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CN110256461B - Fused pyrimidine derivative and preparation method and application thereof - Google Patents

  • ️Tue Apr 07 2020

CN110256461B - Fused pyrimidine derivative and preparation method and application thereof - Google Patents

Fused pyrimidine derivative and preparation method and application thereof Download PDF

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Publication number
CN110256461B
CN110256461B CN201910537029.6A CN201910537029A CN110256461B CN 110256461 B CN110256461 B CN 110256461B CN 201910537029 A CN201910537029 A CN 201910537029A CN 110256461 B CN110256461 B CN 110256461B Authority
CN
China
Prior art keywords
preparation
acid
compound
group
obesity
Prior art date
2019-06-20
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201910537029.6A
Other languages
Chinese (zh)
Other versions
CN110256461A (en
Inventor
杨尊华
房元英
刘荣华
刘燕华
金�一
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangxi University of Traditional Chinese Medicine
Original Assignee
Jiangxi University of Traditional Chinese Medicine
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
2019-06-20
Filing date
2019-06-20
Publication date
2020-04-07
2019-06-20 Application filed by Jiangxi University of Traditional Chinese Medicine filed Critical Jiangxi University of Traditional Chinese Medicine
2019-06-20 Priority to CN201910537029.6A priority Critical patent/CN110256461B/en
2019-09-20 Publication of CN110256461A publication Critical patent/CN110256461A/en
2020-04-07 Application granted granted Critical
2020-04-07 Publication of CN110256461B publication Critical patent/CN110256461B/en
Status Expired - Fee Related legal-status Critical Current
2039-06-20 Anticipated expiration legal-status Critical

Links

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  • 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
  • 150000003839 salts Chemical class 0.000 claims description 11
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    • C07D—HETEROCYCLIC COMPOUNDS
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Abstract

The invention relates to a fused pyrimidine derivative, a preparation method and application thereof, wherein the structure of the fused pyrimidine derivative is shown as formula (I), R is1、R2And R3And X is defined as the specification. The derivatives have good GPR119 agonistic activity, and can be used as medicaments for resisting diabetes, metabolic diseases and obesity. The invention further relates to processes for the preparation of such novel compounds, pharmaceutical compositions containing said compounds as active ingredient and the use of said compounds as medicaments.

Figure DDA0002101430980000011

Description

Fused pyrimidine derivative and preparation method and application thereof

Technical Field

The invention relates to a fused pyrimidine derivative, a preparation method and application thereof, in particular to a fused pyrimidine derivative which can prevent or treat GPR119 related diseases, especially diabetes, metabolic diseases, obesity and other diseases.

Background

According to the US National Cholesterol Education Program (NCEP) ATP III, a diagnosis of metabolic syndrome can be made when a patient shows at least three of ① abdominal obesity, manifested as a male waist circumference of 40 inches (102cm) or more and a female waist circumference of 35 inches (88cm) or more, ② hypertriglyceridemia, manifested as triglycerides of 150mg/dL or more, ③ HDL cholesterol of 40mg/dL or less in men, 50mg/dL or less in women, ④ hypertension, manifested as blood pressure of 130/85mmHg or more, and ⑤ fasting blood glucose of 110mg/dL or more, the prevalence of diabetes mellitus is rapidly increasing due to an increase in lifestyle and a life style of the obese person, and the number of diabetes mellitus is expected to increase from 2030 to 35.4 in the world, in association.

GPR119 is a G-protein coupled receptor that is expressed predominantly in the β cells of the pancreas and K-and L-cells of the intestine in vitro studies show that agonists of GRP119 may be useful for the treatment of diabetes and related conditions by activating the cAMP pathway in gut and pancreas derived cell lines, respectively, since secretion of insulin has been found to be strictly glucose dependent, the onset of hypoglycemia may be largely avoided, in addition, beneficial effects may be expected from the release of intestinal peptides, such as reduced feeding, stimulation of β cells by activating GPR119 may also improve β cell function and β cell mass, studies of GPR119 agonists in rodents show that predicted effects of reduced glucose are shown to some animal studies, decreased feeding and body weight, and increased clinical trials using GPR119 agonists, increased GPR cell mass, increased cholesterol metabolism, increased lipid metabolism, increased cholesterol metabolism, increased blood lipid metabolism, increased cholesterol metabolism, obesity, hypertension, obesity, hypertension, hyperlipidemia, diabetes mellitus, obesity, diabetes mellitus, hypertension, obesity, diabetes mellitus, hypertension, diabetes mellitus, hypertension, diabetes mellitus, hyperlipidemia, diabetes mellitus, hypertension, hyperlipidemia, diabetes mellitus, hyperlipidemia, diabetes mellitus, hypertension, hyperlipidemia, obesity, hyperlipidemia, diabetes mellitus, obesity, hyperlipidemia, obesity, hypertension, obesity, hypertension, obesity, diabetes mellitus, hypertension, obesity.

In view of the fact that low molecular drugs activate GPR119 to have potent hypoglycemic effects and positive effects on pancreatic islet β cells, the present inventors have highlighted their value as a therapeutic agent for type 2 diabetes for improving lipid metabolism, which is a chronic cardiovascular risk factor.

Disclosure of Invention

The present invention provides a novel compound having GPR119 agonist activity, and provides a process for preparing the novel compound having GPR119 agonist activity and a pharmaceutical composition comprising the novel compound as an effective ingredient and useful for treating or preventing diabetes, metabolic diseases, and obesity.

Compounds having GPR119 agonist activity have the structure of formula (I),

Figure BDA0002101430960000021

wherein R is1Selected from the following groups:

Figure BDA0002101430960000022

R2selected from: hydrogen atom, halogen, hydroxyl, nitro, amine group, carboxyl group, cyano group, alkyl group, alkoxy group, ester group, aryl group, heteroaryl group, alkyl group substituted by halogen or hydroxyl group or cyano group, amine group substituted by alkyl group, alkoxy group substituted by halogen or hydroxyl group or cyano group, aryl group substituted by halogen or hydroxyl group or cyano group, heteroaryl group substituted by halogen or hydroxyl group or cyano group;

R3selected from: hydrogen atom, halogen, hydroxyl group, nitro group, cyano group, amino group, carboxyl group, methylsulfonyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

x is selected from: o or NR5；

R4Selected from the following groups:

Figure BDA0002101430960000031

R5selected from: a hydrogen atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkoxy group;

further, in the above-mentioned case,

R2preferably: hydrogen atom, halogen, hydroxy, nitro, amino, carboxyl, cyano, alkyl or alkoxy

R3Preferably a hydrogen atom, halogen, nitro, cyano, methanesulfonyl, alkyl or alkoxy;

R5preferably: a hydrogen atom, an alkyl group;

further, in the above-mentioned case,

R2preferably: a hydrogen atom, a halogen atom or an alkyl group;

R3preferably 2-F-4-Ms,2-F-4-CN,2-Cl-4-Ms, wherein Ms represents methylsulfonyl;

R5preferably: a hydrogen atom;

alkyl is more preferably C1-6Examples of the alkyl group include: methyl, ethyl, propyl, isopropyl,Butyl, isobutyl, tert-butyl, pentyl, isopentyl, and hexyl, and the like;

alkoxy is more preferably C1-6Examples of the alkoxy group include: methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, and the like;

aryl is further preferably C6-10Aryl, more preferably phenyl or naphthyl.

Heteroaryl is further preferably C6-10Heteroaryl, more preferably C6-10The heteroaryl group contains 1 to 3 heteroatoms, and the heteroatoms are preferably N, S or O, more preferably O or N. For example: furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuryl, benzothienyl, indolyl, indazolyl.

In another aspect, the present invention provides stereoisomers, tautomers, enantiomers, diastereomers, racemates of the above-mentioned compounds, and pharmaceutically acceptable salts thereof with acids.

The salt-forming acid may be an organic or inorganic acid, for example: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and carbonic acid; salts with organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, phthalic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like; and lysine, arginine, ornithine, glutamic acid, aspartic acid and other amino acids.

Further, the present invention provides the following compounds or stereoisomers, tautomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts thereof with an acid or a base:

Figure BDA0002101430960000041

Figure BDA0002101430960000051

further, the present invention provides the following compounds or stereoisomers, tautomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts thereof with an acid or a base:

Figure BDA0002101430960000052

Figure BDA0002101430960000061

in another aspect, the invention provides a process for the preparation of a compound of formula (I).

When X is O, the preparation method comprises the following steps:

step (1): with 4, 6-dichloro-5-methoxypyrimidine and R3Substituted aniline as raw material is produced into the compound of formula (II) in organic solvent under alkaline environment

Figure BDA0002101430960000062

Preference is given to using K in an alkaline environment2CO3；

The organic solvent is preferably DMF (N, N-dimethylformamide), DMSO (dimethyl sulfoxide).

Step (2): demethylation of formula (II) in an organic solvent to yield a compound of formula (III)

Figure BDA0002101430960000063

The organic solvent is preferably dichloromethane, acetonitrile or tetrahydrofuran;

preferably BBr is used3Removing methyl;

and (3): reacting the compound shown in the formula (III) with 1-bromo-2-chloroethane under alkaline conditions to generate a compound shown in the formula (IV)

Figure BDA0002101430960000071

Preference is given to using K in an alkaline environment2CO3；

The organic solvent is preferably DMF (N, N-dimethylformamide), DMSO (dimethyl sulfoxide).

And (4): compounds of formula (IV) and R1H reacts in the presence of a Pd catalyst to generate a compound (I) (X is O)

Figure BDA0002101430960000072

The Pd catalyst is preferably Pd2(dba)3。

For X is NR5The synthetic route is as follows:

step (1): with 4, 6-dichloro-5-R5Substituted aminopyrimidines as starting materials with R3The substituted aniline reacts in the presence of Pd catalyst to generate the compound shown in the formula (V)

Figure BDA0002101430960000073

The Pd catalyst is preferably Pd2(dba)3；

Step (2): reacting the compound of formula (V) with 1-bromo-2-chloroethane under alkaline conditions to produce a compound of formula (VI)

Compound (I)

Figure BDA0002101430960000074

Preference is given to using K in an alkaline environment2CO3；

The organic solvent is preferably DMF (N, N-dimethylformamide), DMSO (dimethyl sulfoxide).

And (3): a compound of formula (VI) with R1H reacts in the presence of Pd catalyst to generate a compound of formula (I)

Compound (X is NR)5)

Figure BDA0002101430960000081

The Pd catalyst is preferably Pd2(dba)3。

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In another aspect, the present invention provides a compound of formula (I) as a medicament for the prevention or treatment of GPR 119-related diseases, preferably diabetes, metabolic diseases and obesity.

The compounds of the invention or their physiologically acceptable salts can be used simultaneously, separately or sequentially in combination with one or more known GPR119 actives.

Therapeutic or prophylactic agents comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient can be prepared by using carriers or excipients and other additives which are generally used for formulation. The carrier or excipient for the preparation may be solid or liquid, and examples thereof include: magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cacao butter, and ethylene glycol. Administration may be in any of the following forms: oral administration in the form of tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration in the form of injections such as intravenous injection and intramuscular injection, suppositories, transdermal administration, etc.

The dosage of a compound of the invention to achieve a desired therapeutic effect will depend on a number of factors, such as the particular compound selected, the intended use, the mode of administration and the clinical condition of the patient. The daily dosage will generally be in the range 0.3mg to 100mg (typically 3mg to 50mg) per day per kilogram body weight, for example 3-100 mg/kg/day. The intravenous dose may range, for example, from 0.3mg to 1.0mg/kg, which is suitable for administration as an infusion of from 10ng to 100 ng/kg/min. For this purpose, suitable infusion solutions may contain, for example, 0.1ng to 100mg, typically 1ng to 100mg per ml. Single doses may contain, for example, from 1mg to 10g of active ingredient. Thus, for injection, contain, for example, from 1mg to 100mg, and an orally administrable single-dose formulation such as a tablet or capsule may contain, for example, from 1.0 to 1000mg, typically from 10 to 600 mg. For the prophylaxis and/or treatment of the abovementioned disorders, the compounds of the formula I can be used as compounds per se, but they are preferably present in the form of pharmaceutical compositions with compatible carriers.

Drawings

FIG. 1: blood glucose was measured at each time point for a single dose of example 3 and vildagliptin to C57BL/6cnc mice.

Detailed Description

The following examples are intended to illustrate embodiments of the present invention in more detail, but the present invention is not limited thereto.

Example 1: tert-butyl (endo) -3- ((8- (4-cyano-2-fluorophenyl) -7, 8-dihydro-6H-pyrimido [5,4-b ] [1,4] oxazin-4-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate

Figure BDA0002101430960000091

Step 1: 4- ((6-chloro-5-methoxypyrimidin-4-yl) amino) -3-fluorobenzonitriles

Figure BDA0002101430960000092

In a 100mL two-necked flask were added 4, 6-dichloro-5-methoxypyrimidine (1 g,5.7 mmol), 2-fluoro-4-cyanoaniline (0.6g, 4.4 mmol), potassium carbonate (2.4 g,17 mmol) and 20 mL of DMF in this order. The reaction was warmed to 65 ℃ and stirred overnight. Pouring the reaction solution into ice water, extracting with ethyl acetate for 2 times, washing with saturated sodium chloride for 2 times, drying with anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain a crude product. Purification by silica gel column chromatography (petroleum ether (PE): Ethyl Acetate (EA): 3:1) afforded 0.68 g of a tan solid in 55% yield. MS-ESI: [ M + H ]]+:279.3。

Step 2: 4- ((6-chloro-5-hydroxypyrimidin-4-yl) amino) -3-fluorophenylacetonitrile

Figure BDA0002101430960000093

A100 mL two-necked flask was charged with 4- ((6-chloro-5-methoxypyrimidin-4-yl) amino) -3-fluorobenzonitrile (0.5g,1.9 mmol) and anhydrous 15 mL of dichloromethane. BBr is dripped at room temperature3Dichloromethane solution (5.7 mL,5.7mmol, 1M). Heating the reaction, carrying out reflux reaction for 2h, quenching the reaction with water, extracting with dichloromethane for 2 times, washing with saturated sodium chloride for 2 times, drying with anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain a crude product. Purification by silica gel column chromatography (petroleum ether (PE): Ethyl Acetate (EA) ═ 1:1) afforded 0.2g of a tan solid in 42% yield. MS-ESI: [ M + H ]]+:265.1。

And step 3: 4- (4-chloro-6, 7-dihydro-8H-pyrimido [5,4-b ] [1,4] oxazin-8-yl) -3-fluorophenylacetonitrile

Figure BDA0002101430960000101

In a 50mL single-necked flask were added 4- ((6-chloro-5-hydroxypyrimidin-4-yl) amino) -3-fluorophenylacetonitrile (0.4g,1.4mmol), 1-chloro-2-bromoethane (0.62g,4.3mmol), potassium carbonate (0.6g,4.3mmol) and DMF (10mL) in this order. The reaction was carried out at 40 ℃ overnight, the reaction solution was poured into ice water, extracted with ethyl acetate 2 times, washed with saturated sodium chloride 2 times, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to give a crude product. Purification by silica gel column chromatography (petroleum ether (PE): Ethyl Acetate (EA) ═ 2:1) afforded 0.3g of a tan solid in 72% yield. MS-ESI: [ M + H ]]+:291.5。

And 4, step 4: tert-butyl (endo) -3- ((8- (4-cyano-2-fluorophenyl) -7, 8-dihydro-6H-pyrimido [5,4-b ] [1,4] oxazin-4-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate

Figure BDA0002101430960000102

4- (4-chloro-6, 7-dihydro-8H-pyrimido [5,4-b ] was added to a 50mL reaction flask in sequence][1,4]Oxazin-8-yl) -3-fluoroacetonitrile (0.2g,0.7mmol), endo-N-Boc tropine amine (0.23g,1.0mmol), Pd2(dba)3(0.14mmol)，X-Phos(0.14mmol)，CS2CO3(1.75mmol) and anhydrous dioxane (8 mL). Reaction ofAnd (5) under the protection of liquid nitrogen gas, refluxing and reacting overnight. After the reaction is finished, extracting the reaction solution with ethyl acetate for 2 times, washing with saturated sodium chloride for 2 times, drying with anhydrous sodium sulfate, and evaporating to dryness to obtain a crude product. Purification by silica gel column chromatography (PE: EA ═ 1:1) gave 0.17g of a yellow solid in 52% yield.

1H-NMR(600MHz,CDCl3)δ7.93(s,1H),7.54–7.50(m,1H),7.47(m,2H),5.38(d,J＝7.0Hz,1H),4.46–4.37(m,2H),4.33(m,2H),4.22(s,1H),3.89(s,2H),2.39(s,1H),2.30–2.20(m,1H),2.12(t,J＝7.4Hz,2H),2.07–1.92(m,2H),1.84(d,J＝27.1Hz,2H),1.49(s,9H).HRMS-TOF(m/z)calcd for C25H29FN6O3[M+H]+:481.2285,found 481.2436.

Example 2: tert-butyl-4- ((8- (4-cyano-2-fluorophenyl) -7, 8-dihydro-6H-pyrimido [5,4-b ] [1,4] oxazin-4-yl) amino) piperidine-1-carboxylic acid ester

Figure BDA0002101430960000111

Reference is made to the preparation of example 1.1H-NMR(600MHz,CDCl3)δ7.93(s,1H),7.56–7.51(m,1H),7.48(m,2H),4.83(d,J＝8.1Hz,1H),4.42–4.35(m,2H),4.22–4.11(m,2H),4.11–4.01(m,1H),3.94–3.82(m,2H),2.98(m,2H),2.14–1.99(m,2H),1.49(s,9H),1.41(m,2H).HRMS-TOF(m/z)calcd for C23H27FN6O3[M+H]+:455.2207,found 455.2304.

Example 3: isopropyl (endo) -3- ((8- (4-cyano-2-fluorophenyl) -7, 8-dihydro-6H-pyrimido [5,4-b ] [1,4] oxazin-4-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate

Figure BDA0002101430960000112

Reference is made to the preparation of example 1.1H-NMR(600MHz,CDCl3)δ7.93(s,1H),7.56–7.51(m,1H),7.48(m,2H),5.38(d,J＝6.9Hz,1H),4.98(dt,J＝12.5,6.2Hz,1H),4.43–4.37(m,3H),4.34(m,2H),3.93–3.84(m,2H),2.37(m,1H),2.31–2.18(m,1H),2.13(m,2H),2.02(m,2H),1.87(m,2H),1.28(d,J＝6.2Hz,6H).HRMS-TOF(m/z)calcd for C24H27FN6O3[M+H]+:467.2207,found 467.2282.

Example 4: 4- (4- (((endo) -8- (5-ethylpyrimidin-2-yl) -8-azabicyclo [3.2.1] octan-3-yl) amino) -6, 7-dihydro-8H-pyrimido [5,4-b ] [1,4] oxazin-8-yl) -3-fluorophenylacetonitrile

Figure BDA0002101430960000121

Reference is made to the preparation of example 1.1H-NMR(600MHz,CDCl3)δ8.22(s,2H),7.92(s,1H),7.55–7.51(m,1H),7.47(m,2H),5.52(d,J＝7.2Hz,1H),4.78(s,2H),4.43–4.37(m,2H),4.30(q,J＝6.6Hz,1H),3.92–3.85(m,2H),2.50(q,J＝7.6Hz,2H),2.38(m,2H),2.25–2.18(m,2H),2.13(m,2H),1.89(d,J＝14.2Hz,2H),1.23(t,J＝7.6Hz,3H).HRMS-TOF(m/z)calcd forC26H27FN8O[M+H]+:487.2370,found 487.2462.

Example 5: 4- (4- (((endo) -8- (5-chloropyrimidin-2-yl) -8-azabicyclo [3.2.1] octan-3-yl) amino) -6, 7-dihydro-8H-pyrimido [5,4-b ] [1,4] oxazin-8-yl) -3-fluorophenylacetonitrile

Figure BDA0002101430960000122

Reference is made to the preparation of example 1.1H-NMR(600MHz,CDCl3)δ8.27(s,2H),7.92(s,1H),7.55–7.50(m,1H),7.47(m,2H),5.48(d,J＝7.1Hz,1H),4.76(s,2H),4.44–4.36(m,21H),4.29(q,J＝6.6Hz,1H),3.94–3.84(m,2H),2.34(m,2H),2.22(m,2H),2.15(m,2H),1.91(d,J＝14.2Hz,2H).HRMS-TOF(m/z)calcd for C24H22ClFN8O[M+H]+:493.1667,found 493.1751.

Example 6: tert-butyl ((R) -1- (2- ((endo) -3- ((8- (4-cyano-2-fluorophenyl) -7, 8-dihydro-6H-pyrimido [5,4-b ] [1,4] oxazin-4-yl) amino) -8-azabicyclo [3.2.1] oct-8-yl) acetyl) piperidin-3-yl) carboxylate

Figure BDA0002101430960000131

Reference is made to the preparation of example 1.1H NMR(600MHz,CDCl3)δ7.92(s,1H),7.52(m,1H),7.47(m,2H),5.47–5.32(m,2H),4.44–4.35(m,2H),4.30(m,1H),3.88(m,2H),3.74–3.67(m,3H),3.61–3.15(m,6H),2.49–2.30(m,2H),2.23(m,2H),1.97(m,2H),1.93–1.74(m,6H),1.48(s,9H).HRMS-TOF(m/z)calcd for C32H41FN8O4[M+H]+:621.3313,found 621.3405.

Example 7: tert-butyl 4- (2- ((endo) -3- ((8- (4-cyano-2-fluorophenyl) -7, 8-dihydro-6H-pyrimido [5,4-b ] [1,4] oxazin-4-yl) amino) -8-azabicyclo [3.2.1] oct-8-yl) acetyl) piperidine-1-carboxylate

Figure BDA0002101430960000132

Reference is made to the preparation of example 1.1H-NMR(600MHz,CDCl3)δ7.92(s,1H),7.55–7.50(m,1H),7.47(m,2H),5.34(d,J＝7.1Hz,1H),4.44–4.35(m,2H),4.26(q,J＝6.7Hz,1H),3.91–3.84(m,2H),3.72–3.67(m,2H),3.60(s,2H),3.53–3.47(m,2H),3.43(m,2H),3.32(m,2H),3.28(m,2H),2.29(m,2H),2.21–2.13(m,2H),1.96(m,2H),1.83(d,J＝14.3Hz,2H),1.50(s,9H).HRMS-TOF(m/z)calcd for C31H39FN8O4[M+H]+:607.3157,found 607.3239.

Example 8: isopropyl 4- ((8- (4-cyano-2-fluorophenyl) -7, 8-dihydro-6H-pyrimido [5,4-b ] [1,4] oxazin-4-yl) amino) piperidine-1-carboxylate

Figure BDA0002101430960000133

Reference is made to the preparation of example 1.1H NMR(600MHz,CDCl3)δ7.93(s,1H),7.56–7.51(m,1H),7.48(m,2H),4.95(dt,J＝12.5,6.2Hz,1H),4.83(d,J＝8.1Hz,1H),4.43–4.33(m,2H),4.27–4.08(m,3H),3.93–3.85(m,2H),3.00(t,J＝12.0Hz,2H),2.13–2.04(m,2H),1.50–1.37(m,2H),1.27(d,J＝6.3Hz,6H).HRMS-TOF(m/z)calcd for C22H25FN6O3[M+H]+:441.2050,found 441.2144.

Example 9: 4- (4- ((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) amino) -6, 7-dihydro-8H-pyrimido [5,4-b ] [1,4] oxazin-8-yl) -3-fluorophenylacetonitrile

Figure BDA0002101430960000141

Reference is made to the preparation of example 1.1H NMR(600MHz,CDCl3)δ8.20(s,2H),7.95(s,1H),7.56–7.51(m,1H),7.48(m,2H),4.87(d,J＝8.2Hz,1H),4.68(m,2H),4.42–4.32(m,2H),4.32–4.17(m,1H),3.92–3.84(m,2H),3.24–3.10(m,2H),2.49(q,J＝7.6Hz,2H),2.21–2.12(m,2H),1.50(m,2H),1.21(t,J＝7.6Hz,3H).HRMS-TOF(m/z)calcd for C24H25FN8O[M+H]+:461.2214,found 461.2318.

Example 10: 4- (4- ((1- (5-chloropyrimidin-2-yl) piperidin-4-yl) amino) -6, 7-dihydro-8H-pyrimido [5,4-b ] [1,4] oxazin-8-yl) -3-fluorophenylacetonitrile

Figure BDA0002101430960000142

Reference is made to the preparation of example 1.1H NMR(600MHz,CDCl3)δ8.25(s,2H),7.95(s,1H),7.58–7.51(m,1H),7.48(m,2H),4.86(d,J＝8.1Hz,1H),4.74–4.61(m,2H),4.47–4.33(m,2H),4.28(m,1H),3.96–3.79(m,2H),3.27–3.11(m,2H),2.21–2.12(m,2H),1.48(m,2H).HRMS-TOF(m/z)calcd for C22H20ClFN8O[M+H]+:467.1511,found 467.1613.

Example 11: tert-butyl 4- (2- (4- ((8- (4-cyano-2-fluorophenyl) -7, 8-dihydro-6H-pyrimido [5,4-b ] [1,4] oxazin-4-yl) amino) piperidin-1-yl) acetyl) piperazine-1-carboxylate

Figure BDA0002101430960000151

Reference is made to the preparation of example 1.1H NMR(600MHz,CDCl3)δ7.91(s,1H),7.54–7.49(m,1H),7.46(m,2H),4.84(d,J＝8.1Hz,1H),4.50–4.30(m,2H),4.01(m,1H),3.94–3.81(m,2H),3.59(s,4H),3.51–3.45(m,2H),3.42(s,2H),3.22(s,2H),2.89(m,2H),2.32(m,2H),2.08(m,2H),1.65–1.53(m,2H),1.49(s,9H).HRMS-TOF(m/z)calcd for C29H37FN8O4[M+H]+:581.3000,found 581.3136.

Example 12: GPR119 agonist Activity assay

First, a DNA fragment containing the human GPR119 gene was transfected into HEK293 cells (human embryonic kidney 293 cells), and a cell line stably expressing GPR119 was obtained by culture, and the cell line was seeded on a 96-well plate. Cells were incubated at 37 ℃ with 5% CO2After incubation for 48h under conditions, the culture medium was removed, 100. mu.L of buffer was added, and incubation was carried out at room temperature for 15 min. The test compounds of different concentrations were then administered and incubated for 30min, the buffer removed, 75 μ L of pre-cooled lysate was added and incubated on ice for 20min with appropriate shaking. The lysate was transferred to a 1.5mL centrifuge tube and centrifuged at 13000rpm for 10 min. Taking 50 μ L of supernatant, using HTRF cAMP kit standard procedure, with GSK-1292263 as positive control, determining intracellular cAMP concentration, and obtaining Compound EC from dose-dependent cAMP concentration change50Values for assessing the affinity of a compound for a receptor, the ratio of cAMP stimulated effect of a compound to the maximal effect of GSK-1292263 (% max) was calculated and used to compare the intrinsic activity of a compound for a receptor (IA).

Table 1: hGPR119 agonist Activity test results

Figure BDA0002101430960000152

Figure BDA0002101430960000161

As shown in the above table, it was confirmed that the compound of the present invention, its isomer or pharmaceutically acceptable salt thereof has agonist activity for GPR 119. Thus, the above-described compounds of the examples are expected to have therapeutic or prophylactic effects on diabetes, metabolic diseases, and obesity.

Example 13: oral glucose tolerance test (oGTT) in mice

24C 57BL/6cnc mice were taken, starved overnight, freely drunk, randomly divided into 3 groups according to weight and starvation blood sugar, each group had 8 mice, and orally administered by gavage respectively, after 4h 3g/kg glucose was orally administered by gavage, blood sugar was measured at the time points before and 15, 30, 60, 90 and 120 minutes after administration of sugar, and administration time and weight were recorded. The blood glucose levels before and after administration of glucose at 15, 30, 60, 90 and 120min were measured, and the area under the blood glucose curve (AUC) within 2h was calculated.

AUC0-2h(mmol/L)＝(BG0+BG15)×0.25/2+(BG15+BG30)×0.25/2+(BG30+BG60)×0.5/2+(BG60+BG90)×0.5/2+(BG90+BG120)×0.5/2

BG0、BG15、BG30、BG60、BG90And BG120Respectively represent the blood glucose values before and after administration of sugar at 15, 30, 60, 90 and 120 min.

Average blood sugar reduction rate (blank control group-administration group)/(blank control group) x 100%

After the compound (30mg/kg) and vildagliptin (30mg/kg) in example 3 of the tested medicament are orally administered by intragastric administration and sugar is administered after 4 hours, the area under the curve is obviously reduced, and the sugar reduction rates are respectively 23.4% and 17.9% (shown in figure 1), which indicates that the tested medicament has obvious influence on the oral glucose tolerance of mice.

The present invention has been described in detail in the specific sections, and it is apparent to those skilled in the art that such specific techniques are only preferred exemplary embodiments, not to limit the scope of the present invention. Therefore, the true scope of the invention should be defined by the appended claims and equivalents thereof.

Claims (4)

1.一种稠杂嘧啶衍生物或其医学上可接受的盐、立体异构体，结构如下：1. a condensed heteropyrimidine derivative or its medically acceptable salt, stereoisomer, the structure is as follows:

Figure FDA0002366989170000011

Figure FDA0002366989170000011

 2.一种包含权利要求1所述的稠杂嘧啶衍生物或其医学上可接受的盐和制药学上可接受的载体的药物组合物。2. A pharmaceutical composition comprising the fused heteropyrimidine derivative of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 3.一种权利要求1所述的稠杂嘧啶衍生物在制备预防或治疗与GPR119相关疾病的药物中的用途。3. Use of the condensed heteropyrimidine derivative according to claim 1 in the preparation of a medicament for preventing or treating diseases related to GPR119. 4.根据权利要求3所述的用途，其特征在于所述疾病为糖尿病、代谢性疾病或肥胖。4. Use according to claim 3, characterized in that the disease is diabetes, metabolic disease or obesity.
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