CN106317027A

CN106317027A - Heteroaryl amide derivative and use thereof as TGR5 agonist

Info

Publication number: CN106317027A
Application number: CN201510329937.8A
Authority: CN
Inventors: 吴永谦
Original assignee: Shandong Xuanzhu Pharma Co Ltd
Current assignee: Beijing Sihuan Pharmaceutical Co Ltd
Priority date: 2015-06-15
Filing date: 2015-06-15
Publication date: 2017-01-11

Abstract

The invention belongs to the technical field of medicines, and in particular relates to a heteroaryl amide TGR5 agonist compound represented by formula (I) and pharmaceutically acceptable salts, esters, stereoisomers or prodrugs thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, X1, X2, X3 and Y are as defined in the specification; the invention also relates to preparing methods, pharmaceutical formulations, pharmaceutical compositions and use in preparation of medicines for treatment and / or prevention of diseases related to TGR5 activity regulation of the heteroaryl amide TGR5 agonist compound and the pharmaceutically acceptable salts, esters, stereoisomers or prodrugs thereof.

Description

Heteroaryl amide derivatives and their use as TGR5 agonists

1. Field of the invention

The invention belongs to the technical field of medicines, and particularly relates to a TGR5 agonist compound, pharmaceutically acceptable salt thereof, ester thereof, stereoisomer thereof or prodrug thereof; the invention also relates to a preparation method, a pharmaceutical preparation, a pharmaceutical composition and application of the compounds in preparation of medicines for treating and/or preventing diseases related to modulation of TGR5 activity.

2. Background of the invention

Diabetes is currently in a rapidly growing state worldwide, with over 2.5 billion people directly affected by diabetes worldwide accounting for 6% of the world population, and another 3.18 million people suffering from sugar metabolism deficiency. China has become one of the countries with the fastest global diabetes prevalence rate increase, about 4000 million diabetics and people with impaired glucose tolerance exist at present, the patients are next to India and live second in the world, and diabetes needs to be monitored and treated for life, if the diabetes cannot be well controlled, the secondary cardiovascular diseases, blindness, cerebral apoplexy, diabetic nephropathy, diabetic gangrene and other complications of the patients can be caused, and the health and the life of the people are seriously damaged.

More than 90% of the diabetes is type II diabetes, also called non-insulin dependent diabetes, the capability of the patient to generate insulin in the body is not completely lost, and some patients generate insulin even too much, but the action effect of the insulin is poor, so that the insulin in the body of the patient is relatively deficient. Currently, type ii diabetes is treated at several levels, including diet, exercise, insulin and drug therapy, with over 70% of patients receiving drug therapy, using drugs that mainly include (1) sulfonylureas and glinides that act on pancreatic β cells to promote insulin secretion; (2) biguanides acting on skeletal muscle and adipose tissue to improve insulin sensitivity; (3) thiazolidinediones acting on peroxisome proliferator-activated receptor alpha (PPAR α) and increasing the sensitivity of skeletal muscle and adipose tissue to insulin; (4) an alpha-glucosidase inhibitor acting on alpha-glucosidase to reduce postprandial carbohydrate absorption; while these drugs are generally effective in controlling blood glucose, they can produce a number of side effects, including hypoglycemia, gastrointestinal problems, weight gain, and edema. In addition, effectiveness also declines over time.

GLP-1, an incretin, has effects of promoting insulin secretion, inhibiting glucagon secretion, inhibiting gastric emptying, etc. Research shows that the type II diabetes weakens the secretion of GLP-1, so that the blood sugar level in vivo is increased, and GLP-1 is a peptide compound which cannot be orally taken, so that the clinical application of the GLP-1 is greatly inhibited.

TGR5, also known as GPBAR1, M-BAR, GPR131, GPCR19, BG37 and MGC40597, was first discovered by Vuji Kawamata [ Biochem Biophys Res Commun 298,714-719(2002) ] as a bile acid membrane receptor consisting of 330 amino acids, containing 7 transmembrane domains, being a member of the GPCR family. It is mainly distributed in intestinal tract, adipose tissue, muscle tissue and gallbladder. Activation of TGR5 may play a different role in different cell types, and TGR5 activation in macrophages can reduce inflammatory cytokine production; in adipocytes and muscle cells, TGR5 activation can increase energy expenditure, and in addition to TGR5 being involved in energy balance, bile acid activation of TGR5 can increase intracellular cAMP accumulation, thereby promoting GLP-1 secretion by enteroendocrine cells in mice. According to the expression characteristics and the functional relation of TGR5 histiocyte, the receptor is activated to promote GLP-1 and insulin secretion, which is helpful for blood sugar control.

In recent years, a series of bile acid derivatives with TGR5 activation effects are developed, then a series of small molecules capable of activating TGR5 receptors are sequentially synthesized, and patents WO2010049302, WO2011089099 and CN102850321A disclose a series of triarylcyclic TGR5 agonist compounds with similar structures, and the TGR5 agonists are expected to become potential antidiabetic therapeutic drugs.

Therefore, the variety of TGR5 agonists is enriched, and the antidiabetic drug with high efficiency, low toxicity and small side effect is developed, so the method has very important significance for treating diabetes and improving the living standard of patients.

3. Summary of the invention

The invention provides a compound which is effective as TGR5 agonist, pharmaceutically acceptable salt thereof, ester thereof, stereoisomer thereof or prodrug thereof, and the specific scheme is as follows:

scheme 1, compounds of the following general formula (I), pharmaceutically acceptable salts thereof, esters thereof, stereoisomers thereof or prodrugs thereof:

wherein,

X¹、X²and X³Are each independently selected from CR¹²Or N, and X¹、X²And X³At least one is N;

y is selected from absent, CR¹³R¹³ ^，，NR¹³O or S;

R¹²、R¹³and R¹³ ^，Each independently selected from hydrogen, halogen, amino, hydroxy, cyano, C_1-6Alkyl radicalOf halo C_1-6Alkyl, or C_1-6An alkoxy group;

R¹selected from hydrogen, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, carboxy C_1-6Alkyl, or 3-8 membered cycloalkyl, 3-8 membered cycloalkyl-C optionally substituted with one or more Q1_1-6Alkyl, 3-8 membered heterocyclyl; each Q1 is independently selected from hydroxy, halogen, amino, cyano, nitro, carboxy, C_1-6Alkyl, or C_1-6An alkoxy group;

R²、R³、R⁴、R⁵、R⁶each independently selected from hydrogen, hydroxyl, halogen, nitro, carboxyl, cyano, amino and C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, carboxy C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy, amino C_1-6Alkoxy, carboxyl C_1-6Alkoxy radical, C_1-6Alkylamino, di-C_1-6Alkylamino, aminocarbonyl, C_1-6Alkylaminocarbonyl, di-C_1-6Alkylaminocarbonyl radical, C_1-6Alkylcarbonyl group, C_1-6Alkylcarbonylamino, C_1-6Alkylcarbonyloxy, C_1-6Alkoxycarbonyl, aminosulfonyl, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfonylamino group, C_1-6Alkylaminosulfonyl, di-C_1-6Alkylaminosulfonyl radical, C_1-6alkylsulfonyl-C_1-6Alkoxy radical, C_1-6alkoxy-C_1-6Alkylsulfonyl, or 3-8 membered cycloalkyl optionally substituted with one or more Q2, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; each Q2 is independently selected from hydroxy, halogen, cyano, amino, nitro, carboxy, C_1-6Alkyl or C_1-6An alkoxy group;

or, R¹And R²Together form-Z- (CR)¹⁴R¹⁵) n-and forms a ring with the atom to which it is attached, wherein Z is selected from-CR¹⁶R¹⁷-, O, S, -C (O) -or NR¹⁸(ii) a n is selected from 1,2 or 3;

R¹⁴、R¹⁵、R¹⁶、R¹⁷each independently selected from hydrogen, hydroxy, halogen, amino, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, or 3-8 membered heterocyclyl;

R¹⁸selected from hydrogen, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, carboxy C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-6Alkylcarbonyl group, C_1-6Alkylsulfonyl, or 3-8 membered cycloalkyl optionally substituted with one or more Q3, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, 3-8 membered cycloalkyl-C_1-6Alkyl, 3-8 membered heterocyclyl-C_1-6Alkyl, 5-6 membered heteroaryl-C_1-6Alkyl, phenyl-C_1-6An alkyl group; each Q3 is independently selected from hydroxy, halogen, amino, cyano, nitro, carboxy, C_1-6Alkyl, or C_1-6An alkoxy group;

R⁷、R⁸、R⁹、R¹⁰or R¹¹Each independently selected from hydrogen, hydroxyl, halogen, nitro, carboxyl, cyano, amino and C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, carboxy C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy, amino C_1-6Alkoxy, carboxyl C_1-6Alkoxy radical, C_1-6Alkylamino, di-C_1-6Alkylamino, aminocarbonyl, C_1-6Alkylaminocarbonyl, di-C_1-6Alkylaminocarbonyl radical, C_1-6Alkylcarbonyl group, C_1-6Alkylcarbonylamino, C_1-6Alkylcarbonyloxy, C_1-6Alkoxycarbonyl, aminosulfonyl, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfonylamino group, C_1-6Alkylaminosulfonyl, di-C_1-6Alkylaminosulfonyl radical, C_1-6alkylsulfonyl-C_1-6Alkoxy radical, C_1-6alkoxy-C_1-6Alkylsulfonyl, or C optionally substituted with one or more Q4_2-6Alkenyl radical, C_2-6Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; each Q4 is independently selected from hydroxy, halogen, amino, cyano, nitro, carboxy, C_1-6Alkyl, or C_1-6An alkoxy group;

or, R⁷、R⁸、R⁹、R¹⁰Or R¹¹Any two adjacent groups in (a) together with the carbon atom to which they are attached form a 3-8 membered cycloalkyl group, a 3-8 membered heterocyclyl group, a phenyl group, or a 5-6 membered heteroaryl group.

A compound of scheme 2, scheme 1, pharmaceutically acceptable salts thereof, esters thereof, stereoisomers thereof or prodrugs thereof:

wherein, X³Is N, X¹、X²Each independently selected from CR¹²Or N, and X¹、X²Not N at the same time;

y is selected from CR¹³R¹³ ^，，NR¹³Or O; preferably O;

R¹²selected from hydrogen, halogen, methyl, ethyl, methoxy or trifluoromethyl;

R¹³and R¹³ ^，Each independently selected from hydrogen, halogen, methyl, ethyl or methoxy.

A compound according to scheme 3, scheme 1, pharmaceutically acceptable salts thereof, esters thereof, stereoisomers thereof or prodrugs thereof:

wherein, X¹Is N, X²Is CR¹²，X³Selected from the group consisting of CR¹²Or N;

y is selected from absent or NR¹³；

R¹³selected from hydrogen, methyl or ethyl.

A compound of scheme 4, schemes 1-3, pharmaceutically acceptable salts thereof, esters thereof, stereoisomers thereof or prodrugs thereof:

wherein R is¹Selected from hydrogen, C_1-4Alkyl, halo C_1-4Alkyl, hydroxy C_1-4Alkyl, amino C_1-4Alkyl, carboxy C_1-4Alkyl, or 5-6 membered cycloalkyl, 5-6 membered cycloalkyl-C optionally substituted by 1-3Q 1₁₄Alkyl, 5-6 membered heterocyclyl; each Q1 is independently selected from hydroxy, halogen, amino, cyano, nitro, carboxy, C_1-4Alkyl, or C_1-4An alkoxy group;

R²、R³、R⁴、R⁵、R⁶each independently selected from hydrogen, hydroxy, halogen, amino, C_1-4Alkyl, halo C_1-4Alkyl, hydroxy C_1-4Alkyl, amino C_1-4Alkyl, carboxy C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkoxy, hydroxy C_1-4Alkoxy, amino C_1-4Alkoxy, carboxyl C_1-4Alkoxy radical, C_1-4Alkylamino, di-C_1-4Alkylamino, aminocarbonyl, C_1-4Alkylaminocarbonyl, di-C_1-4Alkylaminocarbonyl radical, C_1-4Alkylcarbonyl group, C_1-4Alkylcarbonylamino, C_1-4Alkylcarbonyloxy, C_1-4Alkoxycarbonyl, aminosulfonyl, C_1-4Alkylsulfonyl radical, C_1-4Alkylsulfonylamino group, C_1-4Alkylaminosulfonyl, di-C_1-4Alkylaminosulfonyl radical, C_1-4alkylsulfonyl-C_1-4Alkoxy radical, C_1-4alkoxy-C_1-4Alkylsulfonyl, or 5-6 membered cycloalkyl optionally substituted with 1-3 of Q2, 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; each Q2 is independently selected from hydroxy, halogen, amino, C_1-4Alkyl, or C_1-4An alkoxy group;

or, R¹And R²Together form-Z- (CR)¹⁴R¹⁵) n-and forms a ring with the atom to which it is attached, wherein Z is selected from the group consisting of-CR¹⁶R¹⁷-, O or NR¹⁸(ii) a n is selected from 1,2 or 3;

R¹⁴、R¹⁵、R¹⁶、R¹⁷each independently selected from hydrogen, hydroxy, halogen, amino, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, or 5-6 membered heterocyclyl;

R¹⁸selected from hydrogen, C_1-4Alkyl, halo C_1-4Alkyl, hydroxy C_1-4Alkyl, carboxy C_1-4Alkyl, amino C_1-4Alkyl radical, C_1-4Alkylcarbonyl group, C_1-4Alkylsulfonyl, or 5-6 membered cycloalkyl optionally substituted with 1-3 of Q3, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, 5-6 membered cycloalkyl-C_1-4Alkyl, 5-6 membered heterocyclyl-C_1-4Alkyl, 5-6 membered heteroaryl-C_1-4Alkyl, phenyl-C_1-4An alkyl group; each Q3 is independently selected from hydroxy, halogen, amino, C_1-4Alkyl, or C_1-4An alkoxy group;

R⁷、R⁸、R⁹、R¹⁰or R¹¹Each independently selected from hydrogen, hydroxy, halogen, amino, C_1-4Alkyl, halo C_1-4Alkyl, hydroxy C_1-4Alkyl, amino C_1-4Alkyl, carboxy C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkoxy, hydroxy C_1-4Alkoxy, amino C_1-4Alkoxy, carboxyl C_1-4Alkoxy radical, C_1-4Alkylamino, di-C_1-4Alkylamino, aminocarbonyl, C_1-4Alkylaminocarbonyl, di-C_1-4Alkylaminocarbonyl radical, C_1-4Alkylcarbonyl group, C_1-4Alkylcarbonylamino, C_1-4Alkylcarbonyloxy, C_1-4Alkoxycarbonyl, aminosulfonyl, C_1-4Alkylsulfonyl radical, C_1-4Alkylsulfonylamino group, C_1-4Alkylaminosulfonyl, di-C_1-4Alkyl radicalAminosulfonyl radicals, C_1-4alkylsulfonyl-C_1-4Alkoxy radical, C_1-4alkoxy-C_1-4Alkylsulfonyl, or 5-6 membered cycloalkyl optionally substituted with 1-3 of Q4, 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; each Q4 is independently selected from hydroxy, halogen, amino, C_1-4Alkyl, or C_1-4An alkoxy group;

or, R⁷、R⁸、R⁹、R¹⁰Or R¹¹Any two adjacent groups in (b) together with the carbon atom to which they are attached form a 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.

A compound of scheme 5, scheme 4, pharmaceutically acceptable salts thereof, esters thereof, stereoisomers thereof or prodrugs thereof:

wherein R is¹And R²Together form-Z- (CR)¹⁴R¹⁵) n-and forms a ring with the atom to which it is attached, wherein Z is selected from O or NR¹⁸(ii) a n is selected from 1 or 2;

R³、R⁴、R⁵、R⁶each independently selected from hydrogen, hydroxy, halogen, amino, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkylamino, di-C_1-4Alkylamino radical, C_1-4Alkoxy, halo C_1-4Alkoxy, or C_1-4An alkylsulfonyl group;

R¹⁴、R¹⁵each independently selected from hydrogen, halogen, C_1-4Alkyl, halo C_1-4Alkyl, or C_1-4An alkoxy group;

R¹⁸selected from hydrogen, C_1-4Alkyl radical, C_1-4Alkylcarbonyl, or C_1-4An alkylsulfonyl group;

R⁷、R¹⁰selected from halogen, R⁷、R¹⁰May be the same or different;

R⁸、R⁹or R¹¹Are independent of each otherSelected from hydrogen, hydroxy, halogen, amino, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkylamino, di-C_1-4Alkylamino radical, C_1-4Alkoxy, halo C_1-4Alkoxy, or C_1-4An alkylsulfonyl group.

A compound of scheme 6, scheme 5, pharmaceutically acceptable salts thereof, esters thereof, stereoisomers thereof or prodrugs thereof:

R¹and R²Together form-Z- (CR)¹⁴R¹⁵) n-and forms a ring with the atom to which it is attached, wherein Z is selected from NR¹⁸(ii) a n is selected from 1 or 2;

R³、R⁴、R⁵、R⁶each independently selected from hydrogen, hydroxy, halogen, amino, methyl, ethyl, trifluoromethyl, methylamino, dimethylamino, methoxy, ethoxy, trifluoromethoxy, or methylsulfonyl;

R¹⁴、R¹⁵each independently selected from hydrogen, halogen, methyl, ethyl, trifluoromethyl, methoxy or ethoxy;

R¹⁸selected from hydrogen, methyl, ethyl, methylcarbonyl or methylsulfonyl;

R⁷、R¹⁰are all selected from chlorine atoms;

R⁸、R⁹or R¹¹Each independently selected from hydrogen, hydroxy, halogen, amino, methyl, ethyl, trifluoromethyl, methylamino, dimethylamino, methoxy, ethoxy, trifluoromethoxy, or methylsulfonyl.

The other technical scheme of the invention is as follows:

y is selected from O;

R¹and R²Together form-Z- (CR)¹⁴R¹⁵) n-and forms a ring with the atom to which it is attached, wherein Z is selected from O or NR¹⁸(ii) a n is selected from 1 or 2;

R⁷、R¹⁰selected from halogen, R⁷、R¹⁰May be the same or different;

R⁸、R⁹or R¹¹Each independently selected from hydrogen, hydroxy, halogen, amino, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkylamino, di-C_1-4Alkylamino radical, C_1-4Alkoxy, halo C_1-4Alkoxy, or C_1-4An alkylsulfonyl group.

Preferably:

R³、R⁴、R⁵、R⁶each independently selected from the group consisting of hydrogen,hydroxy, halogen, amino, methyl, ethyl, trifluoromethyl, methylamino, dimethylamino, methoxy, ethoxy, trifluoromethoxy, or methylsulfonyl;

R¹⁸selected from hydrogen, methyl, ethyl, methylcarbonyl or methylsulfonyl;

R⁷、R¹⁰are all selected from chlorine atoms;

The other technical scheme of the invention is as follows:

X¹is N, X²Is CR¹²，X³Selected from the group consisting of CR¹²Or N;

y is selected from absent or NR¹³；

R¹³selected from hydrogen, methyl or ethyl;

R⁷、R¹⁰selected from halogen, R⁷、R¹⁰May be the same or different;

Preferably:

R¹⁸selected from hydrogen, methyl, ethyl, methylcarbonyl or methylsulfonyl;

R⁷、R¹⁰are all selected from chlorine atoms;

R⁸、R⁹or R¹¹Each independently selected from hydrogen, hydroxy, halogen,amino, methyl, ethyl, trifluoromethyl, methylamino, dimethylamino, methoxy, ethoxy, trifluoromethoxy, or methylsulfonyl.

Preferred compounds of the invention, pharmaceutically acceptable salts, esters, stereoisomers or prodrugs thereof are:

Detailed Description

"absent" as used herein means that when Y is absent, the Y side groups are directly connected by a single bond.

The "halogen" in the present invention means fluorine, chlorine, bromine, iodine, etc., preferably a chlorine atom.

The term "halo" as used herein means that any one of the carbon atoms in a substituent may be substituted with one or more of the same or different halogens. "halogen" is as defined above.

Said "C" of the present invention_1-6The "alkyl group" means a straight chain or branched alkyl group derived from a hydrocarbon moiety having 1 to 6 carbon atoms by removing one hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1-methyl-2-methylpropyl, and the like. Said "C_1-4Alkyl "refers to the above examples containing 1 to 4 carbon atoms.

Said "C" of the present invention_1-6Alkylaminocarbonyl group and di-C_1-6Alkylaminocarbonyl group and C_1-6Alkylcarbonyl group and C_1-6Alkylcarbonylamino group and C_1-6Alkylcarbonyloxy "means" C "respectively_1-6alkyl-NH-C (O) - ", (C)_1-6Alkyl radical)₂N-C(O)-、“C_1-6alkyl-C (O) - "," C_1-6alkyl-C (O) -NH- "," C_1-6alkyl-C (O) -O- "; said "C_1-6Alkyl "is as defined above, preferably" C_1-4Alkyl groups ".

"C" according to the invention_1-6Alkylsulfonyl group "," C_1-6Alkylsulfonylamino group and "C_1-6Alkylaminosulfonyl radical and di-C_1-6Alkylaminosulfonyl "is independently" C_1-6alkyl-S (O)₂-”、“C_1-6alkyl-S (O)₂-NH-”、“C_1-6alkyl-NH-S (O)₂-”、“(C_1-6Alkyl radical)₂N-S(O)₂- "; said "C_1-6Alkyl "is as defined above, preferably" C_1-4Alkyl groups ".

The "hydroxy group C" of the present invention_1-6Alkyl group and amino group C_1-6Alkyl group and carboxyl group C_1-6Alkyl "independently means" C_1-6Alkyl "may be substituted by one or more hydroxy, amino, carboxy groups, preferably 1 to 4, preferably 1 to 3, more preferably 1 to 2; said "C_1-6Alkyl "is as defined above, preferably" C_1-4Alkyl groups ".

"C" according to the invention_2-6The "alkenyl group" means a straight-chain or branched alkenyl group having 2 to 6 carbon atoms containing at least one double bond, and examples thereof include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, and the like, 2-methyl-2-butenyl, 3-methylA group-2-butenyl group, a 1-methyl-3-butenyl group, a 2-methyl-3-butenyl group, a 3-methyl-3-butenyl group, a 1, 1-dimethyl-2-propenyl group, a 1, 2-dimethyl-1-propenyl group, a 1, 2-dimethyl-2-propenyl group, a 1-ethyl-1-propenyl group, a 1-ethyl-2-propenyl group, a 1-hexenyl group, a 2-hexenyl group, a 3-hexenyl group, a 4-hexenyl group, a 5-hexenyl group, a 1-methyl-1-pentenyl group, a 2-methyl-1-pentenyl group, a 3-methyl-1-pentenyl group, a 4-methyl-1-pentenyl group, a, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1-dimethyl-2-butenyl, 1-dimethyl-3-butenyl, 1, 2-dimethyl-1-butenyl, 2-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-4-pentenyl, 1-dimethyl-2-butenyl, 1,1, 2-dimethyl-2-butenyl, 1, 2-dimethyl-3-butenyl, 1, 3-dimethyl-1-butenyl, 1, 3-dimethyl-2-butenyl, 2-dimethyl-3-butenyl, 2, 3-dimethyl-1-butenyl, 2, 3-dimethyl-2-butenyl, 2, 3-dimethyl-3-butenyl, 3-dimethyl-1-butenyl, 3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-methyl-2-butenyl, 2-methyl-3-butenyl, 2, 3-dimethyl-2-butenyl, 2, 3-dimethyl-1-ethyl-1-butenyl, 1, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1, 2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, 1-ethyl-2-methyl-2-propenyl, 1, 3-butadiene, 1, 3-pentadiene, 1, 4-hexadienyl and the like. Preferably "C_2-4Alkenyl ".

The term "C_2-4The alkenyl group "means a specific example containing 2 to 4 carbon atoms among the above examples.

"C" according to the invention_2-6Alkynyl "means a straight chain or branched alkynyl group having 2 to 6 carbon atoms containing at least one triple bond, and examples thereof include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl,4-hexynyl group, 5-hexynyl group, 1-methyl-2-pentynyl group, 1-methyl-3-pentynyl group, 1-methyl-4-pentynyl group, 2-methyl-3-pentynyl group, 2-methyl-4-pentynyl group, 3-methyl-4-pentynyl group, 4-methyl-2-pentynyl group, 1-dimethyl-2-butynyl group, 1-dimethyl-3-butynyl group, 1, 2-dimethyl-3-butynyl group, 2-dimethyl-3-butynyl group, 1-ethyl-2-butynyl group, 1-ethyl-3-butynyl group, 2-methyl-3-pentynyl group, 1-methyl-4-pentynyl group, 1, 1-ethyl-1-methyl-2-propynyl, and the like. Preferably "C_2-4Alkynyl ".

The term "C_2-4Alkynyl "refers to the specific examples containing 2 to 4 carbon atoms in the above examples.

"C" according to the invention_1-6Alkoxy "means" C "as defined hereinbefore_1-6Alkyl "a group attached to the parent molecular moiety through an oxygen atom, i.e." C_1-6alkyl-O- "groups such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy, neopentoxy, n-hexoxy and the like. Said "C_1-4Alkoxy "refers to the above examples containing 1 to 4 carbon atoms, i.e." C_1-4An alkyl-O- "group.

Said "C" of the present invention_1-6Alkoxycarbonyl group and C_1-6alkylsulfonyl-C_1-6Alkoxy group "," C_1-6alkoxy-C_1-6Alkylsulfonyl "means" C "respectively_1-6alkoxy-C (O) - "," C_1-6alkyl-S (O)₂-C_1-6Alkoxy group "," C_1-6alkoxy-C_1-6alkyl-S (O)₂- "; said "C_1-6Alkyl "is as defined above, preferably" C_1-4Alkyl groups "; said "C_1-6Alkoxy "is as defined above, preferably" C_1-4Alkoxy ".

The "hydroxy group C" of the present invention_1-6Alkoxy group and amino group C_1-6Alkoxy group "," carboxyl group C_1-6Alkoxy "means respectively" C_1-6Alkoxy "may be substituted by one or more hydroxy, amino, carboxy groups, preferably 1 to 4, preferably 1 to 3, more preferably1-2; said "C_1-6Alkoxy "is as defined above, preferably" C_1-4Alkoxy ".

The 3-8 membered cycloalkyl refers to a monocyclic ring structure with 3-8 ring atoms and all carbon atoms, and comprises 3-8 membered saturated cycloalkyl and 3-8 membered partially saturated cycloalkyl; examples of "3-8 membered saturated cycloalkyl" include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane; "3-to 8-membered partially saturated cycloalkyl" means a monocyclic cycloalkyl group having at least one double bond and having no aromaticity, and examples thereof include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1, 4-cyclohexadienyl, cycloheptenyl, 1, 4-cycloheptadienyl, cyclooctenyl, 1, 5-cyclooctadienyl and the like. "5-6 membered cycloalkyl" is preferred.

The term "5-6 membered cycloalkyl" refers to the above specific examples having 5-6 ring atoms.

The term "3-to 8-membered heterocyclic group" as used herein means that any one of carbon atoms in the above-mentioned "3-to 8-membered cycloalkyl group" may be substituted with a hetero atom selected from nitrogen, oxygen and/or sulfur atoms, preferably 1 to 3 of any hetero atoms, and includes carbon atoms, nitrogen atoms and sulfur atoms which may be oxo, and includes "3-to 8-membered saturated heterocyclic group" and "3-to 8-membered partially saturated heterocyclic group"; examples of "3-to 8-membered saturated heterocyclic group" include, but are not limited to, aziridinyl, oxetanyl, thietanyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydrothienyl, imidazolidinyl, pyrazolidinyl, 1, 2-oxazolidinyl, 1, 3-oxazolidinyl, 1, 2-thiazolidinyl, 1, 3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, morpholinyl, 1, 4-dioxanyl, 1, 4-oxathianyl, oxaheptane, thiaheptane, azepane, 1, 4-dioxacyclooctyl and the like; "3-to 8-membered partially saturated heterocyclic group" means a heterocyclic group having at least one double bond and having no aromaticity, and examples thereof include, but are not limited to, 4, 5-dihydroisoxazolyl, 4, 5-dihydrooxazolyl, 2, 3-dihydrooxazolyl, 3, 4-dihydro-2H-pyrrolyl, 2, 3-dihydro-1H-pyrrolyl, 2, 5-dihydro-1H-imidazolyl, 4, 5-dihydro-1H-pyrazolyl, 4, 5-dihydro-3H-pyrazolyl, 4, 5-dihydrothiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-thiopyranyl, 4H-thiopyranyl, 2,3,4, 5-tetrahydropyridinyl, 1, 2-isoxazolyl, 1, 4-isoxazolyl, 6H-1, 3-oxazinyl, oxepin, thiepin, 2H-azepine and the like. Preferably a "5-6 membered heterocyclyl".

The term "5-6 membered heterocyclic group" refers to the above specific examples having 5 to 6 ring atoms.

The "5-to 6-membered heteroaryl group" according to the present invention means a cyclic aromatic group having 5 to 6 ring atoms containing at least one hetero atom selected from nitrogen, oxygen and/or sulfur atoms, preferably 1 to 3 hetero atoms, and including carbon, nitrogen and sulfur atoms which may be oxo-substituted, and examples thereof include, but are not limited to, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, 1,2,3, -triazolyl, 1,3, 4-triazolyl, 1,2,5, -triazolyl, 1,2,3, 4-tetrazolyl, 1,2,3, 5-tetrazolyl, isoxazolyl, oxazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2,3, 5-oxadiazolyl, dioxazolyl, 1,2, 3-oxadiazolyl, and the like, 1,2, 5-oxadiazolyl, 1,2,3, 4-oxatriazolyl, isothiazolyl, 1, 3-thiazolyl, pyridyl, pyrimidinyl, pyridazinyl, 1,2, 3-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl, and the like.

The invention also provides a preparation method of the compound, which comprises the following steps:

1. preparation of intermediate 1:

(1) when Y is an oxygen atom, the compound is,

dissolving raw material 1, raw material 2, basic catalyst and Cu (I) in aprotic solvent, heating until the reaction is completed, cooling to room temperature, filtering, adding water and organic solvent (such as ethyl acetate and dichloromethane), separating liquid, washing organic phase with saturated sodium chloride aqueous solution, drying with anhydrous sodium sulfate, filtering, concentrating, purifying by column chromatography to obtain intermediate product, and performing conventional de-esterification reaction to obtain intermediate 1.

In this reaction R' is selected from C_1-6Alkyl, preferably C_1-4Alkyl, X is halogen; the cu (I) source refers to copper (I) salts such as copper (I) bromide and copper (I) iodide or copper (I) complexes that are typically more soluble in organic solvents such as copper tetraacetonitrile hexafluorophosphate. Alternatively, the coupling may be carried out in the presence of copper metal powder, preferably in an aprotic solvent such as N, N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, sulfolane, ethylene glycol, acetonitrile and tetrahydrofuran or mixtures thereof, under heating or microwave-assisted heating (typically to temperatures between 100 ℃ and 200 ℃, or up to the boiling temperature of the solvent); such as potassium carbonate, sodium hydroxide, tert-butyllithium, tert-butylamine, triethylamine, N-ethyldiisopropylamine or pyridine.

(2) When Y is NR¹³When the temperature of the water is higher than the set temperature,

adding the raw material 1, the raw material 3 and an alkaline catalyst into an organic solvent, adding 2-dicyclohexyl phosphorus-2 ',4',6' -triisopropyl biphenyl (477mg,1.0mmol) and a palladium catalyst under the protection of nitrogen, heating for reacting for a plurality of hours, concentrating in vacuum, purifying by column chromatography, and carrying out conventional deesterification on an intermediate to obtain an intermediate 1.

In this reaction R' is selected from C_1-6Alkyl, preferably C_1-4Alkyl, X is halogen; such as 1, 4-dioxane, tetrahydrofuran, N-dimethylformamide; such as potassium carbonate, sodium carbonate, tert-butyllithium, tert-butylamine, triethylamine, N-ethyldiisopropylamine or pyridine; the palladium catalyst is selected from the group consisting of tris (diya)Benzylacetone) dipalladium, tetrakis- (triphenylphosphine) palladium, phenylbis (triphenylphosphine) -palladium chloride, bis (triphenylphosphine) palladium dichloride, dichloro [1, 1' -bis (diphenylphosphino) -ferrocene]Palladium (II) dichloride dichloromethane adduct.

(3) When Y is not present, the compound (A),

dissolving the raw materials 1 and 4 in a mixed solution of an organic solvent and water, adding an alkaline catalyst and a palladium catalyst, heating under the protection of nitrogen until the reaction is finished, cooling, adding water, extracting an organic phase, drying with anhydrous sodium sulfate, purifying by column chromatography, and performing conventional de-esterification on the intermediate to obtain the intermediate 1.

In this reaction R' is selected from C_1-6Alkyl, preferably C_1-4Alkyl, X is halogen; such as 1, 4-dioxane, tetrahydrofuran, N-dimethylformamide; such as potassium carbonate, sodium carbonate, tert-butyllithium, tert-butylamine, triethylamine, N-ethyldiisopropylamine, N-diisopropylethylamine or pyridine; the palladium catalyst is selected from tris (dibenzylideneacetone) dipalladium, tetrakis- (triphenylphosphine) palladium, phenylbis (triphenylphosphine) -palladium chloride, bis (triphenylphosphine) palladium dichloride, dichloro [1, 1' -bis (diphenylphosphino) -ferrocene]Palladium (II) dichloride dichloromethane adduct.

The conventional de-esterification reaction mentioned above means that the ester is subjected to de-alkylation under the catalysis of basic conditions to form the corresponding acid, and the basic catalysts are sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, tert-butyllithium, tert-butylamine, triethylamine, N-ethyldiisopropylamine, N-diisopropylethylamine, etc.

2. Preparation of the target product

The preparation method comprises the following steps:

dissolving the intermediate 1 in an organic solvent, adding an acyl halogenating reagent, adding the raw material 5 and a basic catalyst at low temperature, and reacting for several hours at room temperature. After the reaction is finished, the reaction solution is concentrated and purified by column chromatography to obtain the target product.

The preparation method 2 comprises the following steps:

dissolving the intermediate 2 in an organic solvent, adding an alkaline catalyst at low temperature, adding the raw material 5 while stirring, and reacting for several hours at room temperature. After the reaction is finished, the reaction solution is concentrated and purified by column chromatography to obtain the target product.

The intermediate 2 can be prepared by reacting the intermediate 1 with an acyl halide reagent.

Organic solvents such as tetrahydrofuran, dichloromethane, chloroform, etc. as described in methods 1 and 2; the acid halogenation reagent such as oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, tribenzoate, etc.; such as sodium hydride, potassium carbonate, sodium carbonate, t-butyllithium, N-diisopropylethylamine, N-ethyldiisopropylamine, triethylamine, pyridine, N-dimethylaniline, etc.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰And R¹¹The definitions of the substituents are defined in the specification, the raw materials 1,2,3,4 and 5 are prepared from laboratories, and the intermediate compounds and the preparation method are included in the scope of the invention.

By "pharmaceutically acceptable salt" herein is meant any non-toxic salt of the invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the invention or an inhibitively active metabolite or residue thereof. The term "its inhibitory active metabolite or residue" as used herein means that its metabolite or residue is also a TGR5 agonist.

Pharmaceutically acceptable salts are those salts of the compounds of formula (I) when acidic groups (e.g., COOH, OH, etc.) are present with suitable inorganic or organic cations (bases), including alkali metal salts, alkaline earth metal salts, ammonium salts, and nitrogen-containing organic bases, including but not limited to sodium, potassium; the alkaline earth metal salt includes but is not limited to beryllium (Be), magnesium (Mg), calcium (Ca), strontium (Sr), barium (Ba), radium (Ra) and other metal elements; the nitrogen-containing organic base includes, but is not limited to, aliphatic amines (e.g., ethylenediamine, diethylamine, ethanolamine), cyclic amines (e.g., morpholine, piperidine, piperazine), aromatic amines, alkaloids (e.g., ephedrine, amino acids, theobromine);

when basic groups (e.g. NH, NH) are present in the compounds of formula (I)₂Etc.) with a suitable inorganic or organic anion (acid), including salts of inorganic or organic acids including, but not limited to, formic acid, acetic acid, pivalic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, lactic acid, succinic acid, and the like; the inorganic acids include, but are not limited to, hydrobromic acid, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, nitric acid, and the like.

The "ester" in the invention refers to the ester which can be dehydrated with organic alcohol compounds to form corresponding ester when-COOH group exists in the compound of formula (I); when-OH is present in the compound of formula (I), it may be dehydrated with an organic or inorganic acid to form the corresponding ester; the esters can be hydrolyzed to the corresponding free acids and free alcohols in vivo or in vitro.

"stereoisomers" of the compounds of formula (I) according to the invention mean that enantiomers are formed when asymmetric carbon atoms are present in the compounds of formula (I); when the compound has a carbon-carbon double bond or a cyclic structure, cis-trans isomers can be generated; tautomers can be produced when ketones or oximes are present in the compounds, enantiomers, diastereomers, racemates, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof of all compounds of formula (I), optically active forms can be obtained by resolution of the racemates by asymmetric synthesis or asymmetric chromatography (chromatography using chiral adsorbents or eluents), all of which are included in the scope of the present invention.

The compound of the invention is easy to be a prodrug, and the prodrug is a compound which is obtained by modifying a chemical structure of a drug, has no or little activity in vitro, and releases an active drug to play a drug effect by enzymatic or non-enzymatic conversion in vivo; including "carrier prodrugs" and "biological prodrugs". "Carrier prodrug" means that the active compound is covalently bound to a carrier which transports the active compound, and the carrier is removed by simple hydrolysis in vivo to exert a pharmacological effect on the active compound. Carrier prodrugs tend to be less active or inactive than the parent compound. "biological prodrug" means a biological prodrug which is different from a carrier prodrug in that the active substance does not temporarily bind to the carrier but acts by changing its molecular structure; for example, carboxylic acids, alcohols, and phenolic compounds form esters, and amine compounds form amides. The prodrug of the compound shown in the formula (I) has better solubility than a raw drug, is easier to be absorbed by a human body or a living body, is better converted into the raw drug compound in blood, and exerts the biological activity of the compound.

The present invention also provides a pharmaceutical composition comprising the compound of formula (I), its pharmaceutically acceptable salt, its ester, its stereoisomer or prodrug, and one or more pharmaceutically acceptable carriers, wherein the pharmaceutical composition can be prepared into any clinically or pharmaceutically acceptable dosage form by adding pharmaceutically acceptable carriers such as excipient, binder, moisturizer, disintegrant, thickener, etc. in conventional methods, and can be administered orally, parenterally, by nebulization, rectally, vaginally, peritoneally or topically to patients in need of such treatment, such as tablets, granules, capsules, powders, injections, inhalants, sublingual preparations, syrups, gels, ointments, lotions, suppositories, nasal drops, sprays, transdermal preparations, etc. The parenteral includes subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection or other infusion techniques.

Another embodiment of the present invention is a pharmaceutical composition of a compound of formula (I), a pharmaceutically acceptable salt thereof, an ester thereof, a stereoisomer thereof, or a prodrug thereof, and one or more second therapeutically active agents, wherein the one or more second therapeutically active agents are each independently selected from the following groups of active agents:

(1) a human peroxisome proliferator-activated receptor gamma agonist selected from rosiglitazone, troglitazone, englitazone, balaglitazone, nateglinide or pioglitazone;

(2) biguanides selected from the group consisting of metformin, metformin hydrochloride, buformin and phenformin;

(3) a dipeptide kinase IV inhibitor selected from sitagliptin, sitagliptin phosphate, saxagliptin, alogliptin, linagliptin, vildagliptin, digagliptin and SYR-322;

(4) an incretin selected from a glucagon-like peptide-1 (GLP-1) receptor agonist, a glucagon-like peptide-1 receptor analog, or and a glucose-dependent insulin release peptide;

(5) insulin or an insulin analogue selected from insulin lispro or insulin aspart;

(6) sulfonylureas selected from tolazamide, chlorpropamide, glipizide, glimepiride, glibenclamide, tolbutamide, and acetohexamide;

(7) a-a glycylglycine inhibitor selected from miglitol, acarbose, epalrestat or voglibose;

(8) the cholesterol biosynthesis inhibitor is selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, pitavastatin or cervastatin;

(9) a plasma HDL-raising agent selected from CETP inhibitors, such as anacetrapib, torsipib and dalcetrapib, or PPAR α agonists, such as gemfibrozil, clofibrate, fenofibrate or bezafibrate;

(10) a human peroxisome proliferator-activated receptor (PPAR) dual α/γ agonist selected from the group consisting of moglitazone, nateglinide, ticagrelor, pegliger, faglinide and JT-501;

(11) a bile acid sequestrant selected from anion exchange resins, quaternary amines or ileal bile acid transporter inhibitors;

(12) nicotinyl alcohol, nicotinic acid, nicotinamide or salts thereof;

(13) a cholesterol absorption inhibitor selected from ezetimibe, ezetimibe or avasimibe;

(14) selective stimulin receptor modulators, liver X receptor alpha or beta agonists, antagonists or partial agonists;

(15) microsomal triglyceride transfer protein (MTP) inhibitors;

(16) an insulin secretagogue selected from the group consisting of linagliptin, nateglinide, repaglinide, mitiglinide calcium hydrate, and meglitinide;

(13) an SGLT-2 inhibitor selected from dapagliflozin, canagliflozin, or eggliflozin;

(14) a glucokinase activator;

(15) protein tyrosine phosphatase-1B inhibitors;

(16) a glucagon receptor antagonist;

(17) antiobesity agents, such as fenfluramine, dexfenfluramine, phenntiramine, sibutramine, orlistat, neuropeptide Y1 or Y5 antagonists, neuropeptide Y2 agonists, MC4R agonists, cannabinoid receptor 1 antagonists or inverse agonists, beta-3 adrenoreceptor agonists, nerve growth factor agonists, growth hormone agonists, 5-hydroxytryptamine (5-HT) reuptake transporter inhibitors, Dopamine (DA) reuptake inhibitors, 5-HT/NA/DA reuptake blockers, steroid extracts, CCK-A agonists, growth hormone secretagogue receptor antagonists or inverse agonists, growth hormone releasing peptide antibodies, melanin-aggregating hormone 1R antagonists, melanin-aggregating hormone 2R agonists or antagonists, histamine receptor 3 inverse agonists or antagonists, histamine 1 receptor agonists, histamine receptor antagonists, and the like, Fatty acid synthase inhibitors, acetyl-CoA carboxylase-1 inhibitors, corticotropin releasing factor agonists, galanin antagonists, uncoupling protein-1, uncoupling protein-2 or 3 activators, leptin or leptin derivatives, opioid antagonists, orexin antagonists, BRS3 agonists, glucagon-like peptide-1 agonists, IL-6 agonists, a-MSH agonists, AgRP antagonists, bombesin receptor subtype 3 agonists, 5-hydroxytryptamine 1B agonists, POMC antagonists, ciliary neurotrophic factors or CNTF derivatives, NN2211, topiramate, glucocorticoid antagonists, exendin-4 agonists, 5-hydroxytryptamine receptor 2C agonists, phosphodiesterase inhibitors, fatty acid transporter inhibitors, dicarboxylic acid transporter inhibitors, and the like, A glucose transporter inhibitor;

(18) anti-inflammatory agents, such as cyclooxygenase-2 (COX-2) inhibitors, glucocorticoids, sulfasalazine, thrombin inhibitors, or platelet aggregation inhibitors;

(19) antihypertensives such as β blockers (e.g., angiotensin II receptor antagonists such as losartan, eprosartan, irbesartan, tasosartan, telmisartan or valsartan; angiotensin converting enzyme inhibitors such as enalapril, captopril, cilazapril, ramapril, zofenopril, lisinopril and fosinopril; calcium channel blockers such as nifedipine and diltiazemAnd endothelin antagonists.

Another embodiment of the present invention is the use of a compound of formula (I), a pharmaceutically acceptable salt, ester, stereoisomer or prodrug thereof, for the manufacture of a medicament for the treatment and/or prevention of a disease associated with modulation of TGR5 activity, wherein said disease associated with modulation of TGR5 activity is selected from diabetes, such as type II diabetes or gestational diabetes, impaired fasting glucose, impaired glucose tolerance, insulin resistance, hyperglycemia, obesity, metabolic syndrome, ischemia, myocardial infarction, retinopathy, vascular restenosis, hypercholesterolemia, hypertriglyceridemia, dyslipidemia or hyperlipidemia, a lipid disorder, such as low HDL cholesterol or high HDL cholesterol, hypertension, angina, coronary artery disease, atherosclerosis, cardiac hypertrophy, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, ulcerative colitis, irritable bowel syndrome, allergic diseases, fatty liver, liver fibrosis, cirrhosis, hepatic cholestasis, kidney fibrosis, anorexia nervosa, bulimia nervosa, alzheimer's disease, multiple sclerosis, schizophrenia or cognitive impairment.

The beneficial effects of the compounds of the present invention are further illustrated below, and other compounds of the present invention have the same beneficial effects as some of the compounds of the present invention listed in the test, but this should not be construed as the compounds of the present invention having only the following beneficial effects.

Examples of the experiments 1 In vitro cell Activity assay of Compounds of the invention

And (3) testing the sample: the chemical names and the preparation methods of the compounds 1,2,3,4 and 5 of the present invention are shown in the preparation examples of the respective compounds.

The abbreviations used in the following experiments have the following meanings:

DMSO, DMSO: dimethyl sulfoxide

GPBA: g protein-coupled bile acid receptors

CHO-K1: chinese hamster ovary cell sub-strain

cAMP: adenosine cyclophosphate

Homogeneous phase time-resolved fluorescence technique

The detection principle of the kit is as follows: the Cyclic AMP assay kit is based on homogeneous time-resolved fluorescence technique () Intended to directly quantify the cyclic AMP content in suspended or adherent cells. The detection method is based on the competitive immunological binding between cAMP produced by cells and cAMP labeled with d2 (energy acceptor) dye and anti-cAMP monoclonal antibody labeled with europium Cryptate (Eu3+ -Cryptate, energy donor). The intensity of the detection signal is inversely proportional to the cAMP content in the standard or sample. As well as others based onAs with the experiment, the fluorescence ratio (668/620nm) was calculated to eliminate the physical interference that may be present and the effect of the experimental conditions (e.g., media, serum, biotin, colored compounds, etc.). The experimental method comprises the following steps: the test samples were subjected to cAMP experiments in agonist mode using CHO-K1 cells stably expressing Human GPBA (Cat # C1361-1a) according to the protocol provided by CisBio's HTRF cAMP HiRange Kit.

1. The appropriate amount of the test sample (see Table 1 below) was weighed out and dissolved in 10mM DMSO.

TABLE 1 sample weighing of test articles

2. The test solution is diluted in gradient, the test solution with required concentration is added into the plate hole inoculated with the cells, the final concentration of the test in the hole is ensured to be 1 mu M, and a solvent control is additionally arranged: cells + buffer, incubated at 37 ℃ for 20 min;

3. continuously adding a cAMP and europium Cryptate compound (Eu3+ -Cryptate, energy donor) labeled anti-cAMP monoclonal antibody reagent which is dissolved by a lysis buffer and labeled by a dye d2 (energy acceptor), stopping the reaction, and incubating the reaction system for 60min at room temperature;

4. fluorescence was detected at 620 and 668nm using a FlexStation III (Molecular Devices) instrument with an excitation wavelength of 314nm and the results read.

And (4) processing a result:

the experimental results are presented in the form of "Ratio 668/620 × 10000" (Ratio of fluorescence values at 668nm and 620nm multiplied by 10000). The data in table 2 are all expressed as "mean ± standard deviation".

TABLE 2 Activity of the Compounds of the invention on Human GPBA (TGR5)

As can be seen from table 2, compounds 1,2,3,4 and 5 of the present invention all had good agonistic activity against Human GPBA (TGR 5).

4. Detailed description of the preferred embodiments

The above-mentioned contents of the invention are further described in detail by the following embodiments in the form of specific examples, but it should not be understood that the above-mentioned subject matter of the present invention is limited to the following examples, and all the technologies realized based on the contents of the present invention are within the scope of the present invention.

Preparation of intermediate 1-methyl-1, 2,3, 4-tetrahydroquinoxaline

1)1) preparation of 3, 4-dihydroquinoxalin-2 (1H) -ones

O-phenylenediamine (3g,27.8mmol) and triethylamine (5.8g,57.3mmol) were dissolved in N, N-dimethylformamide (30mL), ethyl 2-bromoacetate (5g,29.9mmol) was added, and the reaction was heated to 80 ℃ and stirred for 4 hours. The reaction solution was cooled to 25 ℃, water (50mL) was added, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1) to obtain the title compound (2.9g, yield 70.5%).

2) Preparation of 4-methyl-3, 4-dihydroquinoxalin-2 (1H) -one

3, 4-Dihydroquinoxalin-2 (1H) -one (2.9g,19.6mmol) was dissolved in methanol (20mL), sodium cyanoborohydride (2.5g,39.7mmol), paraformaldehyde (0.9g) and glacial acetic acid (1mL) were added, and the reaction was stirred at 25 ℃ for 4 hours, then sodium cyanoborohydride (1.2g,19.0mmol), paraformaldehyde (0.45g) and hydrochloric acid (0.5mL) were added, and the reaction was stirred by heating to 50 ℃ for 5 hours. The reaction was cooled to room temperature, adjusted to pH 8 with saturated aqueous sodium bicarbonate, extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (3.0g, 94.5% yield).

3) Preparation of 1-methyl-1, 2,3, 4-tetrahydroquinoxaline

4-methyl-3, 4-dihydroquinoxalin-2 (1H) -one (3.0g,18.5mmol) was dissolved in tetrahydrofuran (50mL), cooled to 0 deg.C, lithium aluminum hydride (2.1g,55.3mmol) was added in portions, and the reaction was continued for 1 hour with slow increase to 25 deg.C after the addition. The reaction solution was quenched with water (50mL), extracted with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to obtain the title compound (2.5g, yield 91.3%).

EXAMPLE 1 preparation of (5- (2, 5-Dichlorophenoxy) pyrimidin-4-yl) (4-methyl-3, 4-dihydroquinoxalin-1 (2H) -yl) methanone

1) Preparation of 5-bromopyrimidine-4-carbonyl chloride

5-bromopyrimidine-4-carboxylic acid (0.6g,2.96mmol) was dissolved in thionyl chloride (10mL), N-dimethylformamide (0.05mL) was added, and the reaction was stirred at 90 ℃ for 3 hours. The reaction was concentrated to dryness, toluene (10mL) was added, and the reaction was concentrated again to dryness, and the resulting crude product was used directly in the next reaction.

2) Preparation of methyl 5-bromopyrimidine-4-carboxylate

The 5-bromopyrimidine-4-carbonyl chloride (0.65g,2.94mmol) obtained in the previous step was dissolved in anhydrous methanol (10mL) and the reaction was stirred at 25 ℃ for 16 hours. The reaction was concentrated to dryness, and the crude product was washed with petroleum ether to give the title compound (0.58g, yield 90.6%)

3) Preparation of methyl 5- (2, 5-dichlorophenoxy) pyrimidine-4-carboxylate

Methyl 5-bromopyrimidine-4-carboxylate (0.47g,2.16mmol), 2, 5-dichlorophenol (0.39g,2.39mmol), potassium carbonate (0.6g,4.34mmol), cuprous iodide (41mg,0.22mmol) and copper powder (41mg,0.64mmol) were dissolved in N, N-dimethylformamide (3mL) and reacted for 0.5 hour by microwave heating to 120 ℃. The reaction solution was cooled to room temperature, filtered, the filtrate was poured into water (20mL), ethyl acetate (20mL × 3) was added for extraction, the organic phases were combined, washed with a saturated aqueous sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1) to obtain the title compound (0.12g, yield 18.5%).

4) Preparation of 5- (2, 5-dichlorophenoxy) pyrimidine-4-carboxylic acid

Methyl 5- (2, 5-dichlorophenoxy) pyrimidine-4-carboxylate (0.12g,0.4mmol) was dissolved in tetrahydrofuran (5mL), and an aqueous solution of sodium hydroxide (1mL,1mmol,1M) was added, followed by stirring at 25 ℃ for 6 hours. Saturated aqueous sodium chloride (10mL) was added, the pH was adjusted to 4 with dilute hydrochloric acid (2M), ethyl acetate (10mL × 3) was added for extraction, the organic phases were combined, washed with saturated aqueous sodium chloride (10mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting crude product was purified by silica gel column chromatography (dichloromethane: methanol ═ 20:1) to obtain the title compound (0.1g, yield 87.7%).

5) Preparation of 5- (2, 5-dichlorophenoxy) pyrimidine-4-carbonyl chloride

5- (2, 5-Dichlorophenoxy) pyrimidine-4-carboxylic acid (0.1g,0.35mmol) was dissolved in thionyl chloride (5mL), N-dimethylformamide (0.05mL) was added, and the reaction was stirred at 90 ℃ for 2 hours. The reaction was concentrated to dryness, toluene (5mL) was added, and the reaction was concentrated again to dryness, and the resulting crude product was used directly in the next reaction.

6) Preparation of (5- (2, 5-dichlorophenoxy) pyrimidin-4-yl) (4-methyl-3, 4-dihydroquinoxalin-1 (2H) -yl) methanone

The crude 5- (2, 5-dichlorophenoxy) pyrimidine-4-carbonyl chloride (0.11g,0.36mmol) was dissolved in anhydrous tetrahydrofuran (5mL), cooled to 0 ℃ in an ice-water bath, triethylamine (152mg,1.5mmol) was added, 1-methyl-1, 2,3, 4-tetrahydroquinoxaline (60mg,0.4mmol) was added with stirring, and the reaction was stirred at 25 ℃ for 16 hours. After completion of the reaction, the reaction liquid was spin-dried, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to obtain the title compound (30mg, yield 20%).

Molecular formula C₂₀H₁₆Cl₂N₄O₂Molecular weight 415.3LC-MS (M/z) 416.1(M + H)⁺)

¹H-NMR(400MHz,CDCl₃):9.09(s,1H),8.33(s,1H),7.48(d,J＝8.4Hz,1H),7.15-7.17(m,1H),6.99-7.03(m,1H),6.52-6.54(m,1H),6.43(d,J＝8.4Hz,1H),6.30-6.34(m,1H),5.80(s,1H),3.48-3.51(m,2H),3.30-3.31(m,2H),2.66(s,3H),

EXAMPLE 2 preparation of (3- (2, 5-Dichlorophenoxy) pyrazin-2-yl) (4-methyl-3, 4-dihydroquinoxalin-1 (2H) -yl) methanone

1) Preparation of ethyl 3-chloropyrazine-2-carboxylate

3-chloropyrazine-2-carboxylic acid (1.59g,10mmol) was dissolved in thionyl chloride (10mL), DMF (0.5mL) was added dropwise, and the reaction was refluxed at 90 ℃ for 2 hours. After the reaction was complete, the solvent was evaporated to dryness, and the oily product was slowly dropped into anhydrous ethanol (20mL) under ice bath, stirred at room temperature for 1 hour, and then concentrated until the solvent was evaporated to dryness to afford the title compound (1.7g, yield 91.1%).

2) Preparation of ethyl 3- (2, 5-dichlorophenoxy) pyrazine-2-carboxylate

Ethyl 3-chloropyrazine-2-carboxylate (1.5g,8.0mmol), 2, 5-dichlorophenol (1.3g,8.0mmol), potassium carbonate (2.2g,16.0mmol), CuI (152mg,0.8mmol) and Cu (152mg,2.4mmol) were dissolved in DMF (15mL)

After microwave reaction for 0.5 hour in the solution, it was cooled to room temperature, filtered, the filtrate was poured into water (50mL), extracted with ethyl acetate (50mL × 2), combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give the title compound (315mg, yield 13%).

3) Preparation of 3- (2, 5-dichlorophenoxy) pyrazine-2-carboxylic acid

Ethyl 3- (2, 5-dichlorophenoxy) pyrazine-2-carboxylate (315mg,1.0mmol) was dissolved in tetrahydrofuran (10mL), and sodium hydroxide solution (2N,1.0mL) was added to stir the reaction at room temperature for 4 hours. After completion of the reaction, a 2N hydrochloric acid solution was added dropwise to the reaction solution, the pH was adjusted to 5, tetrahydrofuran was distilled off under reduced pressure, and then the aqueous phase was extracted with ethyl acetate (10mL × 2), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane: methanol ═ 20:1) to obtain the title compound (160mg, yield 56%).

4) Preparation of 3- (2, 5-dichlorophenoxy) pyrazine-2-formyl chloride

Dissolving 3- (2, 5-dichlorophenoxy) pyrazine-2-formic acid (150mg,0.5mmol) in thionyl chloride (5mL), dropwise adding DMF (0.1mL), refluxing at 90 ℃ for 2 hours, evaporating the solvent to dryness after the reaction is finished to obtain a crude product (170mg), and continuing the next reaction.

5) Preparation of (3- (2, 5-dichlorophenoxy) pyrazin-2-yl) (4-methyl-3, 4-dihydroquinoxalin-1 (2H) -yl) methanone

In an ice bath, 3- (2, 5-dichlorophenoxy) pyrazine-2-carbonyl chloride crude product (170mg) was dissolved in anhydrous tetrahydrofuran (5mL), triethylamine (152mg,1.5mmol) was added, 1-methyl-1, 2,3, 4-tetrahydroquinoxaline (74mg,0.5mmol) was added with stirring, and the reaction was carried out at room temperature for 3 hours. After completion of the reaction, the reaction mixture was evaporated to dryness and purified by column chromatography (petroleum ether: ethyl acetate: 5:1) to obtain the title compound (132mg, yield in 2 steps 63.5%).

The molecular formula is as follows: c₂₀H₁₆C_l2N₄O₂Molecular weight: 415.3LC-MS (m/z): 415.1 (M)⁺)

¹H-NMR(400MHz,DMSO-d₆):8.54(d,J＝2.4Hz,1H),8.26(d,J＝2.4Hz,1H),7.59(d,J＝8.4Hz,1H),7.32(dd,J₁＝8.8Hz,J₂＝6.4Hz,1H),6.94-6.98(m,1H),6.58(d,J＝8Hz,1H),6.25-6.28(m,2H),6.11(d,J＝2.0Hz,1H),3.80-4.4(m,2H),3.38-3.43(m,2H),2.69(s,3H).

Examples 3(3-(2,5- Dichlorophenoxy radical ) Pyridine compound -2- Base of )(4- Methyl radical -3,4- Dihydroquinoxalines -1(2H)- Base of ) Preparation of ketones

1) Preparation of 3-iodopyridine-2-carboxylic acid

2,2,6, 6-tetramethylpiperidine (8.48g,60mmol) was dissolved in tetrahydrofuran (100mL), cooled to-78 deg.C, n-butyllithium (2.5mol/L,16mL,40mmol) was added dropwise, and the mixture was allowed to slowly warm to room temperature for 30 minutes. Cooling to-78 ℃, dropwise adding the mixture into a tetrahydrofuran suspension of pyridine-2-formic acid (2.46g,20mmol), heating to room temperature after dropwise adding, reacting for 30 minutes, cooling to-30 ℃, dropwise adding a tetrahydrofuran solution of iodine simple substance (15.23g,60mmol) into a reaction bottle, heating to room temperature, stirring for 1 hour, adding water, standing overnight, precipitating a solid, and filtering to obtain a target compound (3.3g, yield 66%).

2) Preparation of bis ((3- (2, 5-dichlorophenoxy) pyridine-2-formyl) oxy) copper

3-iodopyridine-2-carboxylic acid (3g,12mmol) was suspended in toluene (100mL), cesium carbonate (11.7g,36mmol), 2, 5-dichlorophenol (1.96g,12mmol) and copper tetraacetonitrile hexafluorophosphate (447mg,1.2mmol) were added, and the mixture was stirred at 110 ℃ overnight. Concentration in vacuo, addition of water (100mL), extraction with ethyl acetate (200 mL. times.2), drying over anhydrous sodium sulfate, and concentration in vacuo afforded the title compound (215mg, 5.6% yield).

3) Preparation of 3- (2, 5-dichlorophenoxy) pyridine-2-carboxylic acid

Bis ((3- (2, 5-dichlorophenoxy) pyridine-2-formyl) oxy) copper (200mg,0.32mmol) was dissolved in 15% sodium hydroxide solution (50mL), reacted at 100 ℃ for 16 hours, cooled to room temperature, adjusted to pH 4-5 with dilute hydrochloric acid, to precipitate a solid, which was filtered with suction to obtain the objective compound (80mg, yield 44.3%).

4) Preparation of (3- (2, 5-dichlorophenoxy) pyridin-2-yl) (4-methyl-3, 4-dihydroquinoxalin-1 (2H) -yl) methanone

3- (2, 5-Dichlorophenoxy) pyridine-2-carboxylic acid (80mg,0.28mmol) was dissolved in dichloromethane (10mL), oxalyl chloride (53.3mg,0.42mmol) and N, N-dimethylformamide (0.05mL) were added under ice-bath, stirring was continued for 1h, the reaction was complete, and concentrated in vacuo. The crude product was dissolved in dichloromethane (10mL), added dropwise to a solution of 1-methyl-1, 2,3, 4-tetrahydroquinoxaline (41.5mg,0.28mmol) and triethylamine (56.6mg,0.56mmol) in dichloromethane under ice-bath, warmed to 25 ℃ for reaction for 16 hours, concentrated in vacuo, and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the target compound (35mg, 30% yield).

Molecular formula C₂₁H₁₇Cl₂N₃O₂Molecular weight 414.3LC-MS (M/z):414.1 (M)⁺)

¹H-NMR(400MHz,MeOD):8.48(s,1H),7.47-7.43(m,2H),7.24-7.22(m,1H),7.11-7.09(m,1H),6.99-6.95(m,1H),6.46-6.37(m,2H),6.28-6.24(m,1H),5.67(d,J＝2.4,1H),3.49(brs,2H),2.61(s,3H).

Example 4(2- (2, 5-dichlorophenyl) pyridin-3-yl) (4-methyl-3, 4-dihydroquinoxalin-1 (2H) -yl) methanone

1) Preparation of ethyl 2- (2, 5-dichlorophenyl) nicotinate

Ethyl 2-chloronicotinate (1.0g,5.4mmol) and (2, 5-dichlorophenyl) boronic acid (1.1g,5.8mmol) were dissolved in 1, 4-dioxane (20mL) and water (5mL), sodium carbonate (1.1g,10.4mmol) and 1, 1-bis (diphenylphosphino) ferrocene dichloropalladium dichloromethane complex (220mg,0.27mmol) were added, and the reaction stirred at 80 ℃ for 16 hours under nitrogen. After completion of the reaction, it was cooled to room temperature, water (100mL) was added, extraction was performed with ethyl acetate (100mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the title compound (870mg, yield 54.4%).

2) Preparation of 2- (2, 5-dichlorophenyl) nicotinic acid

Ethyl 2- (2, 5-dichlorophenyl) nicotinate (300mg,1.0mmol) was dissolved in methanol (20mL) and water (4mL), sodium hydroxide (200mg,5.0mmol) was added, and the reaction was stirred at 50 ℃ for 3 hours. After completion of the reaction, it was cooled to room temperature, the pH was adjusted to 6, water (50mL) was added, ethyl acetate (50 mL. times.3) was extracted, the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound (250mg, yield 93.3%).

3) Preparation of (2- (2, 5-dichlorophenyl) pyridin-3-yl) (4-methyl-3, 4-dihydroquinoxalin-1 (2H) -yl) methanone

2- (2, 5-dichlorophenyl) nicotinic acid (150mg,0.56mmol) was dissolved in tetrahydrofuran (50mL), oxalyl chloride (0.3mL) was added, the reaction was stirred at 20 ℃ for 2 hours, the solvent was evaporated to dryness, the residue was dissolved by adding methylene chloride (30mL), 1-methyl-1, 2,3, 4-tetrahydroquinoxaline (83mg,0.56mmol) was added, and the reaction was stirred at 20 ℃ for 1 hour. After the reaction was completed, it was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 1:1) to obtain the title compound (125mg, yield 56%).

Molecular formula C₂₁H₁₇Cl₂N₃O molecular weight 398.3LC-MS (M/z) 398.1 (M)⁺)

¹H-NMR(400MHz,MeOD):8.66(d,J＝3.6Hz,1H),8.25(d,J＝7.2Hz,1H),7.64(dd,J＝4.8Hz,8.0Hz,1H),7.36(s,2H),6.93(t,J＝8.4Hz,1H),6.52(d,J＝8.0Hz,1H),6.12-6.21(m,3H),2.91-3.10(m,4H),2.70(s,3H).

Examples 5(2-((2,5- Dichloro phenyl ) Amino group ) Pyridine compound -3- Base of )(4- Methyl radical -3,4- Dihydroquinoxalines -1(2H)- Base of ) Preparation of ketones

1) Preparation of ethyl 2- ((2, 5-dichlorophenyl) amino) nicotinate

2, 5-dichloroaniline (810mg,5.0mmol), ethyl 2-chloronicotinate (928mg,5.0mmol) and potassium carbonate (1.38g,10.0mmol) were added to 1, 4-dioxane (100mL), 2-dicyclohexylphosphorus-2 ',4',6' -triisopropylbiphenyl (477mg,1.0mmol) and tris (dibenzylideneacetone) dipalladium (458mg,0.5mmol) were added under nitrogen protection, and the mixture was heated to 100 ℃ for reaction for 12 hours. The reaction was concentrated in vacuo and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 100:1) to give the title compound (1.4g, 90.0% yield) as a white solid.

2) Preparation of 2- ((2, 5-dichlorophenyl) amino) nicotinic acid

Ethyl 2- ((2, 5-dichlorophenyl) amino) nicotinate (1.4g,4.5mmol) was added to a mixed solvent (methanol: tetrahydrofuran: water ═ 1:1:1,30mL), and an aqueous solution (2mL) of lithium hydroxide (567mg,13.5mmol) was added to react at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo, ethyl acetate (50mL) and water (50mL) were added to the residue, the mixture was separated, the aqueous phase was adjusted to pH 3-4 with dilute hydrochloric acid, ethyl acetate (50mL) and water (50mL) were added, the mixture was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (1.0g, 78.5% yield) as a yellow solid.

3) Preparation of 2- ((2, 5-dichlorophenyl) amino) nicotinoyl chloride

2- ((2, 5-dichlorophenyl) amino) nicotinic acid (100mg,0.32mmol) was added to anhydrous dichloromethane (5mL), oxalyl chloride (89mg,0.70mmol) and N, N-dimethylformamide (0.05mL) were added, and the reaction was carried out at room temperature for 2 hours. After the reaction was complete, the system was concentrated in vacuo to give the title compound (90mg crude) which was used in the next step without purification.

4) Preparation of (2- ((2, 5-dichlorophenyl) amino) pyridin-3-yl) (4-methyl-3, 4-dihydroquinoxalin-1 (2H) -yl) methanone

2- ((2, 5-dichlorophenyl) amino) nicotinoyl chloride (90mg crude) was dissolved in methylene chloride (5mL), and 1-methyl-1, 2,3, 4-tetrahydroquinoxaline (44mg,0.30mmol) was added and reacted at room temperature for 12 hours. The reaction was concentrated in vacuo and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 4:1) to give the title compound (51mg, 41.1% yield) as a yellow solid.

Molecular formula C₂₁H₁₈Cl₂N₄O molecular weight 413.3LC-MS (M/z) 414.3(M + H)⁺)

¹H-NMR(400MHz,MeOD):8.26(s,2H),7.50(d,J＝7.6Hz,1H),7.36(d,J＝8.8Hz,1H),6.99-6.92(m,2H),6.83-6.80(m,1H),6.66(d,J＝8.4Hz,1H),6.52(d,J＝8.4Hz,1H),6.38-6.35(m,1H),4.11-4.01(m,2H),3.53-3.50(m,2H),2.93(s,3H).。

Claims

1. A compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, an ester thereof, a stereoisomer thereof, or a prodrug thereof:

wherein,

y is selected from absent, CR¹³R^13，，NR¹³O or S;

R¹²、R¹³and R^13，Each independently selected from hydrogen, halogen, amino, hydroxy, cyano, C_1-6Alkyl, halo C_1-6Alkyl, or C_1-6An alkoxy group;

R²、R³、R⁴、R⁵、R⁶each independently selected from hydrogen, hydroxyl, halogen, nitro, carboxyl, cyano, amino and C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, carboxy C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy, amino C_1-6Alkoxy, carboxyl C_1-6Alkoxy radical, C_1-6Alkylamino, di-C_1-6Alkylamino, aminocarbonyl, C_1-6Alkylaminocarbonyl, di-C_1-6Alkylaminocarbonyl radical, C_1-6Alkylcarbonyl group, C_1-6Alkylcarbonylamino, C_1-6Alkylcarbonyloxy, C_1-6Alkoxycarbonyl, aminosulfonyl, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfonylamino group, C_1-6Alkylaminosulfonyl, di-C_1-6Alkylaminosulfonyl radical, C_1-6alkylsulfonyl-C_1-6Alkoxy radical, C_1-6alkoxy-C_1-6Alkylsulfonyl, or 3-8 membered cycloalkyl optionally substituted with one or more Q2, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; each Q2 is independently selected from hydroxy, halogen, cyano, amino, nitro, carboxy, C_1-6Alkyl, or C_1-6An alkoxy group;

or, R¹And R²Together form-Z- (CR)¹⁴R¹⁵) n-and forms a ring with the atom to which it is attached, wherein Z is selected from the group consisting of-CR¹⁶R¹⁷-, O, S, -C (O) -or NR¹⁸(ii) a n is selected from 1,2 or 3;

R⁷、R⁸、R⁹、R¹⁰or R¹¹Each independently selected from hydrogen, hydroxyl, halogen, nitro, carboxyl, cyano, amino and C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, carboxy C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy, amino C_1-6Alkoxy, carboxyl C_1-6Alkoxy radical, C_1-6Alkylamino, di-C_1-6Alkylamino, aminocarbonyl, C_1-6Alkylaminocarbonyl, di-C_1-6Alkylaminocarbonyl radical, C_1-6Alkylcarbonyl group, C_1-6Alkylcarbonylamino, C_1-6Alkylcarbonyloxy, C_1-6Alkoxycarbonyl, aminosulfonyl, C_1-6Alkylsulfonyl radical, C_1-6Alkyl sulfonamidesBase, C_1-6Alkylaminosulfonyl, di-C_1-6Alkylaminosulfonyl radical, C_1-6alkylsulfonyl-C_1-6Alkoxy radical, C_1-6alkoxy-C_1-6Alkylsulfonyl, or C optionally substituted with one or more Q4_2-6Alkenyl radical, C_2-6Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; each Q4 is independently selected from hydroxy, halogen, amino, cyano, nitro, carboxy, C_1-6Alkyl, or C_1-6An alkoxy group;

2. The compound of claim 1, a pharmaceutically acceptable salt thereof, an ester thereof, a stereoisomer thereof, or a prodrug thereof:

y is selected from CR¹³R^13，，NR¹³Or O;

R¹³and R^13，Each independently selected from hydrogen, halogen, methyl, ethyl or methoxy.

3. The compound of claim 1, a pharmaceutically acceptable salt thereof, an ester thereof, a stereoisomer thereof, or a prodrug thereof:

y is selected from absent or NR¹³；

R¹³is selected from the group consisting of hydrogen,methyl or ethyl.

4. The compound of any one of claims 1-3, a pharmaceutically acceptable salt thereof, an ester thereof, a stereoisomer thereof, or a prodrug thereof:

R⁷、R⁸、R⁹、R¹⁰or R¹¹Each independently selected from hydrogen, hydroxy, halogen, amino, C_1-4Alkyl, halo C_1-4Alkyl, hydroxy C_1-4Alkyl, amino C_1-4Alkyl, carboxy C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkoxy, hydroxy C_1-4Alkoxy, amino C_1-4Alkoxy, carboxyl C_1-4Alkoxy radical, C_1-4Alkylamino, di-C_1-4Alkylamino, aminocarbonyl, C_1-4Alkylaminocarbonyl, di-C_1-4Alkylaminocarbonyl radical, C_1-4Alkylcarbonyl group, C_1-4Alkylcarbonylamino, C_1-4Alkylcarbonyloxy, C_1-4Alkoxycarbonyl, aminosulfonyl, C_1-4Alkylsulfonyl radical, C_1-4Alkylsulfonylamino group, C_1-4Alkylaminosulfonyl, di-C_1-4Alkylaminosulfonyl radical, C_1-4alkylsulfonyl-C_1-4Alkoxy radical, C_1-4alkoxy-C_1-4Alkylsulfonyl, or optionally substituted by 1-3Q 4 substituted 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; each Q4 is independently selected from hydroxy, halogen, amino, C_1-4Alkyl, or C_1-4An alkoxy group;

5. The compound of claim 4, a pharmaceutically acceptable salt thereof, an ester thereof, a stereoisomer thereof, or a prodrug thereof:

R⁷、R¹⁰selected from halogen, R⁷、R¹⁰May be the same or different;

6. The compound of claim 5, a pharmaceutically acceptable salt thereof, an ester thereof, a stereoisomer thereof, or a prodrug thereof:

R¹⁸selected from hydrogen, methyl, ethyl, methylcarbonyl or methylsulfonyl;

R⁷、R¹⁰are all selected from chlorine atoms;

7. The compound of claim 1, a pharmaceutically acceptable salt thereof, an ester thereof, a stereoisomer thereof, or a prodrug thereof:

8. a pharmaceutical formulation comprising a compound of any one of claims 1-7, a pharmaceutically acceptable salt, ester, stereoisomer, or prodrug thereof, and one or more pharmaceutically acceptable carriers, formulated in any one of pharmaceutically acceptable dosage forms.

9. A pharmaceutical composition comprising a compound of any one of claims 1-7, a pharmaceutically acceptable salt thereof, an ester thereof, a stereoisomer thereof, or a prodrug thereof, and one or more second therapeutically active agents selected from:

(2) biguanides selected from metformin, metformin hydrochloride, buformin or phenformin;

(3) a dipeptide kinase IV inhibitor selected from sitagliptin, sitagliptin phosphate, saxagliptin, alogliptin, linagliptin, vildagliptin or digagliptin;

(4) an incretin selected from a glucagon-like peptide-1 receptor agonist, a glucagon-like peptide-1 receptor analog, or a glucose-dependent insulin release peptide;

(6) sulfonylureas selected from tolazamide, chlorpropamide, glipizide or glipizide;

(7) an alpha-glycylglycine inhibitor selected from miglitol, acarbose, epalrestat or voglibose;

(8) a cholesterol biosynthesis inhibitor selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, itavastatin, pitavastatin or cerivastatin;

(9) a plasma high density lipoprotein-elevating agent selected from a CETP inhibitor or a PPAR α agonist;

(10) a human peroxisome proliferator-activated receptor dual α/γ agonist selected from the group consisting of mogroside, nateglinide, tegglinide, pegglitazone and faglitazone;

(12) nicotinyl alcohol, nicotinic acid, nicotinamide or salts thereof;

(14) a selective estrogen receptor modulator, a liver X receptor alpha or beta agonist, antagonist or partial agonist;

(15) microsomal triglyceride transfer protein inhibitors;

(14) a glucokinase activator;

(15) protein tyrosine phosphatase-1B inhibitors;

(16) a glucagon receptor antagonist;

(17) an anti-obesity agent selected from fenfluramine, dexfenfluramine, sibutramine or orlistat;

(18) an anti-inflammatory agent selected from the group consisting of cyclooxygenase-2 inhibitors, glucocorticoids, sulfasalazine, thrombin inhibitors, and platelet aggregation inhibitors;

(19) an antihypertensive selected from losartan, eprosartan, irbesartan, tasosartan, telmisartan, enalapril, captopril, cilazapril, zofenopril, lisinopril, fosinopril or nifedipine.

10. Use of a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt, ester, stereoisomer or prodrug thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of diseases which are associated with modulation of TGR5 activity, wherein the diseases which are associated with modulation of TGR5 activity are selected from diabetes, such as type II diabetes or gestational diabetes, impaired fasting glucose, impaired glucose tolerance, insulin resistance, hyperglycemia, obesity, metabolic syndrome, ischemia, myocardial infarction, retinopathy, vascular restenosis, hypercholesterolemia, hypertriglyceridemia, dyslipidemia or hyperlipidemia, lipid disorders, such as low HDL cholesterol or high HDL cholesterol, hypertension, angina, coronary artery disease, atherosclerosis, cardiac hypertrophy, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, ulcerative colitis, irritable bowel syndrome, allergic diseases, fatty liver, liver fibrosis, cirrhosis, hepatic cholestasis, kidney fibrosis, anorexia nervosa, bulimia nervosa, alzheimer's disease, multiple sclerosis, schizophrenia or cognitive impairment.