Benzooxygen-containing heterocyclic compounds and their medicinal uses

Abstract

The present invention discloses compounds represented by formula Ib or IIb, their cis-trans isomers, enantiomers, diastereomers, racemates, tautomers, solvates, hydrates, or pharmaceutically acceptable salts or mixtures thereof, pharmaceutical compositions containing the compounds, and the use of the compounds as GPR40 agonists, wherein n, E, G 1 , L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 5b , R 6 , R 7 , X 5 , X 6 , X 7 , Y, Y 1 , Z, Z 1 and possible isotopic substitution labels of each element in the compounds are as defined in the specification. [Formula 1] JPEG2023540636000069.jpg33169

Description

[Technical Field]

[0001] The present invention relates to novel benzo oxygen-containing heterocyclic compounds, particularly benzo 5-membered oxygen-containing heterocyclic compounds, which can be used as agonists of GPR40 targets, and can reduce blood glucose levels by stimulating pancreatic islet β cells to release insulin, thereby safely and effectively treating diseases such as type II diabetes. [Background technology]

[0002] Diabetes mellitus is a chronic endocrine and metabolic disease characterized by high blood glucose levels caused by defective insulin secretion, insulin resistance, or a combination of both. Diabetes causes significant damage to various major organ systems in the body, leading to heart disease, stroke, nerve damage, kidney failure, blindness, and infections that can lead to amputation. The disease has many complications and is associated with high rates of disability and mortality.

[0003] Type 2 diabetes accounts for approximately 90% of all diabetes cases. Patients can usually produce their own insulin, but they are unable to produce enough insulin or are unable to utilize it properly. Clinically commonly used antidiabetic drugs include insulin secretagogues, which are first-line hypoglycemic drugs. These drugs include sulfonylureas such as glipizide and non-sulfonylureas such as metformin. The main common side effects of hypoglycemic drugs include gastrointestinal discomfort, edema, and hypoglycemia. In some patients, hypoglycemic side effects include intense hunger, cold sweats, general weakness, palpitations, trembling hands and feet, dizziness, headache, and drowsiness, and in severe cases, coma. Therefore, the research and development of new anti-type 2 diabetes drugs that are safe, free of hypoglycemic side effects, convenient for oral administration, and effective are still a key focus of scientific endeavors.

[0004] Recent studies have shown that free fatty acid receptor 1 (FFAR1), or G protein-coupled receptor 40 (GPR40), plays an important role in stimulating and regulating insulin production. When blood glucose and fatty acids increase after a meal, GPR40 agonists stimulate pancreatic islet β cells to release insulin, thereby lowering blood glucose levels. Therefore, drugs that activate GPR40 can effectively control blood glucose levels by helping diabetic patients release more insulin. This type of drug is characterized by promoting insulin secretion only when blood glucose levels are high, significantly reducing the risk of hypoglycemia. A representative drug of this type is TAK-875, a selective GPR40 agonist developed by Takeda Pharmaceutical Company Limited in Japan. It was in Phase III clinical trials, but studies have shown that TAK-875 has no effect on insulin secretion when blood glucose levels are normal. Clinically, a once-daily dose of 50 mg demonstrated favorable therapeutic effects and good tolerance in patients, with a significantly lower risk of hypoglycemia compared with sulfonylurea control drugs, confirming that TAK-875-induced insulin secretion was blood glucose-dependent. Although TAK-875 demonstrated excellent therapeutic efficacy, Takeda Pharmaceutical Company Limited of Japan terminated its clinical studies in 2013 due to concerns about hepatotoxicity caused by the drug. It is worth noting that research into TAK-875's hepatotoxicity has nothing to do with the drug's mechanism of action, but rather indicates that its molecular structure design is unsafe. Therefore, targeting GPR40 remains an excellent development idea with significant application prospects. [ka]

[0005] Currently published patent applications for GPR40 agonists include WO2005087710, WO2007106469A1, WO2004106276A1, WO2010143733A1, CN103030646A1, WO2013104257A1, and WO2015062486A1. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2005087710 [Patent Document 2] International Publication No. 2007106469 [Patent Document 3] International Publication No. 2004106276 [Patent Document 4] International Publication No. 2010143733 [Patent Document 5] Chinese Patent Publication No. 103030646 [Patent Document 6] International Publication No. 2013104257 [Patent Document 7] International Publication No. 2015062486 [Non-patent literature]

[0007] [Non-Patent Document 1] Remington: The Science and Practice of Pharmacy, 20th edition Philadelphia College of Pharmacy and Science, 2000 Summary of the Invention [Problem to be solved by the invention]

[0008] Thus, despite some progress being made in this field, there remains a great need in the art for GPR40 agonists and related compositions that can specifically activate GPR40 targets for the treatment of diabetes and related metabolic diseases, as well as methods of treating the diseases. [Means for solving the problem]

[0009] The present invention addresses this need and provides other related advantages.

[0010] The present invention relates to compounds capable of activating the GPR40 target, and to cis-trans isomers, enantiomers, diastereomers, racemates, tautomers, solvates, hydrates, or pharmaceutically acceptable salts or mixtures thereof of said compounds. The present invention also relates to pharmaceutically acceptable compositions comprising said compounds, and related methods, for the treatment of diseases such as diabetes and related metabolic disorders that can benefit from activation of the GPR40 target.

[0011] The present invention provides 5-membered benzo oxygen-containing heterocyclic compounds with different structures from existing compounds. The 5-membered benzo oxygen-containing heterocyclic compounds of the present invention have superior inhibitory activity against type II diabetes, can be used more effectively in the treatment of type II diabetes patients, and have superior safety.

[0012] A first aspect of the present invention provides a compound of formula Ib, its cis-trans isomers, enantiomers, diastereomers, racemates, tautomers, solvates, hydrates, or pharmaceutically acceptable salts, or mixtures thereof: [ka] where: n=0, 1 or 2; If n=0, Y does not exist and Y 1 and Z adjacent to Y 1 is directly bonded to form a 5-membered heterocyclic ring; E and G 1 are not directly bonded to form a cyclic compound, E is selected from hydrogen, deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, carboxyl, amino (NH), aminocarbonyl (HNCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, aryl, aryloxy, or heterocyclic aryl; 1is CH, or C(Rb); where Rb is hydrogen, deuterium (D), alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, alkoxycarbonyl, alkanamino, cycloalkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, aryl, aryloxy, heterocyclic, heterocyclic aryl, or heterocyclic aryloxy; or Rb and R 4 and can be linked together to form a cycloalkyl or heterocyclic group; E and G 1 When they bond to form a ring compound, G 1 is -C-; E is -O-, -C(RcRd)-, -OC(RcRd)-, -C(RcRd)O-, or -NRe-; where Rc and Rd are each hydrogen, deuterium (D), alkyl, cycloalkyl, alkenyl, hydrocarbyl, alkoxy, cycloalkoxy, alkoxycarbonyl, alkylamino, cycloalkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, aryl, aryloxy, heterocyclic group, heterocyclic aryl, or heterocyclic aryloxy, and Rc and Rd can be bonded to each other to form a cycloalkyl or heterocyclic group; Re is hydrogen, deuterium (D), alkyl, cycloalkyl, alkylcarbonyl, alkoxycarbonyl, cycloalkoxycarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, alkylsulfonyl, or arylsulfonyl; L 1 and L 2 are each independently -O-, -S-, -C(O)-, -S(O)2-, -CH2-, -C(R f R g )-, -OC(R f R g )-, -C(R f R g )O-, -N(Re)-, -N(Rc)C(R f R g )- or -C(R f R g )N(Re)-; where R f and R gare each hydrogen, deuterium (D), alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, alkoxycarbonyl, alkylamino, cycloalkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, aryl, aryloxy, heterocyclic group, heterocyclic aryl, or heterocyclic aryloxy, and Re is the same as Re in E above; R 1 , R 2 and R 3 are each independently hydrogen, deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, aminocarbonyl (HNCO), alkyl, alkoxy, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonylamino, aryl, aryloxy, or heterocyclic aryl; 2 and L 1 and can be bonded to each other to form a 4- to 8-membered heterocyclic compound, and L 1 is -CH-; R 4 , R 5 and R 5b are each independently hydrogen, deuterium (D), halogen, hydroxyl, amino, nitrile, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, cycloalkoxy, optionally substituted alkenyl, optionally substituted alkynyl, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonylamino, alkoxycarbonylamino, aryl, aryloxy, or heterocycloaryl; 5 and R 5b and can be linked together to form a cycloalkyl, heterocyclic group, or heterocyclic aryl; R 6 is carboxyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, alkylsulfonylaminocarbonyl, cycloalkylsulfonylaminocarbonyl, heterocyclic group, or heterocyclic aryl; or R 6 and ortho-substituent R 5and can be bonded to each other to form a heterocyclic group, or a heterocyclic aryl; X 5 , X 6 and X 7 are each independently hydrogen, deuterium (D), halogen, nitrile, amino, trifluoromethyl, trifluoromethoxy, aminocarbonyl (HNCO), alkyl, heterocycloalkyl, alkoxy, heteroatom-substituted alkoxy, alkylamino (NR i R j ), heteroatom-substituted alkylamino, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonylamino, alkoxycarbonylamino, cycloalkoxycarbonylamino, alkylsulfonylamino, cycloalkylsulfonylamino, aryl, aryloxy, arylaminocarbonyl, arylcarbonylamino, aryloxycarbonylamino, heterocyclic aryl, heterocyclic aryloxy, or heterocyclic arylamino; i and R j are each independently hydrogen, deuterium (D), alkyl, heterocycloalkyl, alkylcarbonyl, alkoxycarbonyl, cycloalkoxycarbonyl, alkylaminocarbonyl, alkylsulfonyl, cycloalkylsulfonyl, aryl, aryloxycarbonyl, arylaminocarbonyl, heterocyclic aryl, or R i and R j and are bonded to each other to form a 3-8 membered heterocycle containing 1-3 heteroatoms; Y and Y 1 are each independently -O-, -S-, -CH2-, -CHF-, -CF2-, -CCl2-, -C(R f R g )-, or -N(Re)-; where R f and R g The definitions of L 1 R in f and R g The definition of Re is the same as the definition of Re in E above; Z and Z 1are each independently -O-, -S-, -CH2-, -CHF-, -CF2-, -C(R f R g )-, -N(Re)-, or -C(O)-; where R f and R g The definitions of L 1 R in f and R g The definition of Re is the same as the definition of Re in E above.

[0013] A second aspect of the present invention provides compounds of formula IIb: [ka] where: n, E, G 1 , L 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 5b , X 5 , X 6 , X 7 , Y, Y 1 , Z are defined as n, E, G in claim 1. 1 , L 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 5b , X 5 , X 6 , X 7 , Y, Y 1 , which is the same as the definition of Z; R 7 is hydroxyl, alkoxy, alkylamino, cycloalkylamino, heterocyclic amino, alkylsulfonylamino, cycloalkylsulfonylamino, aryloxy, heterocyclic aryloxy, arylamino, or heterocyclic arylamino; or R 7 and ortho-substituent R 5 and can be bonded to each other to form a heterocycle.

[0014] In some preferred embodiments, n=0 or 1; If n=0, Y does not exist and Y 1 and the oxygen atom adjacent to Y are directly bonded to each other via a single bond to form a 5-membered heterocycle; When n=1, Y is -CH2-; E and G 1 are not directly bonded to form a cyclic compound, E is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, or alkoxy; G 1 is —CH—, or —C(Rb)—; where Rb is hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkoxy, or Rb and R 4 and are bonded to each other to form a heterocyclic group containing oxygen; R 4 is hydrogen, alkyl, alkoxy, optionally substituted alkynyl, or R 4 and Rb are bonded to each other to form a heterocyclic group containing oxygen; E and G 1 When they are directly bonded to form a cyclic compound, E is -OC(RcRd)-, and G 1 is -C- and R 4 is hydrogen, where Rc and Rd are each independently hydrogen; L 1 is —CH—, or R in formula IIb 2 and L 1 When L and L are bonded to each other to form a 5- or 6-membered heterocyclic compound, 1 is -OCH-; R 1 , R 2 and R 3 are each independently hydrogen, halogen, alkyl, or alkoxy; R 5 is hydrogen, halogen, hydroxyl, amino, alkylamino, alkyl or alkoxy; R 5b is hydrogen, halogen, alkyl or alkoxy; R 7is alkoxy, hydroxyl, alkylsulfonylamino, or cycloalkylsulfonylamino; X 5 is hydrogen, deuterium (D), halogen, nitrile, amino, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylamino (NR i R j ), alkylcarbonylamino, alkylaminocarbonylamino, alkoxycarbonylamino, cycloalkoxycarbonylamino, alkylsulfonylamino, cycloalkylsulfonylamino, aryl, or aryloxycarbonylamino; i and R j are each independently hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, or cycloalkoxycarbonyl; X 6 and X 7 are each independently hydrogen, deuterium (D), halogen, C1-C8 alkylamino, or C1-C8 alkoxycarbonylamino; Y 1 is -CH2-, -CHF-, -CF2-, or -C(CH3)2-; Z is —O— or —CH2—.

[0015] In some more preferred embodiments, n=0 and Y is absent; E and G 1 are not directly bonded to form a cyclic compound, E is hydrogen or halogen; G 1 is -CH-, or -C(Rb)-, where Rb is alkyl, alkenyl, alkynyl, or alkoxy; R 4 is hydrogen, alkyl or alkoxy; E and G 1 are directly bonded to form a cyclic compound, E is -OC(RcRd)-, and G 1 is -C- and R 4 is hydrogen, where Rc and Rd are each independently hydrogen; L 1 is —CH—, or R in formula IIb 2and L 1 When L and L are bonded to each other to form a 5- or 6-membered heterocyclic compound, 1 is -OCH-; R 1 , R 2 and R 3 are each independently hydrogen, halogen, or alkoxy; R 5 is hydrogen, halogen, hydroxyl, amino, alkyl or alkoxy; R 5b is hydrogen, halogen, alkyl or alkoxy; R 7 is selected from alkoxy, hydroxyl, alkylsulfonylamino, or cycloalkylsulfonylamino; X 5 is hydrogen, deuterium (D), halogen, nitrile, amino, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylamino (NR i R j ), alkylcarbonylamino, alkylaminocarbonylamino, alkoxycarbonylamino, cycloalkoxycarbonylamino, alkylsulfonylamino, cycloalkylsulfonylamino, aryl, or aryloxycarbonylamino; i and R j are each independently hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, or cycloalkoxycarbonyl; X 6 is hydrogen, deuterium (D), halogen, C1-C8 alkylamino or C1-C8 alkoxycarbonylamino; X 7 is hydrogen; Y 1 is -CH2-, -CHF-, -CF2-, or -C(CH3)2-; Z is -O-.

[0016] In some specific embodiments, the compounds of the invention have a structure selected from the following group: [ka]

[0017] Another embodiment of the present invention provides a composition comprising (i) a therapeutically effective amount of at least one compound of Formula Ib or IIb, its cis-trans isomer, enantiomer, diastereomer, racemate, tautomer, solvate, hydrate, or pharmaceutically acceptable salt or mixtures thereof, and (ii) a pharmaceutically acceptable diluent and / or excipient.

[0018] The invention also relates to the use of said compound or composition in the manufacture of a medicament for use as a GPR40 agonist.

[0019] The present invention also provides a method for treating or preventing diabetes or the associated metabolic syndrome, comprising administering to a patient a therapeutically effective amount of the compound or composition described above.

[0020] The invention also relates to the use of said compound or composition in the manufacture of a medicament for treating or preventing diabetes or the associated metabolic syndrome.

[0021] In a preferred embodiment, the compound or composition of the present invention is particularly suitable for treating type II diabetes.The compound of the present invention promotes insulin secretion only when the blood glucose level of type II diabetes patients is high, so that the risk of hypoglycemia of patients can be effectively reduced.At the same time, compared with commercially available drugs, the compound of the present invention has better selectivity for GPR40 target and safety.

[0022] The above embodiments and other aspects of the present invention will become apparent from the following detailed description, and to this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds and / or compositions, each of which is incorporated herein by reference in its entirety. DETAILED DESCRIPTION OF THE INVENTION

[0023] Detailed Description of the Invention

[0024] In the following description, several specific details are set forth to provide a thorough understanding of various embodiments of the present invention. However, it should be understood by those skilled in the art that the present invention may be practiced without these details. Unless the context dictates otherwise, throughout the present specification and claims, the word "comprises" and variations thereof, such as "includes" and "comprehensive," are understood to be open and inclusive (i.e., "including, but not limited to").

[0025] References herein to "one embodiment" or "one embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrase "in one embodiment" or "one embodiment" in various places throughout the specification are not necessarily all referring to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0026] I. Definition

[0027] In the present invention, unless otherwise specified, the term "alkyl" refers to branched or straight-chain saturated aliphatic hydrocarbon groups containing 1 to 20 carbon atoms, consisting solely of carbon and hydrogen atoms. In preferred embodiments, the alkyl has 1 to 12 carbon atoms (C1-C12 alkyl), 1 to 8 carbon atoms (C1-C8 alkyl), or 1 to 6 carbon atoms (C1-C6 alkyl) and is connected to the remainder of the molecule by a single bond. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, and various isomers thereof. The alkyl may be optionally substituted with a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, carboxyl, amino (NH), aminocarbonyl (HNCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cycloether group, heterocyclic group, alkylureido, aryl, aryloxy, heterocyclic aryl, heterocyclic aryloxy, fused ring aryl, fused ring heterocyclic aryl, fused ring oxy, fused ring aryloxy, fused ring heterocyclic aryloxy, arylureido, or heterocyclic arylureido.

[0028] In the present invention, unless otherwise specified, the above-mentioned "alkylene group" refers to a secondary group derived by further removing one hydrogen atom from an alkyl group containing 1 to 20 carbon atoms, such as methylene, ethylidene, propylidene, etc.

[0029] In the present invention, unless otherwise specified, the term "aryl" refers to any stable monocyclic, bicyclic, tricyclic, or tetracyclic ring containing up to 7 carbon atoms in each ring, with at least one ring being an aromatic hydrocarbon ring system. Exemplary aryls include hydrocarbon ring systems containing hydrogen, 6-9 carbon atoms, and at least one aromatic ring; hydrocarbon ring systems containing hydrogen, 9-12 carbon atoms, and at least one aromatic ring; hydrocarbon ring systems containing hydrogen, 12-15 carbon atoms, and at least one aromatic ring; or hydrocarbon ring systems containing hydrogen, 15-18 carbon atoms, and at least one aromatic ring. For purposes of the present invention, aryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and can include fused or bridged ring systems. Aryl groups include, but are not limited to, aryl groups derived from benzene, biphenyl, anthracene, azulene, fluorene, indane, indene, naphthalene, phenanthrene, pyrene, and the like. The term "optionally substituted aryl" refers to an aryl group or a substituted aryl group. The aryl may be optionally substituted with a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, carboxyl, amino (NH), aminocarbonyl (HNCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, alkyl-sulfonyl-alkoxy, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cycloether, heterocyclic group, aryl, aryloxy, heterocyclic aryl, fused-ring aryl, fused cycloalkyl, fused cycloalkyl, fused-ring oxy, unsubstituted or benzene or biphenyl containing 1 to 4 of any of the above substituents.

[0030] In the present invention, unless otherwise specified, the above-mentioned "heterocyclic aryl" refers to a stable monocyclic, bicyclic, or tricyclic ring containing up to 7 carbon atoms in each ring, in which at least one ring is aromatic and at least one ring contains 1 to 4 heteroatoms selected from O, N, and / or S. Heterocyclic aryl within this definition includes, but is not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl, benzothiazolyl, benzothienyl, benzofuryl, quinolinyl, isoquinolyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, and tetrahydroquinoline. Furthermore, "heterocyclic aryl" should also be understood to include quaternary ammonium salts or N-oxide derivatives of any nitrogen-containing heterocyclic aryl. The heterocyclic aryl may be optionally substituted with a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, carboxyl, amino (NH), aminocarbonyl (HNCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cycloether group, heterocyclic group, aryl, aryloxy, heterocyclic aryl, fused ring aryl, fused cycloalkyl, fused cycloalkyl, fused ring oxy, unsubstituted or benzene or biphenyl containing 1 to 4 of any of the above substituents.

[0031] In the present invention, unless otherwise specified, the above-mentioned "fused-ring aryl" refers to a stable bicyclic or tricyclic ring in which each ring contains up to 7 atoms, and at least one ring is aromatic. The fused-ring aryl may be optionally substituted with a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, carboxyl, amino (NH), aminocarbonyl (HNCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cycloether group, heterocyclic group, aryl, aryloxy, heterocyclic aryl, fused-ring aryl, fused cycloalkyl, fused cycloalkyl, fused-ring oxy, unsubstituted or benzene or biphenyl containing 1 to 4 of any of the above-mentioned substituents.

[0032] In the present invention, unless otherwise specified, the above-mentioned "fused-ring heterocyclic aryl" refers to a stable bicyclic or tricyclic ring in which each ring contains up to 7 atoms, at least one ring being aromatic and containing 1 to 4 heteroatoms selected from O, N, and / or S. The fused-ring heterocyclic aryl may be optionally substituted with a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, carboxyl, amino (NH), aminocarbonyl (HNCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cycloether group, heterocyclic group, aryl, aryloxy, heterocyclic aryl, fused-ring aryl, fused cycloalkyl, fused cycloalkyl, fused-ring oxy, unsubstituted or benzene or biphenyl containing 1 to 4 of any of the above substituents.

[0033] [Ran 33] TIFF0007804653000005.tif28167 Examples of alkoxy groups include, but are not limited to, -O-methyl (methoxy), -O-ethyl (ethoxy), -O-propyl (propoxy), -O-isopropyl (isopropoxy), and -O-tert-butyl (tert-butoxy).

[0034] In the present invention, unless otherwise specified, the above "alkenyl" refers to a branched or straight chain unsaturated aliphatic alkenyl containing 2 to 20 carbon atoms and 1 to 3 "carbon-carbon double bonds", preferably containing 2 to 10 carbon atoms (C2-C 10 alkenyl), more preferably containing 2 to 8 carbon atoms (C2-C8 alkenyl) or 2 to 6 carbon atoms (C2-C6 alkenyl), and various isomers thereof, connected to the remainder of the molecule by a single bond. Examples of alkenyl include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like. The alkenyl may be optionally substituted with a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, carboxyl, amino (NH2), aminocarbonyl (H2NCO), alkyl, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cycloether group, heterocyclic group, alkylureido, aryl, heterocyclic aryl, fused ring aryl, fused ring heterocyclic aryl, arylureido, or heterocyclic arylureido.

[0035] In the present invention, unless otherwise specified, the above "alkynyl" refers to a branched or straight chain unsaturated aliphatic alkynyl containing 2 to 20 carbon atoms and 1 to 2 "carbon-carbon triple bonds", preferably containing 2 to 10 carbon atoms (C2-C 10and alkynyl), more preferably containing 2 to 8 carbon atoms (C2-C8 alkynyl) or 2 to 6 carbon atoms (C2-C6 alkynyl), and various isomers thereof, connected to the remainder of the molecule by a single bond. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. The alkynyl may be optionally substituted with a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, carboxyl, amino (NH2), aminocarbonyl (H2NCO), alkyl, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cycloether group, heterocyclic group, alkylureido, aryl, heterocyclic aryl, fused ring aryl, fused ring heterocyclic aryl, arylureido, or heterocyclic arylureido.

[0036] [Ran 36] TIFF0007804653000006.tif28167

[0037] [Ran 37] TIFF0007804653000007.tif25167

[0038] In the present invention, unless otherwise specified, the above "arylamino" refers to an amine in which one hydrogen in "NH3" is replaced by aryl, where the definition of aryl is the same as that of aryl above.

[0039] In the present invention, unless otherwise specified, the above "heterocyclic arylamino" refers to an amine in which one hydrogen atom in "NH" is replaced by a heterocyclic aryl, and the definition of the heterocyclic aryl is the same as that of the above heterocyclic aryl.

[0040] In the present invention, unless otherwise specified, the above "cycloalkyl" refers to an all-carbon monocyclic or polycyclic group in which each ring does not contain a double bond or a triple bond. The ring preferably has 3 to 20 carbon atoms, 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, 3 to 5 carbon atoms, 4 carbon atoms, or 3 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The cycloalkyl may be optionally substituted with a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, carboxyl, amino (NH), aminocarbonyl (HNCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cycloether group, heterocyclic group, alkylureido, aryl, aryloxy, heterocyclic aryl, heterocyclic aryloxy, fused ring aryl, fused ring heterocyclic aryl, fused ring oxy, fused ring aryloxy, fused ring heterocyclic aryloxy, arylureido, or heterocyclic arylureido, wherein aryl is defined as above.

[0041] In the present invention, unless otherwise specified, the above "cycloalkenyl" refers to an all-carbon monocyclic or polycyclic group in which one ring or each ring contains one or more "double bonds." The ring preferably has 3 to 20 carbon atoms, 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, 3 to 5 carbon atoms, 4 carbon atoms, or 3 carbon atoms as ring atoms. Examples of cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. The cycloalkenyl may be optionally substituted with a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, carboxyl, amino (NH), aminocarbonyl (HNCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cycloether group, heterocyclic group, alkylureido, aryl, aryloxy, heterocyclic aryl, heterocyclic aryloxy, fused ring aryl, fused ring heterocyclic aryl, fused ring oxy, fused ring aryloxy, fused ring heterocyclic aryloxy, arylureido, or heterocyclic arylureido. When a cycloalkenyl substituent replaces a carbon-carbon double bond and saturates the double bond, a cycloalkyl can be formed.

[0042] In the present invention, unless otherwise specified, the above "cycloether group" refers to a cycloalkyl having an ether group on the ring.

[0043] In the present invention, unless otherwise specified, the above-mentioned "heterocyclic group" refers to an aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from O, N, and S, including bicyclic groups. Therefore, "heterocyclic group" includes the above-mentioned heterocyclic aryls and their dihydro or tetrahydro analogs, and also includes, but is not limited to, benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, isobenzofuryl, and pyridopyridyl. Heterocyclic groups can be linked to other organic small molecule groups through carbon atoms or heteroatoms to form new compounds with medicinal properties.

[0044] In the present invention, unless otherwise specified, the above-mentioned "fused ring aryl" refers to a polycyclic organic compound formed by condensing two or more aryls and / or heterocyclic aryls, and the condensed ring aryl may be substituted in a reasonable manner with alkyl, alkoxy, alkylthio, aryloxy, arylamino, heterocyclic group, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cycloether group, aryl, halogen, carbonyl, hydroxyl, heterocyclic aryl, etc., as defined in the present invention; naphthalene, anthracene, quinone, phenanthrene, fluorene, benzimidazolyl, furfuryl, thienothienyl, acenaphthyl, [ka]

[0045] In the present invention, unless otherwise specified, the above "fused cycloalkyl" refers to a non-aromatic polycyclic ring system formed after one or more double bonds in a fused ring aryl are reduced, and has a carbon number of C 10 - 20 It refers to something that is.

[0046] In the present invention, unless otherwise specified, the above "fused cycloalkylaryl" refers to a group formed after the hydrogen on the carbon of an aryl is replaced with a fused cycloalkyl, and has a carbon number of C 15 - 20 It refers to something that is.

[0047] [Ran 47] TIFF0007804653000009.tif27167

[0048] [Ran 48] TIFF0007804653000010.tif39167

[0049] [Ran 49] TIFF0007804653000011.tif29164

[0050] [Ran 50] TIFF0007804653000012.tif27164

[0051] [Ran 51] TIFF0007804653000013.tif31164

[0052] [Ran 52] TIFF0007804653000014.tif35164

[0053] [Ran 53] TIFF0007804653000015.tif33168

[0054] [Ran 54] TIFF0007804653000016.tif32168

[0055] [Ran 55] TIFF0007804653000017.tif33168

[0056] [Ran 56] TIFF0007804653000018.tif35168

[0057] [Ran 57] TIFF0007804653000019.tif40166

[0058] [Ran 58] TIFF0007804653000020.tif31166

[0059] [Ran 59] TIFF0007804653000021.tif31166

[0060] [Ran 60] TIFF0007804653000022.tif32166

[0061] [Ran 61] TIFF0007804653000023.tif33166

[0062] [Ran 62] TIFF0007804653000024.tif30166

[0063] [Ran 63] TIFF0007804653000025.tif34166

[0064] [Ran 64] TIFF0007804653000026.tif31166

[0065] [Ran 65] TIFF0007804653000027.tif34166

[0066] In the present invention, the term "halogen" refers to a "fluorine, chlorine, bromine or iodine atom."

[0067] [Ran 67] TIFF0007804653000028.tif17166

[0068] [Ran 68] TIFF0007804653000029.tif16166

[0069] [Ran 69] TIFF0007804653000030.tif16166

[0070] [Ran 70] TIFF0007804653000031.tif16166

[0071] [Ran 71] TIFF0007804653000032.tif19160

[0072] [Ran 72] TIFF0007804653000033.tif21160

[0073] [Ran 73] TIFF0007804653000034.tif20160

[0074] [Ran 74] TIFF0007804653000035.tif21160

[0075] [Ran 75] TIFF0007804653000036.tif22160

[0076] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0077] II. Compounds of the Invention

[0078] [Ran 78] TIFF0007804653000037.tif29165 (where R 8We have designed and synthesized five-membered oxygen-containing benzo heterocycles as novel GPR40 target agonists that can effectively treat type II diabetes by innovatively introducing a group (which may be halogen, hydroxyl, amino, carboxyl, alkylsulfonyloxy, arylsulfonyloxy, or an optionally substituted leaving group).

[0079] The present invention generally relates to compounds encompassed by Formula Ib, its cis-trans isomers, enantiomers, diastereomers, racemates, tautomers, solvates, hydrates, or pharmaceutically acceptable salts or mixtures thereof: [ka]

[0080] For compounds of formula Ib, n, E, G 1 , L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 5b , R 6 , Ra, Rb, Rc, Rd, Re, Rf, Rg, Ri, Rj, X 5 , X 6 , X 7 , Y, Y 1 , Z and Z 1 is as defined in the specification.

[0081] Specific embodiments of compounds of formula Ib are also described below.

[0082] In one embodiment, n=0, Y is absent, and Y 1 and Z 1 are directly bonded by a single bond.

[0083] In one embodiment, E and G 1 are linked to form a cyclic compound. In one preferred embodiment, E and G 1 are linked to form a five-membered ring compound. In one preferred embodiment, G 1is -C-, and E is -O-, -C(RcRd)-, -OC(RcRd)-, or -C(RcRd)O-. In one embodiment, Rc and Rd are independently selected from hydrogen, deuterium (D), alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, alkoxycarbonyl, alkylamino, cycloalkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, aryl, aryloxy, heterocyclic, heterocyclicaryl, or heterocyclicaryloxy. In another embodiment, Rc and Rd can be bonded together to form a cycloalkyl or heterocyclic group. In a preferred embodiment, G 1 is -C- and E is -OC(RcRd)- or -C(RcRd)O-, where Rc and Rd are independently selected from hydrogen, deuterium (D), C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl group, C1-C8 alkoxy, C3-C8 cycloalkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkylamino, C3-C8 cycloalkylamino, C1-C8 alkylaminocarbonyl, C3-C8 cycloalkylaminocarbonyl, aryl, aryloxy, heterocyclic group, heterocyclic aryl, or heterocyclic aryloxy. 1 is —C—, and E is —OC(RcRd)— or —C(RcRd)O—, where Rc and Rd are each hydrogen.

[0084] In one embodiment, L 1 and L 2 are each independently selected from —O—, —S—, —C(O)—, —SO—, —CH—, —C(RfRg)—, —OC(RfRg)—, —C(RfRg)O—, —N(Re)—, —N(Rc)C(RfRg)—, or —C(RfRg)N(Re)—. In one preferred embodiment, L 1 and L 2 In another preferred embodiment, in formula Ib, one of R is -CH- and the other is -O-. 2 and L 1 are bonded to each other to form a 5- or 6-membered heterocyclic compound, and L1 and L 2 At least one of is -OCH-.

[0085] In one embodiment, R 1 , R 2 and R 3 are each independently hydrogen, deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, aminocarbonyl (HNCO), C-C alkyl, C-C alkoxy, C-C alkoxycarbonyl, C-C alkylaminocarbonyl, C-C alkylcarbonylamino, aryl, aryloxy, or heterocyclic aryl. 1 , R 2 and R 3 are each independently hydrogen, halogen, or C1-C8 alkoxy.

[0086] In one embodiment, R 4 and R 5 are each independently selected from hydrogen, halogen, hydroxyl, amino, or alkoxy. 4 and R 5 are each independently hydrogen, halogen, or C1-C8 alkoxy.

[0087] In one embodiment, R 6 HA-COR 7 In one preferred embodiment, R 7 is —OH, alkoxy, alkylamino, cycloalkylamino, heterocyclic amino, alkylsulfonylamino, cycloalkylsulfonylamino, aryloxy, heterocyclic aryloxy, arylamino, or heterocyclic arylamino; or R 7 and ortho-substituent R 5 and can be bonded to each other to form a heterocycle. In one preferred embodiment, R 7 is C1-C8 alkoxy, hydroxyl, C1-C8 alkylsulfonylamino, or C3-C8 cycloalkylsulfonylamino.

[0088] In one embodiment, Y 1 -oxygen-, -sulfur-, -CH2-, -CHF-, -CF2-, -CCl2-, -C(R f R g In a preferred embodiment, Y 1 is selected from CH2, -CHF-, CF2, or C(CH3)2.

[0089] In one embodiment, Z and Z 1 are independently -O-, -S-, -CH2-, -CHF-, -CF2-, -C(R f R g )-, -N(Re)-, or -C(O)-; where R f and R g The definition of each of the above L 1 R in f and R g and Re is the same as the definition of Re in E. In a more preferred embodiment, Z and Z 1 In one more preferred embodiment, at least one of Z and Z is -O-. 1 Both are -O-.

[0090] In one embodiment, Z is —O—.

[0091] In one embodiment, Z 1 is -O-.

[0092] In one embodiment, X 5 , X 6 and X 7 are each independently hydrogen, deuterium (D), halogen, nitrile, amino, trifluoromethyl, trifluoromethoxy, aminocarbonyl (HNCO), alkyl, heterocycloalkyl, alkoxy, heteroatom-substituted alkoxy, alkylamino (NR i R j), heteroatom-substituted alkylamino, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonylamino, alkoxycarbonylamino, cycloalkoxycarbonylamino, alkylsulfonylamino, cycloalkylsulfonylamino, aryl, aryloxy, arylaminocarbonyl, arylcarbonylamino, aryloxycarbonylamino, heterocyclic aryl, heterocyclic aryloxy, or heterocyclic arylamino; i and R j are each independently hydrogen, deuterium (D), alkyl, heterocycloalkyl, alkylcarbonyl, alkoxycarbonyl, cycloalkoxycarbonyl, alkylaminocarbonyl, alkylsulfonyl, cycloalkylsulfonyl, aryl, aryloxycarbonyl, arylaminocarbonyl, or heterocyclic aryl; or R i and R j are bonded to each other to form a 3- to 8-membered heterocycle containing 1 to 3 heteroatoms.

[0093] In one embodiment, X 5 is selected from hydrogen, deuterium (D), halogen, nitrile, amino (NH), trifluoromethyl, trifluoromethoxy, C-C alkyl, C-C alkoxy, C-C alkylamino, C-C alkylcarbonylamino, C-C alkylaminocarbonylamino, C-C alkoxycarbonylamino, C-C cycloalkoxycarbonylamino, C-C alkylsulfonylamino, C-C cycloalkylsulfonylamino, aryl, or aryloxycarbonylamino. 5 is selected from hydrogen, deuterium (D), halogen, nitrile, trifluoromethyl, trifluoromethoxy, C1-C8 alkoxycarbonylamino.

[0094] In one embodiment, X 6 and X 7are each independently selected from hydrogen, deuterium (D), halogen, C1-C8 alkylamino, or C1-C8 alkoxycarbonylamino. 6 is selected from hydrogen, deuterium (D), halogen, C1-C8 alkylamino, or C1-C8 alkoxycarbonylamino; X 7 is selected from hydrogen.

[0095] The compounds of the present invention can exist in various isomeric forms, as well as in one or more tautomeric forms, including two single tautomers and mixtures of tautomers. The term "isomer" is intended to encompass all isomeric forms of the compounds of the present invention, including tautomers of said compounds.

[0096] Some of the compounds described herein have asymmetric centers and can therefore exist in different enantiomeric and diastereomeric forms. The compounds of the present invention may be in the form of optical isomers or diastereomers. Thus, the present invention encompasses the use of the compounds of the present invention, as well as their optical isomers, diastereomers, and mixtures thereof (including racemic mixtures) described herein. Optical isomers of the compounds of the present invention can be obtained by known techniques, such as asymmetric synthesis, chiral chromatography, or chemical resolution of stereoisomers using optically active resolving agents.

[0097] Unless otherwise specified, "stereoisomer" refers to one stereoisomer of a compound that is substantially free of other stereoisomers of the compound. Thus, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound contains more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomer of the compound, e.g., more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomer of the compound, or more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomer of the compound, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomer of the compound.

[0098] In the event of a discrepancy between the depicted structure and the name given to the structure, the depicted structure shall prevail. Furthermore, if the stereochemistry of a structure or portion of a structure is not indicated, for example, by a bold or dashed line, the structure or portion of a structure shall be understood to encompass all stereoisomers thereof. However, in cases where multiple chiral centers are present, the structure and name may be represented by a single enantiomer to help describe the relevant stereochemistry. Those skilled in the art of organic synthesis recognize situations in which the compounds are prepared in the same manner as their single enantiomers.

[0099] As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic acid or base salt of the compound of the present invention. Typical pharmaceutically acceptable salts include, for example, alkali metal salts, alkaline earth metal salts, ammonium salts, water-soluble salts, and water-insoluble salts, such as acetate, aminostilbenesulfonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camphorsulfonate, carbonate, chloride, citrate, clavulanate, disodium salt. Acid salts, edetate, edisylate, lauryl sulfate propionate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycolate asanate, hexafluorophosphate, hexylresorcinolate, halamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodate, isothiosulfate, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, methyl bromide, Methyl nitrate, methanesulfonate, mucate, naphthalenesulfonate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methylene-bis-2-hydroxy-3-naphthoate, pamoate), pantothenate, phosphate / diphosphate, picrate, polygalacturonic acid, propionate, p-toluenesulfonate, salicylate, stearate, acetic acid Pharmaceutically acceptable salts include succinate, sulfate, sulfosalicylate, thoronate, tannate, tartrate, 8-chlorotheophylline salt, tosylate, triethyl iodide, and pentanoate. Pharmaceutically acceptable salts may have multiple charged atoms in their structure. In such cases, pharmaceutically acceptable salts may have multiple counter ions. Therefore, pharmaceutically acceptable salts may have one or more charged atoms and / or one or more counter ions.

[0100] The compounds of the present invention can be isotope-labeled, in which one or more atoms are replaced by atoms having different atomic masses or mass numbers. Examples of isotopes that can be incorporated into compounds of formula Ib or IIb include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, or iodine. Examples of such isotopes are, respectively: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 I. These radiolabeled compounds can be used to measure biodistribution, tissue concentrations, and transport and excretion kinetics from biological tissues, including subjects administered the labeled compounds. The labeled compounds are also used to determine therapeutic efficacy, site or mode of action, and binding affinity of candidate therapeutic agents to pharmacologically important targets. Thus, certain radiolabeled compounds of Formula Ib or IIb are useful in drug and / or tissue distribution studies. The radioisotope tritium, i.e. 3 H and carbon-14, i.e. 14 C is particularly useful for this purpose due to its ease of incorporation and readily available means of detection.

[0101] Deuterium, i.e. 2 Substitution with heavy isotopes such as H can confer certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life of deuterium-containing compounds). Substitution of hydrogen with deuterium can reduce the dosage required to achieve a therapeutic effect, making it suitable for use in discovery or clinical settings.

[0102] Positron-emitting isotopes (e.g. 11 C. 18 F, 15 O and 13Substitution with N) can provide labeled analogs of the compounds of the invention that are useful, for example, in positron emission tomography (PET) studies for detecting substance receptor occupancy. Isotopically labeled compounds of Formula Ib or IIb can generally be prepared by conventional techniques known to those skilled in the art using appropriate isotopic labeling reagents, or by methods similar to those described in the Preparations and Examples section below.

[0103] The embodiments of the invention described herein are also intended to encompass in vivo metabolic products of compounds of Formula Ib or IIb. These products may result, for example, from processes such as oxidation, reduction, hydrolysis, amidation, esterification, and the like, which are primarily due to enzymatic activity when a compound of the invention is administered. Accordingly, such compounds are encompassed by the invention and are produced as by-products upon the exertion of enzymatic or non-enzymatic activity on a compound of the invention after the compound of the invention has been administered to a mammal for a period of time sufficient to produce the metabolic product. Metabolites, particularly pharmaceutically active metabolites, are typically identified by administering a detectable dose of a radiolabeled compound of the invention to a subject, such as a rat, mouse, guinea pig, monkey, or human, allowing a sufficient period of time for the process to produce a metabolic product; and isolating the metabolic product from urine, blood, or other biological samples obtained from the subject administered the radiolabeled compound.

[0104] The present invention also provides pharmaceutically acceptable salt forms of compounds of Formula Ib or IIb. The scope of the present invention includes acid addition salts and base addition salts formed by contacting a pharmaceutically suitable acid or a pharmaceutically suitable base with a compound of the present invention.

[0105] "Pharmaceutically acceptable acid addition salts" refers to salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic and organic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids include, for example, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, lauryl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphate, glycol Acids include, but are not limited to, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, bishydroxynaphthoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

[0106] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of the following substances: That is, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hibamine, choline, betaine, phenethylbenzylamine, benzathine penicillin, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0107] Crystallization generally produces solvates of the compounds of the present invention. As used herein, the term "solvate" refers to one or more molecular aggregates containing one or more molecules of the compounds of the present invention and a solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist in the form of hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., as well as corresponding solvates. While the compounds of the present invention may be true solvates, in other cases, the compounds of the present invention may contain only unspecified water or may be a mixture of water and some unspecified solvent.

[0108] "Stereoisomers" refer to compounds in which the same atoms are bonded by the same bonds but which have different three-dimensional structures and are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to molecules of two stereoisomers that are not superimposable and form mirror images of one another.

[0109] The compounds of the present invention, or pharmaceutically acceptable salts thereof, can contain one or more asymmetric centers, thereby giving rise to enantiomers, diastereomers, and other stereoisomeric forms distinguishable with respect to absolute stereochemistry, e.g., (R)- and (S)-, or (D)- or (L)- in the case of amino acids. The present invention is intended to encompass all such possible isomers, as well as their racemic and optically pure forms. Optically active (+)- and (−), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents or resolved by conventional techniques, such as chromatography or fractional crystallization. Conventional techniques for the preparation / separation of individual enantiomers include chiral synthesis from appropriate optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When a compound described herein contains an olefinic double bond or other center of geometric asymmetry, unless otherwise specified, the compound is intended to include both E and Z geometric isomers, as well as all tautomeric forms.

[0110] III. Pharmaceutical Compositions

[0111] In one embodiment, the compound of Formula Ib or IIb is formulated in the form of a pharmaceutically acceptable composition comprising an amount of the compound of Formula Ib or IIb, wherein, after administration of the pharmaceutical composition to a mammal, said amount is effective to treat the particular disease or condition of interest. The pharmaceutical compositions of the present invention may comprise a compound of Formula Ib or IIb in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

[0112] For this purpose, a "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier, all of which are approved by the U.S. Food and Drug Administration as acceptable for humans or veterinary use.

[0113] Furthermore, "mammal" includes humans and domestic animals, such as laboratory animals and domestic pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domestic animals, such as wild animals.

[0114] Pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present invention with a suitable pharmaceutically acceptable carrier, diluent, or excipient, and can be formulated into solid, semi-solid, liquid, or gaseous forms (e.g., tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols). Typical routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal. As used herein, the term parenteral includes subcutaneous, intravenous, intramuscular, and intrasternal injection or infusion techniques. Pharmaceutical compositions of the present invention are formulated so that the active ingredients contained therein are bioavailable after administration of the composition to a patient. The composition administered to a subject or patient may be in the form of one or more dosage units; for example, a tablet may be a single dosage unit, and a container of a compound of the present invention in aerosol form may contain multiple dosage units. Actual methods for preparing such dosage forms are known or apparent to those skilled in the art. See, for example, Non-Patent Document 1: Remington: The Science and Practice of Pharmacy, 20th Edition, Philadelphia College of Pharmacy and Science, 2000. The composition administered in any given case will contain a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof to treat the disease or condition of interest in accordance with the teachings of the present invention.

[0115] The pharmaceutical composition of the present invention may be in solid or liquid form. In one embodiment, the carrier is granular, whereby the composition is, for example, in the form of a tablet or powder. The carrier may also be liquid, where the composition is, for example, a syrup for oral administration, a liquid for injection, or an aerosol that can be used, for example, for administration by inhalation. When intended for oral administration, the pharmaceutical composition is preferably in solid or liquid form, whereby semi-solid, semi-liquid, suspension, and gel form are included in the solid or liquid form contemplated herein.

[0116] As a solid composition for oral administration, the pharmaceutical composition can be formulated into a powder, granules, compressed tablets, pills, capsules, chewing gum, flakes, or the like. Such solid compositions generally contain one or more inert diluents or edible carriers. Additionally, one or more of the following substances may be present: binders such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch, lactose, or dextrin; disintegrating agents such as alginic acid, sodium alginate, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; flavorings such as mint, methyl salicylate, or orange flavoring, and coloring agents.

[0117] When the pharmaceutical composition is in the form of a capsule (eg, a gelatin capsule), it can contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.

[0118] The pharmaceutical composition may be in the form of a liquid, such as an elixir, syrup, solution, emulsion, or suspension. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, preferred compositions may contain, in addition to the compound of the present invention, one or more of a sweetener, a preservative, a dye / colorant, and a flavor enhancer. For compositions intended for administration by injection, one or more of a surfactant, a preservative, a wetting agent, a dispersing agent, a suspending agent, a buffer, a stabilizer, and an isotonic agent may be included.

[0119] Liquid pharmaceutical compositions of the present invention, whether in solution, suspension, or other similar form, may contain one or more of the following adjuvants: sterile diluents such as water for injection, saline solution (preferably saline), Ringer's solution, or isotonic sodium chloride; fixed oils such as synthetic monoglycerides or diglycerides, polyethylene glycol, glycerol, propylene glycol, or other solvents that can be used as solvents or suspension media; antibacterial agents such as benzyl alcohol or methyl p-hydroxybenzoate; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates, and isotonic agents for adjusting tonicity such as sodium chloride or glucose. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic. Saline is a preferred adjuvant. Injectable pharmaceutical compositions are preferably sterile.

[0120] The pharmaceutical composition of the present invention can be prepared by any method known in the field of pharmacy. For example, a pharmaceutical composition intended for administration by injection can be prepared by combining the compound of the present invention with sterile distilled water to form a solution. A surfactant can be added to facilitate the formation of a uniform solution or suspension. A surfactant is a compound that interacts non-covalently with the compound of the present invention to facilitate the dissolution or uniform suspension of the compound in an aqueous delivery system.

[0121] IV. Therapeutic Uses

[0122] A therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof is administered, but the therapeutically effective amount will vary depending on various factors, including the activity of the particular compound used, the metabolic stability and duration of action of the compound, the patient's age, body weight, general health, sex, diet, method and time of administration, excretion rate, concomitant medications, the severity of the particular disease or condition, and the subject being treated.

[0123] An "effective amount" or "therapeutically effective amount" refers to an amount of a compound of the invention that, when administered to a mammal, preferably a human, is sufficient to provide effective treatment of an Mnk-related condition or disease in the mammal (preferably a human). The amount of a compound of the invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, the method of administration, and the age of the mammal being treated, but is routinely determined based on the knowledge of one of ordinary skill in the art and the present invention.

[0124] The compound of the present invention or a pharmaceutically acceptable salt thereof can be administered before, simultaneously with, or after the administration of one or more other therapeutic agents. Such combination therapy includes administering a single pharmaceutical dosage formulation containing the compound of the present invention and one or more other active substances, as well as administering the compound of the present invention and each active substance in separate pharmaceutical dosage formulations. For example, the compound of the present invention and the other active substances can be administered to a patient together in a single oral dosage composition (e.g., a tablet or capsule), or each substance can be administered in a separate oral dosage formulation. When separate dosage formulations are used, the compound of the present invention and one or more other active substances can be administered at substantially the same time (i.e., simultaneously) or at separate, staggered times (i.e., sequentially). It should be understood that combination therapy includes all such administration modes.

[0125] The present invention also further studies and optimizes the structures of GPR40 target agonist compounds of formula Ib-IIb through structure-effect relationship (SAR), which can effectively reduce the risk of hypoglycemia and treat type II diabetes more safely and effectively.

[0126] The benzooxygen-containing heterocyclic compounds of the present invention can lower blood glucose levels by activating GPR40 targets, stimulating pancreatic islet β cells, and releasing insulin. Such compounds of formula Ib-IIb are characterized by promoting insulin secretion only when blood glucose levels are high in type II diabetes patients, thereby effectively reducing the risk of hypoglycemia in patients and having better selectivity and safety for GPR40 targets.

[0127] [Mode for Carrying Out the Invention]

[0128] The present invention will be further described below with reference to examples, but the present invention is not limited to the scope of the examples. Experimental methods for which specific conditions are not specified in the following examples were carried out according to conventional methods and conditions or in accordance with the product instructions.

[0129] The English abbreviations and notes for the chemical reagents and solvents used in the synthesis of the novel benzooxygen-containing heterocyclic compounds of the present invention are all listed together in the Equipment and Materials Description section of the Examples.

[0130] The key innovation of the present invention is to follow synthetic reaction route 1 or 2 shown in Schemes 1 and 2 below, in which starting material RM-1b is first reacted with starting material SM-1 (reagents with the following structures SM-1a and RM-1b), respectively, to prepare target product Ib-IIb or intermediate RM-2b, respectively; 7 is an alkoxyl group (e.g., R 7 =OCH3 or OEt), further LiOH hydrolysis reaction can be carried out to obtain R 7 Each target product can be synthesized in which is a hydroxyl group. [ka]

[0131] The above synthesis reaction route 1b is as follows: [ka]

[0132] In the above synthesis reaction scheme 1b, the procedure is as follows:

[0133] 1. Synthesis of RM-2b: The raw materials RM-Ib (1.0 eq), SM-1b (1.0 eq), and DIAD and PPh3 (1.2 eq) were added to a round-bottom reaction flask in THF (5x), and the mixture was protected with nitrogen. The reaction was monitored and detected by TLC and / or HPLC until completion, and RM-2b (or RM-IIb) was obtained after the usual procedures such as post-treatment.

[0134] 2. Synthesis of target product Ib-IIb: RM-Ib (or RM-IIb, 1 eq) was hydrolyzed in a round-bottom reaction flask with a LiOH-MeOH-HO mixed solution (1:1, 10X), followed by TLC and / or HPLC detection until the reaction was complete. After post-treatment and purification, target product Ib-IIb was obtained.

[0135] Synthesis reaction route 2b is as follows: [ka]

[0136] In the above synthesis reaction scheme 2, the operations are as follows:

[0137] 1. Synthesis of RM-2b: The raw materials RM-Ib (1.0 eq), SM-1b (1.0 eq), and an alkaline reagent (e.g., potassium phosphate or potassium carbonate, 2-3 eq) were added to a round-bottom reaction flask in DMF (5x), respectively, and the reaction was protected by nitrogen purging. The reaction was monitored and detected by TLC and / or HPLC until completion. The reaction solution was slowly poured into 40x ice water with stirring, and RM-Ib (or RM-IIb) was obtained after usual operations such as workup and purification.

[0138] 2. Synthesis of target product IIb: RM-Ib (or RM-IIb) was hydrolyzed in a round-bottom reaction flask with a mixed solution of LiOH and MeOH-HO (1:1, 10X), respectively, and the reaction was monitored by TLC and / or HPLC until completion. After the usual post-treatment and purification procedures, the target product Ib-IIb was obtained.

[0139] n, L in the above-synthesized compounds of formula Ib-IIb 1 , R 1 , R 2 , R 3 , R 5 , R 5b , R 7 , Ra, Rb, Rc, Rd, Re, X 5 , X 6 , Y, Y 1 , and Z are n, L according to claims 1 to 4 of the present invention. 1 , R 1 , R 2 , R 3 , R 5 , R 5b , R 7 , Ra, Rb, Rc, Rd, Re, X 5 , X 6 , Y, Y 1 , and the definition of Z is the same.

[0140] The synthesis reaction examples of the compounds of formula Ib-IIb of the present invention are shown in Table 3 below. The synthesis process of each specific compound with different structure was carried out using the benzooxygen-containing heterocyclic raw material RM-1b in Table 1 and the raw material SM-1 in Table 2, respectively.

[0141] [Table 1] TIFF0007804653000043.tif214153TIFF0007804653000044.tif56156

[0142] [Table 2]

[0143] Using the above starting materials RM-1b and SM1, intermediate RM-2b was synthesized via the synthesis reaction route of Scheme 3 below, and finally, specific compounds of formulae Ib to IIb were synthesized by hydrolysis. Specific reaction examples are as follows.

[0144] [ka]

[0145] In the example synthesis reaction of Scheme 3 above:

[0146] First step reaction: First, the raw material RM-Ib-01 and another raw material SM1-01 were reacted in a solvent (e.g., DMSO or DMF) under the action of an inorganic base (e.g., K3PO4) to obtain a key intermediate compound (RM-Ib-01);

[0147] Second step reaction: Next, the intermediate (RM-2b-01) was hydrolyzed in a solvent (e.g., MeOH or a mixture of methanol and water) under the action of an inorganic base (e.g., LiOH) to obtain the target product Ib-01.

[0148] The intermediate structures of the intermediate compounds RM-2b obtained in the first step reactions of the synthetic reaction routes of the above Schemes 1, 2, and 3 are shown in the following RM-2b structural formula series, respectively; and the structures of the target products of formula IIb obtained in the second step hydrolysis reactions are shown in the following formula IIb structural formula series, respectively.

[0149] [Table 3] TIFF0007804653000048.tif209159TIFF0007804653000049.tif210157TIFF00078046530 00050.tif219156TIFF0007804653000051.tif213156TIFF0007804653000052.tif149166

[0150] [Table 4] TIFF0007804653000054.tif232157TIFF0007804653000055.tif219158TIFF0007804653000056.tif23115 6TIFF0007804653000057.tif200161TIFF0007804653000058.tif232155TIFF0007804653000059.tif47163

[0151] The specific experimental conditions for the reaction in each step and the product analysis results are described in the Examples.

[0152] Specifically, for the synthesis and analysis results of the novel structural compounds of the above formulas Ib to IIb, please refer to the last example of the present invention for details. The chemical properties and chiral purity of each compound were determined by chiral chromatography column HPLC, and the corresponding chemical structures were determined by LC-MS and / or hydrogen nuclear magnetic resonance ( 1 H-NMR analysis.

[0153] The following examples illustrate the synthesis and effects of various intermediates and compounds of the present invention.

[0154] The description of the equipment and materials used in the examples is as follows:

[0155] Infrared spectral data were analyzed by a Thermo Nicolet Fourier Transform AVATAR™ 360 ESP™ infrared instrument and are expressed in units of cm -1 It was expressed as:

[0156] Proton nuclear magnetic resonance spectra were analyzed using a Varian Mercury Plus 400 (400 MHz) nuclear magnetic analyzer. Chemical shifts were expressed in ppm using tetramethylsilane as the internal standard (CHCl3: δ = 7.26 ppm). The recorded data information is as follows: chemical shifts and their splitting and coupling constants (s: singlet; d: doublet; t: triplet; q: quartet; br: broad peak; m: multiplet).

[0157] Mass spectrometry data were analyzed using an LC / MS instrument from Finnigan LCQ Advantage Inc. The molecular weights of the organic carboxylic acid (-COOH) compounds of formula Ib-IIb in the present invention were mainly determined by anion mode ESI-MS [(M-H) + ], but the molecular weights of the ester intermediate compounds of formula RM-IIb and some amino-containing compounds in formula Ib-IIb were determined by positive ion mode ESI-MS [(M+H) + ] was.

[0158] The special raw materials and intermediates used in this invention were processed and provided by Zhannan Technology Co., Ltd., etc., and all other chemical reagents were purchased from reagent suppliers such as Shanghai Reagent Company, Aldrich, and Acros. When the intermediates or products required for the reactions in the synthesis process were insufficient for testing in the next step, the synthesis was repeated multiple times until sufficient amounts were obtained. GPR40 activity tests and pharmacological and toxicological tests of the compounds prepared in this invention were completed by CRO service units in Shanghai, Beijing, and other locations.

[0159] The English abbreviations and notes for the relevant chemical raw materials, reagents and solvents according to the present invention and its examples are as follows:

[0160] AIBN: Azobisisobutyronitrile Boc: tert-butoxycarbonyl (Boc)2O: di-tert-butyl dicarbonate CDI: N,N'-carbonyldiimidazole DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene Et: Ethyl EDCI: N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate NBS: N-bromosuccinimide SOCl2: Thionyl chloride Pd / C: Palladium on carbon DMAP: 4-dimethylaminopyridine HMTA: hexamethylenetetramine DIEA: N,N-diisopropylethylamine Py: pyridine HBr: Hydrobromic acid HCl: Hydrochloric acid HOAc: Glacial acetic acid TFA: Trifluoroacetic acid TsOH: p-toluenesulfonic acid NaOH: Sodium hydroxide LiOH: Lithium hydroxide ACN: acetonitrile DCM: dichloromethane DCE: dichloroethane DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide Et2O: Diethyl ether EA: Ethyl acetate PE: Petroleum ether THF: tetrahydrofuran TBME: Methyl tert-butyl ether [Example]

[0161] Synthesis of Compound IIb-1

[0162] The synthesis reaction is as follows: [ka]

[0163] First step: The starting materials RM-Ib-1 (0.051 g, 0.24 mmol) and SM1-1 (0.050 g, 0.24 mmol, 1.0 eq.) were dissolved in 2 mL of DMF, potassium carbonate (0.050 g, 0.36 mmol, 1.5 eq.) was added with stirring, and the mixture was heated to 90 °C under nitrogen protection and allowed to react overnight to complete the reaction. After confirming the completion of the reaction by HPLC, the reaction mixture was cooled to room temperature, water was added, and ethyl acetate was added for extraction. The combined organic phase was washed with brine, dried, and concentrated to give intermediate RM-IIb-1 (0.1 g). Mass spectrometry confirmed that RM-IIb-1 was a nucleotide analogue of RM-IIb-1. + ]: m / z theoretical value 343.1, actual value 343.0.

[0164] Second step: To the intermediate RM-IIb-1, MeOH (2 mL), THF (1 mL), and aqueous LiOH (1N, 1 mL) were added sequentially and stirred at room temperature for 1 hour. After confirming the completion of the reaction by HPLC, the reaction mixture was neutralized to pH 4 with 1N hydrochloric acid, water was added, and ethyl acetate was added for extraction. The combined organic phases were washed with brine, dried, and finally purified by column chromatography to give the pale yellow solid product IIb-1 (0.040 g). The yield for the two steps was 50.7%. After detection, product IIb-1 1H NMR (400MHz, CDCl3): δ7.07-7.05(m,1H),6.95-6.93(m,1H),6.86-6.79(m,2H),6.52-6.49(m,2H),5.99(s,2H) ),5.01(s,2H),4.78-4.74(m,1H),4.31-4.27(m,1H),3.83-3.80(m,1H),2.83-2.78(m,1H),2.65-2.59(m,1H). Mass spectrometry confirmed that IIb-1 was a methyltransferase (M-H) + ]: m / z theoretical value 327.1, actual value 327.0. [Example]

[0165] Synthesis of Compound IIb-2

[0166] The synthesis reaction is as follows: [ka]

[0167] First step: The starting materials RM-Ib-2 (0.043 g, 0.19 mmol), SM1-1 (0.039 g, 0.19 mmol, 1.0 eq.), and PPh3 (0.146 g, 0.56 mmol, 3 eq.) were dissolved in 4 mL of THF and cooled in an ice-water bath under nitrogen protection. DIAD (0.113 g, 0.56 mmol, 3 eq.) was added with stirring. After the addition was complete, the mixture was stirred in an ice-water bath for 1 h and then incubated overnight at 20-30 °C to complete the reaction. After confirming completion of the reaction by HPLC, the reaction mixture was cooled to room temperature, water was added, and DCM was added for extraction. The combined organic phases were washed with brine, dried, and concentrated to give the crude product; the crude product was separated by TLC scraper to give intermediate RM-IIb-2. Mass spectrometry confirmed that RM-IIb-2 was a methyl group. + ]: m / z theoretical value 421.0, actual value 421.1.

[0168] Second step: To the intermediate RM-IIb-2, MeOH (2 mL), THF (1 mL), and aqueous LiOH (1 N, 1 mL) were added and stirred at room temperature for 1 hour. After confirming the completion of the reaction by HPLC, the reaction mixture was neutralized to approximately pH 4 with 1 N hydrochloric acid, water was added, and ethyl acetate was added for extraction. The organic phases were combined, washed with brine, dried, and finally purified by column chromatography to give the pale yellow solid product IIb-2 (0.025 g). The yield for the two steps was 33%. After detection, product IIb-2 1 H NMR (400MHz, CDCl3): δ7.09-7.05(m,2H),6.92(m,1H),6.50-6.46(m,2H),6.01(s,2H),4.95(s,2H) ),4.79-4.75(m,1H),4.31-4.28(m,1H),3.84-3.79(m,1H),2.84-2.79(m,1H),2.66-2.59(m,1H). Mass spectrometry confirmed that IIb-2 was a methyltransferase (M-H) + ]: m / z theoretical value 405.0, actual value 405.2. [Example]

[0169] Synthesis of Compound IIb-3

[0170] The synthesis method for preparing compound IIb-3 was the same as in Example 1, and product IIb-3 was obtained by etherification and hydrolysis. In this case, compound RM-Ib-3 (0.48 mmol) was used instead of compound RM-Ib-1 in the reaction to obtain intermediate RM-IIb-3, which was then hydrolyzed to obtain white solid product IIb-3 (0.039 g). Yield of the two steps: 20%. Mass spectrometry confirmed that IIb-3 was a methyl group. + ]: m / z theoretical value 405.0, actual value 404.8. [Example]

[0171] Synthesis of Compound IIb-4

[0172] The synthesis method for preparing compound IIb-4 was the same as in Example 1, and product IIb-4 was obtained by etherification and hydrolysis. Instead of compound RM-Ib-1, compound RM-Ib-4 (0.24 mmol) was used in the reaction to obtain intermediate RM-IIb-4, which was then hydrolyzed to obtain pale yellow solid product IIb-4 (0.060 g). The yield of the two steps was 76%. After detection, product IIb-4 1 H NMR (400MHz, CDCl3): δ7.07-7.05(m,1H),6.91-6.86(m,2H),6.81-6.79(m,1H),6.49-6.45(m,2H),5.96(s,2H) ),4.91(s,2H),4.78-4.74(m,1H),4.31-4.27(m,1H),3.83-3.79(m,1H),2.84-2.78(m,1H),2.65-2.59(m,1H). Mass spectrometry confirmed that IIb-4 was a methyl group. + ]: m / z theoretical value 327.1, actual value 327.0. [Example]

[0173] Synthesis of Compound IIb-5

[0174] The synthesis method for preparing compound IIb-5 was the same as in Example 1, and product IIb-5 was obtained by etherification and hydrolysis. In this case, compound RM-Ib-5 (0.54 mmol) was used instead of compound RM-Ib-1 in the reaction to obtain intermediate RM-IIb-5, which was then hydrolyzed to obtain white solid product IIb-5 (0.068 g). The yield of the two steps was 34.8%. After detection, product IIb-5 1 H NMR (400MHz, CDCl3): δ7.08-7.06(m,1H),6.95(s,1H),6.78(s,1H),6.50-6.46(m,2H),6.02(s,2H),4.9 5(s,2H),4.79-4.75(m,1H),4.32-4.28(m,1H),3.83-3.80(m,1H),2.84-2.78(m,1H),2.66-2.59(m,1H). Mass spectrometry confirmed that IIb-5 was a methyl group. + ]: m / z theoretical value 361.1, actual value 360.9. [Example]

[0175] Synthesis of Compound IIb-6

[0176] The synthesis method for preparing compound IIb-6 was the same as in Example 1, and product IIb-6 was obtained by etherification and hydrolysis. Compound RM-Ib-6 (0.41 mmol) was used instead of compound RM-Ib-1 in the reaction to obtain intermediate RM-IIb-6, which was then hydrolyzed to obtain white solid product IIb-6 (0.090 g). The yield of the two steps was 63.6%. After detection, product IIb-6 1 H NMR(400MHz,DMSO):δ7.10-7.09(m,1H),6.92-6.89(m,1H),6.74-6.71(m,1H),6.46-6.44(m,2H),6.08(s,2H) ,4.93(s,2H),4.69-4.64(m,1H),4.19-4.15(m,1H),3.69-3.64(m,1H),2.71-2.65(m,1H),2.48-2.43(m,1H). 19 F NMR (376MHz, DMSO) δ-120.47. Mass spectrometry confirmed that IIb-6 was a methyl group. + ]: m / z theoretical value 345.1, actual value 345.0. [Example]

[0177] Synthesis of compound IIb-7

[0178] The synthesis method for compound IIb-7 was the same as in Example 1, with etherification and hydrolysis to give product IIb-7. Compound RM-Ib-1 was replaced with compound RM-Ib-6 (0.35 mmol), and compound SM1-1 was replaced with compound SM1-2 (0.35 mmol) to give intermediate RM-IIb-7, which was then hydrolyzed to give white solid product IIb-7 (0.085 g). The yield for the two steps was 70.8%. After detection, product IIb-7 1 H NMR (400MHz, CDCl3): δ7.07-7.05(m,1H),6.66-6.63(m,1H),6.56-6.54(m,1H),6.49-6.46(m,2H),6.01(s,2H) ),4.96(s,2H),4.79-4.74(m,1H),4.31-4.27(m,1H),3.84-3.77(m,1H),2.84-2.79(m,1H),2.66-2.59(m,1H); 19 F NMR (376MHz, CDCl3): δ-119.95. Mass spectrometry confirmed that IIb-7 was a methyltransferase (M-H) + ]: m / z theoretical value 345.1, actual value 345.2. [Example]

[0179] Synthesis of compound IIb-8

[0180] The synthesis method for preparing compound IIb-8 was the same as in Example 1, where compound RM-Ib-7 (0.24 mmol) was used instead of compound RM-Ib-1 in the reaction to obtain intermediate RM-IIb-8, which was then hydrolyzed to obtain white solid product IIb-8 (0.059 g). The yield of the two steps was 65.5%. After detection, product IIb-8 1H NMR (400MHz, CDCl3): δ7.09-7.07(m,2H),6.79-6.76(m,1H),6.57-6.54(m,2H),5.35(s,2H),4 .79-4.75(m,1H),4.32-4.25(m,5H),3.84-3.80(m,1H),2.84-2.79(m,1H),2.65-2.59(m,1H). Mass spectrometry confirmed that IIb-8 was a methyl group. + ]: m / z theoretical value 419.0, actual value 418.9. [Example]

[0181] Synthesis of compound IIb-9

[0182] The synthetic method for preparing compound IIb-9 was the same as in Example 2, where compound RM-Ib-8 (0.24 mmol) was used instead of compound RM-Ib-2 in the reaction to obtain intermediate RM-IIb-9, which was then hydrolyzed to obtain white solid product IIb-9 (0.035 g). The yield of the two steps was 45%. Mass spectrometry confirmed that IIb-9 was a methyl group. + ]: m / z theoretical value 419.0, actual value 418.8. [Example]

[0183] Synthesis of Compound IIb-10

[0184] The synthesis method for preparing compound IIb-10 was the same as in Example 1, where compound RM-Ib-9 (0.65 mmol) was used instead of compound RM-Ib-1 to obtain intermediate RM-IIb-10, which was then hydrolyzed to obtain white solid product IIb-10 (0.196 g). The yield of the two steps was 53.2%. After detection, product IIb-10 1H NMR (400MHz, CDCl3): δ7.34(s,1H),7.07-7.05(m,1H),7.00(m,1H),6.48(m,1H),6.51-6.46(m,2H),4.9 8(s,2H),4.79-4.74(m,1H),4.31-4.27(m,5H),3.85-3.78(m,1H),2.84-2.79(m,1H),2.66-2.60(m,1H). Mass spectrometry confirmed that IIb-10 was a methyl group. + ]: m / z theoretical value 375.1, measured value 374.9. [Example]

[0185] Synthesis of Compound IIb-11

[0186] The synthesis method for preparing compound IIb-11 was the same as in Example 2, where compound RM-Ib-10 (0.24 mmol) was used instead of compound RM-Ib-2 in the reaction to obtain intermediate RM-IIb-11, which was then hydrolyzed to obtain white solid product IIb-11 (0.033 g). The yield of the two steps was 37%. Mass spectrometry confirmed that IIb-11 was a methyl group. + ]: m / z theoretical value 359.1, actual value 359.0. [Example]

[0187] Synthesis of Compound IIb-12

[0188] The synthetic method for preparing compound IIb-12 was the same as in Example 2, where compound RM-Ib-11 (0.63 mmol) was used instead of compound RM-Ib-2 in the reaction to obtain intermediate RM-IIb-12, which was then hydrolyzed to obtain pale yellow solid product IIb-12 (0.028 g). The yield of the two steps was 12.8%. Mass spectrometry confirmed that IIb-12 was a methyltransferase (M-H) +]: m / z theoretical value 345.1, measured value 344.9. [Example]

[0189] Synthesis of Compound IIb-13

[0190] The synthetic method for preparing compound IIb-13 was the same as in Example 1, and product IIb-13 was obtained by etherification and hydrolysis. Compound RM-Ib-12 (0.43 mmol) was used instead of compound RM-Ib-1 in the reaction to obtain intermediate RM-IIb-13, which was then hydrolyzed to obtain pale yellow solid product IIb-13 (0.060 g). The yield of the two steps was 40%. After detection, product IIb-13 1 H NMR (400MHz, CDCl3): δ6.92-6.90(m,1H),6.65-6.62(m,1H),6.49-6.39(m,3H),5.90(s,2H),4.90(s ,2H),4.62-4.58(m,1H),4.20-4.16(m,1H),3.64-3.61(m,1H),2.87-2.57(m,1H),2.41-2.19(m,1H). Mass spectrometry confirmed that IIb-13 was a methyltransferase (M-H) + ]: m / z theoretical value 345.0, actual value 345.0. [Example]

[0191] Synthesis of Compound IIb-14

[0192] The synthetic method for preparing compound IIb-14 was the same as in Example 1, where compound RM-Ib-13 (0.22 mmol) was used instead of compound RM-Ib-1 in the reaction to obtain intermediate RM-IIb-14, which was then hydrolyzed to obtain white solid product IIb-14 (0.045 g). The yield of the two steps was 51.3%. After detection, product IIb-14 1H NMR (400MHz, CDCl3): δ7.28(s,1H),7.08-7.06(m,1H),7.00(s,1H),6.51-6.47(m,2H),6.09(s,2H),5.0 0(s,2H),4.79-4.75(m,1H),4.32-4.28(m,1H),3.84-3.79(m,1H),2.84-2.78(m,1H),2.66-2.59(m,1H). Mass spectrometry confirmed that IIb-14 was a methyltransferase (M-H) + ]: m / z theoretical value 395.1, actual value 395.0. [Example]

[0193] Synthesis of Compound IIb-15

[0194] The synthetic method for preparing compound IIb-15 was the same as in Example 1, and product IIb-15 was obtained by etherification and hydrolysis. In this case, compound RM-Ib-14 (0.42 mmol) was used instead of compound RM-Ib-1 in the reaction to obtain intermediate RM-IIb-15, which was then hydrolyzed to obtain white solid product IIb-15 (0.072 g). The yield of the two steps was 54%. After detection, product IIb-15 1 H NMR (400MHz, CDCl3): δ7.34(s,1H),7.08-7.06(m,1H),7.00(s,1H),6.48-6.43(m,2H),6.11(s,2H),4.9 8(s,2H),4.79-4.75(m,1H),4.32-4.28(m,1H),3.83-3.80(m,1H),2.83-2.78(m,1H),2.65-2.59(m,1H). Mass spectrometry confirmed that IIb-15 was a methyltransferase (M-H) + ]: m / z theoretical value 352.1, actual value 352.0. [Example]

[0195] Synthesis of Compound IIb-16

[0196] The synthetic method for preparing compound IIb-16 was the same as in Example 1, and product IIb-16 was obtained by etherification and hydrolysis. In this case, compound RM-Ib-15 (0.39 mmol) was used instead of compound RM-Ib-1 in the reaction to obtain intermediate RM-IIb-16, which was then hydrolyzed to obtain white solid product IIb-16 (0.032 g). The yield of the two steps was 19.7%. After detection, product IIb-16 1 H NMR (400MHz, CDCl3): δ7.51-7.48(m,2H),7.29-7.27(m,2H),7.06-7.04(m,1H),6.47-6.43(m,2H),4.97 (s,2H),4.78-4.74(m,1H),4.30-4.27(m,1H),3.83-3.78(m,1H),2.83-2.77(m,1H),2.65-2.58(m,1H). Mass spectrometry confirmed that IIb-16 was a methyltransferase (M-H) + ]: m / z theoretical value 405.0, actual value 404.8. [Example]

[0197] Synthesis of Compound IIb-17

[0198] The synthetic method for preparing compound IIb-17 was the same as in Example 1, where compound RM-Ib-16 (0.28 mmol) was used instead of compound RM-Ib-1 to obtain intermediate RM-IIb-17, which was then hydrolyzed to obtain white solid product IIb-17 (0.020 g). The yield of the two steps was 15.8%. After detection, product IIb-17 1 H NMR (400MHz, CDCl3): δ7.30-7.18(m,1H),7.10-7.06(m,1H),7.03-7.01(m,1H),6.50-6.46(m,2H),5.07 (s,2H),4.79-4.75(m,1H),4.31-4.27(m,1H),3.84-3.79(m,1H),2.83-2.78(m,1H),2.65-2.58(m,1H). 19F NMR (376MHz, CDCl3): δ-49.74. Mass spectrometry confirmed that IIb-17 was a methyltransferase (M-H) + ]: m / z theoretical value 363.1, actual value 362.9. [Example]

[0199] Synthesis of Compound IIb-18

[0200] The synthetic method for preparing compound IIb-18 was the same as in Example 1, and product IIb-18 was obtained by etherification and hydrolysis. Here, compound RM-Ib-16 (0.22 mmol) was used instead of compound RM-Ib-1 in the reaction, and compound SM1-2 (0.22 mmol) was used instead of compound SM1-1 in the reaction to obtain intermediate RM-IIb-18, which was then hydrolyzed to obtain white solid product IIb-18 (0.009 g). The yield of the two steps was 11.4%. After detection, product IIb-18 1 H NMR (400MHz, CDCl3): δ7.20-7.18(m,1H),7.10-7.03(m,2H),7.01(m,1H),6.51-6.46(m,2H),5.07(s ,2H),4.79-4.75(m,1H),4.32-4.28(m,1H),3.84-3.79(m,1H),2.85-2.79(m,1H),2.66-2.60(m,1H); 19 F NMR (376MHz, CDCl3): δ-49.63. Mass spectrometry confirmed that IIb-18 was a methyltransferase (M-H) + ]: m / z theoretical value 363.1, actual value 363.1. [Example]

[0201] Synthesis of Compound IIb-19

[0202] The synthetic method for preparing compound IIb-19 was the same as in Example 1, where compound RM-Ib-17 (0.91 mmol) was used instead of compound RM-Ib-1 to obtain intermediate RM-IIb-19, which was then hydrolyzed to obtain pale yellow solid product IIb-19 (0.231 g). The yield of the two steps was 72.8%. After detection, product IIb-19 1 H NMR (400MHz, CDCl3): δ7.06-7.04(m,1H),7.00-6.98(m,1H),6.84-6.83(m,2H),6.53-6.48(m,2H),5.02 (s,2H),4.78-4.74(m,1H),4.30-4.23(m,5H),3.83-3.77(m,1H),2.82-2.77(m,1H),2.63-2.57(m,1H). Mass spectrometry confirmed that IIb-19 was a methyltransferase (M-H) + ]: m / z theoretical value 341.1, actual value 341.0. [Example]

[0203] Synthesis of Compound IIb-20

[0204] The synthetic method for preparing compound IIb-20 was the same as in Example 1, where compound RM-Ib-18 (0.64 mmol) was used instead of compound RM-Ib-1 to obtain intermediate RM-IIb-20, which was then hydrolyzed to obtain pale yellow solid product IIb-20 (0.166 g). The yield of the two steps was 71.2%. After detection, product IIb-20 1H NMR (400MHz, CDCl3): δ7.05-7.03(m,1H),6.91-6.89(m,1H),6.80-6.76(m,1H),6.70-6.68(m,1H),6.52-6.49(m,2H),4 .98(s,2H),4.77-4.73(m,1H),4.30-4.26(m,1H),3.82-3.77(m,1H),2.81-2.76(m,1H),2.62-2.55(m,1H),1.69(s,6H). Mass spectrometry confirmed that IIb-20 was a methyl group. + ]: m / z theoretical value 355.1, actual value 355.0. [Example]

[0205] Synthesis of Compound IIb-21

[0206] The synthetic method for preparing compound IIb-21 was the same as in Example 1, where compound RM-Ib-19 (0.57 mmol) was used instead of compound RM-Ib-1 in the reaction to obtain intermediate RM-IIb-21, which was then hydrolyzed to obtain pale yellow solid product IIb-21 (0.072 g). The yield of the two steps was 28.4%. Mass spectrometry confirmed that IIb-21 was a methyltransferase (M-H) + ]: m / z theoretical value 441.0, actual value 440.8. [Example]

[0207] Synthesis of Compound IIb-22

[0208] The synthetic method for preparing compound IIb-22 was the same as in Example 1, where compound RM-Ib-20 (0.43 mmol) was used instead of compound RM-Ib-1 in the reaction to obtain intermediate RM-IIb-22, which was then hydrolyzed to obtain a pale yellow oily substance IIb-22 (0.150 g). The yield of the two steps was 80%. Mass spectrometry confirmed that IIb-22 was a methyltransferase (M-H) + ]: m / z theoretical value 435.0, actual value 434.9. [Example]

[0209] Synthesis of Compound IIb-23

[0210] The synthetic method for preparing compound IIb-23 was the same as in Example 1, and product IIb-23 was obtained by etherification and hydrolysis. Compound RM-Ib-21 (0.13 mmol) was used instead of compound RM-Ib-1 in the reaction to obtain intermediate RM-IIb-23, which was then hydrolyzed to give pale yellow solid product IIb-23 (0.0033 g). The yield for the two steps was 6.2%. Mass spectrometry confirmed that IIb-23 was a methyl group. + ]: m / z theoretical value 397.0, actual value 397.3. [Example]

[0211] Synthesis of Compound IIb-24

[0212] The synthetic method for preparing compound IIb-24 was the same as in Example 1, where compound RM-Ib-22 (0.38 mmol) was used instead of compound RM-Ib-1 in the reaction to obtain intermediate RM-IIb-24, which was then hydrolyzed to obtain pale yellow solid product IIb-24 (0.028 g). The yield for the two steps was 18.8%. Mass spectrometry confirmed that IIb-24 was a methyltransferase (M-H) + ]: m / z theoretical value 397.0, actual value 397.4. [Example]

[0213] Synthesis of Compound IIb-25

[0214] The synthetic method for preparing compound IIb-25 was the same as in Example 1, and product IIb-25 was obtained by etherification and hydrolysis. Compound RM-Ib-5 (0.54 mmol) was used instead of compound RM-Ib-1, and compound SM1-2 (0.54 mmol) was used instead of compound SM1-1 in the reaction to obtain intermediate RM-IIb-25, which was then hydrolyzed to obtain white solid product IIb-25 (0.085 g). The yield of the two steps was 44%. After detection, product IIb-25 1 H NMR (400MHz, CDCl3): δ7.07-7.05(m,1H),6.94(m,1H),6.78-6.77(m,1H),6.50-6.45(m,2H),6.02(s,2H),4 .95(s,2H),4.79-4.74(m,1H),4.31-4.27(m,1H),3.84-3.79(m,1H),2.84-2.79(m,1H),2.66-2.59(m,1H). Mass spectrometry confirmed that IIb-25 was a methyltransferase (M-H) + ]: m / z theoretical value 361.0, actual value 361.0. [Example]

[0215] Synthesis of Compound IIb-26

[0216] The synthetic method for preparing compound IIb-26 was the same as in Example 1, with etherification and hydrolysis to give product IIb-26, where compound RM-Ib-1 was replaced with compound RM-Ib-16 (0.22 mmol) and compound SM1-1 was replaced with compound SM1-3 (0.22 mmol) in the reaction to give intermediate RM-IIb-26, which was then hydrolyzed to give white solid product IIb-26 (0.045 g). Yield of the two steps: 21%. After detection, product IIb-26 1H NMR (400MHz, CDCl3): δ7.33(s,1H),7.32-7.30(m,1H),7.13-7.09(m,1H),7.06-7.02(m,1H),6.50(s,1H),5 .13(s,2H),4.80-4.76(m,1H),4.32-4.29(m,1H),3.845-3.81(m,1H),2.83-2.78(m,1H),2.67-2.60(m,1H). Mass spectrometry confirmed that IIb-26 was a methyltransferase (M-H) + ]: m / z theoretical value 441.0, actual value 441.0. [Example]

[0217] Synthesis of Compound IIb-27

[0218] The synthetic method for preparing compound IIb-27 was the same as in Example 1, with etherification and hydrolysis to give product IIb-27, where compound RM-Ib-1 was replaced with compound RM-Ib-16 (0.22 mmol) and compound SM1-1 was replaced with compound SM1-4 (0.22 mmol) in the reaction to give intermediate RM-IIb-27, which was then hydrolyzed to give white solid product IIb-27 (0.070 g). Yield of the two steps: 28%. After detection, product IIb-27 1 H NMR (400MHz, CDCl3): δ7.43-7.41(m,1H),7.32(s,1H),7.14-7.10(m,1H),7.06-7.04(m,1H),5.08(s ,2H),4.93-4.88(m,1H),4.45-4.41(m,1H),4.00-3.96(m,1H),2.88-2.82(m,2H),2.74-2.67(m,1H); 19 F NMR (376MHz, CDCl3): δ-49.68. Mass spectrometry confirmed that IIb-27 was a methyltransferase (M-H) + ]: m / z theoretical value 520.9, actual value 520.9. [Example]

[0219] Synthesis of Compound IIb-28

[0220] The synthetic method for preparing compound IIb-28 was the same as in Example 1, with etherification and hydrolysis to give product IIb-28, where compound RM-Ib-1 was replaced with compound RM-Ib-16 (0.48 mmol) and compound SM1-1 was replaced with compound SM1-5 (0.48 mmol) in the reaction to give intermediate RM-IIb-28, which was then hydrolyzed to give white solid product IIb-28 (0.070 g). Yield of the two steps: 36%. After detection, product IIb-28 1 H NMR (400MHz, CDCl3): δ7.29-7.26(m,1H),7.18(s,1H),7.12-7.08(m,1H),7.04-7.02(m,1H),6.50(s,2H),5 .14(s,2H),4.80-4.75(m,1H),4.32-4.28(m,1H),3.84-3.80(m,1H),2.83-2.77(m,1H),2.66-2.60(m,1H). Mass spectrometry confirmed that IIb-28 was a methyl group. + ]: m / z theoretical value 397.0, actual value 397.0. [Example]

[0221] Synthesis of Compound IIb-29

[0222] The synthetic method for preparing compound IIb-29 was the same as in Example 1, with etherification and hydrolysis to give product IIb-29, where compound RM-Ib-1 was replaced with compound RM-Ib-16 (1.0 mmol) and compound SM1-1 was replaced with compound SM1-6 (1.0 mmol) in the reaction to give intermediate RM-IIb-29, which was then hydrolyzed to give white solid product IIb-29 (0.070 g). Yield for the two steps: 18%. Mass spectrometry confirmed that IIb-29 was a methyl group. + ]: m / z theoretical value 381.1, actual value 381.0. [Example]

[0223] Synthesis of Compound IIb-30

[0224] The starting material IIb-17 (0.188 g, 0.52 mmol) was dissolved in 1 mL of THF and 1 mL of MTBE. Under nitrogen protection, the mixture was cooled to -78 °C in a dry ice acetone bath. LiHMDS (1 M, 1.4 mL, 1.4 mmol) was added dropwise and stirred for 0.5 h. TMSCl (0.14 g, 1.3 mmol) was added dropwise and stirred for 0.5 h. NBS (0.11 g, 0.62 mmol) was added, and the mixture was allowed to warm slowly to room temperature and react for 5 h to complete the reaction. After confirming completion of the reaction by HPLC, the reaction mixture was added with water, neutralized to approximately pH 2 with 1 N hydrochloric acid, extracted with ethyl acetate, and the combined organic phases were washed with brine, dried, and finally purified by column chromatography to obtain the pale yellow solid product IIb-30 (0.055 g). Yield per step: 24%. Mass spectrometry confirmed that IIb-30 was a methyl group. + ]: m / z theoretical value 441.0, actual value 440.9. [Example]

[0225] Synthesis of Compound IIb-31

[0226] The starting material IIb-30 (0.035 g, 0.08 mmol) was added to concentrated aqueous ammonia (3 mL) and heated in an oil bath at 100 °C for 2.5 hours to complete the reaction. After confirming the completion of the reaction by HPLC, the reaction mixture was concentrated and dried under reduced pressure to obtain the pale yellow solid product IIb-31 (0.025 g). The yield of one step was 83%. Mass spectrometry confirmed that IIb-31 was a nucleotide analogue of IIb-31, and the ESI-MS [(M+H) + ]: m / z theoretical value 380.1, actual value 380.0. [Example]

[0227] Synthesis of Compound IIb-32

[0228] First step: The starting material RM-IIb-17 (0.29 g, 0.78 mmol) was dissolved in 2 mL of THF and cooled to -70 °C in a dry ice acetone bath under nitrogen protection. LiHMDS (1 M, 0.8 mL, 0.8 mmol) was added dropwise and stirred for 0.5 h. A solution of (PhSO2)NF / THF (0.29 g, 0.93 mmol) was added dropwise and the mixture was allowed to warm to room temperature for 2 h to complete the reaction. After confirming completion of the reaction by HPLC, the reaction mixture was added with water, neutralized to pH 2 with 1 N hydrochloric acid, extracted with ethyl acetate, and the combined organic phases were washed with brine, dried, and finally purified by column chromatography to obtain intermediate RM-IIb-30 (0.043 g).

[0229] Second step: To the intermediate RM-IIb-30, MeOH (2 mL), THF (1 mL), and aqueous LiOH (1N, 1 mL) were added sequentially and stirred at room temperature for 1 hour. After confirming the completion of the reaction by HPLC, the reaction mixture was neutralized to approximately pH 4 with 1N hydrochloric acid, water was added, and ethyl acetate was added for extraction. The combined organic phases were washed with brine, dried, and finally purified by column chromatography to give the white solid product IIb-32 (0.018 g). The yield for the two steps was 6%. Mass spectrometry confirmed that IIb-32 was a methyltransferase (M-H) + ]: m / z theoretical value 379.1, actual value 379.0. [Example]

[0230] Synthesis of Compound IIb-33

[0231] First step: The starting material RM-IIb-17 (0.24 g, 0.65 mmol) was dissolved in 2 mL of THF and cooled to -70 °C in a dry ice acetone bath under nitrogen protection. LiHMDS (1 M, 0.8 mL, 0.8 mmol) was added dropwise and stirred for 0.5 h. A solution of (PhSO2)NF / THF (0.24 g, 0.78 mmol) was added dropwise and the mixture was allowed to warm to room temperature for 2 h to complete the reaction. After confirming completion of the reaction by HPLC, water was added to the reaction mixture, and the mixture was neutralized to pH 2 with 1 N hydrochloric acid. Ethyl acetate was added for extraction. The combined organic phase was washed with brine, dried, and finally purified by column chromatography to give intermediates RM-IIb-31 and RM-IIb-32 (0.045 g).

[0232] Second step: To the intermediates RM-IIb-31 and RM-IIb-32, MeOH (2 mL), THF (1 mL), and aqueous LiOH solution (1N, 1 mL) were added sequentially and stirred at room temperature for 1 hour. After confirming the completion of the reaction by HPLC, the reaction mixture was neutralized to approximately pH 4 with 1N hydrochloric acid, water was added, and ethyl acetate was added for extraction. The organic phases were combined, washed with brine, dried, and finally purified by column chromatography to give pale yellow solid products IIb-33 and IIb-34 (0.030 g). Yield for the two steps: 12%. Mass spectrometry confirmed that IIb-33 was a methyl group. + ]: m / z theoretical value 381.1, actual value 381.0. [Example]

[0233] Synthesis of compound IIb-34

[0234] The synthetic method for preparing compound IIb-34 was the same as in Example 1, with etherification and hydrolysis to give product IIb-34, where compound RM-Ib-1 was replaced with compound RM-Ib-16 (0.36 mmol) and compound SM1-1 was replaced with compound SM1-7 (0.36 mmol) to give intermediate RM-IIb-32, which was then hydrolyzed to give white solid product IIb-34 (0.021 g). Yield of the two steps: 14%. Mass spectrometry confirmed that IIb-34 was a methyl group. + ]: m / z theoretical value 399.0, actual value 399.0. [Example]

[0235] Synthesis of Compound IIb-35

[0236] The synthetic method for preparing compound IIb-35 was the same as in Example 1, with etherification and hydrolysis to give product IIb-35. In this case, compound RM-Ib-6 (0.27 mmol) was used instead of compound RM-Ib-1, and compound SM1-8 (0.27 mmol) was used instead of compound SM1-1 to give intermediate RM-IIb-33, which was then hydrolyzed to give pale yellow solid product IIb-35 (0.056 g). The yield for the two steps was 60%. After detection, product IIb-35 1 H NMR (400MHz, CDCl3): δ7.12-7.10(m,1H),6.85(m,1H),6.80-6.78(m,1H),6.69-6.66(m,1H),6.57-6.54(m, 1H),6.01(s,2H),4.99(s,2H),3.56-3.52(m,1H),2.92-2.77(m,3H),2.51-2.41(m,2H),1.81-1.74(m,1H). Mass spectrometry confirmed that IIb-35 was a methyl group. + ]: m / z theoretical value 343.1, actual value 343.0. [Example]

[0237] Synthesis of Compound IIb-36

[0238] The synthetic method for preparing compound IIb-36 was the same as in Example 1, with etherification and hydrolysis to give product IIb-36, where compound RM-Ib-1 was replaced with compound RM-Ib-6 (0.27 mmol) and compound SM1-1 was replaced with compound SM1-9 (0.27 mmol) to give intermediate RM-IIb-34, which was then hydrolyzed to give pale yellow solid product IIb-36 (0.072 g). The yield for the two steps was 75%. After detection, product IIb-36 1 H NMR (400MHz, CDCl3): δ7.31-7.26(m,2H),6.93-6.91(m,2H),6.69-6.68(m,1H),6.66(m,1H),6.01(s,2H),4.99(s,2H),2.64(s,2H),1.45(s,6H). Mass spectrometry confirmed that IIb-36 was a methyl group. + ]: m / z theoretical value 345.1, actual value 345.0. [Example]

[0239] Synthesis of compound IIb-37

[0240] The synthetic method for preparing compound IIb-37 was the same as in Example 1, with etherification and hydrolysis to give product IIb-37, where compound RM-Ib-6 (0.27 mmol) was used instead of compound RM-Ib-1, and compound SM1-10 (0.27 mmol) was used instead of compound SM1-1 to give intermediate RM-IIb-35, which was then hydrolyzed to give pale yellow solid product IIb-37 (0.055 g). Yield of the two steps: 53%. After detection, product IIb-37 1 H NMR (400MHz, CDCl3): δ7.41-7.39(m,2H),6.95-6.92(m,2H),6.67-6.63(m,1H),6.57-6.55 (m,1H),6.03-6.01(m,2H),4.99(s,2H),4.13-4.10(m,2H),3.83-3.82(m,2H),2.98(s,2H). Mass spectrometry confirmed that IIb-37 was a methyl group. + ]: m / z theoretical value 375.1, measured value 374.9. [Example]

[0241] Synthesis of compound IIb-38

[0242] The synthetic method for preparing compound IIb-38 was the same as in Example 2, with etherification and hydrolysis to give product IIb-38, where compound RM-Ib-23 (0.16 mmol) was used instead of compound RM-Ib-2, and compound SM1-2 (0.16 mmol) was used instead of compound SM1-1 to give intermediate RM-IIb-36, which was then hydrolyzed to give white solid product IIb-38 (0.040 g). Yield of the two steps: 44%. Mass spectrometry confirmed that IIb-38 was a methyl group. + ]: m / z theoretical value 567.2, actual value 567.0. [Example]

[0243] Synthesis of Compound IIb-39

[0244] The synthetic method for preparing compound IIb-39 was the same as in Example 1, with etherification and hydrolysis to give product IIb-39, where compound RM-Ib-1 was replaced with compound RM-Ib-5 (0.35 mmol), and compound SM1-1 was replaced with compound SM1-7 (0.35 mmol) to give intermediate RM-IIb-37, which was then hydrolyzed to give white solid product IIb-39 (0.021 g). Yield of the two steps: 15%. Mass spectrometry confirmed that IIb-39 was a methyltransferase (M-H) + ]: m / z theoretical value 397.0, actual value 397.0. [Example]

[0245] Synthesis of Compound IIb-40

[0246] The synthetic method for preparing compound IIb-40 was the same as in Example 2, with etherification and hydrolysis to give product IIb-40, where compound RM-Ib-24 (0.31 mmol) was used instead of compound RM-Ib-2, and compound SM1-2 (0.31 mmol) was used instead of compound SM1-1 to give intermediate RM-IIb-38, which was then hydrolyzed to give white solid product IIb-40 (0.067 g). Yield of the two steps: 47%. Mass spectrometry confirmed that IIb-40 was a methyltransferase (MH) + ]: m / z theoretical value 453.0, actual value 453.0. [Example]

[0247] Synthesis of Compound IIb-41

[0248] The synthesis method for compound IIb-41 was the same as in Example 2, with etherification and hydrolysis to give product IIb-41, where compound RM-Ib-25 (0.10 mmol) was used instead of compound RM-Ib-2, and compound SM1-2 (0.10 mmol) was used instead of compound SM1-1 to give intermediate RM-IIb-39, which was then hydrolyzed to give white solid product IIb-41 (0.014 g). Yield of the two steps: 36%. Mass spectrometry confirmed that IIb-41 was a nucleotide analogue of IIb-41, and the ESI-MS [(M+H) + ]: m / z theoretical value 372.1, actual value 372.1. [Example]

[0249] Synthesis of compound IIb-42

[0250] The synthetic method for preparing compound IIb-42 was the same as in Example 2, with etherification and hydrolysis to give product IIb-42, where compound RM-Ib-26 (0.13 mmol) was used instead of compound RM-Ib-2, and compound SM1-2 (0.13 mmol) was used instead of compound SM1-1 to give intermediate RM-IIb-40, which was then hydrolyzed to give white solid product IIb-42 (0.029 g). Yield for the two steps: 58%. Mass spectrometry confirmed that IIb-42 was a nucleotide analogue of IIb-42, and the ESI-MS [(M+H) + ]: m / z theoretical value 372.1, actual value 372.1. [Example]

[0251] Synthesis of compound IIb-43

[0252] The synthetic method for preparing compound IIb-43 was the same as in Example 2, with etherification and hydrolysis to give product IIb-43, where compound RM-Ib-27 (0.09 mmol) was used instead of compound RM-Ib-2, and compound SM1-2 (0.09 mmol) was used instead of compound SM1-1 to give intermediate RM-IIb-41, which was then hydrolyzed to give white solid product IIb-43 (0.012 g). Yield of the two steps: 31%. After detection, product IIb-43 1 H NMR (400MHz, CDCl3): δ7.06-7.03(m,2H),6.73(s,1H),6.49-6.46(m,2H),5.96(s,2H),4.95(s,2H),4.7 8-4.73(m,1H),4.30-4.26(m,1H),3.82-3.78(m,1H),2.83-2.77(m,1H),2.65-2.58(m,1H),1.49(s,9H). Mass spectrometry confirmed that IIb-43 was a methyl group. + ]: m / z theoretical value 442.1, measured value 442.2. [Example]

[0253] Synthesis of compound IIb-44

[0254] Compound IIb-43 (0.017 g, 0.04 mmol) was added to HCl / MeOH (6 N, 2 mL) and stirred at room temperature for 1 h. After completion of the reaction, the mixture was concentrated to give white solid product IIb-44 (0.015 g). Yield of one step: 91%. Mass spectrometry confirmed that IIb-44 was a nucleotide analogue of IIb-44. + ]: m / z theoretical value 344.1, actual value 344.1. [Example]

[0255] Synthesis of compound IIb-45

[0256] The synthetic method for preparing compound IIb-45 was the same as in Example 2, with etherification and hydrolysis to give product IIb-45, where compound RM-Ib-28 (0.14 mmol) was used instead of compound RM-Ib-2, and compound SM1-2 (0.14 mmol) was used instead of compound SM1-1 to give intermediate RM-IIb-42, which was then hydrolyzed to give white solid product IIb-45 (0.035 g). Yield of the two steps: 66%. Mass spectrometry confirmed that IIb-45 was a methyl group. + ]: m / z theoretical value 357.3, actual value 357.2. [Example]

[0257] Synthesis of compound IIb-46

[0258] The synthetic method for preparing compound IIb-46 was the same as in Example 2, with etherification and hydrolysis to give product IIb-46, where compound RM-Ib-29 (0.12 mmol) was used instead of compound RM-Ib-2, and compound SM1-2 (0.12 mmol) was used instead of compound SM1-1 to give intermediate RM-IIb-43, which was then hydrolyzed to give white solid product IIb-46 (0.030 g). Yield of the two steps: 52%. Mass spectrometry confirmed that IIb-46 was a methyltransferase (M-H) + ]: m / z theoretical value 478.4, actual value 478.3. [Example]

[0259] Synthesis of compound IIb-47

[0260] First step: Compound RM-IIb-41 (0.6 g, 1.31 mmol) was added to HCl / MeOH (6 N, 12 mL) and stirred at room temperature overnight. After completion of the reaction was detected, the mixture was concentrated to give a white solid intermediate product RM-IIb-44 (0.5 g).

[0261] Second step: The starting material RM-IIb-44 (0.050 g, 0.13 mmol) was dissolved in 2 mL of DCM, DMAP (0.039 g, 0.32 mmol) was added, and the mixture was cooled in an ice-water bath. Methyl chloroformate (0.015 g, 0.15 mmol) was added, and the mixture was stirred overnight at room temperature to complete the reaction. After confirming the completion of the reaction by HPLC, the reaction solution was treated and purified by column chromatography to obtain intermediate RM-IIb-45 (0.049 g).

[0262] Third step: To the intermediate RM-IIb-45, MeOH (2 mL), THF (1 mL), and aqueous LiOH (1N, 1 mL) were added sequentially and stirred at room temperature for 1 hour. After confirming the completion of the reaction by HPLC, the reaction mixture was neutralized to approximately pH 4 with 1N hydrochloric acid, water was added, and ethyl acetate was added for extraction. The combined organic phases were washed with brine, dried, and finally purified by column chromatography to give the white solid product IIb-47 (0.047 g). The yield of the two steps was 92%. Mass spectrometry confirmed that IIb-47 was a methyl group. + ]: m / z theoretical value 400.4, actual value 400.3. [Example]

[0263] Synthesis of compound IIb-48

[0264] First step: The starting material RM-IIb-44 (0.050 g, 0.13 mmol) was dissolved in 2 mL of DCM, DMAP (0.039 g, 0.32 mmol) was added, and the mixture was cooled in an ice-water bath. Cyclopentyl chloroformate (0.023 g, 0.15 mmol) was added, and the mixture was stirred overnight at room temperature to complete the reaction. After confirming the completion of the reaction by HPLC, the reaction solution was treated and purified by column chromatography to obtain intermediate RM-IIb-46 (0.050 g).

[0265] Second step: To the intermediate RM-IIb-46, MeOH (2 mL), THF (1 mL), and aqueous LiOH (1N, 1 mL) were added sequentially and stirred at room temperature for 1 hour. After confirming the completion of the reaction by HPLC, the reaction mixture was neutralized to pH 4 with 1N hydrochloric acid, water was added, and ethyl acetate was added for extraction. The combined organic phases were washed with brine, dried, and finally purified by column chromatography to give the white solid product IIb-48 (0.040 g). The yield of the two steps was 70%. Mass spectrometry confirmed that IIb-48 was a methyl group. + ]: m / z theoretical value 454.5, actual value 454.5. [Example]

[0266] Synthesis of Compound IIb-49

[0267] First step: The raw material RM-IIb-44 (0.050 g, 0.13 mmol) was dissolved in 2 mL of DCM, DMAP (0.039 g, 0.32 mmol) was added, and the mixture was cooled in an ice-water bath. Phenyl chloroformate (0.024 g, 0.15 mmol) was added, and the mixture was stirred overnight at room temperature to complete the reaction. After confirming the completion of the reaction by HPLC, the reaction solution was treated and purified by column chromatography to obtain the intermediate (0.050 g).

[0268] Second step: The intermediate was redissolved in 2 mL of DMF, and DMAP (0.025 g, 0.2 mmol) and tert-butylamine (0.015 g, 0.2 mmol) were added. The mixture was stirred at room temperature for 3 hours to complete the reaction. After confirming the completion of the reaction by HPLC, the reaction solution was treated and purified by column chromatography to obtain intermediate RM-IIb-47 (0.040 g).

[0269] Third step: To the intermediate RM-IIb-47, MeOH (2 mL), THF (1 mL), and aqueous LiOH (1N, 1 mL) were added sequentially and stirred at room temperature for 1 hour. After confirming the completion of the reaction by HPLC, the reaction mixture was neutralized to approximately pH 4 with 1N hydrochloric acid, water was added, and ethyl acetate was added for extraction. The combined organic phases were washed with brine, dried, and finally purified by column chromatography to give the white solid product IIb-49 (0.020 g). The yield of the three steps was 35%. Mass spectrometry confirmed that IIb-49 was a methyl group. + ]: m / z theoretical value 441.5, actual value 441.4. [Example]

[0270] Synthesis of Compound IIb-50

[0271] First step: The starting material RM-IIb-44 (0.050 g, 0.13 mmol) was dissolved in 2 mL of DCM, DMAP (0.039 g, 0.32 mmol) was added, and the mixture was cooled in an ice-water bath. Cyclopentyl chloroformate (0.023 g, 0.15 mmol) was added, and the mixture was stirred overnight at room temperature to complete the reaction. After confirming the completion of the reaction by HPLC, the reaction solution was treated and purified by column chromatography to obtain intermediate RM-IIb-48 (0.045 g).

[0272] Second step: To the intermediate RM-IIb-48, MeOH (2 mL), THF (1 mL), and aqueous LiOH (1N, 1 mL) were added sequentially and stirred at room temperature for 1 hour. After confirming the completion of the reaction by HPLC, the reaction mixture was neutralized to approximately pH 4 with 1N hydrochloric acid, water was added, and ethyl acetate was added for extraction. The combined organic phases were washed with brine, dried, and finally purified by column chromatography to give the white solid product IIb-50 (0.020 g). The yield of the two steps was 46%. Mass spectrometry confirmed that IIb-50 was a methyl group. + ]: m / z theoretical value 426.7, actual value 426.4. [Example]

[0273] Synthesis of Compound IIb-51

[0274] First step: The starting material RM-IIb-44 (0.050 g, 0.13 mmol) was dissolved in 2 mL of DCM, DMAP (0.039 g, 0.32 mmol) was added, and the mixture was cooled in an ice-water bath. Isopropylsulfonyl chloride (0.022 g, 0.15 mmol) was added, and the mixture was stirred overnight at room temperature to complete the reaction. After confirming the completion of the reaction by HPLC, the reaction solution was treated and purified by column chromatography to obtain intermediate RM-IIb-49 (0.015 g).

[0275] Second step: To the intermediate RM-IIb-49, MeOH (2 mL), THF (1 mL), and aqueous LiOH (1N, 1 mL) were added sequentially and stirred at room temperature for 1 hour. After confirming the completion of the reaction by HPLC, the reaction mixture was neutralized to approximately pH 4 with 1N hydrochloric acid, water was added, and ethyl acetate was added for extraction. The combined organic phases were washed with brine, dried, and finally purified by column chromatography to give the white solid product IIb-51 (0.009 g). The yield for the two steps was 16%. Mass spectrometry confirmed that IIb-51 was a methyltransferase (MH) + ]: m / z theoretical value 448.5, actual value 448.3. [Example]

[0276] Synthesis of compound IIb-52

[0277] The synthetic method for preparing compound IIb-52 was the same as in Example 2, with etherification and hydrolysis to give product IIb-52, where compound RM-Ib-30 (0.06 mmol) was used instead of compound RM-Ib-2, and compound SM1-2 (0.06 mmol) was used instead of compound SM1-1 to give intermediate RM-IIb-50, which was then hydrolyzed to give white solid product IIb-52 (0.004 g). Yield of the two steps: 15%. Mass spectrometry confirmed that IIb-52 was a methyltransferase (M-H) + ]: m / z theoretical value 411.1, measured value 411.2. [Example]

[0278] Synthesis of compound IIb-53

[0279] The synthetic method for preparing compound IIb-53 was the same as in Example 2, with etherification and hydrolysis to give product IIb-53, where compound RM-Ib-31 (0.24 mmol) was used instead of compound RM-Ib-2, and compound SM1-2 (0.24 mmol) was used instead of compound SM1-1 to give intermediate RM-IIb-51, which was then hydrolyzed to give white solid product IIb-53 (0.018 g). Yield for the two steps: 19%. Mass spectrometry confirmed that IIb-53 was a methyl group, and ESI-MS [(MH) + ]: m / z theoretical value 395.1, measured value 395.2. [Example]

[0280] Synthesis of compound IIb-54

[0281] The synthetic method for preparing compound IIb-54 was the same as in Example 2, with etherification and hydrolysis to give product IIb-54. In this case, compound RM-Ib-32 (0.24 mmol) was used instead of compound RM-Ib-2, and compound SM1-2 (0.24 mmol) was used instead of compound SM1-1 to give intermediate RM-IIb-52, which was then hydrolyzed to give white solid product IIb-54 (0.028 g). The yield for the two steps was 27%. Mass spectrometry confirmed that IIb-54 was a methyl group. + ]: m / z theoretical value 431.0, actual value 431.1. [Example]

[0282] Synthesis of compound IIb-55

[0283] The synthetic method for preparing compound IIb-55 was the same as in Example 2, with etherification and hydrolysis to give product IIb-55, where compound RM-Ib-33 (0.24 mmol) was used instead of compound RM-Ib-2, and compound SM1-2 (0.24 mmol) was used instead of compound SM1-1 to give intermediate RM-IIb-53, which was then hydrolyzed to give white solid product IIb-55 (0.020 g). Yield for the two steps: 22%. Mass spectrometry confirmed that IIb-55 was a methyl group. + ]: m / z theoretical value 381.1, measured value 381.2. [Example]

[0284] Synthesis of Compound IIb-56

[0285] The synthetic method for preparing compound IIb-56 was the same as in Example 2, with etherification and hydrolysis to give product IIb-56, where compound RM-Ib-34 (0.24 mmol) was used instead of compound RM-Ib-2, and compound SM1-2 (0.24 mmol) was used instead of compound SM1-1 to give intermediate RM-IIb-54, which was then hydrolyzed to give white solid product IIb-56 (0.028 g). Yield for the two steps: 30%. Mass spectrometry confirmed that IIb-56 was a methyl group, and ESI-MS [(MH) + ]: m / z theoretical value 397.0, actual value 397.1. [Example]

[0286] Synthesis of compound IIb-57

[0287] The synthetic method for preparing compound IIb-57 was the same as in Example 2, with etherification and hydrolysis to give product IIb-57, where compound RM-Ib-35 (0.23 mmol) was used instead of compound RM-Ib-2, and compound SM1-11 (0.23 mmol) was used instead of compound SM1-1 to give intermediate RM-IIb-55, which was then hydrolyzed to give white solid product IIb-57 (0.018 g). Yield for the two steps: 21%. Mass spectrometry confirmed that IIb-57 was a methyltransferase (M-H) + ]: m / z theoretical value 363.1, actual value 363.2. [Example]

[0288] Synthesis of compound IIb-58

[0289] The synthetic method for preparing compound IIb-58 was the same as in Example 2, with etherification and hydrolysis to give product IIb-58, where compound RM-Ib-36 (0.23 mmol) was used instead of compound RM-Ib-2, and compound SM1-11 (0.23 mmol) was used instead of compound SM1-1 to give intermediate RM-IIb-56, which was then hydrolyzed to give white solid product IIb-58 (0.026 g). Yield of the two steps: 30%. Mass spectrometry confirmed that IIb-58 was a methyl group. + ]: m / z theoretical value 379.0, measured value 379.1. [Example]

[0290] Synthesis of Compound IIb-59

[0291] The synthetic method for preparing compound IIb-59 was the same as in Example 2, with etherification and hydrolysis to give product IIb-59, where compound RM-Ib-27 (0.23 mmol) was used instead of compound RM-Ib-2, and compound SM1-11 (0.23 mmol) was used instead of compound SM1-1 to give intermediate RM-IIb-57, which was then hydrolyzed to give white solid product IIb-59 (0.016 g). Yield of the two steps: 30%. Mass spectrometry confirmed that IIb-59 was a methyl group. + ]: m / z theoretical value 460.1, actual value 460.2. [Example]

[0292] Synthesis of compound IIb-60

[0293] The synthetic method for preparing compound IIb-60 was the same as in Example 2, with etherification and hydrolysis to give product IIb-60, where compound RM-Ib-27 (0.24 mmol) was used instead of compound RM-Ib-2, and compound SM1-8 (0.24 mmol) was used instead of compound SM1-1 to give intermediate RM-IIb-58, which was then hydrolyzed to give white solid product IIb-60 (0.021 g). Yield of the two steps: 20%. Mass spectrometry confirmed that IIb-60 was a methyl group. + ]: m / z theoretical value 442.2, actual value 442.1. [Example]

[0294] Synthesis of Compound IIb-61

[0295] The synthetic method for preparing compound IIb-61 was the same as in Example 1, with etherification and hydrolysis to give product IIb-61, where compound RM-Ib-1 was replaced with compound RM-Ib-16 (0.24 mmol) and compound SM1-1 was replaced with compound SM1-8 (0.24 mmol) to give intermediate RM-IIb-59, which was then hydrolyzed to give white solid product IIb-61 (0.026 g). Yield of the two steps: 30%. Mass spectrometry confirmed that IIb-61 was a methyl group. + ]: m / z theoretical value 361.1, measured value 361.2. [Example]

[0296] Synthesis of compound IIb-62

[0297] The synthetic method for preparing compound IIb-62 was the same as in Example 1, with etherification and hydrolysis to give product IIb-62, where compound RM-Ib-1 was replaced with compound RM-Ib-16 (0.24 mmol) and compound SM1-1 was replaced with compound SM1-12 (0.24 mmol) in the reaction to give intermediate RM-IIb-60, which was then hydrolyzed to give white solid product IIb-62 (0.015 g). Yield of the two steps: 16%. Mass spectrometry confirmed that IIb-62 was a methyltransferase (M-H) + ]: m / z theoretical value 373.1, actual value 373.1. [Example]

[0298] Synthesis of compound IIb-63

[0299] The synthetic method for preparing compound IIb-63 was the same as in Example 2, with etherification and hydrolysis to give product IIb-63. In this case, compound RM-Ib-29 (0.24 mmol) was used instead of compound RM-Ib-2, and compound SM1-8 (0.24 mmol) was used instead of compound SM1-1 to give intermediate RM-IIb-61, which was then hydrolyzed to give white solid product IIb-63 (0.020 g). The yield for the two steps was 17%. Mass spectrometry confirmed that IIb-63 was a methyl group, and ESI-MS [(MH) + ]: m / z theoretical value 476.2, actual value 476.2. [Example]

[0300] Synthesis of compound IIb-64

[0301] The synthetic method for preparing compound IIb-64 was the same as in Example 2, with etherification and hydrolysis to give product IIb-64, where compound RM-Ib-29 (0.24 mmol) was used instead of compound RM-Ib-2, and compound SM1-12 (0.24 mmol) was used instead of compound SM1-1 to give intermediate RM-IIb-62, which was then hydrolyzed to give white solid product IIb-64 (0.015 g). Yield for the two steps: 13%. Mass spectrometry confirmed that IIb-64 was a methyl group. + ]: m / z theoretical value 488.2, actual value 488.3. [Example]

[0302] Method for detecting GPR40 activity of compounds:

[0303] The compounds prepared in the present invention can be preliminarily measured and screened for their effects on GPR40 through the following preclinical in vitro inhibitory activity test experiments, and their therapeutic effects and safety can be further confirmed through clinical trials. Other methods are also apparent to those of ordinary skill in the art. The results of preclinical and clinical trials of the GPR40 agonist TAK-875 previously developed by Takeda Pharmaceutical Company Limited in Japan have shown that the results of in vitro tests are consistent with the results of related in vivo activity tests.

[0304] The compounds of the present invention, or their stereoisomers, tautomers, esterified or amidated prodrugs, or pharmaceutically acceptable salts and mixtures thereof, were tested by evaluating the GPR40 activity of compounds IIb-01 to IIb-64 and one reference compound Ref-1 (TAK-875). Comparison of the test results revealed that the inhibitory activity (EC 50 ) was found to be superior to the reference compound.

[0305] CHO-K1 / GPR40 cells were seeded into a 384-well plate at a seeding density of 10,000 cells / well. The cells were incubated at 37°C in a 5% CO2 incubator for 24 hours. After the experiment, the cell culture medium was discarded, and 30 μl of 1X FLIPR® Calcium 6 dye containing 2.5 mM Probenecid was quickly added to each well and incubated at 37°C for 2 hours in the dark. At the time of measurement, different concentrations of drugs (15 μl / well) were added to the wells, and the fluorescence values ​​were read. The fluorescence excitation wavelength was 494 nm, and the emission wavelength was 516 nm. FLIPR instrument data was calculated as EC50 according to the formula Y = Bottom + (Top - Bottom) / (1 + (EC50 / X)^HillSlope). 50 obtained.

[0306] The GPR40 agonist activity test results of each novel structural compound of formula IIb are listed in the following Tables 3 and 2. Here, the GPR40 agonist activity effect range (EC 50 ) are marked as "A" if they are <10 nM, marked as "B" if they have an activity range of 10-100 nM, and marked as "C" if they have an activity range of >100 nM.

[0307] [Table 5] TIFF0007804653000063.tif79160 [Example]

[0308] Compound Toxicity Screening Test

[0309] Some of the new compounds (IIb-01 to IIb-64) had relatively high activity (EC 50To test the toxicity of compounds IIb-18, IIb-25, and IIb-43 (<10 nM), healthy mice weighing 18 to 22 g were used, and a single dose of 600 mg / kg was administered by oral gavage once. The toxic reactions induced by the experimental animals were observed within five consecutive days to evaluate the toxicity of the test substance to the body. An acute toxicity study (MTD) was conducted, and the results showed that the overall toxicity of this type of compound was very low (LD 50 The results showed that the compound has a potent anti-inflammatory effect (>600), and the survival rate of mice after administration was 100%. During the administration period and the 5-day recovery period, there were no abnormalities in body weight or in vivo or ex vivo observations, and autopsy results showed no abnormal changes in organs such as the heart, liver, lungs, kidneys, or intestines. The compounds tested are generally considered to be safe and non-toxic at appropriate doses.

[0310] Therefore, some highly active compounds of the present invention have been tested by in vitro experiments and not only have good therapeutic effects on type II diabetes, but are also safe and reliable. [Example]

[0311] Method for detecting the bile salt transport effect of compound BSEP (Bile Salt Export Pump):

[0312] In this experiment, we used LC / MS / MS to detect the absorption of the substrate taurocholic acid (TCA) by the BSEP bile salt transporter to preliminarily investigate whether candidate compounds inhibit the transport process. BSEP protein microcapsules with reverse absorption ability were obtained by transfecting Hi5 cells with the BSEP gene. These microcapsules were capable of absorbing and uptake of taurocholic acid (TCA). The principle of this experiment was to conduct a substrate absorption experiment using BSEP protein microcapsules in the simultaneous presence of energy source ATP, the substrate taurocholic acid (TCA), and the candidate compound under test. After a certain period of transport, the remaining energy, substrate, and candidate compound outside the microcapsules were completely washed away and removed. The microcapsules were then cleaved, releasing the absorbed substrate taurocholic acid (TCA). LC / MS / MS was then used to detect taurocholic acid and determine whether the candidate compound inhibited the TCA transport process.

[0313] Sample processing: 1. The compounds were dissolved in 100% DMSO to a concentration of 100 mM and stored in a refrigerator at -20°C until all compounds were completely dissolved. 2. The initial concentration of the sample was 100 mM and serially diluted 2-fold using the Bravo device, resulting in a total of 11 concentration gradients; the lowest concentration was 97.65 μM. 3. The initial concentration of the control compound (Glyburide) was 20 mM and diluted two-fold in the Bravo apparatus, resulting in a total of 11 concentration gradients; the lowest concentration was 19.53 μM. 4. Using the ECHO autosampler, 300 nl of compound was transferred to the center plate. 5. 300 nl of DMSO was also transferred to the positive control (HPE) and negative control (ZPE) wells.

[0314] Experimental procedure steps: 1. 14.7 μl of ATP buffer was added to the corresponding wells of compound and ZPE, respectively. 2. 14.7 μl of AMP buffer was added to the corresponding wells of the HPE. 3. The plate was shaken at 25°C for 10 minutes. 4. 15 μl of BSEP-Hi5-VT Vesicle solution was added to all wells, and the plate was shaken at 25° C. for 40 minutes. 5. Immediately add 5 μl of 0.5M EDTA solution to all wells, followed by 65 μl of buffer B to complete all reactions. 6. Using a pipetting device, 95 μl of the completed reaction mixture was transferred from the compound plate to the filter plate. 7. After placing the receiving plate under the filter plate, the liquid was removed using a centrifuge and the liquid received in the receiving plate was discarded. 8. Add 90 μl of Buffer B to the filter plate, repeat step 7, and then repeat steps 7 and 8 to wash the filter plate a total of three times. 9. The filter plates were allowed to dry overnight. 10. The next day, 81 μl of 80% methanol / water solution was added to the filter plate. 11. After the film was applied, the filter plate was shaken for 15 minutes. 12. Place a new receiver plate under the filter plate and centrifuge for 5 minutes to filter all the liquid in the filter plate into the receiver plate. 13. 13.5 μl of the internal standard solution was added to each well of the receiver plate, and the plate was sealed with sealing film. 14. The content of taurocholic acid in the receiving plate was measured using LC / MS / MS.

[0315] [Table 6] NOTE: If the BSEP inhibitory result (IC50) of a compound shown in Table 4 is lower than 25 µM [for example, the value of Ref-1 (TAK-875) is 7.1, which is significantly lower than 25], the BSEP inhibitory side effect of the compound in question may be a potential risk of liver damage in vivo.

[0316] The activity test results in Tables 3 and 4 above demonstrate the following facts: (1) Among the novel benzoheterocyclic compounds of each type according to the present invention, the activity (EC50) of the 5-membered heterocyclic compounds containing 1 to 2 oxygen atoms is significantly superior to that of the 6-membered heterocyclic compounds having similar structures and containing 1 to 2 oxygen atoms; (2) In the compound of formula IIb according to the present invention, Z 1 The activity of benzooxygen-containing five-membered heterocyclic compounds when is "oxygen (O)" is 1 is "CH2"; (3) the benzooxygen-containing five-membered heterocyclic compounds IIb-18, IIb-25, IIb-43 and IIb-46 of the present invention have very good activity (EC 50 :<10 nM), which is superior to the similar control compound TAK-875, and is a new type of GPR40 agonist that currently has relatively good activity in this research field and is pharmacologically advantageous in terms of activity, safety, etc.

[0317] The three benzooxygen-containing five-membered heterocyclic compounds listed in Table 4 above not only exhibit good activity, but also all have BSEP side effects above 25, which can cause liver damage, significantly superior to TAK-875, a new drug from Takeda Pharmaceutical Company in Japan that has terminated Phase III clinical trials due to liver toxicity issues. Furthermore, the results of the completed acute toxicity study (MTD) showed that the three highly active compounds IIb-18, IIb-25, and IIb-43 listed in Table 4 have superior safety. After oral gavage of the new compounds at a dose of 600 mg / 1 kg for 5 days, the survival rate was 100%, and no abnormalities were observed during the administration period or the 5-day recovery period. Necropsy results also showed no abnormalities. Therefore, some highly active compounds among the novel benzooxygen-containing five-membered heterocyclic compounds IIb designed and synthesized by the present invention are worthy of further animal and clinical testing, as well as popularization and application.

[0318] Therefore, in the innovative research into GPR40 target agonists, the present invention has discovered several compounds (e.g., IIb-18, IIb-25, and IIb-43) with superior activity and efficacy, and the toxicity in acute toxicity tests at high doses of TMD (600 mg / kg / day) was very low, and test results such as BSEP (>25 uM), hERG (>30 uM), and Ames showed that there were no relevant side effects. All relevant results were superior to those of the currently known reference compound TAK-875, laying the foundation for the invention of new GPR40 target agonist drugs with superior GPR40 target selectivity that can safely and effectively treat type II diabetes patients.

[0319] These and other modifications can be made to the embodiments based on the above detailed description. In general, the terms used in the claims should not be construed to limit the claims to the specific embodiments disclosed in the specification and claims, but should be construed to include all possible embodiments subject to the full range of equivalents of the claims as described. Accordingly, the claims are not limited by the content of this disclosure.

Claims

1. A compound of formula IIb, or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 (where, n=0; Y does not exist, Y １ is directly bonded to the adjacent oxygen atom via a single bond to form a 5-membered heterocyclic group together with Z; Y １ Ha-CH ２ -, -CHF-, -CF ２ - and -C(CH ３ ) ２ - selected from the group consisting of; E is G １ directly bonded to form a ring structure; G １ is —C—; E is —OC(RcRd)—; where Rc and Rd are each independently hydrogen; L １ Ha-CH ２ - and; R １ , R ２ and R ３ are each independently hydrogen, halogen, alkyl, or alkoxy; R ４ is hydrogen; R ５ is hydrogen, halogen, hydroxyl, amino, alkylamino, alkyl or alkoxy; R ５ｂ is hydrogen, halogen, alkyl or alkoxy; R ７ is hydroxyl, alkoxy, alkylamino, cycloalkylamino, heterocyclic amino, alkylsulfonylamino, cycloalkylsulfonylamino, aryloxy, heterocyclic aryloxy, arylamino, or heterocyclic arylamino; X ５ represents hydrogen, deuterium (D), halogen, nitrile, amino, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylamino (NR ｉ R ｊ ), alkylcarbonylamino, alkoxycarbonylamino, cycloalkylsulfonylamino, aryl, or aryloxycarbonylamino; ｉ and R ｊ are each independently hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, or cycloalkoxycarbonyl; X ６ and X ７ are each independently hydrogen, deuterium (D), halogen, C1-C8 alkylamino, or C1-C8 alkoxycarbonylamino; Z is —O—; The compound is characterized in that it has a structure selected from the following group: 【Chemistry 2】

2. 10. A composition comprising a compound of claim 1, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent and / or excipient.

3. 10. Use of a compound according to claim 1 in the manufacture of a medicament for use as a GPR40 agonist.

4. 10. Use of a compound according to claim 1 in the manufacture of a medicament for treating or preventing diabetes or the associated metabolic syndrome.

5. 5. The use of the compound according to claim 4, wherein the diabetes is type II diabetes.

6. 10. Use of the composition of claim 2 in the manufacture of a medicament for use as a GPR40 agonist.

7. 10. Use of the composition of claim 2 in the manufacture of a medicament for treating or preventing diabetes or the associated metabolic syndrome.

8. The use of the composition according to claim 7, wherein the diabetes is type II diabetes.

Images