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CN-121985948-A - Preparation of GLP-1R agonist and preparation method thereof

CN121985948ACN 121985948 ACN121985948 ACN 121985948ACN-121985948-A

Abstract

A long-acting injection preparation and a preparation method thereof are provided, wherein the preparation comprises an active compound shown as a formula (I), a compound shown as a formula (II) or a compound 6 or a stereoisomer, a pharmaceutically acceptable salt or a deuterated compound thereof and at least one pharmaceutically acceptable carrier.

Inventors

  • WU JINZI
  • GUO LIGANG
  • DONG KUNHUA

Assignees

  • 歌礼制药(中国)有限公司

Dates

Publication Date
20260505
Application Date
20240808
Priority Date
20230712

Claims (20)

  1. A long-acting injectable formulation comprising an active compound and at least one pharmaceutically acceptable carrier, wherein the active compound is a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt or deuterated compound thereof: Wherein the method comprises the steps of X is selected from-N=or-CR a ;R a is selected from hydrogen atom, halogen or C 1-6 alkyl; Z 3 ,Z 4 ,Z 5 ,Z 6 ,Z 7 ,Z 8 ,Z 9 ,Z 10 ,Z 11 ,Z 12 ,Z 13 Selected from-n=or-c=; Q 1 is selected from C 6-10 aryl or 5 to 10 membered heteroaryl, wherein C 6-10 aryl or 5 to 10 membered heteroaryl is optionally substituted with one to five substituents independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy; Q 2 is selected from 3-to 12-membered heterocyclyl or 5-to 10-membered heteroaryl, wherein 3-to 12-membered heterocyclyl and 5-to 10-membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from halogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6 alkoxy and-NR Qa R Qb , and two C 1-6 alkyl groups together with the carbon atom to which they are attached form a C 3-8 carbocycle, and R Qa and R Qb are independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl and (C 1- 6 alkyl) carbonyl; R 1 ,R 2 and R 3 are each independently selected from hydrogen, C 1-6 alkyl, said C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen atoms, C 1-6 alkoxy and hydroxy; R 4 ,R 5 and R 6 are each independently selected from hydrogen, halogen and C 1-6 alkyl; r 7 and R 8 are independently selected from hydrogen or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen and C 3-15 cycloalkyl, or R 7 and R 8 together with the carbon atom to which they are attached form a C 3-15 carbocyclic ring, wherein C 3-15 carbocyclic ring formed by R 7 and R 8 together is optionally substituted with one to three C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NR 7a R 7b ,C 1-6 alkoxy and 3 to 12 membered heterocyclyl, and R 7a and R 7b are independently selected from hydrogen, C 1-6 alkyl and (C 1-6 alkyl) carbonyl; n 1 is 0,1,2, or 3; n2 is 0,1,2,3,4 or 5; R 9 is selected from the following groups: -CO 2 R 9f and-C (=o) -NR 9g R 9h , and R 9a ,R 9b ,R 9c ,R 9d and R 9g are each independently selected from hydrogen, C 1-6 alkyl and (C 1-6 alkyl) carbonyl, said C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen and C 1-6 alkoxy, R 9e is hydrogen or C 1-6 alkyl optionally substituted with one or more halogen atoms, R 9f is hydrogen or C 1-6 alkyl, R 9h is hydrogen, C 1-6 alkyl, (C 1-6 alkyl) carbonyl, cyano or-S (=o) n3 -R 9i , n3 is 0,1 or 2;R 9i is C 1-6 alkyl; Z 1 is selected from the following groups: Wherein R za is selected from hydrogen, C 1-6 alkyl and (C 1-6 alkyl) carbonyl, R zb and R zc are independently hydrogen or C 1-6 alkyl; n4 is 1,2 or 3, n5 and n6 are independently integers from 0 to 10; Z 2 is selected from the group consisting of C 1-6 alkyl, C 3-15 cycloalkyl, 3 to 12 membered heterocyclyl, C 6-10 aryl, and 5 to 10 membered heteroaryl, wherein C 3-15 cycloalkyl, 3 to 12 membered heterocyclyl, C 6-10 aryl, and 5 to 10 membered heteroaryl are independently optionally substituted with one to five G's, G is selected from the group consisting of: a. oxo; b. halogen; c. Cyano group; d. -NR zd R ze wherein R zd and R ze are independently selected from hydrogen, C 1-6 alkyl and (C 1-6 alkyl) carbonyl, wherein C 1-6 alkyl is optionally substituted with one or more substituents independently selected from hydroxy, halogen and C 1-6 alkoxy; e. -C (=o) -NR zf R zg wherein R zf and R zg are independently selected from hydrogen, C 1-6 alkyl and (C 1-6 alkyl) carbonyl, wherein C 1-6 alkyl is optionally substituted with one or more substituents independently selected from hydroxy, halogen and C 1-6 alkoxy; f. -S (=o) n7 -R zh , wherein n7 is 0,1 or 2;R zh is hydrogen or C 1-6 alkyl; g.C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NR zi R zj 、C 1-6 alkoxy, and 3-to 12-membered heterocyclyl, wherein R zi and R zj are each independently selected from hydrogen or C 1-6 alkyl, and the 3-to 12-membered heterocyclyl is optionally substituted with one or more cyano, C 1-6 alkyl, and a substituent of a 3-to 12-membered heterocyclyl; h.C 1-6 alkoxy, wherein C 1-6 alkoxy is optionally substituted with one or more substituents selected from hydroxy, halogen and C 1-6 alkoxy; i.3 to 12 membered heterocyclyl, wherein the 3 to 12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from C 1-6 alkyl and (C 1-6 alkyl) carbonyl; j.C 6-10 aryl, wherein C 6-10 aryl is optionally substituted with one or more (C 1-6 alkyl) carbonyl groups, and K.5 to 10 membered heteroaryl, wherein 5 to 10 membered heteroaryl is optionally substituted with one or more substituents independently selected from C 1-6 alkyl, C 1-6 alkoxy, -NR zk R zl and 3 to 12 membered heterocyclyl, wherein R zk and R zl are independently selected from hydrogen, C 1-6 alkyl and (C 1-6 alkyl) carbonyl, and wherein 3 to 12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from C 1-6 alkyl and (C 1-6 alkyl) carbonyl.
  2. A long-acting injectable formulation comprising an active compound and at least one pharmaceutically acceptable carrier, wherein the active compound is a compound of formula (II) and stereoisomers, pharmaceutically acceptable salts or deuterated compounds thereof, and at least one pharmaceutically acceptable carrier: Wherein the method comprises the steps of X is selected from-N=or-CR a ;R a is selected from hydrogen atom, halogen or C 1-6 alkyl; Z 3 ,Z 4 ,Z 5 ,Z 6 ,Z 7 ,Z 8 ,Z 9 ,Z 10 ,Z 11 ,Z 12 ,Z 13 Selected from-n=or-c=; z 14 is selected from N or C Q 1 is selected from C 6-10 aryl or 5 to 10 membered heteroaryl, wherein C 6-10 aryl or 5 to 10 membered heteroaryl is optionally substituted with one to five substituents independently selected from halogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 haloalkyl and C 1-6 alkoxy; Q 2 is selected from 3-to 12-membered heterocyclyl or 5-to 10-membered heteroaryl, wherein 3-to 12-membered heterocyclyl and 5-to 10-membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from halogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6 alkoxy and-NR Qa R Qb , and two C 1-6 alkyl groups together with the carbon atom to which they are attached form a C 3-8 carbocycle, and R Qa and R Qb are independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl and (C 1- 6 alkyl) carbonyl; R 1 ,R 2 and R 3 are each independently selected from hydrogen, C 1-6 alkyl, said C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen atoms, C 1-6 alkoxy and hydroxy; R 4 ,R 5 and R 6 are each independently selected from hydrogen, halogen and C 1-6 alkyl; r 7 and R 8 are independently selected from hydrogen or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen and C 3-15 cycloalkyl, or R 7 and R 8 together with the carbon atom to which they are attached form a C 3-15 carbocyclic ring, wherein C 3-15 carbocyclic ring formed by R 7 and R 8 together is optionally substituted with one to three C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NR 7a R 7b ,C 1-6 alkoxy and 3 to 12 membered heterocyclyl, and R 7a and R 7b are independently selected from hydrogen, C 1-6 alkyl and (C 1-6 alkyl) carbonyl; n 1 is 0,1,2, or 3; n2 is 0,1,2,3,4 or 5; R 9 is selected from the following groups: -CO 2 R 9f and-C (=o) -NR 9g R 9h , and R 9a ,R 9b ,R 9c ,R 9d and R 9g are each independently selected from hydrogen, C 1-6 alkyl and (C 1-6 alkyl) carbonyl, said C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen and C 1-6 alkoxy, R 9e is hydrogen or C 1-6 alkyl optionally substituted with one or more halogen atoms, R 9f is hydrogen or C 1-6 alkyl, R 9h is hydrogen, C 1-6 alkyl, (C 1-6 alkyl) carbonyl, cyano or-S (=o) n3 -R 9i , n3 is 0,1 or 2;R 9i is C 1-6 alkyl; Z 1 is selected from the following groups: Wherein R za is selected from hydrogen, C 1-6 alkyl and (C 1-6 alkyl) carbonyl, R zb and R zc are independently hydrogen or C 1-6 alkyl; n4 is 1,2 or 3, n5 and n6 are independently integers from 0 to 10; Z 2 is selected from the group consisting of C 1-6 alkyl, C 3-15 cycloalkyl, 3 to 12 membered heterocyclyl, C 6-10 aryl, and 5 to 10 membered heteroaryl, wherein C 3-15 cycloalkyl, 3 to 12 membered heterocyclyl, C 6-10 aryl, and 5 to 10 membered heteroaryl are independently optionally substituted with one to five G's, G is selected from the group consisting of: a. oxo; b. halogen; c. Cyano group; d. -NR zd R ze wherein R zd and R ze are independently selected from hydrogen, C 1-6 alkyl and (C 1-6 alkyl) carbonyl, wherein C 1-6 alkyl is optionally substituted with one or more substituents independently selected from hydroxy, halogen and C 1-6 alkoxy; e. -C (=o) -NR zf R zg wherein R zf and R zg are independently selected from hydrogen, C 1-6 alkyl and (C 1-6 alkyl) carbonyl, wherein C 1-6 alkyl is optionally substituted with one or more substituents independently selected from hydroxy, halogen and C 1-6 alkoxy; f. -S (=o) n7 -R zh , wherein n7 is 0,1 or 2;R zh is hydrogen or C 1-6 alkyl; g.C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NR zi R zj 、C 1-6 alkoxy, and 3-to 12-membered heterocyclyl, wherein R zi and R zj are each independently selected from hydrogen or C 1-6 alkyl, and the 3-to 12-membered heterocyclyl is optionally substituted with one or more cyano, C 1-6 alkyl, and a substituent of a 3-to 12-membered heterocyclyl; h.C 1-6 alkoxy, wherein C 1-6 alkoxy is optionally substituted with one or more substituents selected from hydroxy, halogen and C 1-6 alkoxy; i.3 to 12 membered heterocyclyl, wherein the 3 to 12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from C 1-6 alkyl and (C 1-6 alkyl) carbonyl; j.C 6-10 aryl, wherein C 6-10 aryl is optionally substituted with one or more (C 1-6 alkyl) carbonyl groups, and K.5 to 10 membered heteroaryl, wherein the 5 to 10 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C 1 - 6 alkyl, C 1 - 6 alkoxy, -NR zk R zl , and 3 to 12 membered heterocyclyl, wherein R zk and R zl are independently selected from the group consisting of hydrogen, C 1-6 alkyl, and (C 1-6 alkyl) carbonyl, and wherein the 3 to 12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C 1-6 alkyl and (C 1-6 alkyl) carbonyl; P (O) R g1 R g2 wherein R g1 or R g2 are independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl.
  3. The formulation of claim 1, wherein the compound of formula (I) further has the structure of formula (III),
  4. The formulation of claim 3, wherein the compound of formula (III) further has the structure of formula (V), Wherein Rm is C 1-6 alkyl.
  5. The formulation of claim 2, wherein the compound of formula (II) further has the structure of formula (IV),
  6. The formulation of claim 5, wherein the compound of formula (IV) further has the structure of formula (VI),
  7. The formulation of claim 2, wherein the compound of formula (II) is selected from any one of the following compounds. Or a stereoisomer, a pharmaceutically acceptable salt or a deuterated compound thereof, and at least one pharmaceutically acceptable carrier, preferably the pharmaceutically acceptable salt is selected from the group consisting of sodium, potassium, calcium and magnesium salts.
  8. The formulation of claim 1, wherein the active compound is compound 1, Or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated compound thereof, and at least one pharmaceutically acceptable carrier. Preferably, the pharmaceutically acceptable salt is selected from: (1) A sodium salt comprising compound 2: Wherein X is the number of crystal water and is selected from 0,0.5,1,2 or 3; (2) A potassium salt comprising the compound 3, Wherein X is the number of crystal water and is selected from 0,0.5,1,2 or 3; (3) A calcium salt comprising the compound 4, Wherein X is the number of crystal water and is selected from 0,0.5,1,2 or 3; (4) A magnesium salt comprising the compound 5, Wherein X is the number of crystal water and is selected from 0,0.5,1,2 or 3.
  9. A long-acting injectable formulation comprising an active compound and at least one pharmaceutically acceptable carrier, wherein the active compound 6 or a stereoisomer, a pharmaceutically acceptable salt or a deuterated compound thereof, and at least one pharmaceutically acceptable carrier: wherein preferably the pharmaceutically acceptable salt is selected from sodium, potassium, calcium, magnesium salts.
  10. A formulation as claimed in any one of claims 1 to 9 wherein the active compound is dissolved in a lipophilic carrier comprising an oily vehicle and an organic solvent to form an oily solution; Preferably, the active compound is selected from compounds 1, 6, 7-15 or stereoisomers, pharmaceutically acceptable salts or deuterated compounds thereof, more preferably compound 1 or pharmaceutically acceptable salts thereof, most preferably compounds 1-5; Preferably, the oily vehicle is selected from one of castor oil, sesame oil, fatty acid glyceride, benzyl benzoate or any mixture thereof, more preferably, the oily vehicle is medium chain fatty acid glyceride; Preferably, the organic solvent is benzyl alcohol or ethanol, and more preferably, the organic solvent is benzyl alcohol.
  11. The formulation of claim 10, wherein the concentration of the active compound or pharmaceutically acceptable salt thereof in the formulation is from 0.1 to 400mg/mL, preferably from 1 to 200mg/mL; wherein the weight ratio of the oily solvent to the organic solvent is 6:4-9:1; Preferably, the weight ratio of the oily solvent to the organic solvent is 7:3-9:1; More preferably, the weight ratio of the oily solvent to the organic solvent is in the range of 8:2.
  12. The formulation of any one of claims 1-9, wherein the active compound is dissolved in a hydrophilic vehicle to form a hydrophilic solution; Preferably, the active compound is selected from compounds 1, 6, 7-15 or stereoisomers, pharmaceutically acceptable salts or deuterated compounds thereof, more preferably compound 1 or pharmaceutically acceptable salts thereof, most preferably compounds 1-5; Preferably, the hydrophilic vehicle comprises one of polyethylene glycol, an organic solvent, and water or any mixture thereof; Preferably, the polyethylene glycol is selected from polyethylene glycol 300, polyethylene glycol 400, more preferably polyethylene glycol 300; Preferably, the organic solvent is selected from benzyl alcohol, ethanol and N-methylpyrrolidone (NMP), more preferably, the organic solvent is selected from one of benzyl alcohol and ethanol.
  13. The formulation of claim 12, wherein the concentration of the active compound or pharmaceutically acceptable salt thereof in the formulation is from 0.1 to 400mg/mL, preferably from 1 to 200mg/mL; wherein the weight ratio of the polyethylene glycol to the organic solvent is 6:4-10:0; More preferably, the weight ratio of the polyethylene glycol to the organic solvent ranges from 7:3 to 10:0, and even more preferably, the weight ratio of the polyethylene glycol to the organic solvent ranges from 9:1 to 10:0; Preferably, the weight ratio of the polyethylene glycol 300 to the organic solvent ranges from 6:4 to 10:0, more preferably, the weight ratio of the polyethylene glycol 300 to the organic solvent ranges from 7:3 to 10:0, and even more preferably, the weight ratio of the polyethylene glycol 300 to the organic solvent ranges from 9:1 to 10:0. Preferably, the weight ratio of the polyethylene glycol 400 to the organic solvent ranges from 6:4 to 10:0, more preferably, the weight ratio of the polyethylene glycol 400 to the organic solvent ranges from 7:3 to 10:0, and even more preferably, the weight ratio of the polyethylene glycol 400 to the organic solvent ranges from 9:1 to 10:0.
  14. The formulation of claim 12, further comprising a pH adjuster selected from one of sodium hydroxide, hydrochloric acid, citric acid, sodium citrate, phosphoric acid, sodium hydrogen phosphate, or any mixture thereof, preferably the pH of the formulation ranges from 4 to 10.
  15. The formulation of claim 12, further comprising a release retardant selected from polylactic-co-glycolic acid (PLGA) or polylactic acid (PLA) in a hydrophilic vehicle in a weight ratio of 1% -10%.
  16. The formulation of claims 1-9, wherein the active compound is dispersed in a stabilizer solution to form a drug-loaded microparticle or nanoparticle suspension; Preferably, the active compound is selected from compounds 1, 6, 7-15 or stereoisomers, pharmaceutically acceptable salts or deuterated compounds thereof, more preferably compound 1 or pharmaceutically acceptable salts thereof, most preferably compounds 1-5; Wherein the stabilizer solution is selected from one or any combination of polyethylene glycol, poloxamer, tween, vitamin E polyethylene glycol succinate (TPGS), distearoyl phosphatidylethanolamine (DSPE) -polyethylene glycol (PEG), polyvinylpyrrolidone, mannitol, hypromellose, sodium carboxymethyl cellulose, methylcellulose, preferably the stabilizer is poloxamer and polyethylene glycol, the polyethylene glycol is polyethylene glycol 400 to 6000, more preferably polyethylene glycol 1000 to 4000, most preferably polyethylene glycol 3350, and the poloxamer is poloxamer 407, poloxamer 338, poloxamer 188;
  17. The formulation of claim 16, wherein the concentration of the active compound or pharmaceutically acceptable salt thereof in the formulation is from 0.1 to 400mg/mL, preferably from 1 to 200mg/mL; Wherein the weight ratio of poloxamer in the drug-loaded microparticle or nanoparticle suspension is 1% -10%, Wherein the weight ratio of polyethylene glycol in the drug-carrying microparticle or nanoparticle suspension is 0.5% -5%; Preferably, the active ingredient in the microparticle or nanoparticle suspension is present in the form of particles having a median particle size of about 0.1 to 10 μm, more preferably the drug-loaded microparticle suspension has a median particle size in the range of 1 to 10 microns, and even more preferably the drug-loaded nanosuspension has a median particle size in the range of 100 to 1000 nanometers.
  18. The formulation of any one of claims 1-9, wherein the active compound is dispersed in a biodegradable polymer solution to prepare a polymer gel solution formulation, the polymer gel solution comprising a polymer gel material and an organic solvent; Preferably, the active compound is selected from compounds 1, 6, 7-15 or stereoisomers, pharmaceutically acceptable salts or deuterated compounds thereof, more preferably compound 1 or pharmaceutically acceptable salts thereof, most preferably compounds 1-5; Wherein, preferably, the high molecular gel material is selected from polylactic acid-glycolic acid copolymer (PLGA), polylactic acid (PLA), polyoxyethylene-polycaprolactone block copolymer, polyoxyethylene-polyoxypropylene block copolymer; Preferably, the polymer gel material is poly (lactic-co-glycolic acid), PLGA; Preferably, the ratio of lactic acid to glycolic acid in the lactic acid-glycolic acid copolymer molecule is 75:25 or 50:50; preferably, the intrinsic viscosity of the lactic acid-glycolic acid copolymer ranges from 0.1 dL/g to 0.3dL/g; Preferably, the organic solvent is selected from one or any combination of N-methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO), benzyl alcohol and benzyl benzoate; Preferably, the concentration of the active compound or pharmaceutically acceptable salt thereof in the formulation is from 0.1 to 400mg/mL, preferably from 1 to 200mg/mL; Preferably, the weight ratio of the lactic acid-glycolic acid copolymer in the polymer gel solution is 10% -80%; Preferably, the organic solvent is selected to have a weight ratio of 20% -90% in the polymer gel solution.
  19. The formulation of any one of claims 1-18, wherein the formulation is suitable for intramuscular or subcutaneous administration.
  20. A method of treating a GLP-1 mediated disease or condition comprising administering to an individual in need thereof a therapeutically effective amount of the formulation of any one of claims 1 to 18.

Description

Preparation of GLP-1R agonist and preparation method thereof Citation of related application The present disclosure claims China patent application No. 202410644340.1 and entitled "preparation of GLP-1R agonist and preparation method thereof" filed 22 and 22 days in 2024 to the national intellectual property office of the people's republic of China, china patent application No. 202410544932.6 and entitled "preparation of GLP-1R agonist and preparation method thereof" filed 1 and 1 day in 2024 to the national intellectual property office of the people's republic of China, the full benefit of the chinese patent application filed at 7.12 of 2023, entitled "formulation of GLP-1R agonist and method for its preparation", filed at 7.12 of the national intellectual property office of the people's republic of China, and the U.S. provisional application filed at 8.8 of 2023, entitled "formulation of GLP-1R agonist and its use (Formulation Comprising of GLP-1R Agonist and Use Thereof)", entitled "formulation of GLP-1R agonist and its use", filed at 8.8 of the U.S. patent and trademark office, is incorporated by reference herein in its entirety. FIELD The present disclosure relates generally to the field of medicine, and more particularly to long acting formulations of long acting GLP-1R agonists, methods of making the same, and uses thereof. Background Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by enteroendocrine cells in the gut in response to a meal. GLP-1 is thought to play a role in postprandial glycemic regulation by directly increasing meal-induced secretion of insulin by pancreatic beta cells, and by delaying transport of food through the gut to promote satiety. GLP-1 mediates intracellular signaling through the GLP-1 receptor (GLP-1R), which belongs to the family of G protein-coupled receptors present on cell membranes and can lead to accumulation of the second messenger cyclic adenosine monophosphate (cAMP) upon activation. Non-alcoholic steatohepatitis (NASH) can be associated with features of the metabolic syndrome, including obesity, type 2 diabetes, insulin resistance, and cardiovascular disease. GLP-1R agonists are currently being widely studied for diseases associated with diabetes, obesity and NASH. GLP-1R agonists include peptides such as exenatide, liraglutide and durraglutide, which have been approved for the treatment of type 2 diabetes. Such peptide drugs are mainly administered by subcutaneous injection. Oral GLP-1 agonists are also under study for the treatment of type 2 diabetes. Some GLP-1R agonists, such as liraglutide, durraglutide and exenatide, are resistant to rapid degradation by dipeptidyl peptidase 4, resulting in a longer half-life than endogenous GLP-1. There remains a need for compounds having desirable therapeutic properties, metabolic characteristics, and/or ease of administration in the treatment of GLP-1R mediated diseases and conditions. The present invention is generally directed to a composition of a long-acting GLP-1R agonist and the delivery of therapeutic drugs to reduce the treatment schedule from daily to weekly or monthly, even less frequent dosing, provide greater patient privacy and satisfaction, and improve treatment regimen compliance. Compared with oral preparations, the long-acting injection has the characteristics of stable blood concentration, long effective acting time of the medicine reaching weeks or even months and reduced administration frequency, and the preparation is developed pertinently, thereby bringing convenience to the treatment of patients and bringing huge social effects. SUMMARY The long-acting injection preparation provided by the application has the characteristics of stable blood concentration, long effective acting time of the medicine reaching weeks or even months and reduced administration frequency. The application provides a long-acting injection preparation comprising an active compound and at least one pharmaceutically acceptable carrier, wherein the active compound is a compound of formula (I), or a stereoisomer, a pharmaceutically acceptable salt or a deuterated compound thereof: Wherein the method comprises the steps of X is selected from-N=or-CR a;Ra is selected from hydrogen atom, halogen or C 1-6 alkyl; Z3,Z4,Z5,Z6,Z7,Z8,Z9,Z10,Z11,Z12,Z13 Selected from-n=or-c=; Q 1 is selected from C 6-10 aryl or 5 to 10 membered heteroaryl, wherein C 6-10 aryl or 5 to 10 membered heteroaryl is optionally substituted with one to five substituents independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy; Q 2 is selected from 3-to 12-membered heterocyclyl or 5-to 10-membered heteroaryl, wherein 3-to 12-membered heterocyclyl and 5-to 10-membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from halogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and-NR QaRQb, and two C 1-6 alkyl groups together with the carbon atom to which they are attached form a C 3-8 carb