WO2022199458A1 - 噻吩类glp-1受体激动剂及其用途 - Google Patents
噻吩类glp-1受体激动剂及其用途 Download PDFInfo
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- WO2022199458A1 WO2022199458A1 PCT/CN2022/081466 CN2022081466W WO2022199458A1 WO 2022199458 A1 WO2022199458 A1 WO 2022199458A1 CN 2022081466 W CN2022081466 W CN 2022081466W WO 2022199458 A1 WO2022199458 A1 WO 2022199458A1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/20—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention relates to the technical field of medicine, in particular to GLP-1 receptor agonist compounds and preparation methods, as well as the use of the compounds in the preparation of medicines for the treatment or prevention of GLP-1 mediated diseases and related diseases.
- Diabetes mellitus is a chronic comprehensive disease mainly caused by glucose metabolism disorder caused by absolute or relative shortage of insulin or decreased sensitivity of target cells to insulin. It is divided into type I diabetes mellitus and type II diabetes mellitus. Among them, type II diabetes is adult-onset diabetes mellitus, an endocrine disease mainly manifested by chronic hyperglycemia caused by insulin resistance and/or insulin secretion defect. Type II diabetes patients account for more than 90% of diabetic patients. According to the Global Diabetes Map, there were approximately 425 million diabetic patients in the world in 2017, of which China ranked first in the world with approximately 114.4 million diabetic patients. It is estimated that by 2045, there will be 629 million people with diabetes worldwide. It can be seen that diabetes is a very common chronic disease all over the world.
- insulin secretagogues mainly the following classes of drugs: insulin secretagogues, metformin, ⁇ -glucosidase inhibitors, insulin sensitizers, sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase -4 (DPP-4) inhibitors, GLP-1 receptor agonists, insulin and its similar drugs, etc.
- DPP-4 dipeptidyl peptidase -4
- GLP-1 receptor agonists are one of the most effective diabetes treatment drugs, and insulin preparations are still the global The most used diabetes drug, about 30-40% of type 2 diabetes patients eventually need to use insulin.
- GLP-1 preparations mainly include exenatide, liraglutide, semaglutide, etc., suitable for metformin, sulfonic acid Patients with type 2 diabetes who cannot adequately control blood sugar when combined with ureides.
- insulin preparations and GLP-1 preparations are basically polypeptide drugs and injection preparations. Even oral semaglutide still has many limitations in drug use. Therefore, it is still necessary to further develop small molecules of GLP-1 receptors. Agonist drugs.
- GLP-1 stimulates insulin secretion in a glucose-dependent manner, and inhibits glucagon secretion in a glucose-dependent manner, so there is no risk of hypoglycemia.
- GLP-1 can increase the amount of insulin produced by beta cells and improve the responsiveness of beta cells to glucose.
- GLP-1 can delay gastric emptying, reduce food intake, and thus have the effect of weight loss.
- GLP-1 also has the unique effect of cardiovascular and cerebrovascular benefits.
- GLP-1 receptor agonists are positioned in the transition stage between oral hypoglycemic drugs and insulin in clinical application, and can be used in combination with other drugs, becoming the fastest growing in the past five years and the fastest growing in the future. Potential hypoglycemic drugs.
- diabetic nephropathy diabetic eye complications (diabetic retinopathy, diabetes-related uveitis, diabetic cataracts), diabetic foot, diabetic cardiovascular complications, diabetic cerebrovascular disease , diabetic neuropathy, obesity, hypertension.
- diabetic eye complications diabetes-related uveitis, diabetic cataracts
- diabetic foot diabetic cardiovascular complications
- diabetic cerebrovascular disease diabetic neuropathy, obesity, hypertension.
- GLP-1 receptor agonists are currently mostly in the form of injection.
- the current progress in the development of known GLP-1 receptor agonist small molecules is as follows:
- WO2009111700A2 discloses a series of oxadiazepine GLP-1 receptor agonist compounds
- WO2010114824A1 discloses a series of substituted azoanthracene derivatives GLP-1 receptor agonist compounds
- WO2017078352A1 discloses a series of ring GLP-1 receptor agonist compounds of hexene derivatives
- KR1020180101671A discloses a series of GLP-1 receptor agonist compounds of heteroaryl substituted pyridine[1,2-a]imidazole derivatives
- WO2018056453A1 discloses A series of GLP-1 receptor agonist compounds of pyrazolopyridine derivatives
- WO2018109607A1 discloses a series of GLP-1 receptor agonist compounds similar to the present application, and the like.
- T 1 and T 2 are each independently selected from CH 2 , NH, O, S;
- W 1 is selected from O, S, CH 2 , NH;
- W 2 is selected from O, NH, CH 2 , CR y ;
- Z 1 , Z 2 , Z 3 , Z 4 are each independently selected from CH, N or C;
- X 1 , X 2 , X 3 are independently selected from CH, N or C, and at most two of X 1 , X 2 , and X 3 are N;
- Ring B is selected from benzene ring or 5-7 membered heteroaromatic ring;
- Ring C is selected from benzene ring, 4-8 membered heterocycle, 5-10 membered spiro ring, 5-10 membered bridged ring and 5-7 membered heteroaromatic ring;
- R 2 is independently selected from hydrogen, oxo, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 alkoxy, -C 1- 6 -cycloalkoxy, cyano, 3-8-membered cycloalkyl, 3-8-membered heterocyclic group, phenyl, 5-8-membered heteroaryl, wherein the halogen, alkyl, alkenyl, alkyne in R 2 group, amino group, alkoxy group, cycloalkoxy group, cycloalkyl group, heterocyclyl group, phenyl group, heteroaryl group can be optionally substituted 1 to 3 times by a substituent independently selected from R x ;
- R 3 is independently selected from hydrogen, oxo, halogen, -CN, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 alkoxy, amine group, amide group, sulfonyl group, sulfonamide group, -OH, -C 3-8 cycloalkyl, 3-8-membered heterocyclic group, 6-10-membered aryl, 5-8-membered heteroaryl, wherein R 3 Under the conditions allowed by the valence, it can be optionally substituted 1-3 times by a substituent independently selected from R y ;
- R 4 is independently selected from hydrogen, halogen, -C 1-3 alkyl, -C 1-3 haloalkyl, -C 1-3 alkoxy, cyano, hydroxyl, amino, amido, sulfonyl, sulfonyl amide group;
- R 5 is independently selected from hydrogen, halogen, hydroxyl, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 1-3 cycloalkyl, wherein the alkyl group in R 5 , alkoxy, cycloalkyl can be optionally composed of halogen, hydroxyl, -NR z , -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 1 under the conditions allowed by the valence ⁇ 3 cycloalkyl substituted 1 to 3 times;
- R 6 is selected from -R z , -OR z , -SR z , -C 1-3 alkyl, -C 1-3 alkylene-R z , -C 0-3 alkylene-amino-R z , -C 0-3 alkylene-carbonyl-R z , -C 0-3 alkylene-amide-R z , -C 0-3 alkylene-sulfonyl-R z , -C 0-3 Alkylene-phosphoryl-R z , -C 0-3 alkylene-sulfonamido-R z , wherein the alkyl, amine, amide, sulfonyl, sulfonamido, phosphorus in the R 6
- the acyl group can be optionally substituted 1 to 3 times by halogen or 1 time by R w under the conditions allowed by the valence;
- R7 is selected from -COOH, -C( Ry ) n0 -COOH, -N( Rz ) n0 -COOH, -SO2 -COOH and -SO2 -NH-COOH, the -C( Ry ) n0 R y in - can be connected to C in the form of main chain and/or branched chain, and R z in -N(R z ) n0 - can be connected to N in the form of main chain and/or branched chain , wherein n 0 is an integer selected from 0, 1 or 2; when n 0 is 2, two R y or R z can be further cyclized into a 3-8 membered carbocyclic or heterocyclic ring;
- n is an integer selected from 0, 1, 2 or 3;
- n is an integer selected from 0, 1 or 2;
- o is an integer selected from 0, 1, 2, 3 or 4;
- p is an integer selected from 0, 1, 2, 3 or 4;
- any two R 1 can be further cyclized into a 3- to 8-membered carbocycle, aromatic ring, heterocycle or aromatic heterocycle. It is selected to be substituted 1-3 times by C 1-3 alkyl, C 1-3 haloalkyl, halogen, cyano, and C 1-3 alkoxy;
- the two R 3 can be further cyclized into a 3- to 8-membered carbocyclic or heterocyclic ring;
- R 1 and R 3 can be further cyclized into a 3- to 8-membered carbocyclic or heterocyclic ring;
- any two R 5 can be further cyclized with ring C to form a 6- to 10-membered spiro or bridged ring, and the formed spiro and bridged rings can be optionally composed of C 1 ⁇ 3 alkyl, C 1-3 haloalkyl, halogen, cyano, C 1-3 alkoxy substituted 1 to 3 times;
- any R 4 and R 5 can be further cyclized into a 5-8 membered ring, and the formed ring can optionally have C 1-3 alkyl, C 1-3 haloalkyl, halogen, cyano, oxo, C 1-3 alkoxy substituted 1-3 times;
- R w is independently selected from -CN, -CH 2 CN, -C 1-3 alkyl, -OH, -C 1-3 alkoxy, amido, sulfonyl, sulfonamido, -NH 2 , -NH -C 1-3 alkyl group, wherein the alkyl group in R w can be optionally composed of C 1-3 alkyl group, C 1-3 haloalkyl group, halogen, cyano, oxo, C 1-3 alkoxy substituted 1-3 times;
- R x is independently selected from hydrogen, halogen, oxo, C 1-6 alkoxy, cyano, hydroxyl, carboxyl, amino, amido, sulfonyl, sulfonamido, -C 1-6 alkyl, - C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, wherein the The alkyl group, alkoxy group, cycloalkyl group, heterocyclic aryl group and heteroaryl group in R x can be optionally composed of C 1-3 alkyl, C 1-3 haloalkyl, halogen, Cyano, oxo, C 1-3 alkoxy are substituted 1 to 3 times or optionally substituted once by hydroxyl;
- R y is independently selected from hydrogen, halogen, oxo, -C 1-3 alkoxy, cyano, hydroxyl, amino, carboxyl, amido, sulfonyl, sulfonamido, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, wherein the R y in the alkyl, Alkenyl, alkynyl, amino, amido, alkoxy, cycloalkyl, heterocyclic, and heteroaryl can be optionally composed of C 1-3 alkyl, C 1-3 haloalkanes under the conditions allowed by the valence base, halogen, cyano, oxo, C 1-3 alkoxy substituted 1-3 times;
- R z is independently selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl, Wherein R z can be optionally composed of C 1-3 alkyl, C 1-3 haloalkyl, halogen, cyano, oxo, C 1-3 alkoxy, 3-6 membered heterocycle under the conditions allowed by the valence The base is substituted 1 to 3 times.
- the ring B can be further selected from:
- ring B is preferably
- the ring C can be further selected from:
- ring C is preferably
- Z 1 and Z 4 are independently selected from CH, N;
- X 1 , X 2 , X 3 are independently selected from CH, N or C, and at most two of X 1 , X 2 , and X 3 are N;
- Y 1 is selected from CH or N;
- Y 2 is selected from CH, N or C;
- Y 3 is selected from CH or N;
- R 2 is independently selected from hydrogen, oxo, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 alkoxy, -C 1- 6 -cycloalkoxy, cyano, 3-8-membered cycloalkyl, 3-8-membered heterocyclic group, phenyl, 5-8-membered heteroaryl, wherein the halogen, alkyl, alkenyl, alkyne in R 2 group, amino group, alkoxy group, cycloalkoxy group, cycloalkyl group, heterocyclyl group, phenyl group, heteroaryl group can be optionally substituted 1 to 3 times by a substituent independently selected from R x ;
- R 3 is independently selected from hydrogen, oxo, halogen, -CN, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 alkoxy, amine group, amide group, sulfonyl group, sulfonamide group, -OH, -C 3-8 cycloalkyl, 3-8-membered heterocyclic group, 6-10-membered aryl, 5-8-membered heteroaryl, wherein R 3 Under the conditions allowed by the valence, it can be optionally substituted 1-3 times by a substituent independently selected from R y ;
- R 4 is independently selected from hydrogen, halogen, -C 1-3 alkyl, -C 1-3 haloalkyl, -C 1-3 alkoxy, cyano, hydroxyl, amino, amido, sulfonyl, sulfonyl amide group;
- R 5 is independently selected from hydrogen, halogen, hydroxyl, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 1-3 cycloalkyl, wherein the alkyl group in R 5 , alkoxy, cycloalkyl can be optionally composed of halogen, hydroxyl, -NR z , -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 1 under the conditions allowed by the valence ⁇ 3 cycloalkyl substituted 1 to 3 times;
- R 6 is selected from -R z , -OR z , -SR z , -C 1-3 alkyl, -C 1-3 alkylene-R z , -C 0-3 alkylene-amino-R z , -C 0-3 alkylene-carbonyl-R z , -C 0-3 alkylene-amide-R z , -C 0-3 alkylene-sulfonyl-R z , -C 0-3 Alkylene-phosphoryl-R z , -C 0-3 alkylene-sulfonamido-R z , wherein the alkyl, amine, amide, sulfonyl, sulfonamido, phosphorus in the R 6
- the acyl group can be optionally substituted 1 to 3 times by halogen or 1 time by R w under the conditions allowed by the valence;
- R7 is selected from -COOH, -C( Ry ) n0 -COOH, -N( Rz ) n0 -COOH, -SO2 -COOH and -SO2 -NH-COOH, the -C( Ry ) n0 R y in - can be connected to C in the form of main chain and/or branched chain, and R z in -N(R z ) n0 - can be connected to N in the form of main chain and/or branched chain , wherein n 0 is an integer selected from 0, 1 or 2; when n 0 is 2, two R y or R z can be further cyclized into a 3-8 membered carbocyclic or heterocyclic ring;
- n is an integer selected from 0, 1, 2 or 3;
- o is an integer selected from 0, 1, 2, 3 or 4;
- p is an integer selected from 0, 1, 2, 3 or 4;
- any two R 1 can be further cyclized into a 3- to 8-membered carbocycle, aromatic ring, heterocycle or aromatic heterocycle. It is selected to be substituted 1-3 times by C 1-3 alkyl, C 1-3 haloalkyl, halogen, cyano, and C 1-3 alkoxy;
- any two R 5 can be further cyclized with ring C to form a 6- to 10-membered spiro or bridged ring, and the formed spiro and bridged rings can be optionally composed of C 1 ⁇ 3 alkyl, C 1-3 haloalkyl, halogen, cyano, C 1-3 alkoxy substituted 1 to 3 times;
- any R 4 and R 5 can be further cyclized into a 5-8 membered ring, and the formed ring can optionally have C 1-3 alkyl, C 1-3 haloalkyl, halogen, cyano, oxo, C 1-3 alkoxy substituted 1-3 times;
- R w is independently selected from -CN, -CH 2 CN, -C 1-3 alkyl, -OH, -C 1-3 alkoxy, amido, sulfonyl, sulfonamido, -NH 2 , -NH -C 1-3 alkyl, wherein the alkyl group in R w can be optionally composed of C 1-3 alkyl, C 1-3 haloalkyl, halogen, cyano, C 1- 3 alkoxy is substituted 1 to 3 times;
- R x is independently selected from hydrogen, halogen, oxo, C 1-6 alkoxy, cyano, hydroxyl, carboxyl, amino, amido, sulfonyl, sulfonamido, -C 1-6 alkyl, - C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, wherein the The alkyl, alkoxy, cycloalkyl, heterocyclylaryl and heteroaryl groups in R x can be optionally substituted 1 to 3 times by halogen or 0 to 1 times by hydroxy under the condition that the valence allows ;
- R y is independently selected from hydrogen, halogen, oxo, -C 1-3 alkoxy, cyano, hydroxyl, amino, carboxyl, amido, sulfonyl, sulfonamido, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl, 3-6 membered heterocyclic group, wherein in the R y , alkyl, alkoxy, cycloalkyl, The heterocyclyl group can be optionally substituted 1 to 3 times with halogen under the conditions allowed by the valence;
- R z is independently selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 4-6 membered heterocycle, 5-6 membered aryl or 5-6 membered heterocycle Aryl, wherein R z can be optionally halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 3-6 membered hetero- The cyclic group is substituted 1 to 3 times.
- any adjacent R 4 and R 5 can be further cyclized into a 5- to 8-membered ring;
- the 5- to 8-membered ring includes C 5-6 carbon ring, 5-8 membered heterocycle, benzene ring, 5-8 membered heteroaromatic ring,
- the formed ring can be optionally composed of alkyl, haloalkyl, halogen, cyano, alkane under the conditions allowed by the compound Oxygen is substituted 1 to 3 times.
- any adjacent R 4 and R 5 can be further cyclized into a 5-8 membered ring, and the 5-8 membered ring can be selected from
- the formed 5- to 8-membered ring can be optionally substituted by C 1-3 alkyl, C 1-3 haloalkyl, halogen, cyano, oxo, C 1-3 alkoxy under the conditions allowed by the valence ⁇ 3 times.
- any adjacent R 4 and R 5 can be further cyclized into a 5- to 8-membered ring, and the 5- to 8-membered ring is preferably:
- the formed 5- to 8-membered ring can be optionally substituted by C 1-3 alkyl, C 1-3 haloalkyl, halogen, cyano, oxo, C 1-3 alkoxy under the conditions allowed by the valence ⁇ 3 times.
- any adjacent R 4 and R 5 can be further cyclized into a 5-8 membered ring, and the 5-8 membered ring can be selected from :
- the formed 5- to 8-membered ring can be optionally substituted by C 1-3 alkyl, C 1-3 haloalkyl, halogen, cyano, oxo, C 1-3 alkoxy under the conditions allowed by the valence ⁇ 3 times.
- the structural unit Can be further selected from:
- the compound of formula I described in the present invention can have the following sub-general formula,
- the n is selected from 1, 2 or 3.
- the p is selected from 0, 1 or 2.
- the R 1 can be further independently selected from -F, -Cl, -CN, -OCH 3 , -OCH 2 CH 3 , -O-cyclopropyl, -CH 3 , - CH2CH3 , -CH2CH2CH3 , - ( CH ) 2CH3 , -COCH3 , -CONH2 , -CF3 , -CHF2 , -CH2F , -CH2CH2F , - CO-cyclopropyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl.
- the R 3 can be further selected from -F, -Cl, -CH 3 , -OCH 3 , -NH 2 , -OH, -CH 2 CH 3 , -CH 2 OH, - NHCH3 , -COCH3 , -SO2CH3 , -OCH2CH3 , -CF3 , -CHF2 , -CH2F , isopropyl , cyclopropyl, fluorocyclopropyl .
- the R y can be further selected from -F, -Cl, methyl, ethyl, trifluoromethyl, difluoromethyl, fluoromethyl, fluoroethyl, methoxy , amino, hydroxyl, propyl, isopropyl, cyclopropyl, cyclobutyl.
- R y in -C(R y ) n0 -COOH of R 7 can be connected to C in the form of main chain and/or branched chain; when R y is connected in the form of main chain When it is on C of R 7 , R y exists in the form of a corresponding subunit; when R y is connected to C of R 7 in a branched form, R y exists in the form of a corresponding saturated group.
- R z in -N(R z ) n0 -COOH of R 7 can be connected to N in the form of main chain and/or branched chain; when R z is connected in the form of main chain When on C of R 7 , R z exists in the form of the corresponding subunit; when R y is connected to the N of R 7 in the form of a branched chain, R z exists in the form of the corresponding saturated group.
- R y in the -C(R y ) n -COOH of R 7 is a methyl group
- the connecting on C in the form of the main chain refers to the The structure is connected (that is, R 7 is -CH 2 - at this time)
- the described connection on C in the form of a branched chain refers to the The structure is connected (that is, R 7 is -CH 3 at this time).
- the R 6 is selected from -R z , -OR z , -SR z , -C 1-3 alkylene-R z , -C 0-3 alkylene-amine -R z , -C 0-3 alkylene-carbonyl-R z , wherein the alkyl group, amine group, amide group, sulfonyl group, sulfonamide group and phosphoryl group in the R 6 can be used under the conditions allowed by the valence Optionally substituted 1 to 3 times by halogen or 1 time by R w .
- the R z can be further selected from: methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, R z can be optionally substituted 1 with halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclic group under the conditions allowed by the valence ⁇ 3 times.
- the R 1 can be further independently selected from -F, -Cl, -CN, -OCH 3 , -OCH 2 CH 3 , -CH 3 , -CH 2 CH 3 , -COCH 3 , -CONH 2 , -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CH 2 F, -CO-cyclopropyl, 5-6 membered heterocyclic group, 5-6 membered heteroaryl group.
- the R 2 can be further independently selected from -H, -CH 3 , -CHF 2 , -CH 2 F, -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 F, -NH 2 , cyclopropyl, 5-6 membered heterocyclic group, 5-6 membered heteroaryl group.
- the R 3 can be further selected from -F, -Cl, -CH 3 , -OCH 3 , -NH 2 , -OH, -CH 2 CH 3 , -CH 2 OH, - NHCH3 , -COCH3 , -SO2CH3 , -OCH2CH3 , -CF3 , -CHF2 , -CH2F , isopropyl , cyclopropyl, fluorocyclopropyl .
- the R 4 can be further selected from -CN, -CH 3 , -OH, -CH 2 OH, -CH 2 OCH 3 , -OCH 3 , -NH 2 , -NHCH 3 , -COCH 3 , -OCH 2 CH 3 .
- the R 5 is selected from -F, -Cl, -CN, -CH 3 , -CH 2 CH 3 , -CF 3 , -CHF 2 , -CH 2 F, -CH 2 OH , -OH , -CH2OCH3 , -OCH3 , -CH2CH2OH , -CH2CH2OCH3 , isopropyl or cyclopropyl .
- the R 7 is selected from -COOH, -CH 2 COOH, -CH 2 CH 2 COOH, -CH(CH 3 )COOH, wherein the R 7 can be valence-allowed Optionally substituted 1-3 times by halogen.
- the present invention provides a series of compounds, which are independently selected from one of the following compounds or any combination thereof:
- the present invention provides a series of compounds, which are independently selected from one of the following compounds or any combination thereof:
- the compounds provided herein, and pharmaceutically acceptable salts thereof, can be used alone or in combination with at least one other therapeutic agent in therapy.
- the present invention provides a pharmaceutical composition, which contains a compound represented by formula I and a pharmaceutically acceptable salt thereof, and one or more other therapeutically active ingredients.
- the present invention also provides a pharmaceutical preparation, which contains the compound shown in formula I and a pharmaceutically acceptable salt thereof, and one or more than two pharmaceutically acceptable carriers; the pharmaceutical preparation is any clinically acceptable A formulation dosage form.
- the compounds provided by the present invention and their pharmaceutically acceptable salts can be formed into solid dosage forms, such as capsules, tablets, pills, lozenges, sugar coatings, granules, powders, ointments, creams, drops, etc.; the present invention
- the provided compounds and pharmaceutically acceptable salts thereof can be in liquid dosage forms such as elixirs, syrups, emulsions, dispersions, suspensions, solutions, sprays and the like.
- the pharmaceutically acceptable carriers and/or pharmaceutically acceptable diluents usable in the pharmaceutical compositions or pharmaceutical formulations of the present invention may be any conventional carriers and/or diluents in the field of pharmaceutical formulations.
- the pharmaceutically acceptable salts of the present invention include acid salts and base salts.
- the pharmaceutically acceptable salts of the present invention can exist in unsolvated as well as solvated forms.
- the present invention also provides compounds of formula I and pharmaceutically acceptable salts thereof, which are used in the preparation of medicaments for the treatment and/or metabolism-related diseases.
- Said metabolism-related diseases include GLP-1 mediation.
- diseases and related diseases including but not limited to: diabetes mellitus, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, hyperlipidemia Insulinemia, etc.; wherein, the diabetes includes, but is not limited to, T1D and/or T2DM, idiopathic T1D, early-onset T2D, latent autoimmune diabetes, juvenile atypical diabetes, gestational diabetes and the like.
- the present invention also provides a method for treating a disease, comprising administering to a patient in need a therapeutically effective amount of a compound represented by formula I and a pharmaceutically acceptable salt thereof, wherein the disease is GLP -1-mediated diseases and related diseases; such diseases include but are not limited to: diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, Obesity, dyslipidemia, hyperinsulinemia, etc.; wherein, the diabetes includes, but is not limited to, T1D and/or T2DM, idiopathic T1D, early-onset T2D, latent autoimmune diabetes, juvenile SARS type diabetes, gestational diabetes, etc.
- diseases include but are not limited to: diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, Obesity, dyslipidemia, hyperinsulinemia
- the compounds of formula I and pharmaceutically acceptable salts thereof provided by the present invention have excellent GLP-1 receptor agonistic activity, and can treat and/or prevent GLP-1-mediated diseases and related diseases.
- the compounds of formula I and pharmaceutically acceptable salts thereof provided by the present invention have excellent GLP-1 receptor agonistic activity, and can treat and/or prevent GLP-1-mediated diseases and related diseases.
- the present invention also provides the use of the above-mentioned compounds or their pharmaceutically acceptable salts in the preparation of medicines related to GLP-1 receptor agonists.
- the GLP-1 receptor agonist-related drug is for the treatment of Type II diabetes, Type I diabetes and obesity.
- the compounds described in the present invention are named according to the chemical structural formula. If the name of the compound is inconsistent with the chemical structural formula when it represents the same compound, the chemical structural formula shall prevail.
- the compounds provided by the present invention and their pharmaceutically acceptable salts can exist in a chiral form, ie, S configuration or R configuration.
- the compounds provided by the present invention and their pharmaceutically acceptable salts may exist in an achiral form.
- the compounds of the present invention include stereoisomers of the compounds.
- the stereoisomers mentioned in the present invention refer to enantiomers when the compound represented by formula I has an asymmetric carbon atom; when the compound has a carbon-carbon double bond or a cyclic structure, a cis Trans-isomers; tautomers are produced when compounds are present in the presence of a ketone or oxime.
- the stereoisomers described in the present invention include but are not limited to: enantiomers, diastereomers, racemates, cis-trans isomers, tautomers isomers, geometric isomers, epimers and mixtures thereof.
- the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
- the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
- Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
- enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
- cis-trans isomer or “geometric isomer” result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
- diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
- Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
- a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric salt is formed by conventional methods known in the art.
- the method performs the resolution of diastereomers, followed by recovery of the pure enantiomers.
- separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg from amine to amine carboxylate).
- the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
- compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
- deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues, without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- salts of the present invention refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
- base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
- acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base
- the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
- substituted in the present invention means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substitution Compounds are stable.
- Oxygen substitution does not occur on aromatic groups.
- optionally substituted means that it may or may not be substituted. Unless otherwise specified, the kind and number of substituents can be arbitrary on the basis of chemical realization.
- any variable eg, R
- its definition in each case is independent.
- the group may optionally be substituted with up to two Rs, with independent options for R in each case.
- combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
- substituent R can be substituted at any position on cyclohexyl or cyclohexadiene.
- substituents do not indicate through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine ring The carbon atom is attached to the substituted group.
- the direction of attachment is arbitrary, for example,
- the linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
- Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- any one or more sites in the group can be linked to other groups by chemical bonds.
- connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group.
- the chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines express.
- a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
- the straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
- the wavy line in the phenyl group indicates that it is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
- the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” refers to a “ring” of 5-7 atoms arranged around it.
- halogen atom in the present invention means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
- Preferred halogen atoms as substituents of the aryl group of the present invention are fluorine atoms and chlorine atoms.
- Preferred halogen atoms as substituents of the alkyl group of the present invention are fluorine atoms and chlorine atoms.
- C 1-6 alkyl groups having halogen atoms as substituents include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, pentafluoroethyl, 2-fluoroethyl, 2,2, 2-trifluoroethyl, 2-chloroethyl, heptafluoropropyl, 3,3,3-trifluoropropyl, 2,3-dichloropropyl, 1-fluoro-3-bromopropyl, 4- bromobutyl, 3,3,3,4,4-pentafluorobutyl, 4,4-dichlorobutyl, 5-iodopentyl, 5,5-difluoropentyl, 6-chlorohexyl and 6, 6,6-Trifluorohexyl.
- C 1-6 alkyl in the present invention is a straight or branched chain alkyl group having 1 to 6 carbons, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1-dimethylpropyl, 1-ethylpropyl , n-hexyl, 4-methylpentyl and 2-ethylbutyl.
- C 1-6 alkoxy in the present invention means a group C 1-6 alkyl-O-, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, 1-methylpropoxy, n-pentyloxy, isopentyloxy, 2-methylbutoxy, 1, 1-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentyloxy and 2-ethylbutoxy.
- aryl in the present invention refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 14 10-membered rings such as phenyl and naphthyl, more preferably phenyl.
- the aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, including benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclyl, wherein the heterocyclyl It is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms and sulfur atoms; or a three-membered nitrogen-containing fused ring containing a benzene ring.
- heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
- Heteroaryl is preferably 5 to 10-membered, more preferably 5- or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl.
- the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a
- Heteroaryl groups can be optionally substituted or unsubstituted.
- the substituents are preferably one or more independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate group.
- 5-6 membered heteroaryl ring and “5-6 membered heteroaryl” are used interchangeably herein.
- the term “5-6 membered heteroaryl” refers to a monocyclic group consisting of 5 to 6 ring atoms with a conjugated ⁇ -electron system, wherein 1, 2, 3 or 4 ring atoms are independently selected from O, S and N heteroatoms, the remainder being carbon atoms, where the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (ie, NO and S(O) p , p is 1 or 2).
- a 5-6 membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom.
- the 5-6 membered heteroaryl groups include 5- and 6-membered heteroaryl groups.
- Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrrolyl and 3-pyrrolyl, etc.) azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,
- alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
- alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
- Alkoxy can be optionally substituted or unsubstituted, when substituted, the substituents are preferably one or more independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkane A thio, carboxyl or carboxylate group.
- haloalkyl refers to an alkyl group substituted with one or more halogens.
- 3- to 8-membered heterocyclic group in the present invention means a non-aromatic cyclic group containing one or more heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, and which may be fully saturated or partially unsaturated.
- the ring may be a 3- to 8-membered monocyclic, bicyclic or spirocyclic ring.
- oxetanyl Including, but not limited to, oxetanyl, azetidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, pyrazolidinyl, thiacyclohexyl, oxanyl, thiaoxanyl, indoline, isodihydro Indolyl, tetrahydroindolyl, quinuclidinyl, azepinyl, etc.
- heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:
- C 3-8 cycloalkyl in the present invention means a monovalent group obtained by removing any single hydrogen atom from a cyclic saturated aliphatic hydrocarbon having 3 to 8 carbons, ie, a ring of 3 to 8 carbons alkyl. Including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- the resulting group may be divalent, such as cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, cyclopentane Alkane-1,1-diyl, cyclohexane-1,1-diyl, cycloheptane-1,1-diyl and cyclooctane-1,1-diyl.
- the cycloalkane rings, carbocyclic rings, and cyclic hydrocarbons in the cycloalkyl group may be cross-linked rings.
- fused ring refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings Can contain one or more double bonds, but none of the rings have a fully conjugated pi electron system.
- the fused ring is preferably 6 to 14 membered, more preferably 7 to 10 membered.
- fused rings can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl . It includes but is not limited to:
- Carbon atoms in fused rings may be optionally replaced by heteroatoms of O, S, N, ie, "fused heterocycles" are also included.
- fused heterocycle refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) t (where t is an integer from 0 to 2) heteroatoms, the rest of the ring atoms are carbon.
- the fused heterocycle is preferably 6 to 14 membered, more preferably 7 to 10 membered.
- fused heterocycles can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/3-membered, 5-membered/4-membered or 5-membered Member/5-membered bicyclic fused heterocyclic group.
- Fused heterocycles include but are not limited to:
- bridged ring in the present invention refers to a 5- to 20-membered all-carbon polycyclic group, wherein any two rings share two carbon atoms that are not directly connected, and the bridged ring may contain one or more double bonds, but None of the rings have a fully conjugated pi electron system.
- the bridged ring is preferably 6 to 14 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged ring groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
- Bridge rings include but are not limited to:
- the carbon atoms in the bridged ring may be optionally replaced by heteroatoms of O, S, N, ie "bridged heterocycles" are also included.
- bridged heterocycle in the present invention refers to a 5- to 14-membered polycyclic heterocycle group, any two rings share two atoms that are not directly connected, and the bridged heterocycle may contain one or more double bonds, but None of the rings has a fully conjugated pi-electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon.
- the bridged heterocycle is preferably 6 to 14 membered, more preferably 7 to 10 membered.
- Bridged heterocycles can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic bridged heterocycles, more preferably bicyclic or tricyclic bridged heterocycles .
- Bridged heterocycles include, but are not limited to:
- spirocycle in the present invention refers to a 5- to 20-membered polycyclic group in which a single carbon atom (called a spiro atom) is shared between the single rings, and the spiro ring may contain one or more double bonds, but none
- the ring has a fully conjugated pi electron system.
- the spiro ring is preferably 6 to 14 membered, more preferably 7 to 10 membered.
- spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl. It includes but is not limited to:
- the carbon atoms in the spiro rings can be optionally replaced by heteroatoms of O, S, N, ie "spiroheterocycles" are also included.
- spiroheterocycle in the present invention refers to a 5- to 20-membered polycyclic heterocyclic group, wherein one atom (called a spiro atom) is shared between the single rings, and one or more ring atoms are selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) heteroatoms and the remaining ring atoms are carbon. Spiroheterocycles can contain one or more double bonds, but none of the rings have a fully conjugated pi electron system.
- the spiroheterocycle is preferably 6 to 14 membered, more preferably 7 to 10 membered.
- spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl. It includes but is not limited to:
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art equivalent replacement. Preferred embodiments include, but are not limited to, the embodiments of the present invention.
- the compounds described in the present invention are named according to the chemical structural formula. If the name of the compound is inconsistent with the chemical structural formula when it represents the same compound, the chemical structural formula shall prevail.
- the mass spectrum of the present invention is obtained by measuring with LC/MS instrument, and the ionization mode can be ESI or APCI.
- GLP-1R-mediated agonist activity was determined by a cell-based functional assay using a homogeneous time-resolved fluorescence (ie, HTRF) cAMP detection kit that measures cAMP levels in cells.
- the method is a competitive immunoassay. It enables direct pharmacological characterization of compounds acting on Gs-coupled receptors in adherent or suspension cells.
- Cell-generated native cAMP or unlabeled cAMP standard curves compete with the D2-labeled cAMP red acceptor for binding to the monoclonal anti-cAMP cryptate europium donor, with a specific signal that is inversely proportional to the concentration of cAMP in the standard or experimental sample.
- the human GLP-1R coding sequence (NCBI reference sequence NP_002053.3) was subcloned into pEGFP-N1 (tsingke), and a cell line stably expressing the receptor was isolated, and GLP-1R was confirmed by observing GFP expression under a fluorescence microscope expression density.
- GFP-GLP-1R cells were cultured in DMEM growth medium, 10% heat-inactivated fetal bovine serum (GEMINI Cat#900-108), 1% Pen-3Trep (Sangom Biotech Cat#E607011-0100)] and incubated in Incubate in a humidified and 5% CO2 incubator at 37 °C.
- DMEM growth medium 10% heat-inactivated fetal bovine serum (GEMINI Cat#900-108), 1% Pen-3Trep (Sangom Biotech Cat#E607011-0100)
- Cells were harvested from T25 tissue culture flasks and centrifuged at 1000 rpm for 5 minutes at room temperature. The cell pellet was then resuspended in 1 ml of stimulation buffer. A 20 ⁇ L sample of cell suspension was counted on a counter STAR IC1000 to determine cell viability and cell count per milliliter. The remaining cell suspension was then adjusted with stimulation buffer to deliver 2000 viable cells per well using a multichannel pipette. Add 5 ⁇ L of cell suspension to each well of the assay plate already containing compound. The plate was sealed and incubated at 37 °C with 5% CO for 30 min.
- d2-labeled cAMP and 5 ⁇ L of anti-cAMP cryptate were added to each well of the assay plate.
- the plate was then incubated at room temperature, and after 60 minutes, the change in HTRF signal was read with a Tecan Spark plate reader with excitation at 340 nm/emission at 615 nm and 665 nm absorbance.
- the raw data were converted to nM cAMP by interpolation from the cAMP standard curve and the percent effect was determined relative to the saturating concentration of the full agonist GLP-17-37 (400 nM) contained on each plate.
- EC50 determinations were made from agonist dose-response curves analyzed with a curve fitting program using a 4-parameter logistic dose-response equation.
- This assay demonstrates that the compounds of the present invention activate GLP-1R signaling through the cAMP pathway and thus act as GLP-1R agonists.
- Experimental data are presented as geometric mean ( EC50s ) based on the number of repetitions listed.
- Experimental material stable cell line HEK-hERG, strain: HEK 293, source: Academy of Military Medical Sciences;
- Extracellular fluid mM: N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) 10, NaCl 145, KCl 4, CaCl 2 2, MgCl 2 1, Glucose 10, with hydroxide Adjust pH to 7.3-7.4 with sodium; adjust osmotic pressure to 290-310mOsm; store at 4°C after filtration.
- HEPES N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid
- EGTA ethylene glycol-bis( ⁇ -aminoethyl ether)-N,N,N',N'-tetraacetic acid
- HEPES 10 HEPES 10
- Na 2 -ATP 4 adjust the pH to 7.2-7.3 with potassium hydroxide
- adjust the osmotic pressure to 290-310mOsm
- Preparation of vehicle control add a certain volume of DMSO to the extracellular solution to make it contain the same content of DMSO as the final test solution (if the test solution contains different DMSO contents, the maximum DMSO content shall prevail) to exclude Interference of DMSO on the cell's own currents.
- Preparation of the test product The above-mentioned 10 mM stock solution is prepared in proportion to the DMSO stock solution of the required concentration (generally 1000/3 times the actual administration concentration), and finally the stock solution is diluted with extracellular fluid to the required concentration for the experiment. Dosing concentration.
- Preparation of positive control solution Weigh an appropriate amount of positive control substance and place it in a suitable container, add a certain volume of DMSO, fully stir or shake to dissolve it, and prepare a 10 mM stock solution, and then prepare a stock solution of the required concentration in proportion. Finally, the stock solution was diluted with extracellular fluid to the dosing concentration required for the experiment.
- the cells were washed with PBS (or DPBS), digested and separated with Tryple solution, and the cells were resuspended with medium and stored in a centrifuge tube, and the supernatant was discarded after centrifugation. , the cells were resuspended with extracellular fluid for use, and stored at 2-8°C. Before patch-clamp recordings, drop cells into the dish to ensure that the cells are at a certain density and that the cells are individually isolated.
- PBS or DPBS
- Test article/positive control Concentration ( ⁇ M) Compounds of the present invention 1. 10 Amitriptyline or Terfenadine 1
- hERG currents were recorded using whole-cell patch-clamp technique.
- the cell suspension was added to a small petri dish and placed on an inverted microscope stage. After the cells have adhered, perfuse with extracellular fluid.
- the recommended flow rate is 1–2 mL/min.
- the glass micro-electrode is drawn by a micro-electrode drawing apparatus in two steps, and the resistance value of the glass micro-electrode is 2-5M ⁇ after filling with the liquid in the electrode.
- the drug was administered by continuous extracellular perfusion from low concentration to high concentration. Start from a low concentration, continue perfusion until the drug effect is stable, and then proceed to the next concentration.
- the blocking effect of each test article and positive control on hERG tail current (N ⁇ 2) will be tested respectively; the actual concentration can be adjusted according to the actual solubility and effect, and it is not regarded as a deviation from the protocol.
- the stable drug effect is defined as: the last 5 stimulation strip current values of each concentration administration period change less than 10% of the mean value (when the current is greater than or equal to 200pA) or less than 30% of the mean value (when the current is less than 200pA), it can be considered that is stable, if not, the concentration data will not be taken.
- IR 100% ⁇ (peak tail current before administration-peak tail current after administration)/peak tail current before administration.
- Detection method LC-MS/MS-11 (8050), internal standard: tolbutamide, MS conditions are testosterone and test compound positive ion ESI; tolbutamide negative ion ESI; mobile phase: mobile phase A is 0.1% FA and water, mobile phase B is 0.1% FA in ACN; column and specifications: ACQUITY UPLC HSS T3 1.8um 2.1*50mm.
- the intermediate reaction materials used in the preparation process were prepared with reference to the preparation method described in WO2018109607A1.
- NBS (279 mg, 1.57 mmol) was added to a mixture of compound 1-1 (200 mg, 1.43 mmol) and BPO (7 mg, 0.03 mmol) in CCl 4 (5 mL), and then the reaction solution was stirred at 80° C. for 8 hours , after which the reaction mixture was quenched with saturated Na2S2O3 solution ( 5 mL ) .
- the solution was extracted with water (20 mL) and DCM (20 mL x 3), the combined organic phases were washed with brine (20 mL), dried ( Na2SO4 ) , filtered and concentrated. Flash chromatography ( SiO2 , 20% EtOAc-hexanes) gave 1-(5-(bromomethyl)thiophen-2-yl)ethan-1-one as compound 1-2 (260 mg, 83%).
- 6-5 (168 mg, 0.380 mmol) was dissolved in a solvent with TsOH.H2O (216.8 mg, 1.140 mmol) in EA (10 mL). The mixture was stirred at 60 °C for 1 h under N2 atmosphere. The mixture was stirred at room temperature for 16 h under N2 atmosphere. Filter, wash the filter cake with EA (5 mL*3), and dry the filter cake to give 6-6 (130 mg).
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Abstract
Description
试剂/仪器 | 供应商 | 型号 |
cAMP-GS DYNAMIC kit | CisBio | 62AM4PEC |
DMEM | CellMax | CGN101.5 |
FBS | Gemini | 900-108 |
1%Pen-3trep | Sangom biotech | E607011-0100 |
IBMX | Meilunbio | MB5226 |
384well plate | Corning | 3824 |
Incubator | Thermo | 3111 |
Microscope | 江南 | XD-202 |
Cell counter | Counter Star | Star IC1000 |
Plate reader | Tecan | Tecan Spark |
化合物编号 | EC 50(nM) |
1 | 4.67 |
2 | 88.78 |
3 | 121 |
4 | 1.0 |
5 | 0.56 |
6 | 0.03 |
7 | 0.02 |
8 | 0.05 |
9 | 0.08 |
10 | 0.05 |
11 | 0.1 |
12 | 0.5 |
13 | 0.47 |
供试品/阳性对照品 | 浓度(μM) |
本发明化合物 | 1、10 |
阿米替林或特非那定 | 1 |
化合物编号 | LMS(t 1/2min) |
1 | 114.9 |
4 | 132.3 |
5 | 37.33 |
7 | 21.25 |
10 | 22.54 |
12 | 59.84 |
Claims (14)
- 式I的化合物及其药学上可接受的盐,其中T 1和T 2分别独立地选自CH 2、NH、O、S;W 1选自O、S、CH 2、NH;W 2选自O、NH、CH 2、CR y;Z 1、Z 2、Z 3、Z 4分别独立地选自CH、N或C;X 1、X 2、X 3分别独立地选自CH、N或C,且X 1、X 2、X 3中至多有两个为N;环B选自苯环或5~7元杂芳环;环C选自苯环、4~8元杂环、5~10元螺环、5~10元桥环及5~7元杂芳环;R 1独立地选自R 2、-羰基-R 2、-羰基-胺基-R 2,-磺酰基-R 2,-酰胺基-R 2,-氧磷基-R 2,-胺基-R 2,-O-R 2,其中R 1中的R 2、胺基、酰胺基、磺酰基、氧磷基可任选地由独立选自R x的取代基取代1~3次;R 2独立地选自氢、氧代、卤素、-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、-C 1~6烷氧基、-C 1~6环烷氧基、氰基、3~8元环烷基、3~8元杂环基、苯基、5~8元杂芳基,其中R 2中的卤素、烷基、烯基、炔基、胺基、烷氧基、环烷氧基、环烷基、杂环基、苯基、杂芳基可任选地由独立选自R x的取代基取代1~3次;R 3独立地选自氢、氧代、卤素、-CN、-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、-C 1~6烷氧基、胺基、酰胺基、磺酰基、磺酰胺基、-OH、-C 3~8环烷基、3~8元杂环基、6~10元芳基、5~8元杂芳基,其中R 3在化合价允许的条件下可任选地由独立选自R y的取代基取代1~3次;R 4独立地选自氢、卤素、-C 1~3烷基、-C 1~3卤代烷基、-C 1~3烷氧基、氰基、羟基、胺基、酰胺基、磺酰基、磺酰胺基;R 5独立地选自氢、卤素、羟基、-CN、-C 1~3烷基、-C 1~3烷氧基、-C 1~3环烷基,其中所述R 5中的烷基、烷氧基、环烷基在化合价允许的条件下可任选地由卤素、羟基、-NR z、-CN、-C 1~3烷基、-C 1~3烷氧基、-C 1~3环烷基取代1~3次;R 6选自-R z、-O-R z、-S-R z、-C 1~3烷基、-C 1~3亚烷基-R z、-C 0~3亚烷基-胺基-R z、-C 0~3亚烷基-羰基-R z、-C 0~3亚烷基-酰胺基-R z、-C 0~3亚烷基-磺酰基-R z、-C 0~3亚烷基-磷酰基-R z、-C 0~3亚烷基-磺酰胺基-R z,其中所述R 6中的烷基、胺基、酰胺基、磺酰基、磺酰胺基、磷酰基在化合价允许的条件下可任选地由卤素取代1~3次或由R w取代1次;R 7选自-COOH、-C(R y) n0-COOH、-N(R z) n0-COOH、-SO 2-COOH和-SO 2-NH-COOH,所述-C(R y) n0-中的R y可以以主链和/或支链的形式连接在C上,所述-N(R z) n0-中的R z可以以主链和/或支链的形式连接在N上,其中n 0是选自0,1或2的整数;当n 0为2时,两个R y或R z可进一步环化为3~8元碳环或杂环;n是选自0、1、2或3的整数;m是选自0、1或2的整数;o是选自0、1、2、3或4的整数;p是选自0、1、2、3或4的整数;当m为2时,其中两个R 3可进一步环化为3~8元碳环或杂环;当m为1或2时,R 1和R 3可进一步环化为3~8元的碳环或杂环;当n大于等于2时,任意两个R 1可进一步环化为3~8元碳环、芳环、杂环或芳杂环,所形成的碳环和杂环在化合价允许的条件下可任选由C 1~3烷基、C 1~3卤代烷基、卤素、氰基、C 1~3烷氧基取代1~3次;当p大于等于2时,任意两个R 5可进一步与环C环化成6~10元螺环或桥环,所形成的螺环和桥环在化合价允许的条件下可任选由C 1~3烷基、C 1~3卤代烷基、卤素、氰基、C 1~3烷氧基取代1~3次;当o不为0且p不为0时,任意R 4和R 5可进一步环化成5~8元环,所形成的环在化合价允许的条件下可任选地有C 1~3烷基、C 1~3卤代烷基、卤素、氰基、氧代、C 1~3烷氧基取代1~3次;R w独立地选自-CN、-CH 2CN、-C 1~3烷基、-OH、-C 1~3烷氧基、酰胺基、磺酰基、磺酰胺基、-NH 2、-NH-C 1~3烷基,其中所述R w中的烷基在化合价允许的条件下可任选地由C 1~3烷基、C 1~3卤代烷基、卤素、氰基、氧代、C 1~3烷氧基取代1~3次;R x独立地选自氢、卤素、氧代、C 1~6烷氧基、氰基、羟基、羧基、胺基、酰胺基、磺酰基、磺酰胺基、-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、-C 3~6环烷基、3~6元杂环基、6~8元芳基、5~8元杂芳基,其中所述R x中烷基、烷氧基、环烷基、杂环基芳基和杂芳基在化合价允许的条件下可任选地由C 1~3烷基、C 1~3卤代烷基、卤素、氰基、氧代、C 1~3烷氧基取代1~3次或任选由羟基取代1次;R y独立地选自氢、卤素、氧代、-C 1~3烷氧基、氰基、羟基、胺基、羧基、酰胺基、磺酰基、磺酰胺基、-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、-C 3~6环烷基、3~6元杂环基,5~6元杂芳基,其中所述R y中烷基、烯基、炔基、胺基、酰胺基、烷氧基、环烷基、杂环基、杂芳基在化合价允许的条件下可任选地由C 1~3烷基、C 1~3卤代烷基、卤素、氰基、氧代、C 1~3烷氧基取代1~3次;R z独立地选自氢、C 1~3烷基、C 1~3烷氧基、C 3~6环烷基、3~6元杂环基、芳基、5~6元杂芳基,其中R z在化合价允许的条件下可任选地由C 1~3烷基、C 1~3卤代烷基、卤素、氰基、氧代、C 1~3烷氧基、3~6元杂环基取代1~3次。
- 根据权利要求1所述的式I化合物,该化合物为式I-2或式I-2’的化合物及其药学上可接受的盐,其中,进一步地,Z 1、Z 4分别独立地选自CH、N;X 1、X 2、X 3分别独立地选自CH、N或C,且X 1、X 2、X 3中至多有两个为N;Y 1选自CH或N;Y 2选自CH、N或C;Y 3选自CH或N;R 1独立地选自R 2、-羰基-R 2、-羰基-胺基-R 2,-磺酰基-R 2,-酰胺基-R 2,-氧磷基-R 2,-胺基-R 2,-O-R 2,其中R 1中的R 2、胺基、酰胺基、磺酰基、氧磷基可任选地由独立选自R x的取代基取代1~3次;R 2独立地选自氢、氧代、卤素、-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、-C 1~6烷氧基、-C 1~6环烷氧基、氰基、3~8元环烷基、3~8元杂环基、苯基、5~8元杂芳基,其中R 2中的卤素、烷基、烯基、炔基、胺基、烷氧基、环烷氧基、环烷基、杂环基、苯基、杂芳基可任选地由独立选自R x的取代基取代1~3次;R 3独立地选自氢、氧代、卤素、-CN、-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、-C 1~6烷氧基、胺基、酰胺基、磺酰基、磺酰胺基、-OH、-C 3~8环烷基、3~8元杂环基、6~10元芳基、5~8元杂芳基,其中R 3在化合价允许的条件下可任选地由独立选自R y的取代基取代1~3次;R 4独立地选自氢、卤素、-C 1~3烷基、-C 1~3卤代烷基、-C 1~3烷氧基、氰基、羟基、胺基、酰胺基、磺酰基、磺酰胺基;R 5独立地选自氢、卤素、羟基、-CN、-C 1~3烷基、-C 1~3烷氧基、-C 1~3环烷基,其中所述R 5中的烷基、烷氧基、环烷基在化合价允许的条件下可任选地由卤素、羟基、-NR z、-CN、-C 1~3烷基、-C 1~3烷氧基、-C 1~3环烷基取代1~3次;R 6选自-R z、-O-R z、-S-R z、-C 1~3烷基、-C 1~3亚烷基-R z、-C 0~3亚烷基-胺基-R z、-C 0~3亚烷基-羰基-R z、-C 0~3亚烷基-酰胺基-R z、-C 0~3亚烷基-磺酰基-R z、-C 0~3亚烷基-磷酰基-R z、-C 0~3亚烷基-磺酰胺基-R z,其中所述R 6中的烷基、胺基、酰胺基、磺酰基、磺酰胺基、磷酰基在化合价允许的条件下可任选地由卤素取代1~3次或由R w取代1次;R 7选自-COOH、-C(R y) n0-COOH、-N(R z) n0-COOH、-SO 2-COOH和-SO 2-NH-COOH,所述-C(R y) n0-中的R y可以以主链和/或支链的形式连接在C上,所述-N(R z) n0-中的R z可以以主链和/或支链的形式连接在N上,其中n 0是选自0,1或2的整数;当n 0为2时,两个R y或R z可进一步环化为3~8元碳环或杂环;n是选自0、1、2或3的整数;o是选自0、1、2、3或4的整数;p是选自0、1、2、3或4的整数;当n大于等于2时,任意两个R 1可进一步环化为3~8元碳环、芳环、杂环或芳杂环,所形成的碳环和杂环在化合价允许的条件下可任选由C 1~3烷基、C 1~3卤代烷基、卤素、氰基、C 1~3烷氧基取代1~3次;当p大于等于2时,任意两个R 5可进一步与环C环化成6~10元螺环或桥环,所形成的螺环和桥环在化合价允许的条件下可任选由C 1~3烷基、C 1~3卤代烷基、卤素、氰基、C 1~3烷氧基取代1~3次;当o不为0且p不为0时,任意R 4和R 5可进一步环化成5~8元环,所形成的环在化合价允许的条件下可任选地有C 1~3烷基、C 1~3卤代烷基、卤素、氰基、氧代、C 1~3烷氧基取代1~3次;R w独立地选自-CN、-CH 2CN、-C 1~3烷基、-OH、-C 1~3烷氧基、酰胺基、磺酰基、磺酰胺基、-NH 2、-NH-C 1~3烷基,其中所述R w中的烷基在化合价允许的条件下可任选地由C 1~3烷基、C 1~3卤代烷基、卤素、氰基、C 1~3烷氧基取代1~3次;R x独立地选自氢、卤素、氧代、C 1~6烷氧基、氰基、羟基、羧基、胺基、酰胺基、磺酰基、磺酰胺基、-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、-C 3~6环烷基、3~6元杂环基、6~8元芳基、5~8元杂芳基,其中所述R x中烷基、烷氧基、环烷基、杂环基芳基和杂芳基在化合价允许的条件下可任选地由卤素取代1~3次或任选由羟基取代0~1次;R y独立地选自氢、卤素、氧代、-C 1~3烷氧基、氰基、羟基、胺基、羧基、酰胺基、磺酰基、磺酰胺基、-C 1~6烷基、-C 2~6烯基、-C 2~6炔基、-C 3~6环烷基、3~6元杂环基,其中所述R y中烷基、烷氧基、环烷基、杂环基在化合价允许的条件下可任选地用卤素取代1~3次;R z独立地选自氢、C 1~3烷基、C 1~3烷氧基、C 3~6环烷基、4~6元杂环、5~6元芳基或5~6元杂芳基,其中R z在化合价允许的条件下可任选地用卤素、氰基、C 1~3烷基、C 1~3烷氧基、C 3~6环烷基、3~6元杂环基取代1~3次。
- 根据权利要求1所述的式I化合物,当o不为0且p不为0时,任意相邻的R 4和R 5可进一步环化为5~8元环;所述的5~8元环包括C 5~6碳环、5~8元杂环、苯环、5~8元杂芳环,形成的环在化合物允许的条件下可任选地由烷基、卤代烷基、卤素、氰基、烷氧基取代1~3次;其中,当o不为0且p不为0时,任意相邻的R 4和R 5可进一步环化成5~8元环,所述的5~8元环可选自: 所成的5~8元环在化合价允许的条件下可任选地由C 1-3烷基、C 1-3卤代烷基、卤素、氰基、氧代、C 1-3烷氧基取代1~3次;和/或,当o不为0且p不为0时,任意相邻的R 4和R 5可进一步环化成5~8元环,所述的5~8 元环优选为: 所成的5~8元环在化合价允许的条件下可任选地由C 1-3烷基、C 1-3卤代烷基、卤素、氰基、氧代、C 1-3烷氧基取代1~3次;
- 根据权利要求1所述的式I化合物,所述的n选自1、2或3;和/或,所述的p选自0、1或2。
- 根据权利要求1所述的式I化合物,所述的R 1可进一步独立地选自-F、-Cl、-CN、-OCH 3、-OCH 2CH 3、-O-环丙基、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-(CH) 2CH 3、-COCH 3、-CONH 2、-CF 3、-CHF 2、-CH 2F、-CH 2CH 2F、-CO-环丙基、5~6元杂环基、5~6元杂芳基;和/或,所述的R 3可进一步选自-F、-Cl、-CH 3、-OCH 3、-NH 2、-OH、-CH 2CH 3、-CH 2OH、-NHCH 3、-COCH 3、-SO 2CH 3、-OCH 2CH 3、-CF 3、-CHF 2、-CH 2F、异丙基、环丙基、氟代环丙基;和/或,所述的R 2可进一步独立地选自-H、-CH 3、-CHF 2、-CH 2F、-CF 3、-CH 2CH 3、-CH 2CH 2F、-NH 2、环丙基、5~6元杂环基、5~6元杂芳基;和/或,所述的R 4可进一步选自-CN、-CH 3、-OH、-CH 2OH、-CH 2OCH 3、-OCH 3、-NH 2、-NHCH 3、-COCH 3、-OCH 2CH 3;和/或,所述的R 5选自-F、-Cl、-CN、-CH 3、-CH 2CH 3、-CF 3、-CHF 2、-CH 2F、-CH 2OH、-OH、-CH 2OCH 3、-OCH 3、-CH 2CH 2OH、-CH 2CH 2OCH 3、异丙基或环丙基;和/或,所述的R 6选自-R z、-O-R z、-S-R z、-C 1~3亚烷基-R z、-C 0~3亚烷基-胺基-R z、-C 0~3亚烷基-羰基-R z,其中所述R 6中的烷基、胺基、酰胺基、磺酰基、磺酰胺基、磷酰基在化合价允许的条件下可任选地由卤素取代1~3次或由R w取代1次;和/或,R 7选自-COOH、-CH 2COOH、-CH 2CH 2COOH、-CH(CH 3)COOH,其中所述R 7在化合价允许的条件下可任选地由卤素取代1~3次。
- 一种药物组合物,其包含权利要求1~11中任一项的式I化合物及其药学上可接受的盐及药学上可接受的药用载体。
- 根据权利要求1~11任一项所述的式I化合物或其药学上可接受的盐在制备治疗GLP-1受体激动剂介导的疾病或相关疾病的药物中的应用。
- 一种用于预防和/或治疗GLP-1介导的疾病和相关疾病的方法,包括对受试者给与治疗有效量的如权利要求1~11中任一项所述的式I化合物或其药学上可接受的盐,其中所述的GLP-1介导的疾病和相关疾病包括但不限于,防糖尿病、高血糖症、胰岛素抗性、葡萄糖耐受不良、糖尿病肾病、糖尿病神经疾病、糖尿病视网膜病变、脂肪细胞功能障碍、肥胖症、血脂异常症、高胰岛素血症。
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- 2022-03-17 EP EP22774119.6A patent/EP4317142A1/en active Pending
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