Aryl derivatives and uses thereof

Abstract

The application provides a kind of aryl derivative of novel structure general formula and specific compound and preparation method and purposes of the compound.Test results show that the compound of the application has excellent proliferation inhibitory effect on FANS cells, can be used for preparing medicine for treating and / or preventing diseases mediated by fatty acid synthetase (fatty acid synthetase, FASN / FAS), has drug potential, and provides a new direction for the development of fatty acid synthetase inhibitor drugs.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to a class of aryl derivative compounds, as well as methods for preparing and using said compounds. Background Technology

[0002] Fatty acid synthase (FASN) plays a fundamental role in cellular metabolism and cell signaling. FASN catalyzes the formation of long-chain fatty acids from acetyl-CoA, malonyl-CoA, and nicotinamide adenine dinucleotide phosphate (NADPH), thereby participating in energy production and storage in the biosynthesis of hormones and other important biological molecules, as well as the formation of cellular structures and intermediates.

[0003] Fatty acid synthase inhibitors can effectively treat non-alcoholic steatohepatitis (NASH) / metabolic dysfunction-associated steatohepatitis (MASH) by reducing excess liver fat (steatohepatitis), reducing inflammation, and slowing fibrosis.

[0004] Furthermore, FASN is a key rate-limiting enzyme in the intracellular fatty acid synthesis pathway, playing a crucial role in maintaining energy metabolism and cell membrane homeostasis within cancer cells. Since normal tissue cells primarily meet their lipid needs through direct uptake of extracellular fatty acids, they synthesize relatively few fatty acids actively within the cell, resulting in typically low FASN expression levels in healthy cells. However, tumor cells, due to their vigorous growth and metabolism, require the synthesis of large amounts of fatty acids intracellularly to meet their own needs; therefore, FASN is often overexpressed in patients with malignant tumors. Increased FASN expression and fatty acid synthesis are common phenotypes in cancer. In addition, studies have shown that fatty acids participate in the synthesis of many important pro-cancer lipid signaling molecules, such as palmitoylated KRAS4A and Wnt, enabling them to localize on the membrane and function normally. Inhibition of FASN disrupts signaling pathways associated with these pro-cancer lipid molecules. In conclusion, FASN is closely related to tumor occurrence, evolution, invasion, and prognosis, and inhibiting FASN is considered one of the most promising pathways for cancer treatment.

[0005] Several FASN inhibitor compounds in development have entered the clinical stage. For example, Denifanstat from Sagimet Biosciences has achieved positive results in clinical studies for the treatment of non-alcoholic steatohepatitis (NASH) and recurrent glioblastoma.

[0006] Although several FASN inhibitor projects are in clinical trials, no drugs have yet been marketed, indicating an unmet market demand for potent and highly specific FASN inhibitors. Summary of the Invention

[0007] The purpose of this invention is to provide a novel fatty acid synthesis inhibitor compound, a method for preparing the compound, and its use in treating fatty acid synthase-mediated diseases.

[0008] In a first aspect, the present invention provides a compound of formula (I), a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound:

[0009] (I)

[0010] in: R1 is H, D, cyano, or optionally substituted: C1-4 alkyl, C1-4 oxaalkyl, C1-4 thiaalkyl, C 3-6 cycloalkyl; wherein optional substitution means that it is optionally replaced by one or more groups selected from D, halogen, cyano, C 1-4 Alkyl, C 1-4 oxane, C 1-4 Thioalkyl, C 3-6 Substituents of cycloalkyl groups; Ring A is C6- 10 Aryl, 5-10 heterocyclic, 5-10 heteroaryl; R A Each occurrence is H, halogen, cyano, D, -C(O)OR aa -C(O)NR a R b -CH2OC(O)R c C can be substituted with either halogen or deuterium. 1-4 Alkyl, C 1-4 oxane, C 1-4 Thioalkyl, C 3-6 cycloalkyl groups, 3-6 membered heterocyclic groups; R aa H, C1-3 alkyl, C 3-6 cycloalkyl groups, 3-6 membered heterocyclic groups; R a R b Each is independently H, D, C1-3 alkyl, C 3-6 cycloalkyl groups, 3-6 membered heterocyclic groups; R c It is a C1-4 alkyl group or an -O-C1-4 alkyl group; Ring B is C 4-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 4-10 Cycloalkenyl, 5-10 membered heteroaryl; R BEach occurrence is H, halogen, oxo group, D, CN, OH, NH2, or optionally substituted with halogen or deuterium: C. 1-4 Alkyl, C 1-4 oxane, C 1-4 Thioalkyl; The ring C is a 4-12 membered heterocyclic group; R C Each occurrence is either H, halogen, D, CN, OH, or optionally substituted with halogen or deuterium: C. 1-4 Alkyl, C 1-4 oxane, C 1-4 Thioalkyl; a, b, and c are 0, 1, 2, 3, or 4 respectively; The heteroatoms in the heterocyclic group and heteroaryl group are independently selected from O, N or S, and the number of heteroatoms is 1, 2 or 3.

[0011] In a preferred embodiment of the invention, R1 is H, D, cyano, or optionally substituted: C1-3 alkyl, C1-3 oxaalkyl, C1-3 thiaalkyl, C 3-4 cycloalkyl; wherein optional substitution means that it is optionally replaced by one or more groups selected from D, halogen, cyano, C 1-3 Alkyl, C 1-3 oxane, C 1-3 Thioalkyl, C 3-6 Substituents of cycloalkyl groups; Further preferably, R1 is H, D, or optionally substituted: C1-3 alkyl, C1-3 oxaalkyl, C 3-4 cycloalkyl; wherein optional substitution means that it is optionally replaced by one or more elements selected from D, halogen, C 1-3 Substituents of alkyl groups; More preferably, R1 is H, D, or optionally substituted: methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl; wherein optional substitution means being optionally substituted by one or more substituents selected from D, F, Cl, Br; In an even more preferred embodiment, R1 is methyl.

[0012] In a preferred embodiment of the present invention, ring A is phenyl, 5-10-membered heterocyclic group, or 5-6-membered heteroaryl; more preferably, ring A is phenyl or 5-6-membered heteroaryl; even more preferably, ring A is a 5-membered heteroaryl containing 2 or 3 nitrogen-containing heteroaryl groups; and even more preferably, ring A is 4H-1,2,4-triazolyl or imidazolyl.

[0013] In a preferred embodiment of the present invention, R A Each occurrence is H, halogen, cyano, D, -C(O)OR aa -C(O)NRa R b -CH2OC(O)R c C 1-3 Alkyl, C 1-3 oxane, C 3-4 cycloalkyl, halogenated C 1-3 Alkyl, Halogenated C 1-3 Oxyalkyl, deuterated C 1-3 Alkyl, deuterated C 1-3 oxane; R aa H, C1-3 alkyl, C 3-6 cycloalkyl groups, 3-6 membered heterocyclic groups; R a R b Each is independently H, D, C1-3 alkyl, C 3-6 cycloalkyl groups, 3-6 membered heterocyclic groups; R c It is a C1-3 alkyl group or an -O-C1-3 alkyl group; Further preferred, R A Each occurrence is H, halogen, cyano, D, -C(O)OR aa -C(O)NR a R b -CH2OC(O)R c C 1-3 Alkyl, C 1-3 oxane, C 3-4 cycloalkyl; R aa It is an H, C1-3 alkyl group; R a R b Each is independently H, D, C1-3 alkyl, C 3-6 cycloalkyl; R c It is a C1-3 alkyl group or an -O-C1-3 alkyl group; Further optimized, R A Each occurrence is H, halogen, cyano, D, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)NCH3CH3, -CH2OC(O)OCH3, -CH2OC(O)CH3, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl; Further optimization, R A Each occurrence is H, F, Cl, Br, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl; and even more preferably, R A Each occurrence is H, Cl, and methyl, respectively.

[0014] In a preferred embodiment of the present invention, ring B is C. 4-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 4-8 Cycloalkenyl, 5-6 membered heteroaryl; more preferably, ring B is C. 5-8 Cycloalkyl, 5-8 membered heterocyclic alkyl; more preferably, ring B is a 5-membered oxygen- or sulfur-containing heterocyclic alkyl, or a 7-membered oxygen- or sulfur-containing spirocyclic alkyl; even more preferably, ring B is... , , , , , , , , The optimal choice is ring B. , , This indicates the junction with the benzene ring.

[0015] In a preferred embodiment of the present invention, ring B is... , This indicates the junction with the benzene ring.

[0016] In a preferred embodiment of the present invention, R B Each occurrence is H, halogen, oxo group, D, CN, OH, NH2, or optionally substituted with halogen or deuterium: C. 1-3 Alkyl, C 1-3 oxane, C 1-3 Thioalkyl; Further preferred, R B Each occurrence is H, F, Cl, Br, oxo group, D, CN, OH, NH2, and optionally substituted with halogen or deuterium: methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy; Further optimized, R B Each occurrence is respectively H, oxo group, D, CN, OH, NH2, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy; and even more preferably, R B Each occurrence is H and methyl, respectively.

[0017] In a preferred embodiment of the present invention, the ring C is a 4-10 membered heterocyclic alkyl; more preferably, the ring C is a 4-8 membered heterocyclic alkyl; even more preferably, the ring C is a 4-6 membered monocyclic alkyl; even more preferably, the ring C is a 4-6 membered nitrogen-containing monocyclic alkyl; even more preferably, the ring C is a nitrogen-containing 4-membered monocyclic alkyl or a nitrogen-containing 6-membered monocyclic alkyl; even more preferably, the ring C is an azahexacyclic butyl or azahexacyclic hexyl.

[0018] In a preferred embodiment of the present invention, R C Each occurrence is either H, halogen, D, CN, OH, or optionally substituted with halogen or deuterium: C. 1-3 Alkyl, C 1-3 oxane; Further preferred, R C The elements appearing each time are H, halogen, D, CN, OH, and C. 1-3 Alkyl, C 1-3 oxane; Further optimization, R C Each occurrence is H, methyl, ethyl, methoxy, and ethoxy, respectively.

[0019] In a preferred embodiment of the present invention, a is 0, 1, 2 or 3; preferably, a is 1, 2 or 3; more preferably, a is 1 or 2.

[0020] In a preferred embodiment of the present invention, b is 0, 1, 2 or 3; preferably, b is 0, 1 or 2.

[0021] In a preferred embodiment of the present invention, c is 0 or 1; preferably, c is 0.

[0022] In a preferred embodiment of the invention, the compound represented by formula (I), the stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, is further represented by formula (II):

[0023] (II)

[0024] Among them, R1, ring B, R B , ring C, R C b and c are as described in equation (I).

[0025] X is either N or CRx; Rx can be H, halogen, cyano, D, or optionally substituted with halogen or deuterium: C 1-4 Alkyl, C 1-4 oxane, C 1-4 Thioalkyl, C 3-4 cycloalkyl; In a preferred embodiment of the present invention, R X For H, halogen, cyano, D, or optionally substituted with halogen or deuterium: C 1-3 Alkyl, C 1-3 oxane, C 3-4 cycloalkyl; Further optimized, R XThe following are the radicals: H, F, Cl, Br, cyano, D, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, and cyclopropyl. Further optimization, R X For H, F, Cl, Br; and even more preferably, R X It is Cl.

[0026] In a preferred embodiment of the present invention, the compound represented by formula (I), the stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, is further represented by formula (III):

[0027] (III)

[0028] Among them, R1, ring C, R C c is as described in equation (I); X is either N or CRx; Rx can be H, halogen, cyano, D, or optionally substituted with halogen or deuterium: C 1-4 Alkyl, C 1-4 oxane, C 1-4 Thioalkyl, C 3-4 cycloalkyl; Y1, Y2, and Y3 are each independently selected from CR Y R Y O, S; and Y1, Y2, Y3 are not simultaneously CR Y R Y ; R Y Individually substituted with H, halogen, oxo group, D, CN, OH, NH2, or optionally substituted with halogen or deuterium: C 1-3 Alkyl, C 1-3 oxane, C 1-3 Thioalkyl; In a preferred embodiment of the present invention, R X For H, halogen, cyano, D, or optionally substituted with halogen or deuterium: C 1-3 Alkyl, C 1-3 oxane, C 3-4 cycloalkyl; Further optimized, R X The following are the radicals: H, F, Cl, Br, cyano, D, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, and cyclopropyl. Further optimization, R X For H, F, Cl, Br; and even more preferably, R X For F, Cl, Br; and even more preferably, R X It is Cl.

[0029] In a preferred embodiment of the present invention, Y1 and Y2 are selected from CR Y R Y Y3 is selected from O or S; Alternatively, Y1 and Y3 are selected from CR Y R Y Y2 is selected from O or S; Alternatively, Y2 and Y3 are selected from CR Y R Y Y1 is selected from O or S.

[0030] In a preferred embodiment of the present invention, R Y The following can be independently H, halogen, oxo group, D, CN, OH, NH2, or optionally substituted with halogen or deuterium: methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy; Further preferred, R Y Each of the following can be independently represented as H, oxo group, D, CN, OH, NH2, methyl, ethyl, n-propyl, isopropyl, methoxy, or ethoxy; more preferably, R Y They are H and methyl groups, respectively.

[0031] In a preferred embodiment of the invention, the compound represented by formula (I), the stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, is further represented by formula (IV):

[0032] (Ⅳ)

[0033] Among them, R1, ring A, ring C, and R A R B R C a and c are as described in equation (I); Y3 is selected from CR Y R Y O, S; R Y Individually substituted with H, halogen, oxo group, D, CN, OH, NH2, or optionally substituted with halogen or deuterium: C 1-3 Alkyl, C 1-3 oxane, C 1-3 Thioalkyl groups.

[0034] In a preferred embodiment of the present invention, Y3 is selected from O or S; more preferably, Y3 is selected from O.

[0035] In a preferred embodiment of the present invention, R YThe following can be independently H, halogen, oxo group, D, CN, OH, NH2, or optionally substituted with halogen or deuterium: methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy; Further preferred, R Y Each of the following can be independently represented as H, oxo group, D, CN, OH, NH2, methyl, ethyl, n-propyl, isopropyl, methoxy, or ethoxy; more preferably, R Y It is H, methyl.

[0036] In a preferred embodiment of the invention, the compound represented by formula (I), the stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, is further represented by formula (V):

[0037] (V)

[0038] Among them, R1, ring C, R A R B R C a and c are as described in equation (I); X is either N or CRx; preferably, X is CRx. Rx can be H, halogen, cyano, D, or optionally substituted with halogen or deuterium: C 1-4 Alkyl, C 1-4 oxane, C 1-4 Thioalkyl, C 3-4 Cycloalkyl; preferably, Rx is H, halogen, cyano, D, optionally substituted with halogen or deuterium: methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, cyclopropyl; more preferably, Rx is H, halogen, cyano, D, optionally substituted with halogen or deuterium: methyl, methoxy; even more preferably, Rx is H, F, Cl, Br.

[0039] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0040] The compounds described in this invention are selected from: ,

[0041] Or its stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts of the compound.

[0042] The object of the present invention also includes providing a method for preparing compounds represented by the above general formula, stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts of the compounds.

[0043] The compound of the general formula can be prepared by a variety of methods, including but not limited to the following:

[0044] X represents a leaving group such as halogen, sulfonate, alkylthioyl, alkylthionyl, or alkylthionyl; R represents hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Heteroalkyl, C 6-10 Aryl, C 5-10 Heteroaryl groups. Other substituents are defined as described in this invention.

[0045] The present invention also provides an intermediate compound of formula (A-1), a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound. (A-1) Where R represents hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Heteroalkyl (e.g., C) 1-6 oxane, C 1-6 Thioalkyl, C 1-6 (azaalkyl), C 6-10 Aryl, C 5-10 Heteroaryl groups and other substituents are defined as described in this invention.

[0046] The present invention also provides a pharmaceutical composition comprising the compound shown in the present invention, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound. Further, the pharmaceutical composition also comprises a pharmaceutically acceptable excipient.

[0047] The object of the present invention also includes the use of the compounds shown in the present invention, stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts of the compounds in the preparation of medicaments for treating and / or preventing diseases mediated by fatty acid synthetase (FASN / FAS).

[0048] In some embodiments, the fatty acid synthetase (FASN / FAS)-mediated diseases include tumors, immune diseases, cerebrovascular diseases, cardiovascular diseases, infectious diseases, nervous system diseases, and metabolic diseases. Preferably, the tumor is a solid tumor. More preferably, the tumor is ovarian cancer.

[0049] The present invention also aims to provide the use of the compounds shown herein, stereoisomers, tautomers, or mixtures thereof, or pharmaceutically acceptable salts of the compounds, in the preparation of medicaments for treating and / or preventing tumors, immune diseases, cerebrovascular diseases, cardiovascular diseases, infectious diseases, nervous system diseases, and metabolic diseases. Preferably, the tumor is a solid tumor. More preferably, the tumor is ovarian cancer.

[0050] The object of the present invention also includes providing a method for preventing and / or treating diseases mediated by fatty acid synthase (FASN / FAS), comprising administering to a patient a therapeutically effective dose of a compound shown in the present invention, a stereoisomer, tautomer, or mixture thereof of the compound, or a pharmaceutically acceptable salt of the compound, or a pharmaceutical composition of the present invention.

[0051] The present invention also aims to provide a method for preventing and / or treating tumors, immune diseases, cerebrovascular diseases, cardiovascular diseases, infectious diseases, nervous system diseases, and metabolic diseases, comprising administering to a patient a therapeutically effective dose of a compound shown in the present invention, a stereoisomer, tautomer, or mixture thereof of the compound, or a pharmaceutically acceptable salt of the compound, or a pharmaceutical composition of the present invention. Preferably, the tumor is a solid tumor. More preferably, the tumor is ovarian cancer.

[0052] The object of the present invention also includes providing the compounds shown in the present invention, stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts of the compounds, for the prevention and / or treatment of diseases mediated by fatty acid synthetase (FASN / FAS).

[0053] The present invention also aims to provide the compounds shown herein, stereoisomers, tautomers, or mixtures thereof, or pharmaceutically acceptable salts of the compounds, for the prevention and / or treatment of tumors, immune diseases, cerebrovascular diseases, cardiovascular diseases, infectious diseases, nervous system diseases, and metabolic diseases; preferably, the tumor is a solid tumor. More preferably, the tumor is ovarian cancer.

[0054] definition

[0055] C in this article m-n This refers to the part having an integer number of carbon atoms within a given range. For example, "C 1-6 "" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

[0056] When any variable (e.g., R1) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group, a site, or an atom is substituted by two R1s, each R1 has an independent option.

[0057] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight-chain or branched group containing 1-20 carbon atoms, preferably containing 1-10 carbon atoms (i.e., C10). 1-10 Alkyl groups, more preferably containing 1-8 carbon atoms (C64- ... 1-8 Alkyl groups, more preferably containing 1-6 carbon atoms (i.e., C64-C ... 1-6 Alkyl), for example, "C 1-6 "Alkyl" refers to a group that is alkyl and has 1 to 6 carbon atoms in its carbon chain (specifically, 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0058] Unless otherwise specified, the term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused cycloalkyl, bridged cycloalkyl, or spirocycloalkyl. For example, a cycloalkyl group may contain 3 to 16 carbon atoms (such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4). Even further, for example, a cycloalkyl group may be selected from monocyclic groups containing 3 to 12 carbon atoms (such as 3 to 10, further such as 3 to 8, 3 to 6). Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Examples of bicyclic cycloalkyl groups include those having 5 to 12, more such as 7 to 12 or 5 to 10 ring atoms arranged in a fused bicyclic arrangement selected from the [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems, or arranged in a bridging bicyclic arrangement selected from bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane and bicyclic [3.2.2]nonane. Other examples of bicyclic cycloalkyl groups include rings arranged in a bicyclic arrangement selected from the [5,6] and [6,6] ring systems.

[0059] Unless otherwise specified, the term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon substituent, which is a non-aromatic structure containing 3-20 ring atoms, wherein one, two, three, or more ring atoms are selected from N, O, or S, and the remaining ring atoms are C. Preferably, it contains 3-12 ring atoms, more preferably 3-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms. The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, pyranyl, etc. Bicyclic or polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0060] Unless otherwise specified, the term "heterocyclic alkyl" refers to a saturated heterocyclic group as defined above.

[0061] Unless otherwise specified, the term "oxaalkyl" refers to an alkyl residue in which one or more carbons (and associated hydrogens) are replaced by oxygen, such as "oxaalkyl" or "oxaalkylalkyl". Examples include methoxy, ethoxy, propoxy, methoxypropyl, etc.

[0062] Unless otherwise specified, the term "thioalkyl" refers to "oxaalkyl" in which the oxygen is replaced by sulfur.

[0063] Unless otherwise specified, the terms "halogen" or "halogenated" refer to F, Cl, Br, and I. The term "halogenated alkyl" refers to an alkyl group as defined above in which one, two, or more hydrogen atoms, or all hydrogen atoms, are replaced by a halogen. Representative examples of halogenated alkyl groups include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, and CF2CF3.

[0064] Unless otherwise specified, "cycloalkenyl" refers to a system composed of monocyclic, bicyclic, and spirocyclic hydrocarbon rings as daughter groups; however, the system is unsaturated, meaning it contains at least one C-C double bond but no aromatic system. Preferably, it contains 3-12 carbon atoms (i.e., C12-C22). 3-12 Cycloalkenyl), more preferably containing 3-10 carbon atoms (C 3-10 Cycloalkenyl), further preferably 3-6 carbon atoms (C 3-6 Cycloalkenyl), 4-6 carbon atoms (C 4-6 Cycloalkenyl), 5-6 carbon atoms (C 5-6 (Cycloalkenyl).

[0065] Unless otherwise specified, the term "aryl" refers to an aromatic carbocyclic system containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms, preferably 6-10 carbon atoms. The term "aryl" may be used interchangeably with the term "aromatic ring." Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthraceneyl, phenanthryl, or pyrene.

[0066] Unless otherwise specified, the term "heteroaryl" refers to an aromatic monocyclic, bicyclic, or polycyclic cyclic system containing a 5-16 member structure, or a 5-14 member structure, a 5-12 member structure, a 5-10 member structure, a 5-8 member structure, or a 5-6 member structure, wherein one, two, three, or more ring atoms are heteroatoms and the remaining atoms are carbon atoms, the heteroatoms being independently selected from O, N, or S, and the number of heteroatoms is preferably one, two, or three. Examples of heteroaryl groups may include, but are not limited to, furanyl, thiophene, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrroloyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purine, indoleyl, isoindoleyl, indazoleyl, benzofuranyl, benzothiophene, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzoimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, and pyrazolo[1,5-a]. Pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, etc.

[0067] Unless otherwise specified, the terms "pharmaceutically acceptable salt" or "medicinal salt" refer to a salt that, within reasonable medical judgment, is suitable for contact with mammalian, particularly human, tissues without excessive toxicity, irritation, allergic reactions, etc., and is proportionate to a reasonable benefit / risk ratio. Medically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of this invention, or solely by reacting a free base or free acid with a suitable reagent.

[0068] The compounds of this invention also include their "isotope derivatives" (such as deuterium). Unless otherwise specified, the term "isotope derivative" refers to compounds of this invention that can exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weights or mass numbers differ from the atomic weights or mass numbers of the most abundant atoms found in nature. Isotopes can be radioactive or non-radioactive isotopes. Commonly used isotopes for isotopic labeling are: hydrogen isotopes, 2 H and3 H; Carbon isotopes: 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially 3 H and 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (… 2 Substitution with H can enhance metabolic stability and prolong the half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, just like non-isotope-labeled compounds.

[0069] The compounds of this invention also include their solvates. Unless otherwise specified, the terms "solvate" or "solvent" refer to the physical association of the compound of this invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the lattice of a crystalline solid, the solvate can be separated. Solvent molecules in the solvate may be present in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" encompasses both solution phases and separable solvates. Solvation methods are well known in the art. Exemplary solvates include, but are not limited to, hydrates, ethanol compounds, methanol compounds, and isopropanol compounds.

[0070] Unless otherwise specified, the term "stereoisomer" refers to compounds having the same chemical structure but with different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and inhibited isomers. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0071] Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called proton transfer tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

[0072] Unless otherwise specified, the term "optional substitution" means that the hydrogen at the substituted site of the group is not substituted, or is substituted by one or more substituents, preferably by one, two, or three substituents, wherein the substituents are preferably selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, nitro, amino, azide, oxo, carboxyl, C 2-6 Alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 oxane, C 3-10 cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocyclic group, C 6-14 Aryl or 5-10 membered heteroaryl rings, wherein the C 2-6 Alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 oxane, C 3-10 cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocyclic group, C 6-14 The aryl or 5-10 membered heteroaryl group may optionally be selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6 The oxoalkyl group is substituted by one or more substituents, wherein the oxoalkyl group refers to a double bond formed by replacing two H atoms at the same substitution position with the same O atom.

[0073] The beneficial effects of this invention are as follows: This invention designs a class of novel compounds, providing a new direction for the development of FASN inhibitors. Experimental results show that the compounds of this invention have excellent inhibitory effects on the proliferation of FASN cells. Detailed Implementation

[0074] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of the present invention. The preferred embodiments and materials shown herein are for illustrative purposes only.

[0075] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or high-performance liquid chromatography (HPLC). The NMR measurements were performed using a Bruker 400 MHz and / or Varian 400 MHz instrument; the LC-MS was performed using an Agilent 1260 Infinity II-6120 / 6125MSD instrument; and the HPLC was performed using a Waters UPCC (CA-352).

[0076] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0077] This invention provides a method for preparing the compound. The compound can be prepared by the following steps.

[0078] Example 1

[0079] Preparation of 4-(1-(7-methyl-4-(5-methyl-4H-1,2,4-triazol-3-yl)-2,3-dihydrobenzofuran-6-carbonyl)piperidin-4-yl)benzyl nitrile (compound 1):

[0080] Step 1: Synthesis of methyl 5-bromo-3-hydroxy-2-methylbenzoate:

[0081] Methyl 3-amino-5-bromo-2-methylbenzoate (15.00 g, 61.45 mmol, 1 eq) was dissolved in 10% sulfuric acid aqueous solution (150 mL). Sodium nitrite aqueous solution (5.09 g, 73.74 mmol, 1.2 eq) was added dropwise to the reaction solution under ice-water bath conditions (20 mL). After the addition was complete, the mixture was brought to room temperature and reacted for 1 hour. Then, 50% sulfuric acid aqueous solution (150 mL) was added to the reaction solution. o The reaction mixture was reacted at C for 1 hour. After cooling, the mixture was diluted with ethyl acetate (500 mL). 3) Extraction, washing with saturated brine (200 mL), drying with anhydrous sodium sulfate, filtration, concentration, and purification of the crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the target product (11.00 g, yield 73%). 1 H NMR (400 MHz, DMSO- d 6) δ 10.26 (s, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 3.81 (s, 3H), 2.23 (s, 3H).

[0082] Step 2: Synthesis of methyl 5-bromo-3-(2,2-diethoxyethoxy)-2-methylbenzoate:

[0083] Methyl 5-bromo-3-hydroxy-2-methylbenzoate (11.00 g, 44.89 mmol, 1 eq) and 2-bromo-1,1-diethoxyethane (17.69 g, 89.77 mmol, 2 eq) were dissolved in N,N-dimethylformamide (150 mL). Potassium carbonate (18.61 g, 134.66 mmol, 3 eq) was added to the reaction solution. o The reaction mixture was sealed in a tube at C for 16 hours. The reaction solution was cooled, and water (200 mL) was added. Extraction was then performed with ethyl acetate (200 mL). 3) Wash with saturated brine (200 mL), dry with anhydrous sodium sulfate, filter, concentrate, and purify the crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the target product (10.00 g, yield 62%). 1 H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 1.9 Hz, 1H), 7.03(d, J = 1.8 Hz, 1H), 4.78 (t, J = 5.2 Hz, 1H), 3.92 (d, J = 5.2 Hz, 2H), 3.81(s, 3H), 3.73 – 3.66 (m, 2H), 3.61 – 3.54 (m, 2H), 2.31 (s, 3H), 1.20 – 1.16(m, 6H).

[0084] Step 3: Synthesis of methyl 4-bromo-7-methylbenzofuran-6-carboxylic acid ester:

[0085] Methyl 5-bromo-3-(2,2-diethoxyethoxy)-2-methylbenzoate (7.00 g, 19.38 mmol, 1 eq) was dissolved in toluene (70 mL), and polyphosphoric acid (8 mL) was added to the reaction solution. o The reaction mixture was reacted at C for 4 hours. The reaction solution was cooled, and 100 mL of water was added. The mixture was then extracted with 100 mL of ethyl acetate. 2) Wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and purify the crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the target product (3.50 g, yield 67%). 1 H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.79 (d, J = 2.2Hz, 1H), 6.83 (d, J = 2.2 Hz, 1H), 3.92 (s, 3H), 2.75 (s, 3H).

[0086] Step 4: Synthesis of methyl 4-bromo-7-methyl-2,3-dihydrobenzofuran-6-carboxylic acid:

[0087] 4-Bromo-7-methylbenzofuran-6-carboxylic acid methyl ester (2.00 g, 7.43 mmol, 1 eq) was dissolved in ethanol (10 mL). 5% rhodium / carbon (1.50 g, 0.73 mmol, 0.1 eq) was added to the reaction solution, and the reaction was carried out at room temperature under a hydrogen atmosphere for 48 hours. The reaction solution was filtered, concentrated, and the crude product was purified by reverse-phase chromatography (C18, 0.1% formic acid aqueous solution / acetonitrile) to obtain the target product (600 mg, yield 30%). 1 H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 4.64 (t, J = 8.9Hz, 2H), 3.87 (s, 3H), 3.25 (t, J = 8.9 Hz, 2H), 2.36 (s, 3H).

[0088] Step 5: Synthesis of methyl 4-cyano-7-methyl-2,3-dihydrobenzofuran-6-carboxylic acid:

[0089] Methyl 4-bromo-7-methyl-2,3-dihydrobenzofuran-6-carboxylic acid (300 mg, 1.11 mmol, 1 eq), tetrakis(triphenylphosphine)palladium (128 mg, 0.11 mmol, 0.1 eq), and zinc cyanide (260 mg, 2.21 mmol, 2 eq) were dissolved in N,N-dimethylformamide (5 mL) and reacted at 140°C under a nitrogen atmosphere for 16 hours. The reaction solution was cooled, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). 3) Wash with saturated brine (20 mL), dry with anhydrous sodium sulfate, filter, concentrate, and purify the crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 95:5) to obtain the target product (200 mg, yield 83%). 1 HNMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 4.71 (t, J = 8.9 Hz, 2H), 3.90 (s, 3H), 3.44 (t, J = 8.9 Hz, 2H), 2.47 (s, 3H).

[0090] Step 6: Synthesis of methyl 4-aminothioformyl-7-methyl-2,3-dihydrobenzofuran-6-carboxylic acid:

[0091] Methyl 4-cyano-7-methyl-2,3-dihydrobenzofuran-6-carboxylate (200 mg, 0.92 mmol, 1 eq), sodium hydrosulfide (77 mg, 1.38 mmol, 1.5 eq), and magnesium chloride (88 mg, 0.92 mmol, 1 eq) were dissolved in N,N-dimethylformamide (5 mL) and reacted at room temperature for 16 hours. Water (20 mL) was added to the reaction solution, and ethyl acetate (30 mL) was used to further dissolve the methyl ester. 3) Extraction, washing with saturated brine (20 mL), drying over anhydrous sodium sulfate, concentration, and purification of the crude product by silica gel column chromatography (tetrahydrofuran = 100%) to obtain the target product (200 mg, yield 86%). LCMS (ESI) [M+H] + =252.2; 1 H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.26 (s, 2H), 4.63 (t, J = 8.9 Hz,2H), 3.89 (s, 3H), 3.60 (t, J = 8.8 Hz, 2H), 2.44 (s, 3H).

[0092] Step 7: Synthesis of methyl 4-(imino(methylthio)methyl)-7-methyl-2,3-dihydrobenzofuran-6-carboxylic acid:

[0093] Methyl 4-aminothioformyl-7-methyl-2,3-dihydrobenzofuran-6-carboxylate (200 mg, 0.8 mmol, 1 eq) and iodomethane (170 mg, 1.2 mmol, 1.5 eq) were dissolved in acetone (5 mL). o The reaction was carried out at C for 2 hours. The reaction solution was cooled, filtered, and the filter cake was washed with acetone (20 mL), dried, and the target product (180 mg, yield 85%) was obtained. 1 H NMR (400 MHz, DMSO- d 6) δ 11.90 (s, 1H), 7.62 (s, 1H), 4.69 (t, J = 8.8Hz, 2H), 3.86 (s, 3H), 3.49 (s, 2H), 2.81 (s, 3H), 2.40 (s, 3H).

[0094] Step 8: Synthesis of methyl 7-methyl-4-(5-methyl-4H-1,2,4-triazol-3-yl)-2,3-dihydrobenzofuran-6-carboxylic acid ester:

[0095] Methyl 4-(imino(methylthio)methyl)-7-methyl-2,3-dihydrobenzofuran-6-carboxylic acid ester (180 mg, 0.68 mmol, 1 eq) and acetylhydrazine (101 mg, 1.36 mmol, 2 eq) were dissolved in acetic acid (5 mL). o The reaction mixture was reacted at C for 16 hours. The reaction solution was concentrated, and water (10 mL) was added, followed by ethyl acetate (20 mL). 3) Extraction, washing with saturated brine (10 mL), drying with anhydrous sodium sulfate, filtration, concentration, and purification of the crude product by silica gel column chromatography (petroleum ether:ethyl acetate = 1:2) to obtain the target product (90 mg, yield 49%). LCMS (ESI) [M+H] + =274.2; 1 H NMR (400 MHz, DMSO- d 6)δ 13.76 (s, 1H), 8.08 (s, 1H), 4.63 (t, J = 8.9 Hz, 2H), 3.84 (s, 3H), 3.56(t, J= 8.9 Hz, 2H), 2.42 (s, 3H), 2.36 (s, 3H).

[0096] Step 9: Synthesis of 7-methyl-4-(5-methyl-4H-1,2,4-triazol-3-yl)-2,3-dihydrobenzofuran-6-carboxylic acid:

[0097] Methyl 7-methyl-4-(5-methyl-4H-1,2,4-triazol-3-yl)-2,3-dihydrobenzofuran-6-carboxylic acid ester (90 mg, 0.33 mmol, 1 eq) was dissolved in methanol (3 mL). 1M sodium hydroxide aqueous solution (5 mL) was added to the reaction solution, and the reaction was carried out at room temperature for 16 hours. The reaction solution was concentrated, water (10 mL) was added, and the pH was adjusted to 3 with saturated citric acid aqueous solution. Ethyl acetate (20 mL) was then added... 3) Extraction, washing with saturated brine (10 mL), drying over anhydrous sodium sulfate, filtration, and concentration to obtain the target product (60 mg, 70% yield). LCMS (ESI) [M+H] + =260.3.

[0098] Step 10: Synthesis of 4-(1-(7-methyl-4-(5-methyl-4H-1,2,4-triazol-3-yl)-2,3-dihydrobenzofuran-6-carbonyl)piperidin-4-yl)benzyl nitrile:

[0099] 4-(piperidin-4-yl)benzyl nitrile (27 mg, 0.14 mmol, 1.5 eq), 7-methyl-4-(5-methyl-4H-1,2,4-triazol-3-yl)-2,3-dihydrobenzofuran-6-carboxylic acid (25 mg, 0.1 mmol, 1 eq), and N,N-diisopropylethylamine (37 mg, 0.29 mmol, 3 eq) were dissolved in N,N-dimethylformamide (3 mL). O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (44 mg, 0.12 mmol, 1.2 eq) was added to the reaction solution, and the reaction was carried out at room temperature for 2 hours. Water (10 mL) was added to the reaction solution, and ethyl acetate (20 mL) was used as the solvent. 3) Extraction, washing with saturated brine (10 mL), drying with anhydrous sodium sulfate, filtration, concentration, and purification of the crude product by prep-HPLC (C18, 0.1% formic acid aqueous solution / acetonitrile) to obtain the target product (9.48 mg, yield 22%). LCMS (ESI) [M+H] + =428.3; 1H NMR (400 MHz, DMSO-) d 6) δ 13.76 (s, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.53 – 7.45 (m,2H), 7.32 (d, J = 42.2 Hz, 1H), 4.71 (d, J = 13.0 Hz, 1H), 4.61 (t, J = 8.8Hz, 2H), 3.52 (t, J = 9.2 Hz, 3H), 3.16 – 3.09 (m, 1H), 2.95 – 2.83 (m, 2H), 2.39 (s, 3H), 2.08 (d, J = 37.6 Hz, 3H), 1.95 – 1.85 (m, 1H), 1.79 – 1.59 (m,2H), 1.54 – 1.39 (m, 1H).

[0100] Example 2

[0101] Preparation of 4-(1-(7-methyl-4-(5-methyl-4H-1,2,4-triazol-3-yl)-2,3-dihydrobenzofuran-6-formyl)azacyclobutane-3-yl)benzyl nitrile (compound 2):

[0102] 7-Methyl-4-(5-methyl-4H-1,2,4-triazol-3-yl)-2,3-dihydrobenzofuran-6-carboxylic acid (25 mg, 0.1 mmol, 1 eq), 4-(azacyclobutane-3-yl)benzyl nitrile (23 mg, 0.14 mmol, 1.5 eq), and N,N-diisopropylethylamine (37 mg, 0.29 mmol, 3 eq) were dissolved in N,N-dimethylformamide (3 mL). O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (44 mg, 0.12 mmol, 1.2 eq) was added to the reaction solution, and the reaction was carried out at room temperature for 16 hours. Water (10 mL) was added to the reaction solution, and ethyl acetate (10 mL) was used as the solvent. 3) Extraction, washing with saturated brine (10 mL), drying with anhydrous sodium sulfate, filtration, concentration, and purification of the crude product by prep-HPLC (C18, 0.1% formic acid aqueous solution / acetonitrile) to obtain the target product (4.43 mg, yield 12%). LCMS (ESI) [M+H]+ =400.3; 1 H NMR (400 MHz, DMSO- d 6) δ 13.71 (s, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.46 (s, 1H), 4.61 (t, J = 8.9 Hz, 2H), 4.48 (t, J = 8.2 Hz,1H), 4.35 – 4.27 (m, 1H), 4.07 (dd, J = 17.8, 9.1 Hz, 2H), 4.00 – 3.85 (m,1H), 3.57 – 3.48 (m, 2H), 2.40 (s, 3H), 2.17 (s, 3H).

[0103] Example 3

[0104] Preparation of 4-(1-(4-(4-chloro-2-methyl-1H-imidazol-5-yl)-7-methyl-2,3-dihydrobenzofuran-6-formyl)piperidin-4-yl)benzyl nitrile (compound 3):

[0105] Step 1: Synthesis of methyl 7-methyl-4-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2,3-dihydrobenzofuran-6-carboxylate:

[0106] Methyl 4-bromo-7-methyl-2,3-dihydrobenzofuran-6-carboxylate (0.60 g, 2.21 mmol, 1 eq), 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (2.35 g, 11.07 mmol, 5 eq), triphenylphosphine (58 mg, 0.22 mmol, 0.1 eq), cesium carbonate (721 mg, 2.21 mmol, 1 eq), and palladium acetate (50 mg, 0.22 mmol, 0.1 eq) were dissolved in N,N-dimethylformamide (10 mL) and reacted at 145 °C for 4 hours under a nitrogen atmosphere. The reaction solution was cooled, and water (30 mL) was added, followed by ethyl acetate (35 mL). 3) Extraction, washing with saturated brine (20 mL), drying with anhydrous sodium sulfate, filtration, concentration, and purification of the crude product by TLC (petroleum ether:ethyl acetate = 1:1) to obtain the target product (400 mg, yield 45%). LCMS (ESI) [M+H] + =403.2; 1 H NMR (400 MHz, CDCl3) δ7.50 (s, 1H), 7.11 (s, 1H), 7.01 (s, 2H), 4.66 (t, J = 8.7 Hz, 2H), 3.91 (s, 3H), 3.44 – 3.40 (m, 2H), 3.24 – 3.20 (m, 2H), 2.51 (s, 3H), 2.31 (s, 3H), 0.91 – 0.88 (m, 2H), 0.00 (s, 9H).

[0107] Step 2: Synthesis of methyl 7-methyl-4-(2-methyl-1H-imidazol-4-yl)-2,3-dihydrobenzofuran-6-carboxylate:

[0108] Methyl 7-methyl-4-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2,3-dihydrobenzofuran-6-carboxylate (400 mg, 0.99 mmol, 1 eq) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added to the reaction solution. The reaction was carried out at room temperature for 16 hours. The reaction solution was concentrated, and the crude product was purified by reverse-phase chromatography (C18, 0.1% formic acid aqueous solution / acetonitrile) to give the target product (180 mg, yield 67%). LCMS (ESI) [M+H] + =273.1.

[0109] Step 3: Synthesis of methyl 4-(5-chloro-2-methyl-1H-imidazol-4-yl)-7-methyl-2,3-dihydrobenzofuran-6-carboxylate:

[0110] Methyl 7-methyl-4-(2-methyl-1H-imidazol-4-yl)-2,3-dihydrobenzofuran-6-carboxylate (150 mg, 0.55 mmol, 1 eq) was dissolved in acetonitrile (5 mL). N-chlorosuccinimide (110 mg, 0.82 mmol, 1.5 eq) was added to the reaction solution, and the reaction was continued at room temperature for 16 hours. LCMS analysis showed product formation. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate = 100%) to obtain the target product (80 mg, yield 47%). LCMS (ESI) [M+H] + =307.0; 1 H NMR (400 MHz, DMSO- d 6) δ 12.30 (s, 1H), 7.44 (s, 1H), 4.61 (t, J =8.8 Hz, 2H), 3.82 (s, 3H), 3.32 (t, 2H), 2.30 (s, 3H), 2.19 (s, 3H).

[0111] Step 4: Synthesis of 4-(4-chloro-2-methyl-1H-imidazol-5-yl)-7-methyl-2,3-dihydrobenzofuran-6-carboxylic acid:

[0112] Methyl 4-(5-chloro-2-methyl-1H-imidazol-4-yl)-7-methyl-2,3-dihydrobenzofuran-6-carboxylate (80 mg, 0.26 mmol, 1 eq) was dissolved in methanol (2 mL). 1M sodium hydroxide aqueous solution (5 mL) was added to the reaction solution, and the reaction was carried out at room temperature for 16 hours. The reaction solution was concentrated, water (2 mL) was added, and the pH was adjusted to 4 with saturated citric acid aqueous solution. Ethyl acetate (10 mL) was then added to the solution. 3) Extraction, washing with saturated brine (15 mL), drying over anhydrous sodium sulfate, filtration, and concentration to obtain the target product (50 mg, yield 66%). LCMS (ESI) [M+H] + =293.1.

[0113] Step 5: Synthesis of 4-(1-(4-(4-chloro-2-methyl-1H-imidazol-5-yl)-7-methyl-2,3-dihydrobenzofuran-6-formyl)piperidin-4-yl)benzyl nitrile:

[0114] 4-(4-chloro-2-methyl-1H-imidazol-5-yl)-7-methyl-2,3-dihydrobenzofuran-6-carboxylic acid (50 mg, 0.17 mmol, 1 eq), 4-(piperidin-4-yl)benzyl nitrile (48 mg, 0.26 mmol, 1.5 eq), and N,N-diisopropylethylamine (66 mg, 0.51 mmol, 3 eq) were dissolved in N,N-dimethylformamide (5 mL) and stirred. O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (71 mg, 0.19 mmol, 1.1 eq) was added to the reaction solution, and the reaction was continued at room temperature for 16 hours. Water (20 mL) was added to the reaction solution, and ethyl acetate (25 mL) was used as a buffer. 3) Extraction, washing with saturated brine (20 mL), drying with anhydrous sodium sulfate, filtration, concentration, and purification of the crude product by prep-HPLC (C18, 0.1% formic acid aqueous solution / acetonitrile) to obtain the target product (19 mg, yield 24%). LCMS (ESI) [M+H] + =461.3; 1 HNMR (400 MHz, DMSO- d 6) δ 12.30 (s, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.48 (s,2H), 6.76 (d, J = 52.8 Hz, 1H), 4.73 – 4.63 (m, 1H), 4.59 (t, J = 8.7 Hz,2H), 3.30 – 3.24 (m, 2H), 3.17 – 3.08 (m, 1H), 2.95 – 2.81 (m, 2H), 2.30 (s,3H), 2.08 (d, J = 36.5 Hz, 3H), 1.89 (s, 1H), 1.80 – 1.23 (m, 4H).

[0115] Referring to Examples 1-3, the compounds of the following examples were prepared:

[0116] Biological testing evaluation

[0117] Experiment Example 1: FASN Cell Proliferation Inhibition Experiment

[0118] 1. Experimental reagents and materials:

[0119] 2. Experimental steps: 2.1 Culture medium Cell growth medium: RPMI 1640 + 10% fetal bovine serum + 1% penicillin-streptomycin Cell culture medium: RPMI 1640 + 10% lipid-lowering serum + 1% penicillin-streptomycin 2.2 Preparation of lipid-lowering serum 1. Fetal bovine serum was mixed with fumed silica overnight at room temperature (20 mg of fumed silica per milliliter of fetal bovine serum). 2. Centrifuge at 2000 xg for 15 minutes.

[0120] 3. Filter the supernatant using a filter with a pore size of 0.45 μm.

[0121] 2.3 Cell seeding and compound incubation

[0122] 1. On day 0, remove the culture medium from the culture flask, wash with DPBS, then add TrypLE™ Express for digestion, and incubate in an incubator for about 5 minutes to detach the cells from the culture flask.

[0123] 2. Neutralize TrypLE™ Express with growth medium, then transfer the cell-containing medium from the culture flask to a centrifuge tube. Centrifuge at 1000 rpm for 5 minutes and discard the supernatant.

[0124] 3. Resuspend the cells in an appropriate growth medium and use a cell counter to determine cell count and cell viability.

[0125] 4. Add growth medium to prepare a cell suspension of 6250 cells / mL.

[0126] 5. Inoculate 250 cells / 40 μL of culture medium into a 384-well plate. The control group is 40 μL of culture medium.

[0127] 6. Centrifuge the 384-well plate at 1000 rpm for 1 minute, then return the plate to the incubator and incubate overnight.

[0128] 7. On day 1, discard the culture medium in the 384-well plate and replace it with 40 μL of experimental culture medium containing 0.05% fatty acid-free bovine serum albumin + 25 μM palmitic acid (dissolved in ethanol, final ethanol content 0.25%) or ethanol (final ethanol content 0.25%).

[0129] 8. The compound was diluted with DMSO to obtain 10 final concentrations, each diluted 4-fold.

[0130] 9. Use Echo to transfer 80 nanoliters of the compound from the compound dilution plate to the cell culture plate, and then return the cell culture plate to the incubator for 7 days.

[0131] 10. On the eighth day, perform CTG testing on the cell plate as described in the "Testing" section.

[0132] 2.4 Detection

[0133] Add 20 μL of Cell Titer Glo reagent to each well of the cell culture plate. Shake at 300 rpm for 2 minutes. Incubate at room temperature for 30 minutes. Detect luminescence using Envision.

[0134] 2.5 Results

[0135] The results for the exemplary compounds are shown in the table below:

[0136] A: IC 50 ≤10nM; B: 10<IC 50 ≤100nM; C: 100<IC 50 ≤200nM.

Claims

1. A compound represented by formula (I), a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound: （I） in: R1 is H, D, cyano, or optionally substituted: C1-4 alkyl, C1-4 oxaalkyl, C1-4 thiaalkyl, C 3-6 cycloalkyl; wherein optional substitution means that it is optionally replaced by one or more groups selected from D, halogen, cyano, C 1-4 Alkyl, C 1-4 oxane, C 1-4 Thioalkyl, C 3-6 Substituents of cycloalkyl groups; Ring A is C6- 10 Aryl, 5-10 heterocyclic, 5-10 heteroaryl; R A Each occurrence is H, halogen, cyano, D, -C(O)OR aa -C(O)NR a R b -CH2OC(O)R c C can be substituted with either halogen or deuterium. 1-4 Alkyl, C 1-4 oxane, C 1-4 Thioalkyl, C 3-6 cycloalkyl groups, 3-6 membered heterocyclic groups; R aa H, C1-3 alkyl, C 3-6 cycloalkyl groups, 3-6 membered heterocyclic groups; R a R b Each is independently H, D, C1-3 alkyl, C 3-6 cycloalkyl groups, 3-6 membered heterocyclic groups; R c It is a C1-4 alkyl group or an -O-C1-4 alkyl group; Ring B is C 4-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 4-10 Cycloalkenyl, 5-10 membered heteroaryl; R B Each occurrence is H, halogen, oxo group, D, CN, OH, NH2, or optionally substituted with halogen or deuterium: C. 1-4 Alkyl, C 1-4 oxane, C 1-4 Thioalkyl; The ring C is a 4-12 membered heterocyclic group; R C Each occurrence is either H, halogen, D, CN, OH, or optionally substituted with halogen or deuterium: C. 1-4 Alkyl, C 1-4 oxane, C 1-4 Thioalkyl; a, b, and c are 0, 1, 2, 3, or 4 respectively; The heteroatoms in the heterocyclic group and heteroaryl group are independently selected from O, N or S, and the number of heteroatoms is 1, 2 or 3.

2. The compound of claim 1, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, R1 is H, D, cyano, or optionally substituted: C1-3 alkyl, C1-3 oxazane, C1-3 thiazane, C 3-4 cycloalkyl; wherein optional substitution means that it is optionally replaced by one or more groups selected from D, halogen, cyano, C 1-3 Alkyl, C 1-3 oxane, C 1-3 Thionyl, C 3-6 Substituents of cycloalkyl groups; Preferably, R1 is H, D, or optionally substituted: C1-3 alkyl, C1-3 oxaalkyl, C 3-4 cycloalkyl; wherein optional substitution means that it is optionally replaced by one or more elements selected from D, halogen, C 1-3 Substituents of alkyl groups; More preferably, R1 is H, D, or optionally substituted: methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl; wherein optional substitution means being optionally substituted by one or more substituents selected from D, F, Cl, Br; In an even more preferred embodiment, R1 is methyl.

3. The compound of claim 1 or 2, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, Ring A is phenyl, 5-10-membered heterocyclic, or 5-6-membered heteroaryl; preferably, ring A is phenyl or 5-6-membered heteroaryl; more preferably, ring A is 5-membered containing 2 or 3 nitrogen-containing heteroaryl groups; even more preferably, ring A is 4H-1,2,4-triazolyl or imidazolyl.

4. The compound according to any one of claims 1-3, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, R A Each occurrence is H, halogen, cyano, D, -C(O)OR aa -C(O)NR a R b -CH2OC(O)R c C 1-3 Alkyl, C 1-3 oxane, C 3-4 cycloalkyl, halogenated C 1-3 Alkyl, Halogenated C 1-3 Oxyalkyl, deuterated C 1-3 Alkyl, deuterated C 1-3 oxane; R aa H, C1-3 alkyl, C 3-6 cycloalkyl groups, 3-6 membered heterocyclic groups; R a R b Each is independently H, D, C1-3 alkyl, C 3-6 cycloalkyl groups, 3-6 membered heterocyclic groups; R c It is a C1-3 alkyl group or an -O-C1-3 alkyl group; Preferred, R A Each occurrence is H, halogen, cyano, D, -C(O)OR aa -C(O)NR a R b -CH2OC(O)R c C 1-3 Alkyl, C 1-3 oxane, C 3-4 cycloalkyl; R aa It is an H, C1-3 alkyl group; R a R b Each is independently H, D, C1-3 alkyl, C 3-6 cycloalkyl; R c It is a C1-3 alkyl group or an -O-C1-3 alkyl group; Further preferred, R A Each occurrence is H, halogen, cyano, D, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)NCH3CH3, -CH2OC(O)OCH3, -CH2OC(O)CH3, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl; Further optimization, R A Each occurrence is H, F, Cl, Br, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl; and even more preferably, R A Each occurrence is H, Cl, and methyl, respectively.

5. The compound according to any one of claims 1-4, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, Ring B is C 4-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 4-8 Cycloalkenyl, 5-6 membered heteroaryl; preferably, ring B is C. 5-8 Cycloalkyl, 5-8 membered heterocyclic alkyl; more preferably, ring B is a 5-membered oxygen- or sulfur-containing heterocyclic alkyl, or a 7-membered oxygen- or sulfur-containing spirocyclic alkyl; even more preferably, ring B is... , , , , , , , , The optimal choice is ring B. , , This indicates the junction with the benzene ring.

6. The compound according to any one of claims 1-5, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, R B Each occurrence is H, halogen, oxo group, D, CN, OH, NH2, or optionally substituted with halogen or deuterium: C. 1-3 Alkyl, C 1-3 oxane, C 1-3 Thioalkyl; Preferred, R B Each occurrence is H, F, Cl, Br, oxo group, D, CN, OH, NH2, and optionally substituted with halogen or deuterium: methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy; Further preferred, R B Each occurrence is respectively H, oxo group, D, CN, OH, NH2, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy; and even more preferably, R B Each occurrence is H and methyl, respectively.

7. The compound according to any one of claims 1-6, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, The ring C is a 4-10 membered heterocyclic alkyl; preferably, the ring C is a 4-8 membered heterocyclic alkyl; more preferably, the ring C is a 4-6 membered monocyclic alkyl; even more preferably, the ring C is a 4-6 membered nitrogen-containing monocyclic alkyl; even more preferably, the ring C is a nitrogen-containing 4-membered monocyclic alkyl or a nitrogen-containing 6-membered monocyclic alkyl; even more preferably, the ring C is an azo-containing heterocyclic butyl or azo-containing heterocyclic hexyl.

8. The compound according to any one of claims 1-7, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, R C Each occurrence is either H, halogen, D, CN, OH, or optionally substituted with halogen or deuterium: C. 1-3 Alkyl, C 1-3 oxane; Preferred, R C The elements appearing each time are H, halogen, D, CN, OH, and C. 1-3 Alkyl, C 1-3 oxane; Further preferred, R C Each occurrence is H, methyl, ethyl, methoxy, and ethoxy, respectively.

9. The compound according to any one of claims 1-8, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, a is 0, 1, 2 or 3; preferably, a is 1, 2 or 3; more preferably, a is 1 or 2.

10. The compound according to any one of claims 1-9, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, b is 0, 1, 2 or 3; preferably, b is 0, 1 or 2.

11. The compound according to any one of claims 1-10, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, c is 0 or 1; preferably, c is 0.

12. The compound according to any one of claims 1-11, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, The compound represented by formula (I), a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is further represented by formula (II): (II) Among them, R1, ring B, R B , ring C, R C b and c are as described in equation (I); X is either N or CRx; Rx can be H, halogen, cyano, D, or optionally substituted with halogen or deuterium: C 1-4 Alkyl, C 1-4 oxane, C 1-4 Thioalkyl, C 3-4 cycloalkyl; Preferred, R X For H, halogen, cyano, D, or optionally substituted with halogen or deuterium: C 1-3 Alkyl, C 1-3 oxane, C 3-4 cycloalkyl; Further preferred, R X The following are the radicals: H, F, Cl, Br, cyano, D, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, and cyclopropyl. Further optimization, R X For H, F, Cl, Br; and even more preferably, R X It is Cl.

13. The compound according to any one of claims 1-11, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, The compound represented by formula (I), its stereoisomers, tautomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, is further represented by formula (III): (Ⅲ) Among them, R1, ring C, R C c is as described in equation (I); X is either N or CRx; Rx can be H, halogen, cyano, D, or optionally substituted with halogen or deuterium: C 1-4 Alkyl, C 1-4 oxane, C 1-4 Thioalkyl, C 3-4 cycloalkyl; Y1, Y2, and Y3 are each independently selected from CR Y R Y O, S; and Y1, Y2, Y3 are not simultaneously CR Y R Y ; R Y Individually substituted with H, halogen, oxo group, D, CN, OH, NH2, or optionally substituted with halogen or deuterium: C 1-3 Alkyl, C 1-3 oxane, C 1-3 Thioalkyl; Preferred, R X For H, halogen, cyano, D, or optionally substituted with halogen or deuterium: C 1-3 Alkyl, C 1-3 oxane, C 3-4 cycloalkyl; Further preferred, R X The following are the radicals: H, F, Cl, Br, cyano, D, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, and cyclopropyl. Further optimized, R X For H, F, Cl, Br; and even more preferably, R X For F, Cl, Br; and even more preferably, R X For Cl; Preferably, Y1 and Y2 are selected from CR Y R Y Y3 is selected from O or S; Alternatively, Y1 and Y3 are selected from CR Y R Y Y2 is selected from O or S; Alternatively, Y2 and Y3 are selected from CR Y R Y Y1 is selected from O or S; Preferred, R Y The following can be independently H, halogen, oxo group, D, CN, OH, NH2, or optionally substituted with halogen or deuterium: methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy; Further preferred, R Y Each of the following can be independently represented as H, oxo group, D, CN, OH, NH2, methyl, ethyl, n-propyl, isopropyl, methoxy, or ethoxy; more preferably, R Y They are H and methyl groups, respectively.

14. The compound according to any one of claims 1-11, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, The compound represented by formula (I), a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is further represented by formula (IV): (Ⅳ) Among them, R1, ring A, ring C, and R A R B R C a and c are as described in equation (I); Y3 is selected from CR Y R Y O, S; R Y Individually substituted with H, halogen, oxo group, D, CN, OH, NH2, or optionally substituted with halogen or deuterium: C 1-3 Alkyl, C 1-3 oxane, C 1-3 Thioalkyl Preferably, Y3 is selected from O or S; more preferably, Y3 is selected from O. Preferred, R Y The following can be independently H, halogen, oxo group, D, CN, OH, NH2, or optionally substituted with halogen or deuterium: methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy; Further preferred, R Y Each of the following can be independently represented as H, oxo group, D, CN, OH, NH2, methyl, ethyl, n-propyl, isopropyl, methoxy, or ethoxy; more preferably, R Y It is H, methyl.

15. The compound according to any one of claims 1-11, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, The compound represented by formula (I), its stereoisomers, tautomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, is further represented by formula (V): (V) Among them, R1, ring C, R A R B R C a and c are as described in equation (I); X is either N or CRx; preferably, X is CRx. Rx can be H, halogen, cyano, D, or optionally substituted with halogen or deuterium: C 1-4 Alkyl, C 1-4 oxane, C 1-4 Thionyl, C 3-4 Cycloalkyl; preferably, Rx is H, halogen, cyano, D, optionally substituted with halogen or deuterium: methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, cyclopropyl; more preferably, Rx is H, halogen, cyano, D, optionally substituted with halogen or deuterium: methyl, methoxy; even more preferably, Rx is H, F, Cl, Br.

16. Compounds, selected from: ， Or its stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts of the compound.

17. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a compound as shown in any one of claims 1-16, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound; further, the pharmaceutical composition also comprises a pharmaceutically acceptable excipient.

18. The use of the compound of any one of claims 1-16, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, or the pharmaceutical composition of claim 17, in the preparation of a medicament for treating and / or preventing diseases mediated by fatty acid synthetase (FASN / FAS); preferably, the fatty acid synthetase (FASN / FAS)-mediated diseases are tumors, immune diseases, cerebrovascular diseases, cardiovascular diseases, infectious diseases, nervous system diseases, or metabolic diseases; more preferably, the tumor is a solid tumor; and even more preferably, the tumor is ovarian cancer.

19. The use of the compound shown in any one of claims 1-16, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, or the pharmaceutical composition of claim 17, in the preparation of a medicament for treating and / or preventing tumors, immune diseases, cerebrovascular diseases, cardiovascular diseases, infectious diseases, nervous system diseases, and metabolic diseases; preferably, the tumor is a solid tumor; more preferably, the tumor is ovarian cancer.

20. An intermediate compound of formula (A-1), a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound. (A-1) in, R represents hydrogen, C represents... 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Heteroalkyl (e.g., C) 1-6 oxane, C 1-6 Thionyl, C 1-6 (azaalkyl), C 6-10 Aryl, C 5-10 The terms "heteroaryl" and "other substituents" are defined as described in any one of claims 1-15.

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