CN114163408B - Benzo oxygen-containing heterocyclic compound and medical application thereof - Google Patents

Abstract

The present invention discloses compounds of formula Ia or IIa, cis-, enantiomer, diastereoisomer, racemate, tautomer, solvate, hydrate, or pharmaceutically acceptable salt or mixture thereof, pharmaceutical compositions containing the compounds and use of the compounds as GPR40 agonists ¹ 、R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ^5b 、R ⁶ 、R ⁷ 、Ra、Rb、Rc、Rd、Re、Rf、Rg、Ri、Rj、X ¹ 、X ² 、X ³ 、X ⁴ 、Y、Y ¹ And the possible isotopic substitution labels of the elements in the compounds are as defined in the specification.

Description

Benzo-oxygen-containing heterocyclic compounds and their medical applications

Technical Field

The present invention relates to a novel benzo-oxygen-containing heterocyclic compound, in particular a benzo-pentacyclic oxygen-containing heterocyclic compound. The compound can be used as an agonist of a GPR40 target, and can reduce blood sugar levels by stimulating pancreatic β cells to release insulin, thereby safely and effectively treating diseases such as type II diabetes.

Background Art

Diabetes is a chronic endocrine and metabolic disease characterized by high blood sugar levels due to insulin secretion defects, insulin resistance, or both. Diabetes can severely damage major organ systems in the body, causing heart disease, stroke, nerve damage, kidney failure, blindness, and infections that may lead to amputation. The disease is prone to complications, and has high disability and mortality rates.

Type II diabetes accounts for about 90% of the total number of diabetes cases. Patients are usually able to produce insulin on their own, but they cannot produce enough insulin or cannot use it properly. Commonly used drugs for the treatment of diabetes in clinical practice include insulin secretagogues, which are currently the first-line hypoglycemic drugs. These drugs include sulfonylureas such as glipizide and non-sulfonylureas such as metformin. The main side effects of hypoglycemic drugs are gastrointestinal discomfort, edema, hypoglycemia, etc. Some patients may experience a strong sense of hunger, cold sweats, general weakness, palpitations, trembling hands and feet, blurred vision, headaches, dazes, etc. due to the side effects of hypoglycemia. In severe cases, coma may occur. Therefore, the development of new anti-type II diabetes drugs with high safety, no hypoglycemia side effects, convenient and effective oral administration is still the direction that scientists are working hard to explore.

Recent studies have found that free fatty acid receptor 1 (FFAR1), or G protein-coupled receptor 40 (GPR40), plays a key role in stimulating and regulating insulin production. When blood glucose and fatty acids rise after a meal, GPR40 agonists lower blood sugar levels by stimulating pancreatic β cells to release insulin. Therefore, drugs that can activate GPR40 can effectively control blood sugar levels by helping diabetic patients release more insulin. The characteristic of this type of drug is that it promotes insulin secretion only when blood sugar concentration is high, thus greatly reducing the risk of hypoglycemia. The representative of this type of drug is TAK-875, developed by Takeda Corporation of Japan. It is a selective GPR40 agonist that has entered Phase III clinical trials. The results of the study showed that when blood sugar levels are normal, TAK-875 has no effect on insulin secretion. Clinically, a dose of 50 mg once a day is used, and patients have good efficacy and good tolerance, and the risk of causing hypoglycemia is significantly lower than that of sulfonylurea drugs in the control group, which verifies that the insulin secretion induced by TAK-875 is blood sugar-dependent. Although TAK-875 showed good efficacy, Japan's Takeda Company terminated its clinical research in 2013 due to the liver toxicity caused by the drug. It is worth mentioning that the study of TAK-875 liver toxicity has nothing to do with the mechanism of action of the drug, but is mainly caused by the unsafe molecular structure design. Therefore, the GPR40 target is still a good development idea with very important application prospects.

Structure of compound TAK-875

A series of patent applications for GPR40 agonists have been disclosed, including WO2005087710, WO2007106469A1, WO2004106276A1, WO2010143733A1, CN103030646A1, WO2013104257A1, WO2015062486A1, etc.

Therefore, although some progress has been made in this field, there is still a great need in the art for GPR40 agonists that can specifically activate the GPR40 target for the treatment of diabetes and related metabolic diseases, as well as related compositions and disease treatment methods. The present invention is intended to meet this need and provide other related advantages.

Summary of the invention

The present invention relates to compounds that activate the GPR40 target, as well as cis-trans isomers, enantiomers, diastereomers, racemates, tautomers, solvates, hydrates, or pharmaceutically acceptable salts or mixtures thereof of the compounds. The present invention also relates to pharmaceutically acceptable compositions comprising the compounds, and related methods for treating conditions that can obtain beneficial effects from activating the GPR40 target, such as diabetes and related metabolic diseases.

The present invention provides a benzo-oxygen-containing heterocyclic compound having a different structure from the existing one. The benzo-oxygen-containing heterocyclic compound of the present invention has better inhibitory activity on type II diabetes, can be used to treat type II diabetes patients more effectively, and has better safety.

The first aspect of the present invention provides a compound represented by formula Ia, its cis-trans isomers, enantiomers, diastereomers, racemates, tautomers, solvates, hydrates, or pharmaceutically acceptable salts or mixtures thereof;

in,

n = 0, 1 or 2;

When n=0, Y does not exist, and ^Y1 and ^Z1 adjacent to Y are directly connected by a single bond to form a five-membered heterocyclic ring;

E ¹ is connected to L and Y ¹ and is selected from -N-, -C(Ra)- or -OC(Ra)-; wherein Ra is selected from: hydrogen, deuterium (D), alkyl, cycloalkyl, alkoxy, cycloalkyloxy, alkoxycarbonyl, alkylamino, cycloalkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, aryl or heteroaryl;

When E is not connected with G ¹ to form a cyclic compound, E is selected from: hydrogen, deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, -CN, -OH, -COOH, -NH ₂ , -H ₂ NCO, alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, aryl, aryloxy, or heteroaryl; G ¹ is CH, or C(Rb); wherein Rb is hydrogen, deuterium (D), alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyloxy, alkoxycarbonyl, alkylamino, cycloalkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, aryl, aryloxy, heterocyclic group, heterocyclic aryl, or heterocyclic aryloxy, or Rb and R ⁴ can be connected to each other to form a cycloalkyl or heterocyclic group;

When E and ^G1 are connected to form a cyclic compound, G1 ^is -C-; E is -O-, -C(RcRd)-, -OC(RcRd)-, -C(RcRd)O-, or -NRe-; wherein Rc and Rd are respectively hydrogen, deuterium (D), alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyloxy, alkoxycarbonyl, alkylamino, cycloalkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, aryl, aryloxy, heterocyclic group, heterocyclic aryl, or heterocyclic aryloxy, and Rc and Rd can be connected to each other to form a cycloalkyl or heterocyclic group; Re is hydrogen, deuterium (D), alkyl, cycloalkyl, alkylcarbonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, alkylsulfonyl, or arylsulfonyl;

_L is -O-, -S-, -C(O)-, -S(O) _2- , _-CH2- , -C(RfRg)-, -OC(RfRg)-, -C( _RfRg )O-, -N(Re) _- , -N( _{Rc ) C} ( _RfRg )-, or -C( _RfRg )N( _Re )-; wherein _Rf and _Rg are independently hydrogen, deuterium (D), _alkyl , cycloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyloxy, alkoxycarbonyl, alkylamino, cycloalkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, aryl, aryloxy, heterocyclyl, heteroaryl, or heteroaryloxy, and Re is defined 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 (H ₂ NCO), alkyl, alkoxy, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonylamino, aryl, aryloxy, or heteroaryl; wherein, in Formula Ia, R ² and L can be connected to form a 4-8 membered heterocyclic compound, and L is -C(H)-O-;

R ⁴ , R ⁵ and R ^5b are each independently hydrogen, deuterium (D), halogen, hydroxyl, amino, nitrile, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, cycloalkyloxy, optionally substituted alkenyl, optionally substituted alkynyl, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonylamino, alkoxycarbonylamino, aryl, aryloxy, or heteroaryl; wherein R ⁵ and R ^5b may be connected to each other to form a cycloalkyl, heterocyclyl, or heteroaryl;

R ⁶ is carboxyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, alkylsulfonylamidecarbonyl, cycloalkylsulfonylamidecarbonyl, heterocyclic group, or heteroaryl group; or R ⁶ and the ortho-substituent R ⁵ may be connected to each other to form a heterocyclic group or a heteroaryl group;

X ¹ , X ² , X ³ and X ⁴ are each independently hydrogen, deuterium (D), halogen, nitrile, amino, trifluoromethyl, trifluoromethoxy, aminocarbonyl (H ₂ NCO), alkyl, heterocycloalkyl, alkoxy, heteroatom-substituted alkyloxy, alkylamino (NR _i R _j ), heteroatom-substituted alkylamino, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonylamino, alkoxycarbonylamino, cycloalkyloxycarbonylamino, alkylsulfonamide, cycloalkylsulfonamide, aryl, aryloxy, arylaminocarbonyl, arylcarbonylamino, aryloxycarbonylamino, heteroaryl, heteroaryloxy, or heteroarylamino; wherein R _i and R j are alkyl, ... _j are each independently hydrogen, deuterium (D), alkyl, heterocycloalkyl, alkylcarbonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, alkylaminocarbonyl, alkylsulfonyl, cycloalkylsulfonyl, aryl, aryloxycarbonyl, arylaminocarbonyl, heteroaryl, or R _i and R _j are linked to form a 3-8 membered heterocyclic ring containing 1-3 heteroatoms;

Y and ^Y1 are each independently -O-, -S-, _-CH2- , -CHF-, _-CF2- , _-CCl2- , -C( _RfRg )-, or -N(Re)-; wherein _Rf and _Rg are defined as _Rf and _Rg in ^L1, respectively, and Re is defined as Re in E _;

^Z1 is -O-, -S-, _-CH2- , -CHF-, _-CF2- , -C( _RfRg )-, -N( _Re )-, or -C(O)-; wherein _Rf and _Rg are defined as _Rf and _Rg in L above, respectively, and Re is defined as Re in E above.

The second aspect of the present invention provides a compound of formula IIa, its cis-trans isomers, enantiomers, diastereomers, racemates, tautomers, solvates, hydrates, or pharmaceutically acceptable salts or mixtures thereof:

in,

n, E, E ¹ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^5b , Ra, Rb, Rc, Rd, Re, Rf, Rg, Ri, Rj, X ¹ , X ² , X ³ , X ⁴ , Y and Y ¹ have the same definitions as described in claim 1;

R ⁷ is hydroxy, alkoxy, alkylamino, cycloalkylamino, heterocyclicamino, alkylsulfonamide, cycloalkylsulfonamide, aryloxy, heterocyclic aryloxy, arylamino, or heterocyclic arylamino; or R ⁷ and the ortho-substituent R ⁵ can be connected to form a heterocycle.

In some preferred embodiments, n=0 or 1;

When n=0, Y does not exist, and ^Y1 and the oxygen adjacent to Y are directly connected by a single bond to form a five-membered heterocyclic ring;

When n=1, Y is -CH ₂ -;

E ¹ is -CH-;

When E is not directly connected to ^G1 to form a cyclic compound, E is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, or alkoxy; ^G1 is -CH-, or -C(Rb)-; wherein Rb is hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkoxy, or Rb and ^R4 are connected to each other to form an oxygen-containing heterocyclic group; ^R4 is hydrogen, alkyl, alkoxy, optionally substituted alkynyl, or ^R4 and Rb are connected to each other to form an oxygen-containing heterocyclic group;

When E and G ¹ are directly connected to form a cyclic compound, E is -OC(RcRd)-; G ¹ is -C-; R ⁴ is hydrogen;

R ¹ , R ² and R ³ are each independently hydrogen, halogen, alkyl or alkoxy;

R ⁵ is hydrogen, halogen, hydroxy, amino, alkylamino, alkyl or alkoxy;

R ^5b is hydrogen, halogen, alkyl or alkoxy;

^R7 is alkoxy, hydroxy, alkylsulfonamide, or cycloalkylsulfonamide;

X ¹ is hydrogen, deuterium (D), halogen, nitrile, amino (NH ₂ ), trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylamino (NR _i R _j ), alkylcarbonylamino, alkylaminocarbonylamino, alkoxycarbonylamino, cycloalkyloxycarbonylamino, alkylsulfonamide, cycloalkylsulfonamide, aryl, or aryloxycarbonylamino;

X ² , X ³ and X ⁴ are each independently hydrogen, deuterium (D), halogen, or trifluoromethyl;

^Y1 is _-CH2- , -CHF-, _-CF2- , or -C( _CH3 ) _2- ;

^Z1 is -O- or _-CH2- ;

Rc and Rd are each independently hydrogen;

Ri and Rj are each independently hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, or cycloalkoxycarbonyl.

In some more preferred embodiments, n=0, Y is absent;

E ¹ is -CH-;

When E is not directly connected to ^G1 to form a cyclic compound, E is hydrogen or halogen; ^G1 is -CH- or -C(Rb)-, wherein Rb is alkyl, alkenyl, alkynyl or alkoxy; ^R4 is hydrogen, alkyl or alkoxy;

E and G ¹ are directly connected to form a cyclic compound, E is -OC(RcRd)-, G ¹ is -C-, R ⁴ is hydrogen, wherein Rc and Rd are each independently hydrogen;

R ¹ , R ² and R ³ are each independently hydrogen, halogen, or alkoxy;

R ⁵ is hydrogen, halogen, hydroxy, amino, alkyl or alkoxy;

R ^5b is hydrogen, halogen, alkyl or alkoxy;

^R7 is selected from: alkoxy, hydroxy, alkylsulfonamide, or cycloalkylsulfonamide;

^Y1 is _-CH2- ;

Z ¹ is -O-;

X ¹ is selected from the group consisting of hydrogen, deuterium (D), halogen, nitrile, amino (NH ₂ ), trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylamino (NR _i R _j ), alkylcarbonylamino, alkylaminocarbonylamino, alkoxycarbonylamino, cycloalkyloxycarbonylamino, alkylsulfonamide, cycloalkylsulfonamide, aryl, or aryloxycarbonylamino, wherein Ri and Rj are each independently hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, or cycloalkyloxycarbonyl;

X ² , X ³ and X ⁴ are each independently hydrogen, deuterium (D), halogen, or trifluoromethyl.

In some specific embodiments, the compounds of the present invention have a structure selected from the group consisting of:

Another aspect of the present invention provides a composition comprising (i) a therapeutically effective amount of at least one compound of Formula Ia or IIa, its cis-trans isomers, enantiomers, diastereomers, racemates, tautomers, solvates, hydrates, or pharmaceutically acceptable salts or mixtures thereof; and (ii) a pharmaceutically acceptable diluent and/or excipient.

The present invention also relates to the use of the compound or composition in preparing a medicament used as a GPR40 agonist.

The present invention also provides a method for treating or preventing diabetes or related metabolic syndrome, comprising administering a therapeutically effective amount of the compound or composition to a patient.

The present invention also relates to the use of the compound or composition in preparing a drug for treating or preventing diabetes or related metabolic syndrome.

In a preferred embodiment, the compound or composition of the present invention is particularly suitable for the treatment of type II diabetes. The compound of the present invention will promote the secretion of insulin only when the blood glucose concentration of patients with type II diabetes is high, thus effectively reducing the risk of hypoglycemia in patients. At the same time, compared with commercially available drugs, the compound of the present invention has better GPR40 target selectivity and safety.

The above embodiments and other aspects of the invention are apparent in the following detailed description. To this end, various references are set forth herein that describe certain background information, processes, compounds and/or compositions in more detail, and each is incorporated herein by reference in its entirety.

DETAILED DESCRIPTION OF THE INVENTION

In the following description, in order to provide a thorough understanding of each embodiment of the present invention, some specific details are set forth. However, it will be appreciated by those skilled in the art that the present invention can be implemented without requiring these details. Unless otherwise indicated in the context, throughout the present specification and claims, the word "comprising" and its variations, for example, "comprising" and "including" are understood to be open and inclusive (i.e., "including (including) but not limited to").

References to "one embodiment" or "an embodiment" in the specification indicate that the specific features, structures, or properties described in conjunction with the embodiment are included in at least one embodiment of the present invention. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing in various places in the specification do not necessarily all refer to the same embodiment. Moreover, the specific features, structures, or properties may be combined in any suitable manner in one or more embodiments.

I. Definitions

In the present invention, when not otherwise specified, the "alkyl" means a branched and straight-chain saturated aliphatic hydrocarbon group including 1 to 20 carbon atoms, which consists only of carbon and hydrogen atoms. In a preferred embodiment, the alkyl has one to twelve carbon atoms (C1-C12 alkyl), one to eight carbon atoms (C1-C8 alkyl) or one to six 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, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, and various isomers thereof. The alkyl group may be optionally substituted with a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxy, carboxyl, amino (NH ₂ ), aminocarbonyl (H ₂ NCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkyloxy, cycloalkyloxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclic, alkylurea, aryl, aryloxy, heterocyclic aryl, heterocyclic aryloxy, fused ring aryl, fused ring heterocyclic aryl, fused ring oxy, fused ring aryloxy, fused ring heterocyclic aryloxy, arylurea, or heterocyclic arylurea.

In the present invention, when not specifically specified, the "aryl" refers to any stable hydrocarbon ring system group that can contain up to 7 carbon atoms per ring, a monocyclic, bicyclic, tricyclic or tetracyclic ring, wherein at least one ring is an aromatic ring. Exemplary aryl groups are hydrocarbon ring system groups containing hydrogen and 6-9 carbon atoms and at least one aromatic ring; hydrocarbon ring system groups containing hydrogen and 9-12 carbon atoms and at least one aromatic ring; hydrocarbon ring system groups containing hydrogen and 12-15 carbon atoms and at least one aromatic ring; or hydrocarbon ring system groups containing hydrogen and 15-18 carbon atoms and at least one aromatic ring. For the purposes of the present invention, the aryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include a fused or bridged ring system. Aryl groups include, but are not limited to, aryl groups derived from the following compositions: benzene, biphenyl, anthracene, azulene, fluorene, indane, indene, naphthalene, phenanthrene, pyrene, etc. "Optionally substituted aryl" refers to: an aryl group or a substituted aryl group. The aryl group may be optionally substituted by a group selected from the following group: deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, carboxyl, amino ( _NH2 ), aminocarbonyl ( _H2NCO ), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, alkyl-sulfonyl-alkoxy, cycloalkyl, cycloalkyloxy, cycloalkyloxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclic group, aryl, aryloxy, heterocyclic aryl, fused ring aryl, fused ring alkyl, fused ring alkyl, fused ring oxy, benzene or biphenyl which is unsubstituted or contains 1 to 4 of the above optional substituents.

In the present invention, when not specifically specified, the "heterocyclic aryl" refers to a stable monocyclic, bicyclic or tricyclic ring containing up to 7 atoms per ring, wherein at least one ring is an aromatic ring, and wherein at least one ring contains 1-4 heteroatoms selected from O, N, and/or S. Heterocyclic aryl within the scope of this definition includes, but is not limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothiazolyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinoline. In addition, "heterocyclic aryl" should also be understood to include any quaternary ammonium salt or N-oxide derivative of a nitrogen-containing heterocyclic aryl. The heterocyclic aromatic group may be optionally substituted by a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, carboxyl, amino (NH ₂ ), aminocarbonyl (H ₂ NCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkyloxy, cycloalkyloxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclic group, aryl, aryloxy, heterocyclic aromatic group, fused ring aromatic group, fused ring alkyl group, fused ring alkyl group, fused ring oxy group, benzene or biphenyl group which is unsubstituted or contains 1 to 4 of the above optional substituents.

In the present invention, when not otherwise specified, the "condensed ring aryl" refers to a stable bicyclic or tricyclic ring with up to 7 atoms in each ring, wherein at least one ring is an aromatic ring. The condensed ring aryl may be optionally substituted by a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, carboxyl, amino (NH ₂ ), aminocarbonyl (H ₂ NCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkyloxy, cycloalkyloxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclic, aryl, aryloxy, heterocyclic aryl, condensed ring aryl, condensed cycloalkyl, condensed cycloalkyl, condensed cycloepoxy, unsubstituted or benzene or biphenyl containing 1 to 4 of the above optional substituents.

In the present invention, when not otherwise specified, the "fused heterocyclic aryl" refers to a stable bicyclic or tricyclic ring with up to 7 atoms in each ring, wherein at least one ring is an aromatic ring and contains 1-4 heteroatoms selected from O, N, and/or S. The fused heterocyclic aryl may be optionally substituted by a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, carboxyl, amino (NH ₂ ), aminocarbonyl (H ₂ NCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkyloxy, cycloalkyloxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclic group, aryl, aryloxy, heterocyclic aryl, fused cyclic aryl, fused cyclic alkyl, fused cyclic alkyl, fused cyclic oxy, benzene or biphenyl which is unsubstituted or contains 1-4 of the above optional substituents.

In the present invention, when there is no special specification, the "alkoxy group" refers to the group formed by connecting an alkyl group and an oxygen atom, that is, R is an alkyl group, which has the same definition as described above for the alkyl group. Examples of alkoxy groups include, but are not limited to: -O-methyl (methoxy), -O-ethyl (ethoxy), -O-propyl (propoxy), -O-isopropyl (isopropoxy), -O-tert-butyl (tert-butoxy), etc.

In the present invention, when not otherwise specified, the "alkenyl" means an unsaturated aliphatic alkenyl group including 2 to 20 carbon atoms, branched or straight chain, containing 1 to 3 "carbon-carbon double bonds", preferably 2 to 10 carbon atoms ( _C2 - _C10 alkenyl), more preferably 2 to 8 carbon atoms ( _C2 - _C8 alkenyl) or 2 to 6 carbon atoms ( _C2 - _C6 alkenyl), and various isomers thereof, which are connected to the rest of the molecule through a single bond. Examples of alkenyl include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, etc. The alkenyl group may be optionally substituted with a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxy, carboxyl, amino (NH ₂ ), aminocarbonyl (H ₂ NCO), alkyl, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkyloxy, cycloalkyloxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclic, alkylurea, aryl, heterocyclic aryl, fused ring aryl, fused ring heterocyclic aryl, arylurea, or heterocyclic arylurea.

In the present invention, when not otherwise specified, the "alkynyl" means an unsaturated aliphatic alkynyl group including 2 to 20 carbon atoms, branched or straight chain groups, containing 1 to 2 "carbon-carbon triple bonds", preferably 2 to 10 carbon atoms (C ₂ -C ₁₀ alkynyl), more preferably 2 to 8 carbon atoms (C ₂ -C ₈ alkynyl) or 2 to 6 carbon atoms (C ₂ -C ₆ alkynyl), and various isomers thereof, which are connected to the rest of the molecule via a single bond. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. The alkynyl group may be optionally substituted with a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxy, carboxyl, amino (NH ₂ ), aminocarbonyl (H ₂ NCO), alkyl, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkyloxy, cycloalkyloxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclic, alkylurea, aryl, heterocyclic aryl, fused ring aryl, fused ring heterocyclic aryl, arylurea, or heterocyclic arylurea.

In the present invention, unless otherwise specified, the "alkylthio" refers to a group formed by connecting an alkyl group to a sulfur atom, that is, R is an alkyl group, which has the same definition as the above-mentioned alkyl group.

In the present invention, when there is no special specification, the "aryloxy group" refers to the group formed by connecting an aryl group and an oxygen atom, that is, Ar is an aryl group, which has the same definition as the above aryl group.

In the present invention, unless otherwise specified, the "arylamine group" refers to an amine group in which one hydrogen in "NH ₃ " is replaced by an aryl group, wherein the definition of the aryl group is the same as that of the above-mentioned aryl group.

In the present invention, unless otherwise specified, the "heterocyclic aromatic amine group" refers to an amine group in which one hydrogen in "NH ₃ " is replaced by a heterocyclic aromatic group, wherein the definition of the heterocyclic aromatic group is the same as that of the above-mentioned heterocyclic aromatic group.

In the present invention, when not specifically specified, the "cycloalkyl" refers to an all-carbon monocyclic or polycyclic group, wherein each ring does not contain double bonds or triple bonds. Preferably, it has 3-20 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, a ring with 4 carbon atoms, or a ring with 3 carbon atoms. Examples of cycloalkyl include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The cycloalkyl group may be optionally substituted by a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxy, carboxyl, amino (NH ₂ ), aminocarbonyl (H ₂ NCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkyloxy, cycloalkyloxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclic, alkylurea, aryl, aryloxy, heterocyclic aryl, heterocyclic aryloxy, fused ring aryl, fused ring heterocyclic aryl, fused ring oxy, fused ring aryloxy, fused ring heterocyclic aryloxy, arylurea, or heterocyclic arylurea, wherein the definition of aryl is the same as that of the above aryl.

In the present invention, when not otherwise specified, the "cycloalkenyl" refers to an all-carbon monocyclic or polycyclic group, in which one or each ring may contain one or more "carbon-carbon double bonds". Preferably, it has 3-20 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, a ring with 4 carbon atoms, or a ring with 3 carbon atoms. Examples of cycloalkenyl include, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl. The cycloalkenyl group may be optionally substituted by a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, carboxyl, amino (NH ₂ ), aminocarbonyl (H ₂ NCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkyloxy, cycloalkyloxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclic, alkylurea, aryl, aryloxy, heterocyclic aryl, heterocyclic aryloxy, fused ring aryl, fused ring heterocyclic aryl, fused ring oxy, fused ring aryloxy, fused ring heterocyclic aryloxy, arylurea, or heterocyclic arylurea. When the substituent of the cycloalkenyl group is substituted on the carbon-carbon double bond and the double bond is saturated, a cycloalkyl group may be formed.

In the present invention, unless otherwise specified, the "cyclic ether group" refers to a cycloalkyl group having an ether group on the ring.

In the present invention, when not specifically specified, the "heterocyclic group" is an aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from O, N and S, and includes a bicyclic group. Therefore, the "heterocyclic group" includes the above-mentioned heterocyclic aromatic groups and their dihydro or tetrahydro analogs, and includes but is not limited to the following "heterocyclic groups": benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, isobenzofuranyl, pyridopyridyl, and the heterocyclic group can be connected with other organic small molecule groups through carbon atoms or heteroatoms to form new compounds with pharmaceutical effects.

In the present invention, when not specifically specified, the "condensed ring aromatic group" refers to two or more aromatic and/or heteroaromatic aromatic groups, and a polycyclic organic compound formed by condensed rings. The condensed ring aromatic group may also be substituted in a reasonable manner by groups such as alkyl, alkoxy, alkylthio, aryloxy, aromatic amino, heterocyclic, cycloalkyl, cycloalkyloxy, cycloalkyloxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, aromatic, halogen, carbonyl, hydroxyl, heteroaromatic, etc. defined in the present invention; wherein - includes but is not limited to naphthalene, anthracene, quinone, phenanthrene, fluorene, benzimidazolyl, furanofuranyl, thienothiphenyl, acenaphthyl,

In the present invention, unless otherwise specified, the "condensed cycloalkyl" refers to a non-aromatic polycyclic system formed by reducing one or more double bonds in a condensed cycloaryl group, wherein the carbon number is "C _10-20 ".

In the present invention, unless otherwise specified, the "condensed cycloalkylaryl" refers to a group formed by replacing the hydrogen on the carbon of an aryl with a condensed cycloalkyl, wherein the number of carbon atoms is "C _15-20 ".

In the present invention, when there is no special specification, the "condensed cycloalkyl" refers to a group formed by a condensed aryl group or a condensed cycloalkyl group connected with oxygen, that is, Ar is a C _10-20 fused ring aryl group or a fused ring alkyl group.

In the present invention, when there is no special specification, the "alkoxycarbonyl" refers to the group formed by connecting an alkoxy group and a carbonyl group, that is, R is a C _1-20 alkyl group.

In the present invention, when there is no special specification, the "aryloxycarbonyl" refers to the group formed by connecting an aryloxy group and a carbonyl group, that is, Ar is a C _6-20 aryl group.

In the present invention, when there is no special specification, the "heterocyclic group" refers to the group formed by connecting a heterocyclic group with oxygen, that is, R is a C _2-20 heterocyclic group.

In the present invention, when there is no special specification, the "alkylamino group" refers to the group formed by connecting an alkyl group and an amine group, that is, R is a C _1-20 alkyl group.

In the present invention, when not otherwise specified, the "alkylaminocarbonyl" refers to a group formed by connecting an alkylamino group and a carbonyl group, that is, R is a C _1-20 alkyl group.

In the present invention, when there is no special specification, the "arylamine group" refers to the group formed by connecting an aryl group and an amine group, that is, Ar is a C _6-20 aryl group.

In the present invention, when there is no special specification, the "heterocyclic amino group" refers to the group formed by connecting a heterocyclic group and an amino group, that is, R is a C _2-20 heterocyclic group.

In the present invention, when there is no special specification, the "arylaminosulfonyl group" refers to the group formed by connecting an arylamine group and a sulfonyl group, that is, Ar is a C _6-20 aryl group.

In the present invention, when not otherwise specified, the "alkylaminosulfonyl group" refers to a group formed by connecting an alkylamino group and a sulfonyl group, that is, R is a C _1-20 alkyl group.

In the present invention, when not otherwise specified, the "heterocyclic aminosulfonyl group" refers to a group formed by connecting a heterocyclic amino group and a sulfonyl group, that is, R is a C _2-20 heterocyclic group.

In the present invention, when not otherwise specified, the "alkylsulfonamide group" refers to a group formed by connecting an alkyl group and a sulfonamide group, that is, R is a C _1-20 alkyl group.

In the present invention, when not otherwise specified, the "heterocyclic sulfonamide group" refers to a group formed by connecting a heterocyclic group and a sulfonamide group, that is, R is a C _2-20 heterocyclic group.

In the present invention, when not otherwise specified, the "arylsulfonamide group" refers to a group formed by connecting an aryl group and a sulfonamide group, that is, Ar is a C _6-20 aryl group.

In the present invention, when not otherwise specified, the "alkylaminosulfonamide" refers to a group formed by connecting an alkylamino group and a sulfonamide group, that is, R is a C _1-20 alkyl group.

In the present invention, unless otherwise specified, the "alkylcarbonylamino" refers to a group formed by connecting an alkyl group to a carbonyl group and then to an amine group, that is, R is a C _1-20 alkyl group.

In the present invention, when there is no special specification, the "alkylurea group" refers to a group formed by connecting an alkyl group and a urea group, that is, R is a C _1-20 alkyl group.

In the present invention, when there is no special specification, the "aryl urea group" refers to a group formed by connecting an aryl group and a urea group, that is, Ar is a C _6-20 aryl group.

In the present invention, unless otherwise specified, the "alkylthiourea group" refers to a group formed by connecting an alkyl group and a thiourea group, that is, R is a C _1-20 alkyl group.

In the present invention, the term "halogen" refers to "fluorine, chlorine, bromine, or iodine".

In the present invention, the term "hydroxyl" refers to

In the present invention, the term "amino group" is represented by

In the present invention, the term "cyano" is represented by

In the present invention, the term "carboxyl" refers to

In the present invention, the term "sulfonyl" refers to

In the present invention, the term "sulfonamide" is represented by

In the present invention, the term "carbonyl" is represented by

In the present invention, the "urea group" is represented by

In the present invention, the "thiourea group" is represented by

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

II. Compounds of the Invention

1) The present invention first designs and introduces the following heterocyclic functional group containing a novel benzo-oxygen-containing heterocyclic ring: (wherein R ⁸ is halogen, hydroxyl, amino, carboxyl, alkylsulfonyloxy, arylsulfonyloxy, or a leaving group that can be substituted), and a class of benzo five-membered oxygen-containing heterocyclic compounds that are new GPR40 target agonists that can effectively treat type II diabetes were synthesized.

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

For the compound of Formula Ia, n, E, ^E1 , ^R1 , R2, ^R3 , ^R4 , ^R5 , ^R5b , Ra, ^Rb , Rc, Rd, Re, Rf, Rg, Ri, Rj, ^X1 , ^X2 , ^X3 , ^X4 , Y and ^Y1 and the subscript "n" are as defined in the specification. Specific embodiments of the compound of Formula Ia are also described below.

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

In one embodiment, E ¹ is -C(Ra)-, wherein Ra is selected from: Ra is hydrogen, deuterium (D), alkyl, cycloalkyl, alkoxy, cycloalkyloxy, alkoxycarbonyl, alkylamino, cycloalkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, aryl, or heteroaryl. In a preferred embodiment, E ¹ is -C(Ra)-, wherein Ra is selected from: hydrogen, deuterium (D), C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C _{1 -C 8 alkoxy, C 3 -C 8 cycloalkyloxy} , C ₁ -C ₈ alkoxycarbonyl, C ₁ -C ₈ alkylamino, C ₃ -C ₈ cycloalkylamino, C ₁ -C ₈ alkylaminocarbonyl, C ₃ -C ₈ cycloalkylaminocarbonyl, aryl, or heteroaryl. In a more preferred embodiment, E ¹ is -CH-.

In one embodiment, E and ^G are connected to form a cyclic compound. In a preferred embodiment, E and ^G are connected to form a five-membered cyclic compound. In a preferred embodiment, ^G is -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, cycloalkyloxy, alkoxycarbonyl, alkylamino, cycloalkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, aryl, aryloxy, heterocyclic, heteroaryl, or heterocyclic aryloxy. In another embodiment, Rc and Rd can be connected to each other to form a cycloalkyl or heterocyclic group. In a preferred embodiment, ^G1 is -C-, E is -OC(RcRd)- or -C(RcRd)O-, wherein Rc and Rd are independently selected from: hydrogen, deuterium (D), _C1 - _C8 alkyl, _C3 - _C8 cycloalkyl, _C2 - _C8 alkenyl, C2 _{- C8} alkynyl, _C1 - _C8 alkoxy, _C3 - _C8 cycloalkyloxy, C1-C8 alkoxycarbonyl, C1- _C8 alkylamino, _{C3 - C8} cycloalkylamino, C1- _C8 alkylaminocarbonyl _{, C3} - _C8 cycloalkylaminocarbonyl, aryl, aryloxy, _heterocyclyl , heteroaryl, or heteroaryloxy. In a more preferred embodiment, _G1 is -C-, E is -OC(RcRd)- or -C( ^RcRd )O-, wherein Rc and Rd are hydrogen.

In one embodiment, L is -O-.

In one embodiment, R ¹ , R ² and R ³ are each independently hydrogen, deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, aminocarbonyl (H ₂ NCO), C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkoxycarbonyl, C _{1 -C 8 alkylaminocarbonyl, C 1 -C 8 alkylcarbonylamino ,} aryl, aryloxy, or heteroaryl. In a preferred embodiment, R ¹ , R ² and R ³ are each independently hydrogen, halogen, or C ₁ -C ₈ alkoxy.

In one embodiment, ^R4 and ^R5 are each independently hydrogen.

In one embodiment, R ⁶ is -COR ⁷ . In a preferred embodiment, R ⁷ is -OH, alkoxy, alkylamino, cycloalkylamino, heterocyclicamino, alkylsulfonamide, cycloalkylsulfonamide, aryloxy, heterocyclic aryloxy, arylamino, or heterocyclic arylamino; or R ⁷ and the ortho-substituent R ⁵ may be connected to form a heterocycle. In a preferred embodiment, R ⁷ is C ₁ -C ₈ alkoxy, hydroxy, C ₁ -C ₈ alkylsulfonamide, or C ₃ -C ₈ cycloalkylsulfonamide.

In one embodiment, Y ¹ is -CH ₂ -.

In one embodiment, Z ¹ is -O-.

In one embodiment, X ¹ , X ² , X ³ and X ⁴ are each independently hydrogen, deuterium (D), halogen, nitrile, amino, trifluoromethyl, trifluoromethoxy, aminocarbonyl (H ₂ NCO), alkyl, heterocycloalkyl, alkoxy, heteroatom-substituted alkyloxy, alkylamino (NR _i R _j ), heteroatom-substituted alkylamino, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonylamino, alkoxycarbonylamino, cycloalkyloxycarbonylamino, alkylsulfonamide, cycloalkylsulfonamide, aryl, aryloxy, arylaminocarbonyl, arylcarbonylamino, aryloxycarbonylamino, heteroaryl, heteroaryloxy, or heteroarylamino; wherein R i and R _j are alkylaminocarbonyl, alkylcarbonylamino, alkylcarbonylamino, alkylcarbonylamino, alkylcarbonylamino, cycloalkyloxycarbonylamino, alkylsulfonamide, cycloalkylsulfonamide, aryl, aryloxy, arylaminocarbonyl, arylcarbonylamino, aryloxycarbonylamino, heteroaryl, heteroaryloxy, or heteroarylamino. R i and R _j are each independently hydrogen, deuterium (D), alkyl, heterocycloalkyl, alkylcarbonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, alkylaminocarbonyl, alkylsulfonyl, cycloalkylsulfonyl, aryl, aryloxycarbonyl, arylaminocarbonyl, heteroaryl, or R _i and R _j are linked to form a 3-8 membered heterocyclic ring containing 1-3 heteroatoms.

In one embodiment, X ¹ is selected from: hydrogen, deuterium (D), halogen, nitrile, amino (NH ₂ ), trifluoromethyl, trifluoromethoxy, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C 1 -C 8 alkylamino, C ₁ -C ₈ alkylcarbonylamino, C ₁ -C ₈ alkylaminocarbonylamino, C ₁ -C ₈ alkoxycarbonylamino, C ₃ -C ₈ cycloalkyloxycarbonylamino, C ₁ -C ₈ alkylsulfonamide, C ₃ -C ₈ cycloalkylsulfonamide, aryl, or aryloxycarbonylamino. In a preferred embodiment, X ¹ is selected from: hydrogen, deuterium (D), halogen, nitrile, trifluoromethyl _, trifluoromethoxy, C _{1 -C 8} alkoxycarbonylamino.

In one embodiment, X ² , X ³ and X ⁴ are each independently hydrogen, deuterium (D), halogen, or trifluoromethyl.

The compounds of the present invention may exist in multiple isomeric forms, as well as 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 tautomeric forms of the compounds.

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

Unless otherwise indicated, "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 is substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers is substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound contains greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, for example, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, or greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound.

If there is a discrepancy between a depicted structure and a name given to that structure, the depicted structure shall prevail. In addition, if the stereochemistry of a structure or portion of a structure is not indicated by, for example, bold or dashed lines, the structure or portion of a structure is to be understood to encompass all stereoisomers thereof. However, in some cases where there is more than one chiral center, the structure and name may be presented in terms of a single enantiomer to aid in describing the relevant stereochemistry. One skilled in the art of organic synthesis will be aware of the situations in which a single enantiomer of the compound is prepared by a process that prepares them.

In the present specification, "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, stilbenesulfonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camphorsulfonate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, propionate lauryl sulfate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycolyl arsanilate, hexafluorophosphate, hexylresorcinate, halamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothiosulfate, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, methyl bromide, methyl The pharmaceutically acceptable salts include nitrate, methanesulfonate, mucate, naphthenate, 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, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, surazate, tannate, tartrate, 8-chlorotheophylline salt, toluenesulfonate, triethiodide, and valerate. Pharmaceutically acceptable salts may have more than one charged atom in their structure. In this case, the pharmaceutically acceptable salt may have multiple counterions. Thus, pharmaceutically acceptable salts may have one or more charged atoms and/or one or more counterions.

The compounds of the present invention may be isotopically labeled in which one or more atoms are replaced by atoms having a different atomic mass or mass number. Examples of isotopes that may be incorporated into compounds of Formula Ia or IIa include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, or iodine. Examples of such isotopes are 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 may be used to measure biodistribution, tissue concentration, and kinetics of transport and excretion from biological tissues, including subjects to which the labeled compounds are administered. Labeled compounds may also be used to determine therapeutic efficacy, site or mode of action, and binding affinity of candidate therapeutics to pharmacologically important targets. Therefore, certain radiolabeled compounds of Formula Ia or IIa may be used for drug and/or tissue distribution studies. The radioactive isotopes tritium, ie, ³ H, and carbon-14, ie, ¹⁴ C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, ² H, can afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life of the deuterated compound).Substitution of deuterium for hydrogen can reduce the dosage required to achieve therapeutic effect and thus may be preferred in discovery or clinical settings.

Substitution with positron emitting isotopes (e.g., ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N) can provide labeled analogs of the compounds of the invention that are useful in positron emission tomography (PET) studies, for example, for detecting substance receptor occupancy. Isotopically labeled compounds of Formula Ia or IIa can generally be prepared by conventional techniques known to those skilled in the art or by analogy to those described in the Preparations and Examples described below, using appropriate isotopically labeled reagents.

Embodiments of the invention described herein are also intended to encompass in vivo metabolites of compounds of formula Ia or IIa. These products may originate, for example, from processes such as oxidation, reduction, hydrolysis, amidation, esterification, etc., which are primarily due to enzymatic activity after administration of the compounds of the invention. Therefore, the present invention includes compounds that are produced in the form of byproducts based on enzymatic or non-enzymatic activity of the compounds of the invention after administration of the compounds of the invention to mammals for a period of time sufficient to produce metabolites. Metabolites, especially metabolites with pharmaceutical activity, are generally identified by administering a detectable dose of a radiolabeled compound of the invention to an object, such as a rat, mouse, guinea pig, monkey, or human being, for a sufficient period of time for metabolism to occur during the process, and, isolating the metabolites from urine, blood, or other biological samples obtained from an object receiving the radiolabeled compound.

The present invention also provides pharmaceutically acceptable salt forms of the compounds of formula Ia or IIa. The present invention encompasses 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.

"Pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed using inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as, but not limited to, 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, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy Ethylsulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, 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, pamoic 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, etc.

"Pharmaceutically acceptable base addition salts" refer to those salts which retain the biological effectiveness and properties of the free acids and which 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 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, hydrabamine, choline, betaine, phenethylbenzylamine, benzathine penicillin, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

Crystallization usually produces a solvate of the compounds of the present invention. The term "solvate" as used herein refers to an aggregate comprising one or more molecules of the compounds of the present invention and one or more molecules of a solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Therefore, the compounds of the present invention may exist in the form of a hydrate, including a monohydrate, a dihydrate, a hemihydrate, a sesquihydrate, a trihydrate, a tetrahydrate, etc., and corresponding solvate forms. The compounds of the present invention may be true solvates, while in other cases, the compounds of the present invention may retain only adventitious water or a mixture of water plus some adventitious solvent.

"Stereoisomer" refers to a compound consisting of the same atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of each other.

The compounds of the invention, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers, giving rise to enantiomers, diastereomers, and other stereoisomeric forms that may be determined in terms of absolute stereochemistry, such as (R)- or (S)-, or, for amino acids, such as (D)- or (L)-. The present invention is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing/isolating individual enantiomers include chiral synthesis from suitable 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 the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

III. Pharmaceutical Compositions

In one embodiment, the compound of Formula Ia or IIa is formulated in the form of a pharmaceutically acceptable composition, which comprises an amount of the compound of Formula Ia or IIa that is effective in treating a particular disease or condition of interest after administration of the pharmaceutical composition to a mammal. The pharmaceutical compositions of the present invention may comprise a compound of Formula Ia or IIa in combination with a pharmaceutically acceptable carrier, diluent or excipient.

In this regard, "pharmaceutically acceptable carriers, diluents or excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier, all of which are approved by the U.S. Food and Drug Administration as being acceptable to humans or livestock.

In addition, "mammal" includes humans and domestic animals, such as experimental animals and domestic pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domestic animals, such as wild animals, and the like.

The pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention with a suitable pharmaceutically acceptable carrier, diluent or excipient, and can be made into a solid, semisolid, liquid or gaseous preparation, for example, tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical routes for administering such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhaled, parenteral, sublingual, buccal, rectal, vaginal, and intranasal. The term parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion techniques. The pharmaceutical composition of the present invention is formulated to allow the active ingredients contained therein to be bioavailable after the composition is administered to the patient. The composition to be administered to the subject or patient can be in the form of one or more dosage units, for example, a tablet can be a single dosage unit, and a container of the compound of the present invention in the form of an aerosol can contain multiple dosage units. Actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). In any case, the composition to be administered contains 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 invention.

The pharmaceutical composition of the present invention can be in solid or liquid form. In one aspect, the carrier is a particle, so that the composition is, for example, in tablet or powder form. The carrier can be a liquid, wherein the composition is, for example, an oral syrup, an injectable liquid, or an aerosol, which can be used, for example, for inhalation administration. When intended for oral administration, the pharmaceutical composition is preferably in solid or liquid form, wherein semi-solid, semi-liquid, suspension and gel forms are included in the solid or liquid forms contemplated herein.

As a solid composition for oral administration, the pharmaceutical composition can be formulated into the form of powder, granules, compressed tablets, pills, capsules, chewing gum, thin slices, etc. Such solid compositions will generally contain one or more inert diluents or edible carriers. In addition, one or more of the following substances may be present: a binder such as carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, tragacanth gum or gelatin; an excipient such as starch, lactose or dextrin, a disintegrant such as alginic acid, sodium alginate, Primogel, corn starch, etc.; a lubricant such as magnesium stearate or Sterotex; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; a flavoring agent such as mint, methyl salicylate or orange flavoring; and a coloring agent.

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

The pharmaceutical composition can be in liquid form, such as an elixir, syrup, solution, emulsion or suspension. As two examples, the liquid can be for oral administration or for delivery by injection. If oral administration is intended, in addition to the compounds of this invention, the preferred composition may contain one or more sweeteners, preservatives, dyes/colorants and flavor enhancers. For compositions intended to be administered by injection, one or more of a surfactant, preservative, wetting agent, dispersant, suspending agent, buffer, stabilizer and isotonic agent may be included.

Liquid pharmaceutical compositions of the present invention, whether they are solutions, suspensions or other similar forms, may include one or more of the following adjuvants: sterile diluents, such as water for injection, saline solutions, preferably physiological saline, Ringer's solution, 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 parabens; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates, and agents for adjusting tonicity, such as sodium chloride or glucose. Parenteral preparations can be packaged in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. Injectable pharmaceutical compositions are preferably sterile.

The pharmaceutical compositions of the present invention can be prepared by any method known in the pharmaceutical field. For example, a pharmaceutical composition intended to be administered by injection can be prepared by combining the compounds of the present invention with sterile, distilled water to form a solution. Surfactants can be added to promote the formation of a uniform solution or suspension. Surfactants are compounds that interact non-covalently with the compounds of the present invention, thereby promoting the dissolution or uniform suspension of the compounds in an aqueous delivery system.

IV. Therapeutic Applications

A compound of the invention or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount which varies depending on a variety of factors, including the activity of the particular compound employed, the metabolic stability and duration of action of the compound, the patient's age, weight, general health, sex, diet, mode and time of administration, rate of excretion, co-administration, severity of the particular disease or condition, and the subject being treated.

"Effective amount" or "therapeutically effective amount" refers to an amount of the compound of the present invention that is sufficient to provide effective treatment for Mnk-related disorders or diseases in the mammal (preferably human) when administered to a mammal, preferably human, as described below. The amount of the compound of the present invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the disorder and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their knowledge and the content of the present invention.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, may also 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 comprising a 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 a separate pharmaceutical dosage formulation. For example, the compounds of the present invention and other active substances may be administered to a patient together in a single oral dosage composition (e.g., tablets or capsules), or each substance may be administered in a separate oral dosage formulation. When using separate dosage formulations, the compounds of the present invention and one or more other active agents may 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 of these regimens.

The present invention further studies and optimizes the structure of the GPR40 target agonist compound formula Ia-IIa through structure-activity relationship (SAR), and can effectively reduce the risk of hypoglycemia, thereby treating type II diabetes more safely and effectively.

The benzo-oxygen-containing heterocyclic compounds of the present invention can lower blood sugar levels by activating the GPR40 target to stimulate pancreatic β cells to release insulin, and the characteristics of such formula Ia-IIa compounds are that they can promote insulin secretion only when the blood sugar concentration of patients with type II diabetes is high, thereby effectively reducing the risk of hypoglycemia in patients and having better GPR40 target selectivity and safety.

Specific implementation method:

The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or according to the product specifications.

The English abbreviations of the chemical reagents and solvents used in the process of synthesizing the novel benzo-oxygen-containing heterocyclic compounds of the present invention are all summarized in the instrument and raw material description section of the examples.

The key innovation of the present invention is to firstly react the raw material RM-1a with the raw material SM-1 (such as the reagent with the structure of SM-1a or RM-1b below) to prepare the target product Ia-IIa or the intermediate RM-2a according to the synthetic reaction route 1a or 2a shown in the following schemes 1a and 2a; when ^R7 is an alkoxy group (such as: ^R7 = _OCH3 or OEt), each target intermediate product in which ^R7 in formula IIa of the present invention is a hydroxyl group can be synthesized by LiOH hydrolysis reaction.

The general synthetic reaction route is as follows:

Scheme 1a: Synthesis of compounds of formula Ia-IIa

The operation according to the above-mentioned synthetic reaction scheme 1a is as follows:

1. Synthesis of RM-2a: In a round-bottomed reaction flask, raw materials RM-Ia (1.0 eq), SM-1b (1.0 eq), and DIAD and PPh ₃ (1.2 eq) were added to THF (5x), respectively, and nitrogen was replaced and protected. The reaction was tracked and detected by TLC and HPLC until the reaction was completed. After conventional operations such as post-treatment, RM-2a (or RM-IIa) was obtained;

2. Synthesis of target products Ia-IIa: RM-Ia (or RM-IIa, 1 eq) was hydrolyzed in a mixed solution of LiOH and MeOH-H ₂ O (1:1, 10X) in a round-bottom reaction bottle. After TLC detection until the reaction was completed, the target products Ia-IIa were obtained after conventional operations such as post-treatment and purification.

In the above-synthesized compounds of formula Ia-IIa, n, ^R1 , ^{R2, R3} , ^R5 , ^R5b , ^R7 , Ra, Rb, ^Rc , Rd, Re, Rf, Rg, Ri, Rj, ^X1 , ^X2 , ^X3 , ^X4 , Y and ^Y1 therein have the same definitions as n, ^R1 , ^R2 , ^R3 , R5, ^R5b , ^R7 , Ra, ^Rb , Rc, Rd, Re, Rf, Rg, Ri, Rj, ^X1 , ^X2 , ^X3 , ^X4 , Y and Y1 in claims 1 to ⁴ of the present invention, respectively. The synthetic reaction examples of the compounds of Formula Ia-IIa of the present invention are shown in the following Scheme 2a. Specifically, in the preparation process of each compound with different structures, the benzo-oxygen-containing heterocyclic raw material RM-1a in Table 1 and Table 2 and the raw material SM-1 in Table 3 are used to successfully synthesize them:

Table 1: Raw materials SM-Ia-01 to SM-Ia-23 used in the present invention and their structures

Table 2: Raw materials SM1-01 to SM1-12 used in the present invention and their structures

The above raw materials RM-1a and SM1 are used, and then the intermediate RM-2a is prepared by the synthetic reaction route 2a in the following scheme 2a, and finally the specific compounds of formula Ia-IIa are synthesized by hydrolysis reaction. The specific reaction examples are as follows:

Scheme 2a: Example of Synthesis of Compounds of Formula Ia-IIa

In the synthetic route 2a reaction example of the above scheme 2a:

The first step reaction: firstly, the raw material RM-Ia-01 and another raw material SM1-01 are reacted with a coupling reagent (such as DIAD, PPh ₃ ) in a solvent (such as THF) to obtain a key intermediate compound (RM-2a-01);

The second step reaction: The intermediate (RM-2a-01) is then hydrolyzed in a solvent (such as MeOH or a mixed solvent of methanol and water) under the action of an inorganic base (such as LiOH) to obtain the target product IIa-01.

The intermediate structures of the intermediate compounds RM-IIa obtained by the first step reaction of the synthetic reaction routes in the above schemes 1 and 2 are shown in the following RM-IIa structural formula series; and the target products of formula IIa are obtained by the second step hydrolysis reaction, and their structures are shown in the following formula IIa structural formula series:

RM-IIa structural formula series:

Formula IIa structural series

The specific experimental conditions and product analysis results of each step of the reaction are listed in the examples.

Specific synthesis and analysis results of each of the novel structural compounds of Formula Ia-IIa are detailed in the last embodiment of the present invention. The chemical and chiral asymmetric purity of each compound is determined by chiral chromatographic column HPLC, and the corresponding chemical structure is characterized by LC-MS and/or hydrogen nuclear magnetic resonance ( ¹ H-NMR) and other analyses.

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

The instruments and raw materials involved in the embodiments are described as follows:

The infrared spectrum data were obtained by using a FourierTransform AVATAR ^™ 360E.SP ^™ infrared spectrometer from Thermo Nicolet, and are expressed in cm ^-1 .

The H NMR spectrum was obtained by Varian Mercury Plus 400 (400 MHz) NMR analysis. Chemical shifts were recorded with tetramethylsilane as the internal standard and expressed in ppm (CHCl ₃ : δ=7.26 ppm). The recorded data information is as follows: chemical shift and its splitting and coupling constants (s: singlet; d: doublet; t: triplet; q: quartet; br: broad peak; m: multiplet).

The mass spectrometry data were analyzed by a liquid chromatography mass spectrometer (LCMS) of Finnigan LCQ Advantage, except for other requirements. The molecular weight of the organic carboxylic acid (-COOH) compounds of formula Ia-IIa of the present invention is mainly in the negative ion mode ESI-MS [(MH) ⁺ ], but the molecular weight of the ester intermediate compound of formula RM-IIa and some amine-containing compounds in Ia-IIa is in the positive ion mode ESI-MS [(M+H) ⁺ ].

The special raw materials and intermediates involved in the present invention are provided by Zannan Technology Co., Ltd., etc. All other chemical reagents are purchased from reagent suppliers such as Shanghai Reagent Company, Aldrich, and Acros. If the intermediates or products required for the reaction during the synthesis are not enough for the next step, the synthesis is repeated several times until a sufficient amount is obtained. The GPR40 activity test and pharmacology, toxicology and other tests of the compounds prepared by the present invention are completed by CRO service units in Shanghai and Beijing.

The English abbreviations of the chemical raw materials, reagents and solvents involved in the present invention and its embodiments are as follows:

AIBN: Azobisisobutyronitrile

Boc: tert-Butyloxycarbonyl

(Boc) ₂ O: Di-tert-butyl dicarbonate

CDI: N,N'-Carbonyldiimidazole

DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

Et: Ethyl

EDCI: N-ethyl-Nˊ-(3-dimethylaminopropyl)carbodiimide hydrochloride

HATU: 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

NBS: N-bromosuccinimide

SOCl ₂ ：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: tert-butyl methyl ether

A series of compounds IIa-1 to IIa-48 of formula IIa were synthesized according to the following general synthetic method:

Example 1

Synthesis of compound IIa-1

Step 1: Dissolve the raw materials RM-Ia-1 (0.052 g, 0.24 mmol.), SM1-1 (0.050 g, 0.24 mmol, 1.0 eq.) and PPh3 (0.126 g, 0.48 mmol, 2 eq.) in 2 L of THF, protect with nitrogen, cool in an ice-water bath, add DIAD (0.097 g, 0.48 mmol, 2 eq.) while stirring, stir in an ice-water bath for 1 h after adding, 20-30 degrees, react overnight, and the reaction is complete. After HPLC shows that the reaction is completed, the reaction solution is cooled to room temperature, water is added, DCM is added for extraction, the organic phase is combined, washed with brine, dried, and concentrated to obtain a crude product; the crude product is separated by TLC scraper to obtain the intermediate product RM-IIa-1 (0.029 g);

Mass spectrometry analysis confirmed that the ESI-MS [(M+H) ⁺ ]: m/z theoretical value of RM-IIa-1 was 405.0, and the measured value was 405.0.

Step 2: Add MeOH (2 mL), THF (1 mL) and LiOH aqueous solution (1N, 1 mL) to the intermediate product RM-IIa-1 (0.029 g), stir at room temperature for 1 h. After HPLC shows that the reaction is completed, neutralize the reaction solution with hydrochloric acid (1N) to a pH of about 4, add water, add ethyl acetate for extraction, combine the organic phases, wash with brine and dry, and finally separate and purify by column chromatography to obtain a light yellow solid product IIa-1 (0.016 g), with a two-step yield of 21%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-1 was 389.0, and the measured value was 389.0.

Example 2

Synthesis of compound IIa-2

The synthetic method for preparing compound IIa-2 is the same as that in Example 1, and the product IIa-2 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-2 (0.23 mmol) is used in the reaction instead of compound RM-Ia-4 to obtain intermediate RM-IIa-2, and the intermediate is hydrolyzed to obtain a light yellow solid product IIa-2 (0.016 g), and the two-step yield is 17.8%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-2 was 389.0, and the measured value was 389.0.

Example 3

Synthesis of compound IIa-3

The synthetic method for preparing compound IIa-3 is the same as that in Example 1, and the product IIa-3 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-3 (0.24 mmol) is used in the reaction instead of compound RM-Ia-4 to obtain intermediate RM-IIa-3, and the intermediate is hydrolyzed to obtain a light yellow solid product IIa-3 (0.030 g), and the two-step yield is 32%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-3 was 389.0, and the measured value was 389.0.

Example 4

Synthesis of compound IIa-4

The raw materials RM-Ia-4 (0.052 g, 0.24 mmol.), SM1-1 (0.050 g, 0.24 mmol, 1.0 eq.) and PPh3 (0.126 g, 0.48 mmol, 2 eq.) were dissolved in 2 L of THF. Under nitrogen protection and ice-water bath cooling, DIAD (0.097 g, 0.48 mmol, 2 eq.) was added with stirring. After the addition, it was stirred in an ice-water bath for 1 h at 20-30 degrees. The reaction was allowed to react overnight. The reaction was completed. After the reaction was completed, HPLC showed that the reaction solution was cooled to room temperature, water was added, DCM was added for extraction, the organic phases were combined, washed with brine, dried, and concentrated to obtain a crude product; the crude product was separated by TLC scraper to obtain the intermediate RM-IIa-4; MeOH (2 mL), THF (1 mL) and LiOH aqueous solution (1N, 1 mL) were added to the intermediate and stirred at room temperature for 1 h. After the reaction was completed, HPLC showed that the reaction solution was neutralized with hydrochloric acid (1N) to a pH of about 4, water was added, ethyl acetate was added for extraction, the organic phases were combined, washed with brine, dried, and finally separated and purified by column chromatography to obtain a light yellow solid product IIa-4 (0.024 g), with a two-step yield of 25%.

After detection, the ¹ H NMR (400 MHz, DMSO) of the product IIa-4: δ7.53-7.51 (m, 1H), 7.42-7.40 (m, 1H), 7.13-7.11 (m, 1H), 6.89-6.86 (m, 1H), 6.45-6.41 (m, 2H), 6.09-6.08 (m, 1H), 4.81-4.76 (m, 1H), 4.70-4.65 (m, 1H), 4.56-4.53 (m, 1H), 4.19-4.00 (m, 1H), 3.67-3.64 (m, 1H), 2.64-2.63 (m, 1H), 2.60-2.59 (m, 1H).

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-4 was 311.1, and the measured value was 311.2.

Example 5

Synthesis of compound IIa-5

The synthetic method for preparing compound IIa-5 is the same as that in Example 1, and the product IIa-5 is obtained by two-step reaction of etherification and hydrolysis, wherein compound SM1-2 (0.55 mmol) is used in the reaction instead of compound SM1-1 to obtain intermediate RM-IIa-5, and the intermediate is hydrolyzed to obtain a light yellow solid product IIa-5 (0.015 g), and the two-step yield is 7%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-5 was 389.0, and the measured value was 389.1.

Example 6

Synthesis of Compound IIa-6

The synthetic method for preparing compound IIa-6 is the same as that in Example 1, and the product IIa-6 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-5 (0.42 mmol) is used in the reaction instead of compound RM-Ia-4 to obtain intermediate RM-IIa-6, and the intermediate is hydrolyzed to obtain a light yellow solid product IIa-6 (0.050 g), and the two-step yield is 30.6%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-6 was 389.0, and the measured value was 388.9.

Example 7

Synthesis of compound IIa-7

The synthetic method for preparing compound IIa-7 is the same as that in Example 1, and the product IIa-7 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-6 (0.55 mmol) is used in the reaction instead of compound RM-Ia-4 to obtain intermediate RM-IIa-7, and the intermediate is hydrolyzed to obtain a light yellow solid product IIa-7 (0.0023 g), and the two-step yield is 1.2%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-7 was 345.1, and the measured value was 345.0.

Example 8

Synthesis of compound IIa-8

The synthetic method for preparing compound IIa-8 is the same as that in Example 1, and the product IIa-8 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-7 (0.32 mmol) is used in the reaction instead of compound RM-Ia-4 to obtain intermediate RM-IIa-8, and the intermediate is hydrolyzed to obtain a brown solid product IIa-8 (0.038 g), and the two-step yield is 36.3%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-8 was 329.1, and the measured value was 329.0.

Example 9

Synthesis of compound IIa-9

The synthetic method for preparing compound IIa-9 is the same as that in Example 1, and the product IIa-9 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-8 (0.39 mmol) is used in the reaction instead of compound RM-Ia-4 to obtain intermediate RM-IIa-9, and the intermediate is hydrolyzed to obtain a brown solid product IIa-9 (0.015 g), and the two-step yield is 32%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-9 was 403.0, and the measured value was 403.1.

Example 10

Synthesis of compound IIa-10

The synthetic method for preparing compound IIa-10 is the same as that in Example 1, and the product IIa-10 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-9 (0.48 mmol) is used in the reaction instead of compound RM-Ia-4 to obtain intermediate RM-IIa-10, and the intermediate is hydrolyzed to obtain a light yellow solid product IIa-10 (0.013 g), and the two-step yield is 7.1%.

After detection, the product IIa-10 had ¹ H NMR (400 MHz, CDCl ₃ ): δ7.54-7.49 (m, 2H), 7.04-6.96 (m, 2H), 6.34 (m, 2H), 5.79-5.78 (m, 1H), 4.72-4.68 (m, 3H), 4.27-4.25 (m, 1H), 3.80-3.75 (m, 1H), 3.00 (m, 1H), 2.75-2.66 (m, 1H). ¹⁹ F NMR (376 MHz, CDCl ₃ ): δ-61.92.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-10 was 379.1, and the measured value was 379.0.

Embodiment 11

Synthesis of compound IIa-11

The synthetic method for preparing compound IIa-11 is the same as that in Example 1, and the product IIa-11 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-10 (0.23 mmol) is used instead of compound RM-Ia-4, and compound SM1-2 (0.23 mmol) is used instead of compound SM1-1 to obtain intermediate RM-IIa-11, and the intermediate is hydrolyzed to obtain a white solid product IIa-11 (0.024 g), and the two-step yield is 26.6%.

After detection, the product IIa-11 had a molecular weight (400 MHz, CDCl ₃ ): δ7.48-7.46 (m, 1H), 7.35-7.33 (m, 1H), 7.10-7.08 (m, 1H), 6.85-6.81 (m, 1H), 6.43-6.40 (m, 2H), 5.93-5.91 (m, 1H), 4.82-4.67 (m, 3H), 4.33-4.30 (m, 1H), 3.86-3.81 (m, 1H), 2.86-2.81 (m, 1H), 2.68-2.62 (m, 1H).

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-11 was 391.0, 390.0, and the measured value was 389.9, 390.9.

Example 12

Synthesis of compound IIa-12

The synthetic method for preparing compound IIa-12 is the same as that in Example 1, and the product IIa-12 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-11 (0.48 mmol) is used in the reaction instead of compound RM-Ia-4 to obtain intermediate RM-IIa-12, and the intermediate is hydrolyzed to obtain a white solid product IIa-12 (0.011 g), and the two-step yield is 6.8%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-12 was 336.1, and the measured value was 336.0.

Example 13

Synthesis of compound IIa-13

The synthetic method for preparing compound IIa-13 is the same as that in Example 1, and the product IIa-13 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-7 (0.48 mmol) is used instead of compound RM-Ia-4, and compound SM1-2 (0.48 mmol) is used instead of compound SM1-1 to obtain intermediate RM-IIa-13, and the intermediate is hydrolyzed to obtain a white solid product IIa-13 (0.020 g), and the two-step yield is 10.9%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-13 was 379.1, and the measured value was 379.0.

Embodiment 14

Synthesis of compound IIa-14

The synthetic method for preparing compound IIa-14 is the same as that in Example 1, and the product IIa-14 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-12 (0.47 mmol) is used instead of compound RM-Ia-4, and compound SM1-2 (0.47 mmol) is used instead of compound SM1-1 to obtain intermediate RM-IIa-14, and the intermediate is hydrolyzed to obtain a white solid product IIa-14 (0.025 g), and the two-step yield is 13.7%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-14 was 389.0, and the measured value was 389.1.

Embodiment 15

Synthesis of compound IIa-15

The synthetic method for preparing compound IIa-15 is the same as that in Example 1, and product IIa-15 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-13 (0.26 mmol) is used instead of compound RM-Ia-4, and compound SM1-2 (0.26 mmol) is used instead of compound SM1-1 to obtain intermediate RM-IIa-15, and the intermediate is hydrolyzed to obtain white solid product IIa-15 (0.010 g), and the two-step yield is 10%.

After testing, the product IIa-15 had ¹ H NMR (400 MHz, CDCl ₃ ): δ7.53-7.58 (m, 2H), 7.11-7.09 (m, 1H), 7.03-6.99 (m, 1H), 6.43-6.41 (m, 2H), 5.88-5.86 (m, 1H), 4.82-4.71 (m, 3H), 4.34-4.30 (m, 1H), 3.88-3.80 (m, 1H), 2.87-2.81 (m, 1H), 2.69-2.62 (m, 1H); ¹⁹ F NMR (376 MHz, CDCl ₃ ): δ-61.90.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-15 was 389.0, and the measured value was 388.9.

Example 16

Synthesis of compound IIa-16

The synthetic method for preparing compound IIa-16 is the same as that in Example 1, and product IIa-16 is obtained through two-step reactions of etherification and hydrolysis, wherein compound RM-Ia-14 (0.39 mmol) is used instead of compound RM-Ia-4, and compound SM1-2 (0.39 mmol) is used instead of compound SM1-1 to obtain intermediate RM-IIa-16, and the intermediate is hydrolyzed to obtain a white solid product IIa-16 (0.060 g), with a two-step yield of 39.2%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-16 was 379.1, and the measured value was 379.2.

Embodiment 17

Synthesis of compound IIa-17

The synthetic method for preparing compound IIa-17 is the same as that in Example 1, and product IIa-17 is obtained through two-step reactions of etherification and hydrolysis, wherein compound RM-Ia-10 (0.37 mmol) is used instead of compound RM-Ia-4, and compound SM1-3 (0.37 mmol) is used instead of compound SM1-1 to obtain intermediate RM-IIa-17, and the intermediate is hydrolyzed to obtain a white solid product IIa-17 (0.052 g), with a two-step yield of 30%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-17 was 468.9, and the measured value was 469.0.

Embodiment 18

Synthesis of compound IIa-18

The synthetic method for preparing compound IIa-18 is the same as that in Example 1, and the product IIa-18 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-10 (0.37 mmol) is used instead of compound RM-Ia-4, and compound SM1-4 (0.37 mmol) is used instead of compound SM1-1 to obtain intermediate RM-IIa-18, and the intermediate is hydrolyzed to obtain a white solid product IIa-18 (0.076 g), and the two-step yield is 37%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-18 was 546.8, and the measured value was 546.7.

Embodiment 19

Synthesis of compound IIa-19

The synthetic method for preparing compound IIa-19 is the same as that in Example 1, and product IIa-19 is obtained through two-step reactions of etherification and hydrolysis, wherein compound RM-Ia-10 (0.37 mmol) is used instead of compound RM-Ia-4, and compound SM1-5 (0.37 mmol) is used instead of compound SM1-1 to obtain intermediate RM-IIa-19, and the intermediate is hydrolyzed to obtain a white solid product IIa-19 (0.057 g), with a two-step yield of 36%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-19 was 423.0, and the measured value was 423.0.

Embodiment 20

Synthesis of Compound IIa-20

The synthetic method for preparing compound IIa-20 is the same as that in Example 1, and the product IIa-20 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-10 (0.46 mmol) is used instead of compound RM-Ia-4 in the reaction, and compound SM1-6 (0.46 mmol) is used instead of compound SM1-1 to obtain intermediate RM-IIa-20, and the intermediate is hydrolyzed to obtain a white solid product IIa-20 (0.018 g), and the two-step yield is: 9%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-20 was 407.0, and the measured value was 407.1.

Embodiment 21

Synthesis of compound IIa-21

The synthetic method for preparing compound IIa-21 is the same as that in Example 1, and product IIa-21 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-10 (0.21 mmol) is used in the reaction instead of compound RM-Ia-4 to obtain intermediate RM-IIa-21, and the intermediate is hydrolyzed to obtain white solid product IIa-21 (0.020 g), and the two-step yield is 24%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-21 was 389.0, and the measured value was 388.9.

Embodiment 22

Synthesis of compound IIa-22

The raw material IIa-21 (0.250 g, 0.64 mmol.) was dissolved in 2 mL of THF and 2 mL of MTBE, cooled to -78 degrees in a dry ice acetone bath under nitrogen protection, and LiHMDS (1 M, 1.7 mL, 1.7 mmol.) was added dropwise, stirred for 0.5 h, TMSCl (0.173 g, 1.6 mmol.) was added dropwise, stirred for 0.5 h, NBS (0.137 g, 0.77 mmol) was added, slowly warmed to room temperature, reacted for 3 h, and the reaction was completed. HPLC showed that after the reaction was completed, water was added to the reaction solution, and hydrochloric acid (1 N) was added to neutralize to a pH of about 2, ethyl acetate was added for extraction, and the organic phases were combined, washed with brine and dried, and finally separated and purified by column chromatography to obtain a light yellow solid product IIa-22 (0.055 g), with a one-step yield of 18%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-22 was 468.9, and the measured value was 469.1.

Embodiment 23

Synthesis of compound IIa-23

Add concentrated aqueous ammonia (3 mL) to the raw material IIa-22 (0.030 g, 0.064 mmol) and heat in an oil bath at 100 degrees for 1.5 h to complete the reaction. After HPLC showed that the reaction was completed, the reaction solution was concentrated and dried under reduced pressure to obtain a light yellow solid product IIa-23 (0.020 g), with a one-step yield of 18%.

Mass spectrometry analysis confirmed that the ESI-MS [(M+H) ⁺ ]: m/z theoretical value of IIa-23 was 404.0, and the measured value was 404.0.

Embodiment 24

Synthesis of compound IIa-24

The raw material RM-IIa-21 (0.1 g, 0.24 mmol.) was dissolved in 2 mL of THF, cooled to -70 degrees in a dry ice acetone bath under nitrogen protection, LiHMDS (1 M, 0.37 mL, 0.37 mmol.) was added dropwise, stirred for 0.5 h, 3-phenyl-2 (phenylsulfonyl) oxaziridine/THF (0.1 g, 0.37 mmol) solution was added dropwise, slowly warmed to room temperature, reacted for 2 h, and the reaction was completed. HPLC showed that after the reaction was completed, water was added to the reaction solution, and hydrochloric acid (1N) was added to neutralize to a pH of about 2. Ethyl acetate was added for extraction, and the organic phases were combined, washed with brine and dried. Finally, column chromatography was used for separation and purification to obtain intermediate RM-IIa-22 (0.10 g). MeOH (2 mL), THF (1 mL) and LiOH aqueous solution (1N, 1 mL) were added to the intermediate in sequence, and the mixture was stirred at room temperature for 1 h. HPLC showed that after the reaction was completed, the reaction solution was neutralized with hydrochloric acid (1N) to a pH of about 4, water was added, and ethyl acetate was added for extraction. The organic phases were combined, washed with brine and dried. Finally, column chromatography was used for separation and purification to obtain a light yellow solid product IIa-24 (0.020 g), with a two-step yield of 20%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-24 was 405.0, and the measured value was 405.0.

Embodiment 25

Synthesis of compound IIa-25

The raw material RM-IIa-21 (0.2 g, 0.49 mmol.) was dissolved in 2 mL of THF, cooled to -70 degrees in a dry ice acetone bath under nitrogen protection, LiHMDS (1 M, 0.8 mL, 0.8 mmol.) was added dropwise, stirred for 0.5 h, (PhSO ₂ )NF/THF (0.2 g, 0.64 mmol) solution was added dropwise, slowly warmed to room temperature, reacted for 2 h, and the reaction was completed. HPLC showed that after the reaction was completed, water was added to the reaction solution, and hydrochloric acid (1N) was added to neutralize to a pH of about 2. Ethyl acetate was added for extraction, and the organic phases were combined, washed with brine and dried. Finally, column chromatography was used for separation and purification to obtain intermediates RM-IIa-23 and RM-IIa-24 (0.035 g). MeOH (2 mL), THF (1 mL) and LiOH aqueous solution (1N, 1 mL) were added to the intermediate in sequence, and the mixture was stirred at room temperature for 1 h. HPLC showed that after the reaction was completed, the reaction solution was neutralized with hydrochloric acid (1N) to a pH of about 4, water was added, and ethyl acetate was added for extraction. The organic phases were combined, washed with brine and dried. Finally, column chromatography was used for separation and purification to obtain light yellow solid products IIa-25 and IIa-26 (60%:30%, 0.015 g), with a two-step yield of 7%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-25 was 407.0, and the measured value was 407.0.

Embodiment 26

Synthesis of Compound IIa-26

The synthetic method for preparing compound IIa-26 is the same as that in Example 1, and product IIa-26 is obtained through two-step reactions of etherification and hydrolysis, wherein compound RM-Ia-10 (0.29 mmol) is used instead of compound RM-Ia-4, and compound SM1-7 (0.29 mmol) is used instead of compound SM1-1 to obtain intermediate RM-IIa-24, and the intermediate is hydrolyzed to obtain white solid product IIa-26 (0.045 g), with a two-step yield of 36%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-26 was 425.0, and the measured value was 425.0.

Embodiment 27

Synthesis of compound IIa-27

The synthetic method for preparing compound IIa-27 is the same as that in Example 1, and product IIa-27 is obtained by two-step reaction of etherification and hydrolysis, wherein compound SM1-8 (0.29 mmol) is used in the reaction instead of compound SM1-1 to obtain intermediate RM-IIa-25, and the intermediate is hydrolyzed to obtain white solid product IIa-27 (0.045 g), and the two-step yield is 36%.

After detection, ¹ H NMR (400 MHz, CDCl ₃ ) of product IIa-27: δ7.48-7.46 (m, 1H), 7.33-7.31 (m, 1H), 7.15-7.13 (m, 3H), 6.85-6.72 (m, 3H), 5.95-5.93 (m, 1H), 4.77-4.69 (m, 2H), 3.60-3.54 (m, 1H), 2.90-2.77 (m, 3H), 2.53-2.47 (m, 2H), 1.78-1.63 (m, 1H).

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-27 was 387.0, and the measured value was 386.9.

Embodiment 28

Synthesis of compound IIa-28

The synthetic method for preparing compound IIa-28 is the same as that in Example 1, and product IIa-28 is obtained through two-step reactions of etherification and hydrolysis, wherein compound RM-Ia-10 (0.30 mmol) is used instead of compound RM-Ia-4, and compound SM1-8 (0.30 mmol) is used instead of compound SM1-1 to obtain intermediate RM-IIa-26, and the intermediate is hydrolyzed to obtain white solid product IIa-28 (0.040 g), with a two-step yield of 34%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-28 was 387.0, and the measured value was 386.8.

Embodiment 29

Synthesis of compound IIa-29

The synthetic method for preparing compound IIa-29 is the same as that in Example 1, and product IIa-29 is obtained through two-step reactions of etherification and hydrolysis, wherein compound RM-Ia-9 (0.29 mmol) is used instead of compound RM-Ia-4, and compound SM1-7 (0.29 mmol) is used instead of compound SM1-1 to obtain intermediate RM-IIa-27, and the intermediate is hydrolyzed to obtain white solid product IIa-29 (0.050 g), and the two-step yield is 41%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-29 was 415.0, and the measured value was 415.0.

Embodiment 30

Synthesis of compound IIa-30

The raw material IIa-15 (0.020 g, 0.052 mmol.) was dissolved in 5 mL of DCE, CDI (0.017 g, 0.105 mmol.) was added, and the reaction was carried out at 50 degrees for 0.5 h, and then cyclopropylsulfonamide (0.095 g, 0.078 mmol.) and DBU (0.020 g, 0.13 mmol.) were added, and the reaction was carried out at 50 degrees overnight to complete the reaction. HPLC showed that after the reaction was completed, water was added to the reaction solution, and hydrochloric acid (1 N) was added to neutralize to a pH of about 2, and ethyl acetate was added to extract, and the organic phases were combined, washed with brine and dried, and finally separated and purified by column chromatography to obtain a light yellow solid product IIa-30 (0.010 g), with a one-step yield of 40%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-30 was 482.1, and the measured value was 482.2.

Embodiment 31

Synthesis of compound IIa-31

The synthetic method for preparing compound IIa-31 is the same as that in Example 1, and the product IIa-31 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-9 (0.24 mmol) is used instead of compound RM-Ia-4, and compound SM1-11 (0.24 mmol) is used instead of compound SM1-1 to obtain intermediate RM-IIa-28, and the intermediate is hydrolyzed to obtain a white solid product IIa-31 (0.028 g), and the two-step yield is 29%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-31 was 397.1, and the measured value was 397.2.

Embodiment 32

Synthesis of compound IIa-32

The synthetic method for preparing compound IIa-32 is the same as that in Example 1, and the product IIa-32 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-15 (0.24 mmol) is used instead of compound RM-Ia-4, and compound SM1-2 (0.24 mmol) is used instead of compound SM1-1 to obtain intermediate RM-IIa-29, and the intermediate is hydrolyzed to obtain a white solid product IIa-32 (0.024 g), and the two-step yield is 30%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-32 was 426.2, and the measured value was 426.1.

Embodiment 33

Synthesis of compound IIa-33

Compound IIa-32 (0.020 g, 0.06 mmol) was added to HCl/MeOH (6N, 2 mL), stirred at room temperature for 1 h, and the reaction was detected to be complete. The mixture was concentrated to give a white solid product IIa-33 (0.017 g), with a one-step yield of 78%.

Mass spectrometry analysis confirmed that the ESI-MS [(M+H) ⁺ ]: m/z theoretical value of IIa-33 was 328.1, and the measured value was 328.2.

Embodiment 34

Synthesis of compound IIa-34

The synthetic method for preparing compound IIa-34 is the same as that in Example 1, and the product IIa-34 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-16 (0.24 mmol) is used instead of compound RM-Ia-4 in the reaction, and compound SM1-2 (0.24 mmol) is used instead of compound SM1-1 to obtain intermediate RM-IIa-30, and the intermediate is hydrolyzed to obtain a white solid product IIa-34 (0.032 g), and the two-step yield is 34%.

Mass spectrometry analysis confirmed that the ESI-MS [(M+H) ⁺ ]: m/z theoretical value of IIa-34 was 356.2, and the measured value was 356.3.

Embodiment 35

Synthesis of compound IIa-35

Compound RM-IIa-29 (0.6 g, 1.36 mmol) was added to HCl/MeOH (6N, 12 mL), stirred at room temperature overnight, and the reaction was detected to be complete. The mixture was concentrated to obtain a white solid intermediate product RM-IIa-31 (0.5 g).

The raw material RM-IIa-31 (0.050 g, 0.13 mmol.) was dissolved in 2 mL of DCM, DMAP (0.039 g, 0.32 mmol) was added, and methyl chloroformate (0.015 g, 0.15 mmol) was added under ice-water bath cooling, and the reaction was stirred at room temperature overnight to complete the reaction. After HPLC showed that the reaction was completed, the reaction solution was post-treated by column chromatography to obtain intermediate RM-IIa-32 (0.045 g), MeOH (2 mL), THF (1 mL) and LiOH aqueous solution (1 N, 1 mL) were added to the intermediate in sequence, and stirred at room temperature for 1 h. After HPLC showed that the reaction was completed, the reaction solution was neutralized with hydrochloric acid (1 N) to a pH of about 4, water was added, and ethyl acetate was added for extraction, and the organic phase was combined, washed with brine and dried, and finally separated and purified by column chromatography to obtain a white solid product IIa-35 (0.040 g), with a two-step yield of 80%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-35 was 384.1, and the measured value was 384.1.

Embodiment 36

Synthesis of compound IIa-36

The raw material RM-IIa-31 (0.050 g, 0.13 mmol.) was dissolved in 2 mL of DCM, DMAP (0.039 g, 0.32 mmol) was added, and cyclopentyl chloroformate (0.023 g, 0.15 mmol) was added under ice-water cooling, and the reaction was stirred at room temperature overnight to complete the reaction. After HPLC showed that the reaction was completed, the reaction solution was post-treated and purified by column chromatography to obtain intermediate RM-IIa-33 (0.052 g), MeOH (2 mL), THF (1 mL) and LiOH aqueous solution (1 N, 1 mL) were added to the intermediate in sequence, and stirred at room temperature for 1 h. After HPLC showed that the reaction was completed, the reaction solution was neutralized with hydrochloric acid (1 N) to a pH of about 4, water was added, and ethyl acetate was added for extraction, and the organic phase was combined, washed with brine and dried, and finally separated and purified by column chromatography to obtain a white solid product IIa-36 (0.042 g), with a two-step yield of 73%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-36 was 438.2, and the measured value was 438.1.

Embodiment 37

Synthesis of compound IIa-37

The raw material RM-IIa-31 (0.050 g, 0.13 mmol.) was dissolved in 2 mL of DCM, DMAP (0.039 g, 0.32 mmol) was added, and phenyl chloroformate (0.024 g, 0.15 mmol) was added under ice-water bath cooling, and the reaction was stirred at room temperature overnight to complete the reaction. After HPLC showed that the reaction was completed, the reaction solution was post-treated by column chromatography to obtain an intermediate (0.050 g), which was then dissolved in 2 mL of DMF, DMAP (0.025 g, 0.2 mmol) and tert-butylamine (0.015 g, 0.2 mmol) were added, and the reaction was stirred at room temperature for 3 h to complete the reaction. After HPLC showed that the reaction was completed, the reaction solution was post-treated and separated and purified by column chromatography to obtain intermediate RM-IIa-34 (0.043 g). MeOH (2 mL), THF (1 mL) and LiOH aqueous solution (1N, 1 mL) were added to the intermediate in sequence and stirred at room temperature for 1 h. After HPLC showed that the reaction was completed, the reaction solution was neutralized with hydrochloric acid (1N) to a pH of about 4, water was added, and ethyl acetate was added for extraction. The organic phases were combined, washed with brine and dried, and finally separated and purified by column chromatography to obtain a white solid product IIa-37 (0.025 g), with a two-step yield of 45%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-37 was 425.2, and the measured value was 425.1.

Embodiment 38

Synthesis of compound IIa-38

The raw material RM-IIa-31 (0.050 g, 0.13 mmol.) was dissolved in 2 mL of DCM, DMAP (0.039 g, 0.32 mmol) was added, and cyclopentyl chloroformate (0.023 g, 0.15 mmol) was added under ice-water bath cooling, and the reaction was stirred at room temperature overnight to complete the reaction. After HPLC showed that the reaction was completed, the reaction solution was post-treated and purified by column chromatography to obtain intermediate RM-IIa-35 (0.042 g), MeOH (2 mL), THF (1 mL) and LiOH aqueous solution (1 N, 1 mL) were added to the intermediate in sequence, and stirred at room temperature for 1 h. After HPLC showed that the reaction was completed, the reaction solution was neutralized with hydrochloric acid (1 N) to a pH of about 4, water was added, and ethyl acetate was added for extraction, and the organic phase was combined, washed with brine and dried, and finally separated and purified by column chromatography to obtain a white solid product IIa-38 (0.024 g), with a two-step yield of 45%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-38 was 410.2, and the measured value was 410.1.

Embodiment 39

Synthesis of compound IIa-39

The raw material RM-IIa-31 (0.050 g, 0.13 mmol.) was dissolved in 2 mL of DCM, DMAP (0.039 g, 0.32 mmol) was added, and isopropylsulfonyl chloride (0.022 g, 0.15 mmol) was added under ice-water cooling, and the reaction was stirred at room temperature overnight to complete the reaction. After HPLC showed that the reaction was completed, the reaction solution was post-treated and purified by column chromatography to obtain the intermediate RM-IIa-36 (0.013 g), and MeOH (2 mL), THF (1 mL) and LiOH aqueous solution (1 N, 1 mL) were added to the intermediate in sequence, and stirred at room temperature for 1 h. After HPLC showed that the reaction was completed, the reaction solution was neutralized with hydrochloric acid (1 N) to a pH of about 4, water was added, and ethyl acetate was added for extraction, and the organic phases were combined, washed with brine and dried, and finally separated and purified by column chromatography to obtain a white solid product IIa-39 (0.010 g), with a two-step yield of 18%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-39 was 432.1, and the measured value was 432.2.

Embodiment 40

Synthesis of compound IIa-40

The synthetic method for preparing compound IIa-40 is the same as that in Example 1, and the product IIa-40 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-17 (0.24 mmol) is used instead of compound RM-Ia-4, and compound SM1-2 (0.24 mmol) is used instead of compound SM1-1 to obtain intermediate RM-IIa-37, and the intermediate is hydrolyzed to obtain a white solid product IIa-40 (0.034 g), and the two-step yield is 33%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-40 was 426.2, and the measured value was 426.3.

Embodiment 41

Synthesis of compound IIa-41

The synthetic method for preparing compound IIa-41 is the same as that in Example 1, and product IIa-41 is obtained through two-step reactions of etherification and hydrolysis, wherein compound RM-Ia-18 (0.24 mmol) is used instead of compound RM-Ia-4, and compound SM1-2 (0.24 mmol) is used instead of compound SM1-1 to obtain intermediate RM-IIa-38, and the intermediate is hydrolyzed to obtain white solid product IIa-41 (0.026 g), with a two-step yield of 27%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-41 was 395.1, and the measured value was 395.2.

Embodiment 42

Synthesis of compound IIa-42

The synthetic method for preparing compound IIa-42 is the same as that in Example 1, and the product IIa-42 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-19 (0.24 mmol) is used instead of compound RM-Ia-4, and compound SM1-2 (0.24 mmol) is used instead of compound SM1-1 to obtain intermediate RM-IIa-39, and the intermediate is hydrolyzed to obtain a white solid product IIa-42 (0.022 g), and the two-step yield is 23%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-42 was 395.1, and the measured value was 395.2.

Embodiment 43

Synthesis of compound IIa-43

The synthetic method for preparing compound IIa-43 is the same as that in Example 1, and the product IIa-43 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-20 (0.24 mmol) is used instead of compound RM-Ia-4, and compound SM1-2 (0.24 mmol) is used instead of compound SM1-1 to obtain intermediate RM-IIa-40, and the intermediate is hydrolyzed to obtain a white solid product IIa-43 (0.035 g), and the two-step yield is 30%.

Mass spectrometry analysis confirmed that the ESI-MS [(M+H) ⁺ ]: m/z theoretical value of IIa-43 was 480.2, and the measured value was 480.3.

Embodiment 44

Synthesis of compound IIa-44

The synthetic method for preparing compound IIa-44 is the same as that in Example 1, and the product IIa-44 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-21 (0.24 mmol) is used instead of compound RM-Ia-4, and compound SM1-2 (0.24 mmol) is used instead of compound SM1-1 in the reaction to obtain intermediate RM-IIa-41, and the intermediate is hydrolyzed to obtain a white solid product IIa-44 (0.032 g), and the two-step yield is 32%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-44 was 415.2, and the measured value was 415.1.

Embodiment 45

Synthesis of compound IIa-45

The synthetic method for preparing compound IIa-45 is the same as that in Example 1, and product IIa-45 is obtained by two-step reaction of etherification and hydrolysis, wherein compound SM1-9 (0.42 mmol) is used in the reaction instead of compound SM1-1 to obtain intermediate RM-IIa-42, and the intermediate is hydrolyzed to obtain white solid product IIa-45 (0.030 g), and the two-step yield is 18%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-45 was 389.0, and the measured value was 388.9.

Embodiment 46

Synthesis of Compound IIa-46

The synthetic method for preparing compound IIa-46 is the same as that in Example 1, and product IIa-46 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-13 (0.24 mmol) is used instead of compound RM-Ia-4, and compound SM1-12 (0.24 mmol) is used instead of compound SM1-1 to obtain intermediate RM-IIa-43, and the intermediate is hydrolyzed to obtain white solid product IIa-46 (0.038 g), and the two-step yield is 40%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-46 was 389.1, and the measured value was 389.2.

Embodiment 47

Synthesis of compound IIa-47

The synthetic method for preparing compound IIa-47 is the same as that in Example 1, and product IIa-47 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-22 (0.38 mmol) is used instead of compound RM-Ia-1 in the reaction, and compound SM1-2 (0.38 mmol) is used instead of compound SM1-1 to obtain intermediate RM-IIa-44, and the intermediate is hydrolyzed to obtain white solid product IIa-47 (0.110 g), and the two-step yield is 66%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-47 was 434.0, and the measured value was 434.1.

Embodiment 48

Synthesis of compound IIa-48

The synthetic method for preparing compound IIa-48 is the same as that in Example 1, and the product IIa-48 is obtained by two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-23 (0.35 mmol) is used instead of compound RM-Ia-1 in the reaction, and compound SM1-2 (0.35 mmol) is used instead of compound SM1-1 to obtain intermediate RM-IIa-45, and the intermediate is hydrolyzed to obtain a white solid product IIa-48 (0.075 g), and the two-step yield is 46%.

Mass spectrometry analysis confirmed that the ESI-MS [(MH) ⁺ ]: m/z theoretical value of IIa-48 was 459.0, and the measured value was 459.1.

Embodiment 49

GPR40 activity detection method of compounds:

The compounds prepared by the present invention can be preliminarily screened for their effects on GPR40 by the following preclinical in vitro inhibitory activity test experiments, and then further confirmed for efficacy and safety by clinical trials. Other methods are also obvious to those with ordinary skills in the art. The GPR40 agonist TAK-875 previously developed by Takeda Company of Japan showed in preclinical and clinical trial results that the results of the in vitro test were consistent with the results of the relevant in vivo activity test.

The compounds of the present invention, or their stereoisomers, tautomers, esterified or amidated prodrugs, or their pharmaceutically acceptable salts and mixtures thereof, were tested in an evaluation experiment on GPR40 activity using compounds IIa-01 to IIa-48 and a reference compound Ref-1 (TAK-875). Comparison of the test results revealed that many compounds had better inhibitory activity (EC ₅₀ ) than the reference compounds.

CHO-K1/GPR40 cells were seeded in a 384-well plate at a seeding density of 10,000 cells/well. The cells were cultured in a 37°C, 5% CO2 incubator for 24 hours. After the experiment, the cell culture medium was discarded and 30 μl of 1X 2.5 mM Probenecid was quickly added to each well. Calcium 6 dye, and incubate at 37°C in the dark for 2 hours. During the assay, different concentrations of drug (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, EC ₅₀ was obtained according to the formula Y = Bottom + (Top-Bottom) / (1 + (EC50/X)^HillSlope).

The GPR40 agonist activity test results of each novel structural compound of Formula IIa are listed in the following Table 3; wherein, the GPR40 agonist activity effect range (EC ₅₀ ) of the compound of the present invention is <10 nM and is marked as "A"; the activity range is 10-100 nM and is marked as "B"; the activity range is >100 nM and is marked as "C".

Table 3: GPR40 agonist activity test results of the compound of formula IIa

Embodiment 50

Compound toxicity screening test

In order to test the toxicity of some highly active (EC ₅₀ <10nM) compounds (IIa-11, IIa-15, IIa-40 and IIa-48) among the new compounds (IIa-01 to IIa-48), the present invention uses healthy mice weighing 18-22g, all of which are administered with a single dose of 600mg/kg, once by gavage, and observes the toxicity produced by the experimental animals for 5 consecutive days to evaluate the toxicity of the test substance to the body, and conducts an acute toxicity (Acute Toxocity Study, MTD) test. The results show that the overall toxicity of the compounds is very small (LD ₅₀ :>600), the survival rate of mice after administration is 100%, and no abnormalities occur in body weight and in vitro and in vivo observations during the medication and 5-day recovery period. The autopsy results also show that there are no abnormal changes in various organs such as the heart, liver, lungs, kidneys, intestines, etc. in the body. It is generally believed that the tested compounds are safe and non-toxic within an appropriate dose. For this reason, several highly active compounds of the present invention have been determined by in vitro experiments, and not only have good therapeutic effects on type II diabetes, but are also safe and reliable.

Embodiment 51

BSEP (Bile Salt Export Pump) bile salt transport effect detection method of compounds:

In this experiment, the method of using LC/MS/MS to detect the absorption capacity of BSEP bile salt transporter for substrate taurocholic acid (TCA) was used to conduct a preliminary study on whether the candidate compound has an inhibitory effect on the transport process of BSEP transporter. BSEP protein micromembrane vesicles with reverse absorption capacity were obtained by transfecting Hi5 cells with BSEP gene. This micromembrane vesicle can absorb and take up taurocholic acid TCA. The principle of this experiment is to conduct a substrate absorption experiment of BSEP protein micromembrane vesicles under the condition of the simultaneous presence of energy ATP, substrate taurocholic acid TCA and candidate compounds to be tested. After a certain transport action time, the remaining energy, substrate and candidate compounds outside the micromembrane vesicles are completely washed away, and the micromembrane vesicles are cleaved to release the absorbed substrate taurocholic acid TCA, and then LC/MS/MS is used to detect taurocholic acid TCA to determine whether the candidate compound inhibits the TCA transport process.

Sample processing:

1. Dissolve the compounds in 100% DMSO to 100 mM and store them in a -20°C refrigerator until all compounds are completely dissolved.

2. The sample starting concentration was 100 mM and was diluted 2-fold using the Bravo instrument, with 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 it was diluted 2-fold using the Bravo instrument, with a total of 11 concentration gradients; the lowest concentration was 19.53 μM.

4. Use ECHO automatic pipette to transfer 300 nl of compound to the middle plate.

5. 300 nl DMSO was also transferred to each of the positive control (HPE) wells and the negative control (ZPE) wells.

Experimental steps:

1. Add 14.7 μl of ATP buffer to the corresponding wells of the compound and ZPE.

2. Add 14.7 μl of AMP buffer to the corresponding wells of HPE.

Incubate on a 3.25°C shaker for 10 minutes.

4. Add 15ul of BSEP-Hi5-VT Vesicle solution to all wells and shake the plate at 25 degrees Celsius for 40 minutes.

5. Immediately add 5ul of 0.5M EDTA solution to all wells, and then add 65ul of buffer B to complete the reaction.

6. Use a pipetting device to transfer 95 μl of liquid from the compound plate where the reaction is completed to the filter plate.

7. After placing the liquid receiving plate under the filter plate, use a centrifuge to remove the liquid and discard the liquid received in the receiving plate.

8. Add 90 μl of buffer B to the filter plate and repeat step 7. Repeat steps 7 and 8 to wash the filter plate three times.

9. Allow the filter plate to dry overnight.

10. The next day, add 81 μl of 80% methanol/water solution to the filter plate.

11. After applying the membrane to the filter plate, vibrate the plate for 15 minutes.

12. Place a new liquid receiving plate under the filter plate and centrifuge for 5 minutes to filter all the liquid in the filter plate into the receiving plate.

13. Add 13.5 μl of internal standard solution to each well of the liquid receiving plate and seal the plate with sealing film.

14. Use LC/MS/MS to detect the content of taurocholic acid in the receiving plate.

Table 4: Comparison of optimized GPR40 agonist activities and their potential side effects

Note: When the BSEP inhibition results (IC50) of the compounds shown in Table 4 are lower than 25 μM [such as: the value of Ref-1 (TAK-875) is 7.1, which is significantly lower than 25], the BSEP inhibition side effect of the compound may lead to the potential risk of liver damage in vivo.

The activity test results in Tables 3 and 4 above show that: (1) the activity (EC50) of the five-membered heterocyclic compounds containing 1-2 oxygen atoms in the various novel benzo-heterocyclic compounds of the present invention is significantly better than that of the six-membered heterocyclic compounds of the same structure containing 1-2 oxygen atoms; (2) the activity of the benzo-oxygen-containing five-membered heterocyclic compounds of the formula IIa of the present invention when Z ¹ is "oxygen (O)" is better than that of the corresponding compounds of the same structure when Z ¹ is "CH ₂ "; (3) the benzo-oxygen-containing five-membered heterocyclic compounds IIa-05, IIa-10, IIa-11, IIa-13, IIa-15, IIa-21, IIa-32, IIa-40, IIa-41, IIa-42 and IIa-48 of the present invention show good activity against the GPR40 target (EC ₅₀ : <10nM), which is superior to the similar control compound TAK-875. It is a new GPR40 agonist with better activity in this research field and has drug-like advantages in terms of activity and safety.

The benzo-oxygenated five-membered heterocyclic compounds listed in Table 4 above not only show good activity, but also the BSEP side effect results that may cause liver damage are all greater than 25, which is significantly better than the TAK-875 new drug of Takeda Company of Japan, which terminated the clinical phase III trial due to liver toxicity problems. The completed acute toxicity (Acμte Toxocity Stμdy, MTD) test results show that the active compounds IIa-11, IIa-15, IIa-40 and IIa-48 listed in Table 4 have good safety. The survival rate of mice after oral administration of 600 mg/kg of the new compound is 100% after 5 days, and no abnormalities occur during the medication and 5-day recovery period. No abnormalities are found in the autopsy results. Therefore, several highly active compounds in the new benzo-oxygenated five-membered heterocyclic compound IIa designed and synthesized by the present invention are worth further animal and clinical trials and promotion and application.

The present invention discovered several compounds with better active effects (such as: IIa-11, IIa-15, IIa-40 and IIa-48) in the innovative research of GPR40 target agonists, and the toxicity of the acute toxicity test of TMD high dose (600 mg/kg/day) was very low, and the test results of BSEP (>25uM), hERG (>30uM) and Ames showed that there were no related side effects. The relevant results were better than the currently known reference compound TAK-875. At present, the foundation has been laid for the invention of a new GPR40 target agonist drug with good GPR40 target selectivity and the ability to safely and effectively treat patients with type 2 diabetes.

These and other changes can be made to the embodiments in light of the above detailed description. In general, the terms used in the claims should not be considered to limit the claims to the specific embodiments disclosed in the specification and claims, but should be considered to include all possible embodiments that follow the full scope of equivalents to the listed claims. Therefore, the claims are not limited by the present disclosure.

Claims (5)

1. A compound of formula IIa: or a pharmaceutically acceptable salt thereof, in: n=0, Y does not exist, Y ¹ is directly connected to the oxygen in the ortho position of Y by a single bond to form a five-membered heterocyclic ring; Y ¹ is -CH ₂ -; E ¹ is -CH-; E and G ¹ are directly connected to form a cyclic compound, G ¹ is -C-, E is -OC(RcRd)-, Rc and Rd are each independently hydrogen; 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, or cycloalkylsulfonamide; X ¹ is hydrogen, deuterium (D), halogen, nitrile group, amino group (NH ₂ ), trifluoromethyl group, trifluoromethoxy group, alkyl group, alkoxy group, alkylamino group (NR _i R _j ), Alkylaminocarbonylamino, alkoxycarbonylamino, cycloalkoxycarbonylamino, alkylsulfonamide, cycloalkylsulfonamide, aryl, or aryloxycarbonylamino; X ² , X ³ and X ⁴ are each independently hydrogen, deuterium (D), halogen, or trifluoromethyl; Ri and Rj are each independently hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, or cycloalkoxycarbonyl. 2. The compound of claim 1, wherein the compound has a structure selected from the group consisting of: 3. A composition comprising the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent and/or excipient. 4. Use of a compound according to claim 1 or 2 or a composition according to claim 3 for the preparation of a medicament for use as a GPR40 agonist. 5. Use of the compound of claim 1 or 2 or the composition of claim 3 in the preparation of a medicament for the treatment or prevention of type II diabetes.