was washed with 10 mL of water, and the cake was collected. The cake was dissolved in 120 mL of ethanol and 20 mL of water, the temperature of the reaction system was raised to 100 °C and stirred for 30 minutes, the reaction system was slowly cooled to room temperature, a white solid was precipitated, the cake was washed with 10 mL of water, and the solid was collected. The solid was suspended in water (25 mL), hydrochloric acid (6M, 3.25 mL) was added, and the reaction system was stirred at room temperature for two and a half hours. The white solid was filtered, the cake was washed with 1 mL of water, the solid was collected, and the cake was concentrated under reduced pressure to remove the solvent to obtain compound WX001_5.

[0117] SFC analysis method: Column type: Chiralpak IG-3 (100×4.6 mm I.D., 3 μm); Mobile phase: A: CO2, B: [MeOH (containing 0.1% IPAm)], Gradient: B%: 5% - 40%, 3 min. The peak time of WX001_5 was 1.196 min.

[0118] Step 9: Synthesis of Compound WX001_12 Under room temperature and nitrogen gas protection, compound WX001_5 (150 mg, 562.55 μmol) was dissolved in dichloromethane (3 mL), N,N-dimethylformamide (411.19 μg, 5.63 μmol) was added, the reaction system was cooled to 0 °C, oxalyl chloride (107.11 mg, 843.82 μmol) was added dropwise, the reaction system was stirred at 25 °C for 1 hour, and concentrated under reduced pressure to remove the solvent. The residue was dissolved in dichloromethane (3 mL), a dichloromethane (2 mL) solution of compound WX001_4 (218.62 mg, 675.06 μmol) and N,N-diisopropylethylamine (145.41 mg, 1.13 mmol) were added dropwise, and the reaction system was stirred at room temperature for 2 hours. After the reaction was completed, it was concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 7 / 3, volume ratio) to obtain compound WX001_12. 11H NMR (400 MHz, CDCl3) δ: 8.17 (d, J = 2.4 Hz, 1H), 7.58 (d, J = 5.3 Hz, 1H), 7.42 - 7.31 (m, 4H), 7.21 (dd, J = 2.2, 8.3 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 3.68 (t, J = 7.8 Hz, 1H), 3.47 - 3.34 (m, 1H), 2.84 - 2.76 (m, 1H), 2.74 - 2.64 (m, 1H), 2.49 - 2.39 (m, 1H), 2.02 - 1.92 (m, 1H), 1.90 - 1.80 (m, 1H), 1.68 - 1.61 (m, 1H), 1.59 - 1.49 (m, 2H), 1.41 - 1.31 (m, 2H), 1.30 - 1.27 (m, 1H), 1.23 (d, J = 3.3 Hz, 9H), 1.09 - 1.01 (m, 1H), 0.96 (d, J = 7.2 Hz, 3H). Step 10: Synthesis of Compound WX001 Under room temperature and nitrogen gas protection, in a pre-dried reaction flask, dissolve Compound WX001_12 (150 mg, 262.02 μmol) in ethyl acetate (3 mL), add hydrochloric acid - ethyl acetate (4 M, 3 mL), stir the reaction system at room temperature for 10 hours. After the reaction is completed, concentrate under reduced pressure to remove the solvent. The obtained residue was separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl) to obtain Compound WX001. MS-ESI m / z: 516.2 [M + H] + . 11H NMR (400 MHz, DMSO-d6) δ: 11.92 (s, 1H), 9.81 (s, 1H), 7.51 - 7.42 (m, 4H), 7.39 - 7.35 (m, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.06 - 7.00 (m, 1H), 4.12 (d, J = 10.7 Hz, 1H), 3.41 - 3.34 (m, 1H), 2.76 - 2.69 (m, 1H), 2.65 (dd, J = 4.2, 15.6 Hz, 1H), 2.46 - 2.38 (m, 1H), 1.96 - 1.87 (m, 1H), 1.85 - 1.75 (m, 1H), 1.64 - 1.31 (m, 4H), 1.27 - 1.09 (m, 2H), 0.98 - 0.89 (m, 1H), 0.80 (d, J = 7.0 Hz, 3H). Example 2

[0119] [Chemical formula]

[0120] Step 1: Synthesis of Compounds WX002 and WX003 Compound WX001 was separated by a chiral column (column type: Phenomenex-Cellulose-2 (250 mm × 30 mm, 10 μm); mobile phase: A (CO2) and B (ethanol containing 0.1% aqueous ammonia); gradient: B% = 30% - 30%, 5 min) to obtain Compound WX002 and Compound WX003, respectively.

[0121] SFC analysis method: column type: Lux Cellulose-2, 50 × 4.6 mm I.D., 3 μm; mobile phase: A: CO2, B: [EtOH (containing 0.1% IPAm)], gradient: B%: 5% - 50%, 3 min.

[0122] WX002 (retention time: 1.154 min): MS-ESI m / z: 516.2 [M + H] + .ee value: 98.32%. 11H NMR (400 MHz, DMSO-d6) δ: 9.82 (s, 1H), 7.46 (s, 4H), 7.40 - 7.28 (m, 2H), 7.03 (d, J = 8.3 Hz, 1H), 4.12 (d, J = 10.1 Hz, 1H), 3.45 - 3.41 (m, 1H), 2.72 - 2.60 (m, 2H), 2.45 - 2.30 (m, 1H), 1.99 - 1.74 (m, 2H), 1.65 - 1.32 (m, 4H), 1.29 - 1.08 (m, 2H), 0.93 (s, 1H), 0.80 (d, J = 6.4 Hz, 3H).

[0123] WX003 (Retention time: 1.416 min): MS-ESI m / z: 516.2 [M+H] + . ee value: 95.24%. 1 1H NMR (400 MHz, DMSO-d6) δ: 9.82 (s, 1H), 7.46 (s, 4H), 7.40 - 7.28 (m, 2H), 7.03 (d, J = 8.3 Hz, 1H), 4.12 (d, J = 10.1 Hz, 1H), 3.58 - 3.47 (m, 1H), 2.72 - 2.60 (m, 2H), 2.45 - 2.30 (m, 1H), 1.99 - 1.74 (m, 2H), 1.65 - 1.32 (m, 4H), 1.29 - 1.08 (m, 2H), 0.93 (s, 1H), 0.80 (d, J = 6.4 Hz, 3H).

[0124] Example 4

[0125] [Chemical formula]

[0126] Synthesis route:

[0127] [Chemical formula]

[0128] Step 1: Synthesis of Compound WX004_2 Under a nitrogen gas protection atmosphere at room temperature, dissolve Compound WX004_1 (7.8 g, 27.52 mmol) in methanol (80 mL), add iron powder (7.68 g, 137.59 mmol), dropwise add an aqueous solution of ammonium chloride (11.78 g, 220.14 mmol) in water (40 mL), stir the reaction system at 70 °C for 12 hours. After the reaction is completed, filter, wash the cake with methanol (50 mL × 2), collect the filtrate, and concentrate it under reduced pressure to remove the solvent. Add water (50 mL) for dilution, extract with ethyl acetate (100 mL × 2), and combine the organic phases. Wash the organic phase successively with saturated brine (50 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 5 / 1, volume ratio) to obtain Compound WX004_2.

[0129] Step 2: Synthesis of Compound WX004_3 Under a nitrogen gas protection atmosphere at 0 °C, add sodium hydride (1.10 g, 27.42 mmol, purity: 60%) to N,N-dimethylformamide (50 mL) in one batch, slowly dropwise add a solution of Compound WX004_2 (2.78 g, 10.97 mmol) in N,N-dimethylformamide (30 mL) to the reaction system, stir the reaction system at 0 °C for 0.5 hour, then dropwise add p-methoxybenzyl chloride (4.09 g, 26.10 mmol, 3.55 mL). After the dropping is completed, warm the reaction system to 25 °C and stir for 12 hours. After the reaction is completed, slowly pour the reaction system into water (50 mL) for quenching, add ethyl acetate (100 mL) for dilution, separate the liquid, collect the organic phase, extract the aqueous phase with ethyl acetate (50 mL × 3), and combine the organic phases. Wash the organic phase with saturated brine (50 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to remove the solvent. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 5 / 1, volume ratio) to obtain Compound WX004_3. 11H NMR (400 MHz, CDCl3) δ: 7.36 - 7.23 (m, 6H), 7.18 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.5 Hz, 4H), 4.18 (s, 4H), 3.89 (s, 6H). Step 3: Synthesis of Compound WX004_5 Under room temperature and nitrogen gas protection atmosphere, WX004_4 (500 mg, 3.84 mmol) and methoxymethylamine hydrochloride (412.32 mg, 4.23 mmol) were dissolved in ethyl acetate (10 mL), N-methylmorpholine (1.17 g, 11.53 mmol, 1.27 mL) was added, then 1-propanephosphonic anhydride (3.67 g, 5.76 mmol, 3.43 mL, 50% ethyl acetate solution) was added dropwise, and the mixture was stirred at 20 °C for 12 hours. After the reaction was completed, the reaction solution was poured into water (20 mL) to quench the reaction system, the liquid was separated, the organic phase was collected, ethyl acetate (10 mL × 2) was added to the aqueous phase for extraction, and the organic phases were combined. The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 19 / 1 - 3 / 1, volume ratio) to obtain Compound WX004_5. 1 1H NMR (400 MHz, CDCl3) δ: 3.67 (s, 3H), 3.20 (s, 3H), 2.41 (d, J = 2.5 Hz, 6H). Step 4: Synthesis of Compound WX004_6 Under room temperature and a nitrogen gas protection atmosphere, compound WX004_3 (1.57 g, 3.18 mmol) was dissolved in tetrahydrofuran (17 mL), cooled to -70 °C, and 2 M isopropylmagnesium chloride·tetrahydrofuran solution (1.59 mL, 3.18 mmol) was added. After the dropping was completed, the temperature was raised to -40 °C and stirred for 0.5 h. Then, a solution of compound WX004_5 (220 mg, 1.27 mmol) in tetrahydrofuran (5 mL) was added dropwise. After the dropping was completed, the temperature was raised to 20 °C and stirred for 12 h. After the reaction was completed, the reaction solution was slowly poured into a saturated ammonium chloride solution (50 mL) to quench the reaction system. The liquid was separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the obtained crude product was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 24 / 1) to obtain the target compound WX004_6. 1 H NMR (400 MHz, CDCl3) δ: 7.52 - 7.45 (m, 2H), 7.41 (s, 1H), 7.20 (d, J = 8.4 Hz, 4H), 6.82 (d, J = 8.6 Hz, 4H), 4.17 (s, 4H), 3.78 (s, 6H), 2.44 (d, J = 2.2 Hz, 6H). Step 5: Synthesis of compound WX004_7 Under room temperature and a nitrogen gas protection atmosphere, tert-butyl diethylphosphonoacetate (235.39 mg, 933.18 μmol) was dissolved in tetrahydrofuran (5 mL), and a 1 M potassium tert-butoxide·tetrahydrofuran solution (1.03 mL, 1.03 mmol) was added dropwise at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 0.5 h. Next, a solution of WX004_6 (447.9 mg, 933.18 μmol) in tetrahydrofuran (3 mL) was added dropwise. After the addition was complete, the mixture was stirred at 20 °C for 12 h. After the reaction was completed, the reaction solution was poured into ice water (10 mL) for quenching, ethyl acetate (15 mL × 3) was added for extraction, the organic phases were combined, saturated brine (10 mL) was added to the organic phase for washing, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the obtained crude product was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 99 / 1 - 97 / 3) to obtain the target compound WX004_7. 1 H NMR (400 MHz, CDCl3) δ: 7.37 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.6 Hz, 4H), 6.85 - 6.80 (m, 4H), 6.62 (dd, J = 2.0, 8.0 Hz, 1H), 6.51 (d, J = 1.6 Hz, 1H), 5.74 (s, 1H), 4.13 (s, 4H), 3.78 (s, 6H), 1.87 (d, J = 2.4 Hz, 6H), 1.22 (s, 9H) Step 6: Synthesis of compound WX004_8 Under an argon gas protection atmosphere, platinum carbon (100 mg, purity: 5%) was added to a dried reaction flask, tetrahydrofuran (2 mL) was added to moisten it, a solution of compound WX004_7 (300 mg, 518.93 μmol) in tetrahydrofuran (2 mL) was added, replaced with hydrogen gas three times, and reacted at 20 °C and hydrogen gas (15 psi) for 12 h. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, the cake was washed with tetrahydrofuran (10 mL × 3), the filtrates were combined, concentrated under reduced pressure to remove the solvent, and the obtained crude product was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 99 / 1 - 24 / 1, volume ratio) to obtain the target compound WX004_8.

[0130] Step 7: Synthesis of Compound WX004_9 Under protection of room temperature and nitrogen gas, dissolve Compound WX004_8 (78 mg, 134.45 μmol) in a mixed solvent of dichloromethane (3.5 mL) and water (0.6 mL), cool it to 0 °C, add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (92.28 mg, 406.54 μmol) in one portion, and stir at 20 °C for 2 hours. After completion of the reaction, add saturated aqueous sodium bicarbonate solution (20 mL) to the reaction solution, stir for 0.5 hour, then separate the layers, collect the organic phase, extract the aqueous phase with dichloromethane (10 mL × 2), and combine the organic phases. Dry the organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to remove the solvent, and separate and purify the obtained crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 19 / 1, volume ratio) to obtain the target compound WX004_9.

[0131] Step 8: Synthesis of Compound WX004_10 Under room temperature and a nitrogen gas protection atmosphere, compound WX001_5 (55.71 mg, 208.93 μmol) was dissolved in dichloromethane (1 mL), cooled to 0 °C, oxalyl chloride (45.72 μL, 522.32 μmol) was added dropwise, 1 drop of N,N-dimethylformamide was added, and the mixture was stirred at 20 °C for 1 hour. It was concentrated under reduced pressure to remove the solvent. After adding dichloromethane (1 mL) to dissolve it, it was concentrated under reduced pressure again to obtain a crude product. The crude product was dissolved in dichloromethane (1 mL), and at 0 °C, it was added dropwise to a dichloromethane (1 mL) solution of compound WX004_9 (71 mg, 208.93 μmol) and N,N-diisopropylethylamine (67.51 mg, 522.32 μmol), and stirred at 20 °C for 12 hours. After the reaction was completed, the reaction solution was poured into water (10 mL) for quenching, dichloromethane (5 mL × 3) was added for extraction, and the organic phases were combined. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained crude product was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 46 / 1 - 17 / 3, volume ratio) to obtain the target compound WX004_10. 1 H NMR (400 MHz, CDCl3) δ: 8.11 (d, J = 1.6 Hz, 1H), 7.59 (d, J = 5.6 Hz, 1H), 7.41 - 7.31 (m, 4H), 7.25 (dd, J = 2.0, 8.4 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 3.69 - 3.65 (m, 1H), 3.47 - 3.43 (m, 1H), 3.41 - 3.33 (m, 1H), 2.67 - 2.49 (m, 2H), 1.90 - 1.82 (m, 6H), 1.33 (d, J = 2.4 Hz, 9H), 0.96 (d, J = 7.2 Hz, 3H). Step 9: Synthesis of compound WX004 Under room temperature and nitrogen gas protection atmosphere, compound WX004_10 (100 mg, 169.94 μmol) was dissolved in ethyl acetate (0.5 mL), hydrochloric acid·ethyl acetate (4 M, 2 mL) was added, and the reaction system was stirred at 25 °C for 1 hour. After the reaction was completed, the solvent was directly removed by concentration under reduced pressure. The obtained residue was separated and purified by preparative HPLC (mobile phase: acetonitrile / water, acidic system: 0.04% HCl) to obtain the target compound WX004. MS-ESI m / z: 531.9 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 12.16 (s, 1H), 9.84 (d, J = 3.1 Hz, 1H), 7.52 - 7.43 (m, 4H), 7.39 - 7.32 (m, 2H), 7.04 - 6.92 (m, 1H), 4.13 (d, J = 10.8 Hz, 1H), 3.41 - 3.34 (m, 2H), 2.65 - 2.57 (m, 1H), 2.55 - 2.54 (m, 1H), 1.83 - 1.73 (m, 6H), 0.80 (d, J = 6.8 Hz, 3H). Example 5

[0132]

Chemical Structure

[0133] Step 1: Synthesis of Compounds WX005 and WX006 Compound WX004 was first separated by a chiral column (column type: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: A (CO2) and B (isopropanol containing 0.1% diisopropylamine); gradient: B% = 33% - 33%, 5 min), and then separated and purified by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl) to obtain compound WX005 and compound WX006 respectively.

[0134] SFC analysis method: Column type: Chiralpak IC-3 (100×4.6 mm I.D., 3 μm); Mobile phase: A: CO2, B: [IPA (containing 0.1% IPAm)], Gradient: B%: 5% - 40%, 3 min.

[0135] WX005 (Retention time: 1.874 min): MS-ESI m / z: 532.1 [M+H] + . ee value: 100%. 1 H NMR (400 MHz, DMSO_d6) δ: 12.16 (s, 1H), 9.85 (s, 1H), 7.50 - 7.42 (m, 4H), 7.36 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 6.97 (dd, J = 2.0, 8.4 Hz, 1H), 4.13 (d, J = 10.8 Hz, 1H), 3.43 - 3.39 (m, 2H), 2.64 - 2.58 (m, 1H), 2.54 - 2.52 (m, 1H), 1.86 - 1.70 (m, 6H), 0.80 (d, J = 6.8 Hz, 3H).

[0136] WX006 (Retention time: 2.003 min): MS-ESI m / z: 532.1 [M+H] + . ee value: 92.44%. 1 H NMR (400 MHz, DMSO_d6) δ: 12.14 (s, 1H), 9.84 (s, 1H), 7.53 - 7.41 (m, 4H), 7.40 - 7.30 (m, 2H), 6.97 (d, J = 8.0 Hz, 1H), 4.13 (d, J = 10.8 Hz, 1H), 3.39 - 3.36 (m, 2H), 2.63 - 2.58 (m, 1H), 2.54 - 2.53 (m, 1H), 1.86 - 1.71 (m, 6H), 0.80 (d, J = 6.8 Hz, 3H).

[0137] Example 7

[0138]

Chemical formula

[0139] Synthesis route:

[0140]

Chem.

[0141] Step 1: Synthesis of compound WX007_1 Under a nitrogen gas protection atmosphere at room temperature, 4-fluorophenylmagnesium bromide (13.86 mL, 4.62 mmol, 1 M tetrahydrofuran solution) was placed in a dried reaction flask, cooled to -30 °C under nitrogen gas protection, and a solution of compound WX004_5 (0.8 g, 4.62 mmol) in tetrahydrofuran (10 mL) was added dropwise. After the addition was complete, the temperature was raised to 20 °C and stirred for 12 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous ammonium chloride solution (20 mL) to quench the reaction system, extracted with ethyl acetate (10 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 97 / 3, volume ratio) to obtain the target compound WX007_1.

[0142] Step 2: Synthesis of compound WX007_2 Under a nitrogen gas protection atmosphere at room temperature, fuming nitric acid (6.02 g, 95.54 mmol, 4.30 mL, purity: 95%) was placed in a dried reaction flask and cooled to -10 °C. Compound WX007_1 (390 mg, 1.87 mmol) was slowly added in one portion and stirred at 0 °C for 1 hour. After the reaction was completed, the reaction solution was slowly poured into ice water (10 mL) to quench the reaction system, extracted with ethyl acetate (15 mL × 2), the organic phases were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 97 / 3, volume ratio) to obtain the target compound WX007_2.

[0143] Step 3: Synthesis of Compound WX007_3 Under a nitrogen gas protection atmosphere at room temperature, tert-butyl diethylphosphonoacetate (318.79 mg, 1.26 mmol) was dissolved in tetrahydrofuran (3 mL), cooled to 0 °C under nitrogen gas protection, and 1 M potassium tert-butoxide·tetrahydrofuran solution (1.39 mL, 1.39 mmol) was added dropwise. After the addition was complete, the mixture was stirred for 0.5 h. Then, a solution of Compound WX007_2 (320 mg, 1.26 mmol) in tetrahydrofuran (3 mL) was added dropwise, and the mixture was stirred at 20 °C for 12 h. After the reaction was completed, the reaction solution was poured into water (20 mL), extracted with ethyl acetate (10 mL×3), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 97 / 3, volume ratio) to obtain the target compound WX007_3. 1 H NMR (400 MHz, CDCl3) δ: 7.76 (dd, J = 2.0, 7.0 Hz, 1H), 7.34 - 7.30 (m, 1H), 7.27 - 7.22 (m, 1H), 5.91 (s, 1H), 2.14 (d, J = 2.4 Hz, 6H), 1.27 (s, 9H). Step 4: Synthesis of Compound WX007_4 Under an argon gas protection atmosphere, platinum carbon (150.00 mg, purity: 5%) was placed in a reaction flask, and tetrahydrofuran (3 mL) was added to moisten it. A solution of Compound WX007_3 (300 mg, 853.86 μmol) in tetrahydrofuran (2 mL) was added. The mixture was replaced with hydrogen gas three times and reacted at 20 °C and a hydrogen gas atmosphere of 15 psi for 12 h. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, the cake was washed with tetrahydrofuran (5 mL), the filtrates were combined, concentrated under reduced pressure to remove the solvent, and the target compound WX007_4 was obtained. The crude product was directly charged into the next step.

[0144] Step 5: Synthesis of Compound WX007_5 Under room temperature and a nitrogen gas protection atmosphere, compound WX001_5 (340 mg, 1.28 mmol) was dissolved in dichloromethane (4 mL), cooled to 0 °C, oxalyl chloride (404.62 mg, 3.19 mmol, 279.05 μL) was added dropwise, then 1 drop of N,N-dimethylformamide was added, and the mixture was stirred at 20 °C for 1 hour. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to remove the solvent. The residue was dissolved in dichloromethane (1 mL), and the prepared acyl chloride was added dropwise at 0 °C to a dichloromethane (2 mL) solution of compound WX007_4 (210 mg, 649.40 μmol) and N,N-diisopropylethylamine (209.82 mg, 1.62 mmol, 282.78 μL), and the mixture was stirred at 20 °C for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 49 / 1 - 17 / 3, volume ratio) to obtain the target compound WX007_5.

[0145] Step 6: Synthesis of compound WX007 Under room temperature and a nitrogen gas protection atmosphere, compound WX007_5 (70 mg, 122.38 μmol) was dissolved in hydrochloric acid - ethyl acetate solution (4 M, 2 mL), and the reaction system was stirred at 20 °C for 2 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to remove the solvent. The residue was separated and purified by preparative HPLC (mobile phase: acetonitrile / water, acidic system: 0.04% HCl) to obtain the target compound WX007. MS-ESI m / z: 515.9 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 12.12 (s, 1H), 10.06 (s, 1H), 7.58 - 7.61 (m, 1H), 7.49 - 7.42 (m, 4H), 7.18 - 7.10 (m, 1H), 6.96 - 6.88 (m, 1H), 4.11 (dd, J = 2.6, 10.6 Hz, 1H), 3.37 (s, 2H), 2.63 - 2.57 (m, 1H), 2.52 - 2.51 (m, 1H), 1.82 - 1.72 (m, 6H), 0.79 (d, J = 7.0 Hz, 3H). Example 8

[0146]

Chem.

[0147] Step 1: Synthesis of Compounds WX008 and WX009 Compound WX007 was first separated by a chiral column (column type: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: A (CO2) and B (isopropanol containing 0.1% aqueous ammonia); gradient: B% = 20% - 20%, 4 min), and then separated and purified by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl) to obtain Compound WX008 and Compound WX009, respectively.

[0148] SFC analysis method: column type: Chiralpak IC - 3, 50 × 4.6 mm I.D., 3 μm; mobile phase: A: CO2, B: [IPA (containing 0.1% IPAm)], gradient: B%: 5% - 50%, 3 min.

[0149] WX008 (retention time: 0.966 min): MS - ESI m / z: 515.9 [M + H] + . ee value: 100%. 1 H NMR (400 MHz, DMSO_d6) δ: 12.13 (s, 1H), 10.07 (s, 1H), 7.60 (dd, J = 2.2, 7.4 Hz, 1H), 7.50 - 7.43 (m, 4H), 7.15 (dd, J = 8.4, 10.8 Hz, 1H), 6.95 - 6.89 (m, 1H), 4.12 (d, J = 10.8 Hz, 1H), 3.42 - 3.36 (m, 2H), 2.64 - 2.57 (m, 1H), 2.55 - 2.52 (m, 1H), 1.85 - 1.72 (m, 6H), 0.80 (d, J = 7.0 Hz, 3H). WX009 (retention time: 1.021 min): MS - ESI m / z: 516.2 [M + H] + . ee value: 90.3%. 11H NMR (400 MHz, DMSO-d6) δ: 12.13 (s, 1H), 10.07 (s, 1H), 7.61 (dd, J = 2.2, 7.4 Hz, 1H), 7.49 - 7.44 (m, 4H), 7.15 (dd, J = 8.4, 10.8 Hz, 1H), 6.94 - 6.91 (m, 1H), 4.12 (d, J = 10.8 Hz, 1H), 3.42 - 3.38 (m, 2H), 2.65 - 2.57 (m, 1H), 2.64 - 2.57 (m, 1H), 1.92 - 1.60 (m, 6H), 0.79 (d, J = 7.0 Hz, 3H). Example 10

[0150]

Chemical formula

[0151] Synthesis route:

[0152]

Chemical formula

[0153] Step 1: Synthesis of Compound WX010_1 Under room temperature and nitrogen gas protection atmosphere, 4-methylphenylmagnesium chloride (2.89 mL, 5.77 mmol, 2 M tetrahydrofuran solution) was placed in a dried reaction flask, cooled to -30 °C under nitrogen gas protection, and a solution of Compound WX004_5 (0.4 g, 2.31 mmol) in tetrahydrofuran (5 mL) was added dropwise. After the addition was complete, the temperature was raised to 20 °C and stirred for 12 hours to react. After the reaction was completed, the reaction solution was poured into a saturated aqueous ammonium chloride solution (20 mL) to quench the reaction system, extracted with ethyl acetate (10 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 97 / 3, volume ratio) to obtain the target compound WX010_1.

[0154] Step 2: Synthesis of Compound WX010_2 Under a nitrogen gas protection atmosphere at room temperature, fuming nitric acid (1.12 g, 17.77 mmol, 0.80 mL, purity: 95%) was placed in a dried reaction flask, cooled to -10 °C, and compound WX010_1 (120 mg, 587.55 μmol) was slowly added in portions. The mixture was stirred at 0 °C for 1 hour. After the reaction was completed, the reaction solution was slowly poured into ice water (10 mL) to quench the reaction system, extracted with ethyl acetate (5 mL × 2), the organic phases were combined, washed with a saturated aqueous sodium bicarbonate solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 97 / 3, volume ratio) to obtain the target compound WX010_2. 1 H NMR (400 MHz, CDCl3) δ: 8.53 (d, J = 1.8 Hz, 1H), 8.06 (dd, J = 1.8, 8.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 2.69 (s, 3H), 2.63 (d, J = 2.4 Hz, 6H). Step 3: Synthesis of Compound WX010_3 Under a nitrogen gas protection atmosphere at room temperature, tert-butyl diethylphosphonoacetate (86.03 mg, 341.04 μmol) was dissolved in tetrahydrofuran (1 mL), cooled to 0 °C under nitrogen gas protection, and 1 M potassium tert-butoxide·tetrahydrofuran solution (375.14 μL, 375.14 μmol) was added dropwise. After the addition was complete, the mixture was stirred for 0.5 hour, then a solution of compound WX010_2 (85 mg, 341.04 μmol) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at 20 °C for 12 hours. After the reaction was completed, the reaction solution was poured into water (20 mL), ethyl acetate (10 mL × 3) was added for extraction, the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 97 / 3, volume ratio) to obtain the target compound WX010_3.

[0155] Step 4: Synthesis of Compound WX010_4 Under an argon gas protective atmosphere, platinum carbon (40.00 mg, purity: 5%) was placed into a reaction flask, and tetrahydrofuran (3 mL) was added to moisten it. A solution of compound WX010_3 (80 mg, 230.30 μmol) in tetrahydrofuran (1 mL) was added. It was replaced with hydrogen gas three times and stirred for 12 hours under a hydrogen gas atmosphere at 20 °C and 15 psi. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, the cake was washed with tetrahydrofuran (5 mL), the filtrates were combined, concentrated under reduced pressure to remove the solvent, and compound WX010_4 was obtained. The crude product was directly fed into the next step.

[0156] Step 5: Synthesis of Compound WX010_5 Under a nitrogen gas protective atmosphere at room temperature, compound WX001_5 (70.12 mg, 262.98 μmol) was dissolved in dichloromethane (4 mL) and cooled to 0 °C. Oxalyl chloride (69.54 mg, 547.88 μmol, 47.96 μL) was added dropwise, then 1 drop of N,N-dimethylformamide was added, and it was stirred at 20 °C for 1 hour. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to remove the solvent, the residue was dissolved in dichloromethane (1 mL), and the prepared dichloromethane solution of acyl chloride was added dropwise to a dichloromethane (2 mL) solution of compound WX010_4 (70 mg, 219.15 μmol) and N,N-diisopropylethylamine (70.81 mg, 547.88 μmol, 95.43 μL) at 0 °C, and it was stirred at 20 °C for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 49 / 1 - 17 / 3, volume ratio) to obtain the target compound WX010_5. 11H NMR (400 MHz, CDCl3) δ: 7.45 (s, 1H), 7.42 - 7.28 (m, 4H), 7.05 (d, J = 7.2 Hz, 1H), 6.90 (s, 1H), 6.82 (d, J = 7.6 Hz, 1H), 3.65 (dd, J = 4.8, 8.4 Hz, 1H), 3.42 (t, J = 7.8 Hz, 2H), 2.63 - 2.49 (m, 2H), 2.03 (d, J = 8.2 Hz, 3H), 1.84 (s, 6H), 1.33 (s, 9H), 0.95 (d, J = 7.2 Hz, 3H). Step 6: Synthesis of Compound WX010 Under room temperature and nitrogen gas protection atmosphere, Compound WX010_5 (118 mg, 207.73 μmol) was dissolved in hydrochloric acid - ethyl acetate solution (4 M, 2.95 mL), and the reaction system was stirred at 20 °C for 2 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to remove the solvent. The residue was separated and purified by preparative HPLC (mobile phase: acetonitrile / water, acidic system: 0.04% HCl) to obtain the target compound WX010. MS - ESI m / z: 512.0 [M + H] + . 1 1H NMR (400 MHz, DMSO_d6) δ: 12.10 (s, 1H), 9.60 (d, J = 4.0 Hz, 1H), 7.46 (d, J = 1.3 Hz, 4H), 7.11 - 7.04 (m, 1H), 7.04 - 6.96 (m, 1H), 6.89 - 6.82 (m, 1H), 3.97 (d, J = 10.8 Hz, 1H), 3.45 - 3.35 (m, 2H), 2.62 - 2.55 (m, 1H), 2.52 (d, J = 1.9 Hz, 1H), 1.96 (d, J = 15.4 Hz, 3H), 1.82 - 1.72 (m, 6H), 0.81 (d, J = 7.0 Hz, 3H). Example 11

[0157]

Chemical Structure

[0158] Step 1: Synthesis of Compounds WX011 and WX012 Compound WX010 was first separated by a chiral column (column type: DAICEL CHIRALCEL OX (250 mm × 30 mm, 10 μm); mobile phase: A (CO2) and B (isopropanol containing 0.1% aqueous ammonia); gradient: B% = 30% - 30%, 7 min), and then separated and purified by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl) to obtain Compound WX011 and Compound WX012, respectively.

[0159] SFC analysis method: column type: Chiralcel OX - 3, 50 × 4.6 mm I.D., 3 μm; mobile phase: A: CO2, B: [IPA (containing 0.1% IPAm)], gradient: B%: 5% - 50%, 3 min.

[0160] WX011 (retention time: 1.119 min): MS - ESI m / z: 512.2 [M + H] + . ee value: 100%. 1 H NMR (400 MHz, DMSO_d6) δ: 12.10 (s, 1H), 9.61 (s, 1H), 7.46 (s, 4H), 7.08 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 1.6 Hz, 1H), 6.86 (dd, J = 1.6, 7.8 Hz, 1H), 3.97 (d, J = 10.6 Hz, 1H), 3.44 - 3.34 (m, 2H), 2.62 - 2.56 (m, 1H), 2.52 (d, J = 1.9 Hz, 1H), 1.95 (s, 3H), 1.83 - 1.73 (m, 6H), 0.81 (d, J = 7.0 Hz, 3H). WX012 (retention time: 1.208 min): MS - ESI m / z: 512.2 [M + H] + . ee value: 100%. 11H NMR (400 MHz, DMSO-d6) δ: 12.09 (s, 1H), 9.60 (s, 1H), 7.46 (s, 4H), 7.08 (d, J = 8.0 Hz, 1H), 6.99 (s, 1H), 6.86 (d, J = 7.8 Hz, 1H), 3.97 (d, J = 10.8 Hz, 1H), 3.46 - 3.33 (m, 2H), 2.62 - 2.54 (m, 1H), 2.52 (s, 1H), 1.98 (s, 3H), 1.82 - 1.72 (m, 6H), 0.81 (d, J = 7.0 Hz, 3H). Example 13

[0161]

Chemical formula

[0162] Synthesis route:

[0163]

Chemical formula

[0164] Step 1: Synthesis of compound WX013_2 Under room temperature and nitrogen gas protection atmosphere, WX013_1 (8.0 g, 47.01 mmol) and methoxymethylamine hydrochloride (5.04 g, 51.72 mmol) were dissolved in ethyl acetate (150 mL), N-methylmorpholine (14.27 g, 141.04 mmol, 15.51 mL) was added, and then 1-propanephosphonic anhydride (44.88 g, 70.52 mmol, 41.94 mL, 50% ethyl acetate solution) was added dropwise. The mixture was stirred at 20 °C for 12 hours. After the reaction was completed, the reaction solution was poured into water (100 mL) to quench the reaction system, the liquid was separated, the organic phase was collected, ethyl acetate (200 mL × 2) was added to the aqueous phase for extraction, and the organic phases were combined. The combined organic phase was washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1, volume ratio) to obtain compound WX013_2. 1 H NMR (400 MHz, DMSO_d6) δ: 3.65 (s, 3H), 3.61 (s, 3H), 3.08 (s, 3H), 2.26 (s, 6H).

[0165] Step 2: Synthesis of compound WX013_3 Under room temperature and nitrogen gas protection atmosphere, WX013_2 (2.7 g, 12.66 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL). The solution was cooled to 0 °C under nitrogen gas protection atmosphere, and a tetrahydrofuran solution of 3M phenylmagnesium bromide (6.33 mL, 18.99 mmol) was slowly added dropwise. After the addition was completed, the mixture was stirred at 0 °C for 0.5 hour, then warmed to 20 °C and stirred for 12 hours. After the reaction was completed, the reaction solution was slowly poured into saturated ammonium chloride solution (100 mL) to quench the reaction system, extracted with ethyl acetate (50 mL × 2), and the organic phases were combined. The combined organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 9 / 1, volume ratio) to obtain compound WX013_3. 11H NMR (400 MHz, CDCl3) δ: 8.00 - 7.96 (m, 2H), 7.61 - 7.55 (m, 1H), 7.51 - 7.43 (m, 2H), 3.73 (s, 3H), 2.56 (s, 6H). Step 3: Synthesis of Compound WX013_4 Under room temperature and in a nitrogen gas - protected atmosphere, WX013_3 (2.1 g, 9.12 mmol) was dissolved in anhydrous dichloromethane (25 mL). It was cooled to 0 °C under a nitrogen gas - protected atmosphere, and m - chloroperbenzoic acid (2.78 g, 13.68 mmol, purity: 85%) was slowly added in one batch. After addition, it was stirred at 20 °C for 2 hours, cooled to 0 °C, then m - chloroperbenzoic acid (2.78 g, 13.68 mmol, purity: 85%) was added, the temperature was raised to 20 °C and stirred for 12 hours. After the reaction was completed, the reaction solution was slowly poured into saturated sodium sulfite solution (50 mL) to quench the reaction system, extracted with dichloromethane (20 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 19 / 1 - 17 / 3, volume ratio) to obtain compound WX013_4.

[0166] Step 4: Synthesis of Compound WX013_5 Under room temperature and in a nitrogen gas - protected atmosphere, WX013_4 (1.0 g, 4.06 mmol) was dissolved in hydrochloric acid - methanol solution (4 M, 20.00 mL), the temperature was raised to 50 °C and stirred for 4 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to remove the solvent. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 19 / 1 - 7 / 3, volume ratio) to obtain compound WX013_5. 1 1H NMR (400 MHz, CDCl3) δ: 3.69 (s, 3H), 2.85 (s, 1H), 2.22 (s, 6H).

[0167] Step 5: Synthesis of Compound WX013_6 Under room temperature and in a nitrogen gas protection atmosphere, WX013_5 (374 mg, 2.63 mmol) was dissolved in anhydrous dichloromethane (20 mL), 1,8-bis(dimethylamino)naphthalene (2.31 g, 10.79 mmol) and trimethyloxonium tetrafluoroborate (1.21 g, 8.16 mmol) were added respectively, and after addition, the mixture was stirred at 20 °C for 2 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was washed successively with 2 M dilute hydrochloric acid (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 9 / 1, volume ratio) to obtain compound WX013_6. 1 H NMR (400 MHz, CDCl3) δ: 3.70 (s, 3H), 3.31 (s, 3H), 2.18 (s, 6H).

[0168] Step 6: Synthesis of compound WX013_7 Under room temperature and in a nitrogen gas protection atmosphere, WX013_6 (322 mg, 2.06 mmol) was dissolved in a mixed solution of tetrahydrofuran (6 mL), methanol (2 mL) and water (2 mL), lithium hydroxide hydrate (173.04 mg, 4.12 mmol) was added, and after addition, the mixture was stirred at 20 °C for 12 hours. After the reaction was completed, water (10 mL) was added to the reaction solution for dilution, the pH was adjusted to about 2 - 3 with 1 M dilute hydrochloric acid, ethyl acetate (10 mL) was added for dilution, the liquid was separated, the organic phase was collected, ethyl acetate (10 mL × 2) was added to the aqueous phase for extraction, and the organic phases were combined. The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain compound WX013_7, and the crude product was directly put into the next step.

[0169] Step 7: Synthesis of compound WX013_8 Under room temperature and nitrogen gas protection atmosphere, WX013_7 (265 mg, 1.86 mmol) and methoxymethylamine hydrochloride (218.21 mg, 2.24 mmol) were dissolved in ethyl acetate (3 mL), 1-propylphosphine (754.23 mg, 7.46 mmol, 819.82 μL) was added dropwise, and then tri-n-propylcyclic phosphate anhydride (1.78 g, 2.80 mmol, 1.66 mL, 50% ethyl acetate solution) was added dropwise. The mixture was stirred at 20 °C for 12 hours. After the reaction was completed, the reaction solution was poured into water (10 mL) to quench the reaction system. The liquid was separated, the organic phase was collected, ethyl acetate (10 mL × 2) was added to the aqueous phase for extraction, and the organic phases were combined. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 19 / 1 - 17 / 3, volume ratio) to obtain compound WX013_8. 1 H NMR (400 MHz, CDCl3) δ: 3.67 (s, 3H), 3.32 (s, 3H), 3.20 (s, 3H), 2.23 (s, 6H). Step 8: Synthesis of compound WX013_9 Under room temperature and nitrogen gas protection atmosphere, 4-fluorophenylmagnesium bromide (4.54 mL, 4.54 mmol, 1 M tetrahydrofuran solution) was placed in a dried reaction flask, cooled to -30 °C under nitrogen gas protection, and a solution of compound WX013_8 (280 mg, 1.51 mmol) in tetrahydrofuran (5 mL) was added dropwise. After the addition was completed, the temperature was raised to 20 °C and the mixture was stirred for 2 hours to react. After the reaction was completed, the reaction solution was poured into saturated ammonium chloride aqueous solution (10 mL) to quench the reaction system, extracted with ethyl acetate (10 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 19 / 1, volume ratio) to obtain the target compound WX013_9.

[0170] Step 9: Synthesis of compound WX013_10 Under room temperature and a nitrogen gas protection atmosphere, fuming nitric acid (3 g, 47.61 mmol, 2.14 mL, purity: 95%) was placed in a dried reaction flask and cooled to -10 °C. Compound WX013_9 (160 mg, 675.98 μmol) was slowly added in batches and stirred at 0 °C for 2 hours. After the reaction was completed, the reaction solution was slowly poured into ice water (10 mL) to quench the reaction system, extracted with ethyl acetate (5 mL × 2), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 9 / 1, volume ratio) to obtain the target compound WX013_10. 1 H NMR (400 MHz, CDCl3) δ: 8.45 (d, J = 2.0 Hz, 1H), 8.09 (dd, J = 2.0, 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 3.37 (s, 3H), 2.44 (s, 6H). Step 10: Synthesis of Compound WX013_11 Under room temperature and a nitrogen gas protection atmosphere, tert-butyl diethylphosphonoacetate (148.65 mg, 589.30 μmol) was dissolved in tetrahydrofuran (2 mL), cooled to 0 °C under nitrogen gas protection, and 1 M potassium tert-butoxide·tetrahydrofuran solution (648.23 μL, 648.23 μmol) was added dropwise. After the addition was completed, it was stirred for 0.5 hour, and then a tetrahydrofuran (1 mL) solution of compound WX013_10 (166 mg, 589.30 μmol) was added dropwise and stirred at 20 °C for 2 hours. After the reaction was completed, the reaction solution was poured into water (10 mL), ethyl acetate (10 mL × 3) was added for extraction, saturated brine (30 mL) was added to the organic phase for washing, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 20 / 1, volume ratio) to obtain the target compound WX013_11. 11H NMR (400 MHz, CDCl3) δ: 7.61 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.25 - 7.21 (m, 1H), 5.91 (s, 1H), 3.29 (s, 3H), 1.97 (s, 6H), 1.28 (s, 9H) Step 11: Synthesis of Compound WX013_12 Under an argon gas protective atmosphere, platinum carbon (80.00 mg, purity: 5%) was placed in a reaction flask, and tetrahydrofuran (1.5 mL) was added to moisten it. A solution of Compound WX013_11 (160 mg, 421.24 μmol) in tetrahydrofuran (1.5 mL) was added. The mixture was replaced with hydrogen gas three times and stirred for 16 hours under a hydrogen gas atmosphere at 20 °C and 15 psi. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, the cake was washed with tetrahydrofuran (5 mL), the filtrates were combined, concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 9 / 1, volume ratio) to obtain the target compound WX013_12.

[0171] Step 12: Synthesis of Compound WX013_13 At room temperature and under a nitrogen gas protective atmosphere, Compound WX001_5 (97.76 mg, 366.62 μmol) was dissolved in dichloromethane (1 mL) and cooled to 0 °C. Oxalyl chloride (77.56 mg, 611.03 μmol, 53.49 μL) was added dropwise, then 1 drop of N,N-dimethylformamide was added, and the mixture was stirred at 20 °C for 1 hour. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to remove the solvent. The residue was dissolved in dichloromethane (1 mL), and the prepared acyl chloride was added dropwise to a solution of Compound WX013_12 (86 mg, 244.41 μmol) and N,N-diisopropylethylamine (78.97 mg, 611.03 μmol, 106.43 μL) in dichloromethane (1 mL) at 0 °C, and the mixture was stirred at 20 °C for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 19 / 1 - 9 / 1, volume ratio) to obtain the target compound WX013_13. 11H NMR (400 MHz, CDCl3) δ: 8.11 (s, 1H), 7.58 (d, J = 5.6 Hz, 1H), 7.42 - 7.30 (m, 4H), 7.24 (dd, J = 1.4, 8.2 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 3.71 - 3.65 (m, 1H), 3.39 (t, J = 7.5 Hz, 2H), 3.23 (s, 3H), 2.66 - 2.47 (m, 2H), 1.71 - 1.63 (m, 6H), 1.32 (d, J = 2.4 Hz, 9H), 0.96 (d, J = 7.2 Hz, 3H) Step 13: Synthesis of Compound WX013 Under room temperature and nitrogen gas protection atmosphere, compound WX013_13 (105 mg, 174.86 μmol) was dissolved in hydrochloric acid - ethyl acetate solution (4 M, 4 mL), and the reaction system was stirred at 20 °C for 2 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to remove the solvent. The residue was separated and purified by preparative HPLC (mobile phase: acetonitrile / water, acidic system: 0.04% HCl) to obtain the target compound WX013. MS - ESI m / z: 544.2 [M + H] + . 1 1H NMR (400 MHz, DMSO - d6) δ: 11.87 (s, 1H), 9.83 (d, J = 2.8 Hz, 1H), 7.51 - 7.41 (m, 4H), 7.38 - 7.30 (m, 2H), 6.96 (dd, J = 2.1, 8.3 Hz, 1H), 4.13 (d, J = 10.5 Hz, 1H), 3.30 - 3.24 (m, 2H), 3.10 (d, J = 1.3 Hz, 3H), 2.62 - 2.55 (m, 1H), 2.52 (d, J = 1.9 Hz, 1H), 1.60 - 1.49 (m, 6H), 0.80 (d, J = 7.0 Hz, 3H). Example 14

[0172]

Chemical Structure

[0173] Step 1: Synthesis of Compounds WX014 and WX015 Compound WX013 was first separated by a chiral column (column type: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: A (CO2) and B (isopropanol containing 0.1% aqueous ammonia); gradient: B% = 30% - 30%, 10 min), and then separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl) to obtain Compound WX014 and Compound WX015, respectively.

[0174] SFC analysis method: column type: (S,S)-WHELK-O1, 50 × 4.6 mm I.D., 3.0 μm; mobile phase: A: n-hexane, B: [ethanol (containing 0.1% TFA)], gradient: B%: 5% - 50%, 6 min.

[0175] WX014 (retention time: 3.051 min): MS-ESI m / z: 544.2 [M+H] + . ee value: 100%. 1 H NMR (400 MHz, DMSO_d6) δ: 12.11 (s, 1H), 9.83 (s, 1H), 7.50 - 7.42 (m, 4H), 7.37 - 7.31 (m, 2H), 6.96 (dd, J = 2.0, 8.3 Hz, 1H), 4.13 (d, J = 10.5 Hz, 1H), 3.30 - 3.23 (m, 2H), 3.10 (s, 3H), 2.62 - 2.55 (m, 1H), 2.47 - 2.44 (m, 1H), 1.64 - 1.43 (m, 6H), 0.81 (d, J = 7.2 Hz, 3H). WX015 (retention time: 3.194 min): MS-ESI m / z: 544.2 [M+H] + . ee value: 100%. 11H NMR (400 MHz, DMSO-d6) δ: 12.11 (s, 1H), 9.82 (s, 1H), 7.52 - 7.42 (m, 4H), 7.38 - 7.29 (m, 2H), 6.95 (dd, J = 2.1, 8.3 Hz, 1H), 4.13 (d, J = 10.7 Hz, 1H), 3.30 - 3.24 (m, 2H), 3.09 (s, 3H), 2.61 - 2.55 (m, 1H), 2.53 - 2.52 (m, 1H), 1.60 - 1.48 (m, 6H), 0.80 (d, J = 7.0 Hz, 3H). Example 16

[0176]

Chemical formula

[0177] Synthesis route:

[0178]

Chemical formula

[0179] Step 1: Synthesis of compound WX016_2 Under room temperature and nitrogen gas protection atmosphere, WX016_1 (1.0 g, 9.79 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 °C under nitrogen gas protection, Dess-Martin oxidant (4.98 g, 11.75 mmol) was added in one batch, the temperature was raised to 20 °C and stirred for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution (20 mL) was added to the reaction solution, stirred for 0.5 hour, layered, the organic phase was collected, the aqueous phase was extracted with dichloromethane (10 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound WX016_2.

[0180] Step 2: Synthesis of compound WX016_3 Under room temperature and nitrogen gas protection atmosphere, tert-butyl diethylphosphonoacetate (1.01 g, 4.00 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0 °C under nitrogen gas protection, and 1 M potassium tert-butoxide·tetrahydrofuran solution (4.39 mL, 4.39 mmol) was added dropwise. After the addition was completed, the mixture was stirred for 0.5 h, then compound WX016_2 (400 mg, 4.00 mmol) was added dropwise, and the mixture was stirred at 20 °C for 2 h. After the reaction was completed, the reaction solution was poured into water (20 mL), ethyl acetate (10 mL×3) was added for extraction, saturated brine (30 mL) was added to the organic phase for washing, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~9 / 1, volume ratio) to obtain the target compound WX016_3. 1 H NMR (400 MHz, CDCl3) δ: 6.76-6.85 (m, 1H), 5.89-5.97 (m, 1H), 4.45-4.54 (m, 1H), 3.90-3.98 (m, 1H), 3.80-3.88 (m, 1H), 2.05-2.16 (m, 1H), 1.88-1.97 (m, 2H), 1.66-1.74 (m, 1H), 1.49 (s, 9H). Step 3: Synthesis of Compounds WX016_4 and WX016_5 Compound WX016_3 was first separated and purified by a chiral column (column type: REGIS(S,S)WHELK-O1 (250 mm×25 mm, 10 μm); mobile phase: A (CO2) and B (isopropanol containing 0.1% ammonia water); gradient: B% = 30%~30%, 10 min) to obtain compound WX016_4 and compound WX016_5 respectively.

[0181] SFC analysis method: column type: WK, 100×4.6 mm I.D., 3 μm; mobile phase: A: CO2, B: [isopropanol (containing 0.1% IPAm)], gradient: B%: 10%~50%, 4 min.

[0182] WX016_4 (retention time: 0.635 min): ee value: 100%.1 1H NMR (400 MHz, CDCl3) δ: 6.81 (dd, J = 5.2, 15.6 Hz, 1H), 5.93 (dd, J = 1.4, 15.4 Hz, 1H), 4.52 - 4.46 (m, 1H), 3.98 - 3.90 (m, 1H), 3.88 - 3.80 (m, 1H), 2.17 - 2.07(m, 1H), 1.98 - 1.91 (m, 2H), 1.75 - 1.65 (m, 1H), 1.49 (s, 9H) WX016_5 (Retention time: 0.804 min): ee value: 100%. 1 1H NMR (400 MHz, CDCl3) δ: 6.81 (dd, J = 5.2, 15.6 Hz, 1H), 5.93 (dd, J = 1.4, 15.6 Hz, 1H), 4.52 - 4.46 (m, 1H), 3.97 - 3.90 (m, 1H), 3.87 - 3.80 (m, 1H), 2.18 - 2.08 (m, 1H), 1.99 - 1.90 (m, 2H), 1.74 - 1.66 (m, 1H), 1.49 (s, 9H). Step 4: Synthesis of compound WX016_6 Under room temperature and a nitrogen gas protection atmosphere, chloro(1,5-cyclooctadiene)rhodium(I) (dimer) (15.54 mg, 31.52 μmol) and 2,2-bis(diphenylphosphino)-1,1-binaphthyl (4.51 mg, 7.25 μmol) were dissolved in tetrahydrofuran (3 mL), and stirred at 20 °C for 15 minutes. Under room temperature and a nitrogen gas protection atmosphere, 3-amino-4-chlorophenylboronic acid pinacol ester (319.70 mg, 1.26 mmol) was dissolved in a mixed solvent of isopropanol (1.5 mL) and tetrahydrofuran (3 mL), compound WX016_4 (250.00 mg, 1.26 mmol), 1,5-cyclooctadiene (13.64 mg, 126.10 μmol) and potassium hydroxide (84.90 mg, 1.51 mmol) were added, the temperature was raised to 60 °C, the catalyst prepared above was added under nitrogen gas protection, and stirred at 60 °C for 12 hours. After completion of the reaction, the reaction solution was poured into water (10 mL) to quench the reaction system, ethyl acetate (10 mL × 3) was added for extraction, the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated and purified by column chromatography (eluent: 19 / 1 - 7 / 3, volume ratio) to obtain compound WX016_6.

[0183] Step 5: Synthesis of compound WX016_8 Under room temperature and nitrogen gas protection atmosphere, compound WX001_5 (204.59 mg, 767.27 μmol) was dissolved in anhydrous dichloromethane (4 mL), cooled to 0 °C, oxalyl chloride (243.47 mg, 1.92 mmol, 167.91 μL) was added dropwise, then 1 drop of N,N-dimethylformamide was added, and the mixture was stirred at 20 °C for 1 hour. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to remove the solvent. The residue was dissolved in anhydrous dichloromethane (5 mL), and the prepared acyl chloride was added dropwise to a dichloromethane (2 mL) solution of compound WX016_6 (250.00 mg, 767.27 μmol) and N,N-diisopropylethylamine (247.91 mg, 1.92 mmol, 334.10 μL) at 0 °C, and the mixture was stirred at 20 °C for 12 hours. After the reaction was completed, the reaction solution was poured into water (10 mL) to quench the reaction system, the liquid was separated, and the organic phase was collected. The aqueous phase was extracted with dichloromethane (10 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 19 / 1 - 7 / 3, volume ratio) to obtain the target compound WX016_8.

[0184] Step 6: Synthesis of compound WX016_10 Under room temperature and nitrogen gas protection atmosphere, compound WX016_10 (300.00 mg, 522.23 μmol) was dissolved in ethyl acetate (1 mL), hydrochloric acid - ethyl acetate solution (4 M, 5 mL) was added, and the mixture was stirred at 20 °C for 5 hours to react. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the crude product was separated and purified by preparative HPLC (mobile phase: acetonitrile / water, acidic system: 0.04% HCl) to obtain the target compound WX016_10.

[0185] Step 7: Synthesis of compounds WX016 and WX017 First, compound WX016_10 was separated and purified by a chiral column (column type: Phenomenex-Cellulose-2 (250 mm × 30 mm, 10 μm); mobile phase: A (CO2) and B (ethanol containing 0.1% aqueous ammonia); gradient: B% = 30% - 30%, 5 min) to obtain compound WX016 and compound WX017 respectively.

[0186] SFC analysis method: column type: Lux Cellulose-2, 50 × 4.6 mm I.D., 3 μm; mobile phase: A: CO2, B: [isopropanol (containing 0.1% IPAm)], gradient: B%: 5% - 50%, 5 min.

[0187] WX016 (retention time: 1.239 min): MS-ESI m / z: 517.9 [M+H] + . ee value: 99.66%. 1 H NMR (400 MHz, DMSO_d6) δ: 11.93 (s, 1H), 9.81 (s, 1H), 7.49 - 7.43 (m, 4H), 7.40 (d, J = 1.9 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.06 (dd, J = 1.9, 8.3 Hz, 1H), 4.11 (d, J = 10.6 Hz, 1H), 3.94 - 3.84 (m, 1H), 3.63 - 3.47 (m, 2H), 3.42 - 3.37 (m, 1H), 3.06 - 2.99 (m, 1H), 2.65 - 2.59 (m, 2H), 1.90 - 1.78 (m, 1H), 1.75 - 1.62 (m, 1H), 1.60 - 1.48 (m, 1H), 1.45 - 1.32 (m, 1H), 0.80 (d, J = 7.1 Hz, 3H). WX017 (retention time: 1.542 min): MS-ESI m / z: 517.9 [M+H] + . ee value: 99.70%. 11H NMR (400 MHz, DMSO-d6) δ: 11.93 (s, 1H), 9.83 (s, 1H), 7.49 - 7.43 (m, 4H), 7.41 (d, J = 1.8 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.08 (dd, J = 1.9, 8.4 Hz, 1H), 4.12 (d, J = 10.5 Hz, 1H), 3.86 - 3.77 (m, 1H), 3.75 - 3.67 (m, 1H), 3.66 - 3.57 (m, 1H), 3.44 - 3.38 (m, 1H), 3.00 - 2.91 (m, 1H), 2.83 - 2.76 (m, 1H), 2.45 - 2.40 (m, 1H), 1.78 - 1.66 (m, 2H), 1.60 - 1.50 (m, 1H), 1.41 - 1.29 (m, 1H), 0.80 (d, J = 7.1 Hz, 3H). Step 8: Synthesis of Compound WX016_7 Under room temperature and nitrogen gas protection atmosphere, chloro(1,5-cyclooctadiene)rhodium(I) (dimer) (15.54 mg, 31.52 μmol) and 2,2-bis(diphenylphosphino)-1,1-binaphthyl (4.51 mg, 7.25 μmol) were dissolved in tetrahydrofuran (3 mL) and stirred at 20 °C for 15 minutes. Under room temperature and nitrogen gas protection atmosphere, 3-amino-4-chlorophenylboronic acid pinacol ester (319.70 mg, 1.26 mmol) was dissolved in a mixed solvent of isopropanol (1.5 mL) and tetrahydrofuran (3 mL), compound WX016_5 (250.00 mg, 1.26 mmol), 1,5-cyclooctadiene (13.64 mg, 126.10 μmol), and potassium hydroxide (84.90 mg, 1.51 mmol) were added, the temperature was raised to 60 °C, and the catalyst prepared above was added under nitrogen gas protection, and the mixture was stirred at 60 °C for 12 hours. After the reaction was completed, the reaction solution was poured into water (10 mL) to quench the reaction system, ethyl acetate (10 mL × 3) was added for extraction, the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The crude product was separated and purified by column chromatography (eluent: 19 / 1 - 7 / 3, volume ratio) to obtain compound WX016_7.

[0188] Step 9: Synthesis of Compound WX016_9 Under room temperature and nitrogen gas protection atmosphere, Compound WX001_5 (109.66 mg, 411.26 μmol) was dissolved in anhydrous dichloromethane (2 mL) and cooled to 0 °C. Oxalyl chloride (156.60 mg, 1.23 mmol, 108.00 μL) was added dropwise, and then 1 drop of N,N-dimethylformamide was added. The reaction system was stirred at 0 °C for 1 hour. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to remove the solvent. The residue was dissolved in anhydrous dichloromethane (2 mL), and Compound WX016_7 (134.00 mg, 411.26 μmol) and N,N-diisopropylethylamine (132.88 mg, 1.03 mmol, 179.08 μL) were sequentially added at 0 °C, and the mixture was stirred at 25 °C for 12 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to remove the solvent. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 19 / 1 - 7 / 3, volume ratio) to obtain the target compound WX016_9.

[0189] Step 10: Synthesis of Compounds WX018 and WX019 Under room temperature and nitrogen gas protection atmosphere, Compound WX016_9 (174.00 mg, 302.89 μmol) was dissolved in ethyl acetate (1 mL), hydrochloric acid - ethyl acetate solution (4 M, 5 mL) was added, and the mixture was stirred at 25 °C for 1.5 hours to react. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to remove the solvent. The obtained residue was separated and purified by preparative HPLC (mobile phase: acetonitrile / water, acidic system: 0.04% HCl) to obtain the target compounds WX018 and WX019.

[0190] SFC analysis method: Column type: Chiralpak IC-3, 50×4.6 mm I.D., 3 μm; Mobile phase: A: CO2, B: [isopropanol (containing 0.1% IPAm)], Gradient: B%: 5% - 50%, 3 min.

[0191] WX018 (Retention time: 1.286 min): MS-ESI m / z: 517.9 [M+H] +. ee value: 100%. 1 H NMR (400 MHz, DMSO_d6) δ: 12.03 (s, 1H), 9.81 (s, 1H), 7.49 - 7.43 (m, 4H), 7.43 - 7.41 (m, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.06 (dd, J = 2.0, 8.4 Hz, 1H), 4.12 (d, J = 10.6 Hz, 1H), 3.94 - 3.86 (m, 1H), 3.62 - 3.47 (m, 2H), 3.41 - 3.34 (m, 1H), 3.07 - 2.98 (m, 1H), 2.63 - 2.60 (m, 1H), 2.57 - 2.53 (m, 1H), 1.90 - 1.78 (m, 1H), 1.75 - 1.62 (m, 1H), 1.60 - 1.49 (m, 1H), 1.45 - 1.34 (m, 1H), 0.80 (d, J = 7.1 Hz, 3H). WX019 (Retention time: 1.226 min): MS - ESI m / z: 517.9 [M + H] + . ee value: 92.60%. 1 H NMR (400 MHz, DMSO_d6) δ: 11.94 (s, 1H), 9.83 (s, 1H), 7.51 - 7.43 (m, 4H), 7.42 - 7.39 (m, 1H), 7.38 - 7.34 (m, 1H), 7.08 (dd, J = 2.0, 8.4 Hz, 1H), 4.12 (d, J = 10.6 Hz, 1H), 3.85 - 3.77 (m, 1H), 3.75 - 3.67 (m, 1H), 3.65 - 3.58 (m, 1H), 3.41 - 3.35 (m, 1H), 3.00 - 2.92 (m, 1H), 2.80 (dd, J = 4.6, 15.9 Hz, 1H), 2.46 - 2.40 (m, 1H), 1.79 - 1.66 (m, 2H), 1.56 (dd, J = 6.0, 13.5 Hz, 1H), 1.41 - 1.30 (m, 1H), 0.80 (d, J = 7.1 Hz, 3H). Biological test: Test Example 1. In vitro activity test 1. cGMP expression test based on lnCap cells 1. Experimental Procedures 1) Preparation of Solutions ● 10% BSA (Bovine Serum Albumin) 10 g of BSA was dissolved in 100 mL of double-distilled water (ddH2O) to obtain 10% BSA. ● 10 mM ODQ Stock Solution 1 mg of ODQ powder was weighed and dissolved in 534 μl of DMSO to obtain a 10 mM ODQ solution, which was aliquoted and stored frozen at -20 °C in a refrigerator. ● Washing Buffer (50 mL)

[0192]

Table 1

[0193]

Table 2

[0194] a) 50 μL of cGMP-D2 (D2-labeled cyclic guanosine monophosphate) was added to 1 mL of lysis buffer and mixed uniformly. b) 50 μL of anti-cGMP cryptate (Eu 3+ cryptate-labeled anti-cyclic guanosine monophosphate antibody) was added to 1 mL of lysis buffer and mixed uniformly.

[0195] 2) Dilution of Compounds (1) The compound was diluted to 10 mM with DMSO. (2) The compound was diluted stepwise, and each compound was diluted in a 10-fold concentration gradient and 100 nL of each was added to a 96-well plate.

[0196] 3) Preparation of LNCap Cells (1) LNCap medium: RPMI1640 + 10% fetal bovine serum + 1% double antibody.

[0197] (2) The phosphate buffer, trypsin, and medium used during cell passage were preheated in a 37°C water bath. (3) Cells were removed from the 37°C, 5% CO2 incubator, and the old medium in the culture flask was removed with a pipette.

[0198] (4) 5 mL of phosphate buffer was added to the culture flask with a pipette, the cells were rinsed, and then the liquid was discarded. (5) 3 mL of trypsin was added to the culture flask with a pipette, shaken, and the liquid was discarded. The culture flask was placed in the incubator.

[0199] (6) After about 2 minutes, the culture flask was taken out. After confirming that all the cells were separated, 9 mL of medium was added to the culture flask with a pipette, pipetting was repeated, and the cell suspension was transferred to a 50 mL centrifuge tube.

[0200] (7) 0.7 mL of the cell suspension was added to the counting chamber with a pipette and counted with ViCell XR. The remaining cells were centrifuged at 1000 rpm for 5 minutes, and the supernatant was removed. (8) 10 mL of washing buffer was added to wash the cells, centrifuged at 1000 rpm for 5 minutes, and the supernatant was removed.

[0201] (9) Assay buffer was added to adjust the cell concentration to 3×10 6 / mL. 4) Preparation and addition of OQD solution (1) 1:1000 of a 10 mM ODQ stock solution was taken and added to the cell solution.

[0202] (2) After thorough mixing, 10 μL / well was added to the microplate. 5) Preparation of cGMP standard curve (1) A 1 mM cGMP stock solution was diluted to 10 μM with assay buffer. Then, it was diluted 4-fold with 11 concentration gradients.

[0203] (2) The diluted cGMP was added to the microplate at 10 μL / well. 6) Addition of the detection reagent and reading of the plate (1) 5 μL / well of cGMP-D2 was transferred to a 384-well microplate. 5 μL / well of anti-cGMP cryptate was transferred to a 96-well microplate. Centrifugation was performed at 1500 rpm for 1 minute.

[0204] (2) Incubation was carried out at room temperature for 1 hour. (3) Read at 665 / 615 with Envision. 7) Data analysis (1) cGMP standard curve: A standard curve was created using GraphPad Prism based on the cGMP concentration and the ratio of 665 / 615.

[0205] (2) Conversion of the HTRF (Homogeneous Time-Resolved Fluorescence) ratio (665 / 615) to the cGMP concentration: In GraphPad Prism, the HTRF ratio (665 / 615) was copied to the ratio column of the cGMP standard curve, and the "Log inhibitor vs response - variable slope" analysis was performed, and "Interpolate" was selected to convert the HTRF ratio (665 / 615) to the cGMP concentration.

[0206] (3) Compound activation curve: A curve was created using the "Log agonist vs response - variable slope" analysis method of GraphPad Prism based on the converted cGMP concentration and the compound concentration.

[0207]

Table 3

[0208] Experimental conclusion: The compound of the present invention can effectively stimulate sGC and increase the cGMP level. Test Example 2. Research on the metabolic stability of hepatocytes in vitro 1. Experimental purpose: The purpose of this study is to evaluate the stability of compounds in hepatocytes of different species.

[0209] 2. Experimental procedure: Several 96-well sample precipitation plates named T0, T15, T30, T60, T90, T0-MC, T90-MC and blank matrix were prepared respectively. The recovery medium and culture medium were taken out in advance and placed in a 37°C water bath for preheating. The frozen hepatocytes of different species were taken out from the liquid nitrogen tank and immediately immersed in a 37°C water bath (about 90 seconds). After thawing and loosening the cryopreserved parts, they were respectively poured into centrifuge tubes containing 40 mL of recovery medium, gently inverted to resuspend the cells in the recovery medium. Under room temperature conditions, centrifuged at 100×g for 5 minutes, the supernatant was removed, the hepatocytes were resuspended in an appropriate volume of culture medium, and the cell viability was calculated using the trypan blue staining method. 198 μL of hepatocyte suspension (0.51×10 6 cells / mL) was added to the preheated culture plate. The culture control group added 198 μL of culture medium without hepatocytes to the T0-MC and T120-MC culture plates. All culture plates were pre-cultured in a 37°C incubator for 10 minutes. Next, 2 μL of the working solutions of the test substance and the control compound were added, mixed uniformly, and immediately the culture plate was placed on the shaker in the incubator, and the timer was started to initiate the reaction. Two replicate samples were prepared at each time point for each compound. The culture conditions were 37°C, saturated humidity, and 5% CO2. The final concentration of the test substance in the test system was 1 μM, the final concentration of the control substance was 3 μM, and the final concentration of hepatocytes was 0.5×10 6It was cells / mL, the final concentration of the total organic solvent was 0.96%, and among them, the final concentration of DMSO was 0.1%. When the culture at the corresponding time point was completed, the culture plate was taken out, 25 μL of the mixed solution of the compound, the control compound and the cells was taken out, and added to a sample plate containing 125 μL of the stop solution (an acetonitrile solution containing 200 ng / mL of tolbutamide and labetalol). In the case of the blank sample plate, 25 μL of the culture medium without hepatocytes was directly added. After all the sample plates were sealed, they were shaken on a shaker at 600 rpm for 10 minutes and then centrifuged at 3220×g for 20 minutes. The supernatants of the test substance and the control substance were diluted with ultrapure water at a ratio of 1:3. After all the samples were uniformly mixed, they were analyzed using the LC / MS / MS method.

[0210] The experimental results were as shown in Table 2.

[0211]

Table 4

[0212] Experimental conclusion: The compound of the present invention has good stability in human-derived hepatocytes and has moderate clearance and half-life. Test Example 3: Research on in vivo pharmacokinetic properties Experimental purpose: The purpose of this research is to measure the pharmacokinetic parameters of the compound in male SD rats.

[0213] Experimental materials: Sprague Dawley rats (male, 200 - 300 g, 7 - 9 weeks old, Shanghai SLAC) Experimental method: In this project, four male SD rats were used. Two rats in one group were intravenously injected at a dose of 2 mg / kg and a concentration of 0.4 mg / mL, and the other two rats in another group were orally administered at a dose of 10 mg / kg and a concentration of 1 mg / mL; Plasma samples were collected at 0.083 (only for the intravenous injection group), 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. Then, the collected samples were analyzed by LC-MS / MS and data were collected. The collected analytical data were used to calculate the relevant pharmacokinetic parameters using Phoenix WinNonlin 6.3 software.

[0214] The experimental results are as shown in Table 3.

[0215]

Table 5

[0216] Conclusion: The compound of the present invention has good clearance, half-life and oral bioavailability.

Claims

1. A compound represented by formula (II) or a pharmaceutically acceptable salt thereof. 【Chemical 1】 (However, R １ is R ２ , [Chemical Formula 2] and -L-R ３ selected from R ２ is selected from cyclopentyl, C ４－６ bicycloalkyl and 4- to 5-membered heterocycloalkyl, and said cyclopentyl, C ４－６ bicycloalkyl and 4- to 5-membered hetero Each chloroalkyl is independently optionally substituted with one, two or three Rs ａ and R ３ is selected from C ３－６ cycloalkyl and 4- to 5-membered heterocycloalkyl, and said C ３－６ cycloalkyl and 4- to 5-membered heterocycloalkyl are each independently optionally substituted with 1, 2 or 3 R ｂ groups, L is selected from -O-, -OCH ２ -, -CH(R ｃ ), -C(R ｄ R ｅ ), and is selected from R ａ and R ｂ each independently is halogen, CN, C １－３ alkyl and C １－３ alkoxy, selected from, said C １－３ alkyl and C １－３ alkoxy each independently is optionally substituted by 1, 2 or 3 R ｆ groups, R ｃ , R ｄ and R ｅ are each independently selected from halogen and C １－３ alkyl, R ｆ is selected from halogen, R ４ is selected from halogen and C １－３ alkyl, T １ is selected from CH and N, "Hetero" in said "heterocycloalkyl" represents 1, 2 or 3 heteroatoms or heteroatomic groups each independently selected from O, NH, S and N.)

2. R ａ and R ｂ is independently selected from F and methoxy, respectively, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R ｃ , R ｄ and R ｅ is independently selected from F and methyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. R ｆ is a compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from F.

5. R ２ is [Chemical Formula 3] selected from, said 【Chemical Formula 4】 is independently optionally substituted with one, two or three Rs each ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is substituted by.

6. R ２ is [Chemical Formula 5] selected from, the compound according to claim 5 or a pharmaceutically acceptable salt thereof.

7. R ３ is ​ selected from, said 【Chemical Formula 7】 which is optionally substituted by one, two or three Rs ｂ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is substituted by ｂ .

8. R ３ is 【Chemical 8】 selected from, the compound according to claim 7 or a pharmaceutically acceptable salt thereof.

9. L is selected from -O-, -OCH ２ -, and -C(CH ３ ) ２ -, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

10. R １ is 【Chemical Formula 9】 selected from, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. R ４ is a compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from F, Cl and methyl.

12. selected from the following formulas, the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 【Chemical 10】 (However, R １ , R ４ and T １ are as defined in claim 1.)

13. selected from the following formulas, a compound represented by the following formula or a pharmaceutically acceptable salt thereof. 【Chemical 11】 【Chem.】

14. selected from the following formulas, the compound according to claim 13 or a pharmaceutically acceptable salt thereof. 【Chemical Formula 12】 【Chem.】

15. selected from the following formulas, the compound according to claim 14 or a pharmaceutically acceptable salt thereof. 【Chemical 13】 【Chem.】

16. Use of the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease associated with soluble guanylate cyclase activation.

17. The use according to claim 16, wherein the disease associated with soluble guanylate cyclase activation is chronic kidney disease.

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