CN114805336A - Condensed imidazole compound, preparation method and application thereof in medicine - Google Patents
Condensed imidazole compound, preparation method and application thereof in medicine Download PDFInfo
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- CN114805336A CN114805336A CN202210061595.6A CN202210061595A CN114805336A CN 114805336 A CN114805336 A CN 114805336A CN 202210061595 A CN202210061595 A CN 202210061595A CN 114805336 A CN114805336 A CN 114805336A
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- pharmaceutically acceptable
- acceptable salt
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- 238000000034 method Methods 0.000 claims abstract description 18
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- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
- A61P3/04—Anorexiants; Antiobesity agents
-
- 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
- A61P3/06—Antihyperlipidemics
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- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
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- Cardiology (AREA)
- Obesity (AREA)
- Hematology (AREA)
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- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Child & Adolescent Psychology (AREA)
- Gastroenterology & Hepatology (AREA)
- Urology & Nephrology (AREA)
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- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present disclosure relates to fused imidazole compounds, processes for their preparation and their use in medicine. Specifically, the disclosure relates to a fused imidazole compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and an application of the compound as a therapeutic agent, in particular to an application of the compound as a GLP-1 receptor agonist and an application of the compound in preparation of drugs for treating and/or preventing diabetes.
Description
Technical Field
The disclosure belongs to the field of medicines, and relates to a fused imidazole compound, a preparation method thereof and application thereof in medicines. In particular, the disclosure relates to a fused imidazole compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and an application of the compound as a GLP-1 receptor agonist in the field of diabetes treatment.
Background
Diabetes mellitus is a metabolic disease of multiple etiologies characterized by chronic hyperglycemia accompanied by disturbances in the metabolism of sugars, lipids and proteins caused by defects in insulin secretion or action. Diabetes is a very ancient disease, and is caused by the fact that the blood glucose concentration is increased due to the absolute or relative lack of insulin in a human body, and then a large amount of sugar is discharged from urine, and symptoms such as polydipsia, diuresis, polyphagia, emaciation and the like appear.
Generally, there are two types of diabetes. Type I diabetics, i.e. insulin-dependent diabetics, produce little or no insulin themselves. Insulin is a hormone used in the body to regulate glucose utilization. Type II diabetics, i.e. insulin independent diabetics, have the same or higher plasma insulin levels than non-diabetic patients. However, such patients develop resistance to insulin, which stimulates glucose and lipid metabolism in major insulin-sensitive tissue cells, such as muscle, liver, adipose tissue, and the like. Even with elevated plasma insulin levels, the patient's significant resistance to insulin cannot be overcome.
Insulin resistance, in addition to being produced by a reduction in the number of insulin receptors, has insulin receptor defects, and the mechanism has not been fully understood to date. The insulin-responsive resistance results in failure of insulin to activate glucose uptake, oxidation, and storage in muscle tissue, to effectively inhibit lipolysis in adipose tissue, and to regulate glucose production and secretion in the liver.
Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by L-cells of the lower digestive tract. GLP-1 plays a corresponding role by binding with a specific receptor which is widely existed, and organs in which the GLP-1 receptor is definitely existed at present comprise islet cells, gastrointestinal tract, lung, brain, kidney, hypothalamus and cardiovascular system, and GLP-1 receptor may exist in liver, adipose tissue and skeletal muscle. GLP-1 not only acts on beta cells to promote insulin secretion, but also acts on alpha cells to inhibit glucagon secretion. There is generally no significant difference in serum GLP-1 levels in patients with normal glucose tolerance, impaired glucose tolerance, and type II diabetes. However, the response of beta cells to GLP-1 after eating is deficient, and under certain conditions, the response is obviously enhanced after the continuous infusion of GLP-1. Since the duration of action of human self-GLP-1 is very short (t 1/2<1.5 minutes by intravenous injection), human self-GLP-1 is not suitable for clinical treatment of diabetes.
Peptide GLP-1 receptor agonists (e.g., liraglutide, exenatide, etc.) have the effects of lowering fasting and postprandial glucose and improving blood glucose in type II diabetic patients. However, because of the poor oral bioavailability of peptidic GLP-1, which is inconvenient to take, agonists of the small molecule GLP-1 receptor with good oral bioavailability are highly desirable.
Published GLP-1 receptor small molecule agonist patent applications include WO2009111700A2, WO2010114824A1, WO2018109607A1, WO2019239319A1, WO2018056453A1 and the like.
Disclosure of Invention
The object of the present disclosure is to provide a compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
q is Q1 or Q2,
ring B is phenyl or 5 or 6 membered heteroaryl;
ring C is 5 or 6 membered heterocyclyl;
ring a is 6-to 10-membered aryl or 5-to 10-membered heteroaryl;
when in useWhen it is a single bond, M is a nitrogen atom or CR 9 (ii) a When in useWhen it is a double bond, M is a carbon atom;
Z 1 、Z 2 、Z 3 and Z 4 Are the same or different and are each independently CR 10 Or a nitrogen atom;
each R is 1 The same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R 2 selected from the group consisting of hydrogen atoms, alkyl groups, cycloalkyl groups, and heterocyclic groups; wherein said alkyl, cycloalkyl and heterocyclyl are optionally substituted with a group selected from halogen, alkyl, alkoxy, haloalkyl,Haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
each R is 3 The same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, oxo, cyano, amino, nitro, hydroxy, cycloalkyl, and heterocyclyl;
each R is 4 The same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, and heterocyclyl;
each R is 5 The same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, and heterocyclyl;
each R is 6 The same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, and heterocyclyl;
R 7 and R 8 The same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, and heterocyclyl;
R 9 selected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, amino groups, hydroxyl groups, and hydroxyalkyl groups;
R 10 the same or different at each occurrence and are each independently selected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, and heterocyclic groups;
n is 0, 1,2 or 3;
m is 0, 1,2,3, 4 or 5;
p is 0, 1,2 or 3;
q is 0, 1 or 2; and is
g is 0, 1,2,3, 4 or 5.
In some preferred embodiments of the present disclosure, the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl or pyridyl; preferably phenyl.
In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IG):
wherein:
G 1 is a carbon atom or a nitrogen atom;
M、Q、R 1 to R 3 N and m are as defined in formula (I).
In some preferred embodiments of the present disclosure, the compound represented by formula (I) or formula (IG), or a pharmaceutically acceptable salt thereof, is a compound represented by formula (II), or a pharmaceutically acceptable salt thereof:
wherein:
ring A, ring C, M, R 1 To R 6 N, m, p, q and g are as defined in formula (I).
In some preferred embodiments of the present disclosure, the compounds of formula (I), (IG) and (II), or pharmaceutically acceptable salts thereof, whereinSelected from:
R 5a 、R 5b 、R 5c and R 5d The same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, and heterocyclyl; preferably, R 5a 、R 5b 、R 5c And R 5d Are the same or different and are each independently a hydrogen atom or C 1-6 An alkyl group;
ring A, R 4 、R 6 P and g are as defined in formula (I);
preferably, the first and second electrodes are formed of a metal,is composed ofR 5a Selected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, and heterocyclic groups; preferably, R 5a Is a hydrogen atom or C 1-6 An alkyl group; ring A, R 4 、R 6 P and g are as defined in formula (I).
In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (IG), and the general formula (II), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of compounds represented by the general formula (II-1), the general formula (II-2), and the general formula (II-3), or a pharmaceutically acceptable salt thereof:
wherein:
R 5a 、R 5b 、R 5c and R 5d The same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, and heterocyclyl; preferably, R 5a 、R 5b 、R 5c And R 5d Are the same or different and are each independently a hydrogen atom or C 1-6 An alkyl group;
R 9 selected from hydrogen atom, C 1-6 Alkyl and hydroxy; preferably, R 9 Is a hydrogen atom;
ring A, R 1 To R 4 、R 6 N, m, p and g are as defined in formula (I).
In some preferred embodiments of the present disclosure, the compound represented by formula (I) and formula (IG), or a pharmaceutically acceptable salt thereof, is a compound represented by formula (III), or a pharmaceutically acceptable salt thereof:
wherein:
ring A, Z 1 、Z 2 、Z 3 、Z 4 、M、R 1 、R 2 、R 3 、R 6 To R 8 N, m and g are as defined in formula (I).
In some preferred embodiments of the present disclosure, the compound represented by formula (I), formula (IG), formula (II), and formula (III), or a pharmaceutically acceptable salt thereof, wherein: m is CR 9 ;R 9 Selected from hydrogen atoms, C 1-6 Alkyl and hydroxy; preferably, M is CR 9 ;R 9 Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound represented by formula (I), formula (IG), formula (II-1), formula (II-2), formula (II-3), and formula (III), or a pharmaceutically acceptable salt thereof, wherein:is composed ofR 6 And g is as defined in formula (I).
In some preferred embodiments of the present disclosure, the compounds of formula (I), (IG) and (III), or pharmaceutically acceptable salts thereof, wherein: z 1 、Z 2 、Z 3 And Z 4 Are the same or different and are each independently CR 10 ,R 10 As defined in formula (I); or Z 1 Is a nitrogen atom, Z 2 、Z 3 And Z 4 Are the same or different and are each independently CR 10 ,R 10 As defined in claim 1; preferably, Z 1 、Z 2 、Z 3 And Z 4 Are the same or different and are each independently CR 10 ,R 10 Is the same or different at each occurrence and is each independently selected from the group consisting of hydrogen, halogen and C 1-6 An alkyl group; or Z 1 Is a nitrogen atom, Z 2 、Z 3 And Z 4 Are the same or different and are each independently CR 10 ,R 10 Is the same or different at each occurrence and is each independently selected from the group consisting of hydrogen, halogen and C 1-6 An alkyl group.
In some preferred embodiments of the present disclosure, the compound represented by formula (I), formula (IG), formula (II-1), formula (II-2), formula (II-3), and formula (III), or a pharmaceutically acceptable salt thereof, wherein: r 1 Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound represented by formula (I), formula (IG), formula (II-1), formula (II-2), formula (II-3), and formula (III), or a pharmaceutically acceptable salt thereof, wherein: r 2 Is C 1-6 An alkyl group; wherein said C 1-6 Alkyl is optionally selected from halogen, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, cyano, amino, hydroxy, 3-to 6-membered cycloalkyl and 3-to 6-membered heterocyclyl; preferably, R 2 Is C 1-6 An alkyl group; wherein said C 1-6 Alkyl is optionally substituted with one 3-to 6-membered heterocyclyl; more preferably, R 2 Is composed of
In some preferred embodiments of the present disclosure, the compound of formula (IG), or a pharmaceutically acceptable salt thereof, wherein:is composed ofG 1 Is a carbon atom or a nitrogen atom; r 1 And n is as defined in formula (I); preferably, the first and second electrodes are formed of a metal,is composed ofG 1 Is a carbon atom or a nitrogen atom; r 1 Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compounds of formula (II), formula (II-1), formula (II-2), formula (II-3), and formula (III), or pharmaceutically acceptable salts thereof, wherein:is composed ofR 1 And n is as defined in formula (I); preferably, the first and second electrodes are formed of a metal,is composed ofR 1 Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound represented by formula (I), formula (IG), formula (II-1), formula (II-2), formula (II-3), and formula (III), or a pharmaceutically acceptable salt thereof, wherein: each R is 3 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl and oxo; preferably, R 3 Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound of formula (I), formula (IG), formula (II-1)A compound represented by the general formula (II-2) or the general formula (II-3), or a pharmaceutically acceptable salt thereof, wherein: each R is 4 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C 1-6 An alkyl group; preferably, R 4 Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compounds of formula (I) and formula (II), or pharmaceutically acceptable salts thereof, wherein: each R is 5 Are the same or different and are each independently a hydrogen atom or C 1-6 An alkyl group.
In some preferred embodiments of the present disclosure, the compound of formula (II-1), formula (II-2), formula (II-3), or a pharmaceutically acceptable salt thereof, wherein: r 5a 、R 5b 、R 5c And R 5d Are the same or different and are each independently a hydrogen atom or C 1-6 An alkyl group.
In some preferred embodiments of the present disclosure, the compound represented by the general formula (II-1), or a pharmaceutically acceptable salt thereof, wherein: r 5a Is a hydrogen atom or C 1-6 An alkyl group; preferably, R 5a Is a hydrogen atom or a methyl group.
In some preferred embodiments of the present disclosure, the compound represented by the general formula (II-2), or a pharmaceutically acceptable salt thereof, wherein: r 5a 、R 5b And R 5c Are the same or different and are each independently a hydrogen atom or C 1-6 An alkyl group; preferably, R 5a 、R 5b And R 5c The same or different, and each independently is a hydrogen atom or a methyl group.
In some preferred embodiments of the present disclosure, the compound represented by the general formula (II-3), or a pharmaceutically acceptable salt thereof, wherein: r 5a 、R 5c And R 5d Are the same or different and are each independently a hydrogen atom or C 1-6 An alkyl group; r 5a 、R 5c And R 5d The same or different, and each independently is a hydrogen atom or a methyl group.
In some preferred embodiments of the present disclosure, the compounds of formula (I), formula (IG), formula (II-1), formula (II-2), formula (II-3) and formula (III)A compound of formula (i), or a pharmaceutically acceptable salt thereof, wherein: each R is 6 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C 1-6 An alkyl group; preferably, each R 6 Are the same or different and are each independently a hydrogen atom or a halogen.
In some preferred embodiments of the present disclosure, the compounds of formula (I), (IG) and (III), or pharmaceutically acceptable salts thereof, wherein: r 7 And R 8 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C 1-6 An alkyl group; preferably, R 7 And R 8 Are all hydrogen atoms.
In some preferred embodiments of the present disclosure, the compound represented by formula (I), formula (IG), formula (II-1), formula (II-2), formula (II-3), and formula (III), or a pharmaceutically acceptable salt thereof, wherein: g is 0, 1 or 2.
In some preferred embodiments of the present disclosure, the compounds of formula (I), (IG) and (II), or pharmaceutically acceptable salts thereof, wherein: q is 0 or 1.
In some preferred embodiments of the present disclosure, the compound represented by formula (I), formula (IG), formula (II-1), formula (II-2), formula (II-3), and formula (III), or a pharmaceutically acceptable salt thereof, wherein: n is 0 or 1.
In some preferred embodiments of the present disclosure, the compound represented by formula (I), formula (IG), formula (II-1), formula (II-2), formula (II-3), and formula (III), or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1 or 2.
In some preferred embodiments of the present disclosure, the compound represented by formula (I), formula (IG), formula (II-1), formula (II-2), and formula (II-3), or a pharmaceutically acceptable salt thereof, wherein: p is 0 or 1.
In some preferred embodiments of the present disclosure, the compound of formula (IG), or a pharmaceutically acceptable salt thereof,
wherein:
m is CH or a nitrogen atom;
q is selected from:
G 1 Is a carbon atom or a nitrogen atom;
R 1 is a hydrogen atom;
R 2 is C 1-6 An alkyl group; wherein said C 1-6 Alkyl is optionally substituted with one 3-to 6-membered heterocyclyl;
R 3 is a hydrogen atom;
R 4 is a hydrogen atom;
R 5a 、R 5b 、R 5c and R 5d Are the same or different and are each independently a hydrogen atom or C 1-6 An alkyl group;
each R is 6 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C 1-6 An alkyl group; and is
g is 0, 1 or 2.
In some preferred embodiments of the present disclosure, the compound of formula (IG), or a pharmaceutically acceptable salt thereof,
wherein:
m is CH or a nitrogen atom;
G 1 Is a carbon atom or a nitrogen atom;
R 1 is a hydrogen atom;
R 2 is C 1-6 An alkyl group; wherein said C 1-6 Alkyl is optionally substituted with one 3-to 6-membered heterocyclyl;
R 3 is a hydrogen atom;
R 4 is a hydrogen atom;
R 5a is a hydrogen atom or C 1-6 An alkyl group;
each R is 6 Are the same or different and are each independently a hydrogen atom or a halogen; and is
g is 0, 1 or 2.
In some preferred embodiments of the present disclosure, the compound represented by the general formula (II-1), or a pharmaceutically acceptable salt thereof,
wherein:
R 1 Is a hydrogen atom;
R 2 is C 1-6 An alkyl group; wherein said C 1-6 Alkyl is optionally substituted with one 3-to 6-membered heterocyclyl;
R 3 is a hydrogen atom;
R 4 is a hydrogen atom;
R 5a is a hydrogen atom or C 1-6 An alkyl group;
each R is 6 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C 1-6 An alkyl group;
R 9 is a hydrogen atom; and is
g is 0, 1 or 2.
Table a typical compounds of the present disclosure include, but are not limited to:
another aspect of the present disclosure relates to compounds of formula (IA), or a pharmaceutically acceptable salt thereof,
wherein:
R w is C 1-6 An alkyl group;
ring B, M, Q, R 1 To R 3 N and m are as defined in formula (I). Which is an intermediate for the preparation of the compounds of general formula (I).
Another aspect of the present disclosure relates to compounds of formula (IGA), or a pharmaceutically acceptable salt thereof,
wherein:
R w is C 1-6 An alkyl group;
M、Q、G 1 、R 1 to R 3 N and m are as defined in formula (IG). Which is an intermediate in the preparation of compounds of general formula (IG).
Another aspect of the present disclosure relates to compounds of formula (IIA), or a pharmaceutically acceptable salt thereof,
wherein:
R w is C 1-6 An alkyl group;
ring A, ring C, M, R 1 To R 6 N, m, p, q and g are as defined in formula (II). Which is an intermediate for the preparation of compounds of general formula (II).
Another aspect of the present disclosure relates to a compound of formula (II-1A), or a pharmaceutically acceptable salt thereof,
wherein:
R w is C 1-6 An alkyl group;
ring A, R 1 To R 4 、R 5a 、R 6 、R 9 N, m, p and g are as defined in the general formula (II-1). Which is an intermediate for the preparation of the compound of formula (II-1).
Another aspect of the present disclosure relates to a compound of formula (II-2A), or a pharmaceutically acceptable salt thereof,
wherein:
R w is C 1-6 An alkyl group;
ring A, R 1 To R 4 、R 5a 、R 5b 、R 5c 、R 6 、R 9 N, m, p and g are as defined in the general formula (II-2). Which is an intermediate for the preparation of the compound of formula (II-2).
Another aspect of the present disclosure relates to a compound of formula (II-3A), or a pharmaceutically acceptable salt thereof,
wherein:
R w is C 1-6 An alkyl group;
ring A, R 1 To R 4 、R 5a 、R 5c 、R 5d 、R 6 、R 9 N, m, p and g are as defined in the general formula (II-3). Which is an intermediate for the preparation of the compound of formula (II-3).
Another aspect of the present disclosure relates to a compound of formula (IIIA), or a pharmaceutically acceptable salt thereof,
wherein:
R w is C 1-6 An alkyl group;
ring A, Z 1 To Z 4 、M、R 1 To R 3 、R 6 To R 8 N, m and g are as defined in formula (III). Which is an intermediate for the preparation of the compound of formula (III).
Table B typical intermediate compounds of the present disclosure include, but are not limited to:
another aspect of the present disclosure relates to a method of preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprising:
the compound of the general formula (IA) undergoes hydrolysis reaction to obtain the compound of the general formula (I) or the pharmaceutically acceptable salt thereof
Wherein:
R w is C 1-6 An alkyl group;
Another aspect of the present disclosure relates to a method of preparing a compound of formula (IG), or a pharmaceutically acceptable salt thereof, comprising:
the compound of the general formula (IGA) undergoes hydrolysis reaction to obtain the compound of the general formula (IG), or pharmaceutically acceptable salt thereof
Wherein:
R w is C 1-6 An alkyl group;
M、Q、G 1 、R 1 to R 3 N and m are as defined in formula (IG).
Another aspect of the present disclosure relates to a method of preparing a compound of formula (II), or a pharmaceutically acceptable salt thereof, comprising:
the compound of the general formula (IIA) undergoes hydrolysis reaction to obtain the compound of the general formula (II) or pharmaceutically acceptable salt thereof
Wherein:
R w is C 1-6 An alkyl group;
ring A, ring C, M, R 1 To R 6 N, m, p, q and g are as defined in formula (II).
Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (II-1), or a pharmaceutically acceptable salt thereof, comprising:
the compound of the general formula (II-1A) undergoes hydrolysis reaction to obtain the compound of the general formula (II-1) or pharmaceutically acceptable salt thereof
Wherein:
R w is C 1-6 An alkyl group;
ring A, R 1 To R 4 、R 5a 、R 6 、R 9 N, m, p and g are as defined in the general formula (II-1).
Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (II-2), or a pharmaceutically acceptable salt thereof, comprising:
the compound of the general formula (II-2A) undergoes hydrolysis reaction to obtain the compound of the general formula (II-2) or pharmaceutically acceptable salt thereof
Wherein:
R w is C 1-6 An alkyl group;
ring A, R 1 To R 4 、R 5a 、R 5b 、R 5c 、R 6 、R 9 N, m, p and g are as defined in the general formula (II-2).
Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (II-3), or a pharmaceutically acceptable salt thereof, comprising:
the compound of the general formula (II-3A) undergoes hydrolysis reaction to obtain the compound of the general formula (II-3) or pharmaceutically acceptable salt thereof
Wherein:
R w is C 1-6 An alkyl group;
ring A, R 1 To R 4 、R 5a 、R 5c 、R 5d 、R 6 、R 9 N, m, p and g are as defined in the general formula (II-3).
Another aspect of the present disclosure relates to a method of preparing a compound of formula (III), or a pharmaceutically acceptable salt thereof, comprising:
the compound of the general formula (IIIA) undergoes hydrolysis reaction to obtain the compound of the general formula (III) or pharmaceutically acceptable salt thereof
Wherein:
R w is C 1-6 An alkyl group;
ring A, Z 1 To Z 4 、M、R 1 To R 3 、R 6 To R 8 N, m and g are as defined in formula (III).
Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure represented by formula (I), formula (IG), formula (II-1), formula (II-2), formula (II-3), formula (III), and table a, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
The disclosure further relates to the use of a compound of formula (I), formula (IG), formula (II-1), formula (II-2), formula (II-3), formula (III) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for agonizing a GLP-1 receptor.
The present disclosure further relates to the use of a compound of formula (I), formula (IG), formula (II-1), formula (II-2), formula (II-3), formula (III) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, nonalcoholic steatohepatitis (NASH), parkinson's disease, dementia, insulin resistance and liver insulin resistance; preferably in the manufacture of a medicament for the treatment and/or prevention of type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis and cardiovascular disease.
The disclosure further relates to the use of a compound of formula (I), formula (IG), formula (II-1), formula (II-2), formula (II-3), formula (III) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of idiopathic type I diabetes, adult latent immune diabetes (LADA), young adult onset diabetes (MODY), gestational diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension and coronary heart disease.
The disclosure also relates to a method of agonizing a GLP-1 receptor comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (IG), formula (II-1), formula (II-2), formula (II-3), formula (III), and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
The present disclosure also relates to a method of treating and/or preventing type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, nonalcoholic steatohepatitis (NASH), parkinson's disease, dementia, insulin resistance, and liver insulin resistance; preferably type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis and cardiovascular diseases, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (IG), formula (II-1), formula (II-2), formula (II-3), formula (III) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
The present disclosure also relates to a method of treating and/or preventing idiopathic type I diabetes, latent immune diabetes in adults (LADA), juvenile adult onset diabetes (MODY), gestational diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension, and coronary heart disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (IG), formula (II-1), formula (II-2), formula (II-3), and formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
The disclosure further relates to a compound of formula (I), formula (IG), formula (II-1), formula (II-2), formula (II-3), formula (III) and table a, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, for use as a medicament.
The disclosure also relates to compounds of formula (I), formula (IG), formula (II-1), formula (II-2), formula (II-3), formula (III) and Table A, or pharmaceutical compositions comprising the same, for use as GLP-1 receptor agonists.
The present disclosure further relates to a compound represented by formula (I), formula (IG), formula (II-1), formula (II-2), formula (II-3), formula (III) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and/or prevention of type I diabetes, type II diabetes, malnutrition-associated diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, nonalcoholic steatohepatitis (NASH), parkinson's disease, dementia, insulin resistance and hepatic insulin resistance; preferably for the treatment and/or prevention of type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis and cardiovascular diseases.
The present disclosure further relates to compounds of formula (I), formula (IG), formula (II-1), formula (II-2), formula (II-3), formula (III) and table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of idiopathic type I diabetes, adult latent immune diabetes (LADA), juvenile adult onset diabetes (MODY), gestational diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension and coronary heart disease.
"diabetic complications" are complications arising from diabetes or hyperglycemia, and may be acute or chronic complexes. The term "acute complex" includes ketoacidosis and infectious diseases (e.g., skin infections, soft tissue infections, infections of the biliary system, respiratory infections, urinary tract infections), "chronic complex" includes, for example, microangiopathies (e.g., nephropathy, retinopathy), neuropathies (e.g., sensory nerve disorders, motor nerve disorders, autonomic nerve disorders) and gangrene. The major diabetic complexes include diabetic retinopathy, diabetic nephropathy and diabetic neuropathy.
"coronary heart disease" includes myocardial infarction and angina pectoris.
"dementia" includes, for example, Alzheimer's disease, (early-onset dementia) EOD, vascular dementia, and diabetic dementia.
The active compounds may be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers to formulate compositions of the disclosure by conventional methods. Thus, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of the present disclosure may also be formulated in sustained release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.
As a general guide, the active compound is preferably administered in a unit dose or in a manner such that the patient can self-administer it in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled liquid, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be 0.1 to 1000 mg.
The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.
Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water soluble carrier or an oil vehicle.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.
The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.
The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection or microemulsion may be injected into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.
The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspensions may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be prepared into injections.
The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
Dispersible powders and granules of the compounds of the present disclosure can be administered by the addition of water to prepare an aqueous suspension. These pharmaceutical compositions may be prepared by mixing the active ingredient with dispersing or wetting agents, suspending agents, or one or more preservatives.
As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, and the like; in addition, the optimal treatment regimen, such as mode of treatment, daily amount of compound or type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.
Description of the terms
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms (i.e., C) 1-20 Alkyl groups). The alkyl group is preferably an alkyl (i.e., C) group having 1 to 12 (e.g., 1,2,3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms 1-12 Alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C) 1-6 Alkyl groups). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutylA group, a tert-butyl group, a sec-butyl group, a n-pentyl group, a1, 1-dimethylpropyl group, a1, 2-dimethylpropyl group, a 1-ethylpropyl group, a 2-methylbutyl group, a 3-methylbutyl group, a n-hexyl group, a 1-ethyl-2-methylpropyl group, a1, 1, 2-trimethylpropyl group, a1, 1-dimethylbutyl group, a1, 2-dimethylbutyl group, a2, 2-dimethylbutyl group, a1, 3-dimethylbutyl group, a 2-ethylbutyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a2, 3-dimethylbutyl group, a n-heptyl group, a 2-methylhexyl group, a 3-methylhexyl group, a 4-methylhexyl group, a 5-methylhexyl group, a2, 3-dimethylpentyl group, a1, 2-dimethylpropyl group, a1, 1, 2-dimethylpropyl group, 1, 2-dimethylbutyl group, a1, 2-dimethylbutyl group, 2-1, 2-dimethylbutyl group, 2-dimethyl-2, 2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-, 2, 4-dimethylpentyl group, 2-dimethylpentyl group, 3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2, 3-dimethylhexyl group, 2, 4-dimethylhexyl group, 2, 5-dimethylhexyl group, 2-dimethylhexyl group, 3-dimethylhexyl group, 4-dimethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2-diethylpentyl group, n-decyl group, 3-diethylhexyl group, 2-ethylhexyl group, 2, 2-diethylhexyl, and various branched isomers thereof, and the like. Most preferably lower alkyl having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having 1 to 20 (e.g., 1,2,3. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms (i.e., C) 1-20 Alkylene). The alkylene group preferably has 1 to 12 (e.g., 1,2,3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C) 1-12 Alkylene), more preferably alkylene having 1 to 6 carbon atoms (i.e., C) 1-6 Alkylene). Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH) 2 -), 1-ethylidene (-CH (CH) 3 ) -), 1, 2-ethylene (-CH) 2 CH 2 ) -, 1-propylene (-CH (CH) 2 CH 3 ) -), 1, 2-propylene (-CH) 2 CH(CH 3 ) -), 1, 3-propylene (-CH) 2 CH 2 CH 2 -) 1, 4-butylene (-CH 2 CH 2 CH 2 CH 2 -) and the like. Alkylene groups may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio and oxo.
The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is defined as above, having 2 to 12 (e.g., 2,3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C) 2-12 Alkenyl). The alkenyl group preferably has 2 to 6 carbon atoms (i.e., C) 2-6 Alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, it is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2,3. 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms. The alkynyl group preferably has 2 to 6 carbon atoms (i.e., C) 2-6 Alkynyl). The alkynyl group may be substituted or unsubstituted, and when substituted, it is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "alkoxy" refers to-O- (alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, and butoxy, and the like. Alkoxy groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being selected from one or more of deuterium atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, preferably 3 to 12 carbon atoms (i.e., 3 to 12 membered cycloalkyl), more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms (i.e., 3 to 8 membered cycloalkyl), and most preferably 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl groups.
The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). Spirocycloalkyl groups are classified as mono-or polyspirocycloalkyl (e.g., a bis-spiro cycloalkyl), preferably mono-or bis-spiro alkyl, depending on the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:
the term "fused cyclic alkyl" 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 of the rings may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into polycyclic fused cycloalkyl groups such as bicyclic, tricyclic, tetracyclic, etc., according to the number of constituent rings, preferably bicyclic or tricyclic fused cycloalkyl groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/3-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic cycloalkyl groups. Non-limiting examples of fused ring alkyl groups include:
the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic, etc. polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic, or tetracyclic bridged cycloalkyl groups, and more preferably bicyclic or tricyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:
the cycloalkyl ring includes a cycloalkyl group as described above (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl orOn a heterocycloalkyl ring, wherein the ring to which the parent structure is attached is cycloalkyl, non-limiting examples includeEtc.; preference is given to
Cycloalkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent having from 3 to 20 ring atoms, wherein one or more ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., to form a sulfoxide or sulfone), with the remaining ring atoms being carbon. Preferably 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1-4 (e.g., 1,2,3 and 4) are heteroatoms (i.e., 3-to 12-membered heterocyclyl); more preferably 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), of which 1-3 (e.g., 1,2, and 3) are heteroatoms (i.e., 3-to 8-membered heterocyclyl); more preferably 3 to 6 ring atoms, of which 1 to 3 are heteroatoms (i.e. a 3 to 6 membered heterocyclic group); most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms (i.e. a 5 or 6 membered heterocyclyl). Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.
The term "spiroheterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group which shares a single atom (referred to as the spiro atom) between single rings, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), with the remaining ring atoms being carbon. It may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). Spiro heterocyclic groups are classified into a mono-spiro heterocyclic group or a multi-spiro heterocyclic group (e.g., a double-spiro heterocyclic group), preferably a mono-spiro heterocyclic group or a double-spiro heterocyclic group, depending on the number of spiro atoms shared between rings. Most preferred is a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered mono spiroheterocyclyl group. Non-limiting examples of spiro heterocyclic groups include:
the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of the rings may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e. to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic, etc. polycyclic fused heterocyclic groups according to the number of constituting rings, preferably bicyclic or tricyclic fused heterocyclic groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic, etc. polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic, or tetracyclic bridged heterocyclic groups, and more preferably bicyclic or tricyclic bridged heterocyclic groups. Non-limiting examples of bridged heterocyclic groups include:
the heterocyclyl ring includes a heterocyclyl (including monocyclic, spiroheterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring as described above, wherein the ring to which the parent structure is attached is a heterocyclyl, non-limiting examples of which include:
The heterocyclyl group may be substituted or unsubstituted and when substituted may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. Such aryl rings include those wherein the aryl ring as described above is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
aryl groups may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1,2,3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g., 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered (i.e., 5 or 6 membered heteroaryl), such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
heteroaryl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived from the parent ring atom by removal of one hydrogen atom, or residues derived from the parent ring atom by removal of two hydrogen atoms from the same or two different ring atoms, i.e., "cycloalkylene", "heterocyclylene", "arylene", "heteroarylene".
The term "amino protecting group" refers to a group that is easily removed by introduction onto an amino group in order to keep the amino group unchanged during the reaction at other sites of the molecule. Non-limiting examples include (trimethylsilane) ethoxymethyl, tetrahydropyranyl, t-butyloxycarbonyl (Boc), acetyl, benzyl, benzyloxycarbonyl (Cbz), allyl, and p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro.
The term "hydroxy protecting group" is a suitable group known in the art for hydroxy protection. Non-limiting examples include: trimethylsilyl (TMS), Triethylsilyl (TES), Triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl and the like.
The term "cycloalkyloxy" refers to cycloalkyl-O-wherein cycloalkyl is as defined above.
The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
The term "alkylthio" refers to an alkyl-S-group wherein alkyl is as defined above.
The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "hydroxy" refers to-OH.
The term "mercapto" refers to-SH.
The term "amino" refers to the group-NH 2 。
The term "cyano" refers to — CN.
The term "nitro" means-NO 2 。
The term "oxo" or "oxo" means "═ O".
The term "carbonyl" refers to C ═ O.
The term "carboxy" refers to-C (O) OH.
The term "carboxylate" refers to-C (O) O (alkyl), -C (O) O (cycloalkyl), (alkyl) C (O) O-or (cycloalkyl) C (O) O-, wherein alkyl and cycloalkyl are as defined above.
The compounds of the present disclosure include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms. For example, having the structure of the present disclosure, replacing hydrogen with "deuterium" or "tritium", or 18 F-fluorine labeling: ( 18 Isotope of F) instead of fluorine, or with 11 C-, 13 C-, or 14 C-enriched carbon (C 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 c-, or 14 C-isotopes) instead of carbon atoms are within the scope of the present disclosure. Such compounds are useful as analytical tools or probes in, for example, biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. The various deuterated forms of the compounds of the present disclosure mean that each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane in tetrahydrofuran, deuterated lithium aluminum hydrides, deuterated iodoethanes, and deuterated iodomethanes, among others. Deuterations can generally retain activity comparable to non-deuterated compounds and can achieve better metabolic stability when deuterated at certain specific sites, thereby achieving certain therapeutic advantages.
The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomers" refers to isomers that are identical in structure but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (-) -and (+) -isomers, (R) -and (S) -enantiomers, diastereomers, (D) -and (L) -isomers, tautomers, atropisomers, conformers, and mixtures thereof (e.g., racemates, mixtures of diastereomers). Additional asymmetric atoms may be present in substituents in the compounds of the present disclosure. All such stereoisomers, as well as mixtures thereof, are included within the scope of the present disclosure. Optically active (-) -and (+) -isomers, (R) -and (S) -enantiomers, and (D) -and (L) -isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. An isomer of a compound of the present disclosure may be prepared by asymmetric synthesis or chiral auxiliary, or, when a basic functional group (e.g., amino group) or an acidic functional group (e.g., carboxyl group) is contained in a molecule, a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then diastereoisomeric resolution is performed by a conventional method known in the art to obtain a pure isomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.
In the chemical structures of the compounds described in this disclosure, the bond "/" represents an unspecified configuration, i.e., if a chiral isomer is present in the chemical structure, the bond "/" may beOrOr at the same time containAndtwo configurations.
The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. It includes all possible tautomers, i.e. in the form of a single isomer or in the form of a mixture of said tautomers in any ratio. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, and the like. Examples of lactam-lactam equilibria are shown below:
when referring to pyrazolyl, it is understood to include any one of the following two structures or a mixture of two tautomers:
all tautomeric forms are within the scope of the disclosure, and the naming of the compounds does not exclude any tautomers.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably 1 to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. Those skilled in the art are able to ascertain (by experiment or theory) without undue effort, substitutions that are possible or impossible. For example, an amino or hydroxyl group having a free hydrogen may be unstable in combination with a carbon atom having an unsaturated (e.g., olefinic) bond.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable salts" refers to salts of the disclosed compounds which are safe and effective for use in a mammalian body and which possess the requisite biological activity. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to an amount of drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of a therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate therapeutically effective amount in an individual case can be determined by a person skilled in the art according to routine tests.
The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.
As used herein, the singular forms "a", "an" and "the" include plural references and vice versa unless the context clearly dictates otherwise.
When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is meant that the parameter may vary by ± 10%, and sometimes more preferably within ± 5%. As will be appreciated by those skilled in the art, when the parameters are not critical, the numbers are generally given for illustrative purposes only and are not limiting.
Synthesis of the Compounds of the disclosure
In order to achieve the purpose of the present disclosure, the present disclosure adopts the following technical solutions:
scheme one
The preparation method of the compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof comprises the following steps:
the compound of the general formula (IA) undergoes hydrolysis reaction under alkaline condition to obtain the compound of the general formula (I) or pharmaceutically acceptable salt thereof
Wherein:
R w is C 1-6 An alkyl group;
Scheme two
The preparation method of the compound shown in the general formula (IG) or the pharmaceutically acceptable salt thereof comprises the following steps:
the compound of the general formula (IGA) undergoes hydrolysis reaction under alkaline condition to obtain the compound of the general formula (IG), or pharmaceutically acceptable salt thereof
Wherein:
R w is C 1-6 An alkyl group;
M、Q、G 1 、R 1 to R 3 N and m are as defined in formula (IG).
Scheme three
The preparation method of the compound shown in the general formula (II) or the pharmaceutically acceptable salt thereof comprises the following steps:
the compound of the general formula (IIA) undergoes hydrolysis reaction under alkaline condition to obtain the compound of the general formula (II) or pharmaceutically acceptable salt thereof
Wherein:
R w is C 1-6 An alkyl group;
ring A, ring C, M, R 1 To R 6 N, m, p, q and g are as defined in formula (II).
Scheme four
The preparation method of the compound shown in the general formula (II-1) or the pharmaceutically acceptable salt thereof comprises the following steps:
the compound of the general formula (II-1A) undergoes hydrolysis reaction under alkaline condition to obtain the compound of the general formula (II-1) or pharmaceutically acceptable salt thereof
Wherein:
R w is C 1-6 An alkyl group;
ring A, R 1 To R 4 、R 5a 、R 6 、R 9 N, m, p and g are as defined in the general formula (II-1).
Scheme five
The preparation method of the compound shown in the general formula (II-2) or the pharmaceutically acceptable salt thereof comprises the following steps:
the compound of the general formula (II-2A) undergoes hydrolysis reaction under alkaline condition to obtain the compound of the general formula (II-2) or pharmaceutically acceptable salt thereof
Wherein:
R w is C 1-6 An alkyl group;
ring A, R 1 To R 4 、R 5a 、R 5b 、R 5c 、R 6 、R 9 N, m, p and g are asAs defined in the general formula (II-2).
Scheme six
The preparation method of the compound shown in the general formula (II-3) or the pharmaceutically acceptable salt thereof comprises the following steps:
the compound of the general formula (II-3A) undergoes hydrolysis reaction under alkaline condition to obtain the compound of the general formula (II-3) or pharmaceutically acceptable salt thereof
Wherein:
R w is C 1-6 An alkyl group;
ring A, R 1 To R 4 、R 5a 、R 5c 、R 5d 、R 6 、R 9 N, m, p and g are as defined in the general formula (II-3).
Scheme seven
The preparation method of the compound shown in the general formula (III) or the pharmaceutically acceptable salt thereof comprises the following steps:
the compound of the general formula (IIIA) undergoes hydrolysis reaction under alkaline condition to obtain the compound of the general formula (III) or pharmaceutically acceptable salt thereof
Wherein:
R w is C 1-6 An alkyl group;
ring A, Z 1 To Z 4 、M、R 1 To R 3 、R 6 To R 8 N, m and g are as defined in formula (III).
The reagents providing basic conditions in the above synthesis schemes include organic bases including but not limited to triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, or potassium tert-butoxide, and inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide, and potassium hydroxide; lithium hydroxide or lithium hydroxide monohydrate is preferred.
The reactions of the above synthetic schemes are preferably carried out in solvents including, but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide and mixtures thereof.
Detailed Description
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10 -6 The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard Tetramethylsilane (TMS).
MS was determined using a FINNIGAN LCQAD (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 HPLC.
Chiral HPLC analytical determination Agilent 1260DAD HPLC was used.
High Performance liquid preparation A preparative chromatograph was used from Waters 2767, Waters 2767-SQ Detector 2, Shimadzu LC-20AP and Gilson-281.
Chiral preparation was performed using Shimadzu LC-20AP preparative chromatograph.
The CombiFlash rapid preparation instrument uses CombiFlash Rf200(TELEDYNE ISCO).
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Silica gel column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Average inhibition rate of kinase and IC 50 The values were determined with a NovoStar microplate reader (BMG, Germany).
Known starting materials of the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & co.kg, Acros Organics, Aldrich Chemical Company, nephelo Chemical science and technology (Accela ChemBio Inc), dare chemicals, and the like.
In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.
An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.
The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.
The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.
The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: n-hexane/dichloromethane system, D: ethyl acetate/dichloromethane/n-hexane, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
Example 1
2- ((4- (2- (benzo [ d ] thiazol-2-ylmethyl) benzo [ d ] [1,3] dioxolan-4-yl) piperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid 1
First step of
2- ((4-Bromobenzo [ d ] [1,3] dioxolan-2-yl) methyl) benzo [ d ] thiazole 1b
The compound 2-ethynylbenzo [ d ] thiazole 1a (807mg, 5.07mmol, prepared by the method disclosed in example intermediate S29, page 13 of the specification of patent application CN 110627610A) was dissolved in toluene (10mL), 3-bromocatechol (958mg, 5.07mmol, Toshibara Chinesota), triruthenium dodecacarbonyl (64.8mg, 101. mu. mol, Tobara Tettata, Ltd.) were added, and stirring was carried out at 100 ℃ for 16 hours. Cooled, concentrated, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1B (170mg, yield: 9.6%) and compound 1c (48mg, yield: 2.7%).
MS m/z(ESI):349.8[M+1]。
Second step of
4- (2- (benzo [ d ] thiazol-2-ylmethyl) benzo [ d ] [1,3] dioxolan-4-yl) -3, 6-dihydropiperidine-1 (2H) -carboxylic acid tert-butyl ester 1d
Compound 1b (170mg, 0.49mmol) was dissolved in 1, 4-dioxane (10mL), and 3.6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-1-boronic acid pinacol ester (166mg, 0.54mmol), sodium carbonate (103mg, 0.97mmol), tetrakis (triphenylphosphine) palladium (56mg, 48. mu. mol), water (2mL), under nitrogen, was heated to 90 ℃ and stirred for 4 hours. Cooled to room temperature, concentrated and purified by silica gel column chromatography with eluent system B to give the title compound 1d (209mg, yield: 95%).
MS m/z(ESI):451.1[M+1]。
The third step
4- (2- (benzo [ d ] thiazol-2-ylmethyl) benzo [ d ] [1,3] dioxolan-4-yl) piperidine-1-carboxylic acid tert-butyl ester 1e
Compound 1d (209mg, 0.46mmol) was dissolved in ethyl acetate (20mL), 10% palladium on carbon (50mg, 0.12mmol) was added, stirred at room temperature under 1 atmosphere of hydrogen for 3 hours, filtered, and the filtrate was concentrated to give crude title compound 1e (161mg), which was used in the next step without purification.
MS m/z(ESI):453.0[M+1]。
The fourth step
2- ((4- (piperidin-4-yl) benzo [ d ] [1,3] dioxolan-2-yl) methyl) benzo [ d ] thiazole 4-methylbenzenesulfonate 1f
Compound 1e (91mg, 0.20mmol) was dissolved in ethyl acetate (5mL), p-toluenesulfonic acid monohydrate (80mg, 0.42mmol) was added, stirred at room temperature for 14 hours, and concentrated under reduced pressure to give crude title compound 1f (105mg), which was used in the next step without purification.
MS m/z(ESI):353.1[M+1]。
The fifth step
Methyl 2- ((4- (2- (benzo [ d ] thiazol-2-ylmethyl) benzo [ d ] [1,3] dioxolan-4-yl) piperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylate 1H
Compound 1f (105mg, 0.20mmol) was dissolved in acetonitrile (5mL), the compound methyl (S) -2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-benzo [ d ] imidazole-6-carboxylate 1g (58mg, 0.20mmol, prepared using the method disclosed in intermediate 23 on page 69 of the specification in patent application WO2018109607A 1) was added, potassium carbonate (140mg, 1.01mmol) was added, and the mixture was heated to 50 ℃ and stirred for 5 hours. Cooled to room temperature, the reaction liquid was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 1h (63mg, yield: 51.5%).
MS m/z(ESI):611.2[M+1]。
The sixth step
2- ((4- (2- (benzo [ d ] thiazol-2-ylmethyl) benzo [ d ] [1,3] dioxolan-4-yl) piperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid 1
Compound 1h (63mg, 0.10mmol) was dissolved in acetonitrile (5mL), and lithium hydroxide monohydrate (3mg, 0.07mmol) and water (1mL) were added at room temperature to react at 40 ℃ for 16 hours. Cooled to room temperature, adjusted to pH 6-7 with 5% aqueous citric acid, extracted with ethyl acetate (20 mL. times.2), the combined organic layers were concentrated, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 1(21mg, yield: 35.2%).
MS m/z(ESI):597.1[M+1]。
1 H NMR(500MHz,DMSO-d 6 )δ12.76(s,1H),8.26(d,1H),8.05(dd,1H),7.97(d,1H),7.80(dd,1H),7.64(d,1H),7.48(tdd,1H),7.44–7.38(m,1H),6.75–6.69(m,3H),5.11–5.03(m,1H),4.75(ddd,1H),4.61(ddd,1H),4.51–4.45(m,1H),4.36(dt,1H),3.93(d,1H),3.85(d,2H),3.77(d,1H),2.99(d,1H),2.85(s,1H),2.74–2.66(m,1H),2.64–2.56(m,1H),2.44–2.35(m,1H),2.33–2.02(m,3H),1.72(d,4H)。
Example 2
2- ((4- (2- (4-chloro-2-fluorobenzyl) -2-methylbenzo [ d ] [1,3] dioxolan-4-yl) piperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid 2
First step of
4-chloro-1- (2, 2-dimethoxypropyl) -2-fluorobenzene 2b
Compound 1- (4-chloro-2-fluorophenyl) propan-2-one 2a (1.0g, 5.36mmol) was dissolved in 4mL of methanol, and trimethyl orthoformate (1.14g, 10.71mmol) and p-toluenesulfonic acid monohydrate (50.97mg, 0.27mmol) were added in this order, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, 5mL of a saturated sodium bicarbonate solution was added, extraction was performed with 40mL of ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title product 2b (1.1g, yield: 88%).
Second step of
4-bromo-2- (4-chloro-2-fluorobenzyl) -2-methylbenzo [ d ] [1,3] dioxolane 2c
Compound 2b (1.1g, 4.73mmol) was dissolved in 20mL of toluene, followed by the addition of 3-bromocatechol (938mg, 4.96mmol, Leyan science) and p-toluenesulfonic acid monohydrate (45mg, 0.24mmol), under nitrogen, and the reaction flask was placed in an oil bath preheated to 90 ℃ in advance and refluxed for 2 hours. Cooled to room temperature, diluted with 25mL of dichloromethane and poured into 20mL of saturated sodium bicarbonate solution, extracted with 50mL of dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 2c (0.66g, yield: 39%).
The third step
4- (2- (4-chloro-2-fluorobenzyl) -2-methylbenzo [ d ] [1,3] dioxan-4-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 2d
Compound 2c (300mg, 0.84mmol), 3.6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-1-boronic acid pinacol ester (311mg, 1.01mmol, Shaoshi technologies Co., Ltd.), tetrakis (triphenylphosphine) palladium (97mg, 83.9. mu. mol) and sodium carbonate (178mg, 1.68mmol) were mixed and dissolved in 28mL of a mixed solution of 1, 4-dioxane and water (V: V ═ 5:1), heated to 90 ℃ under nitrogen protection, and reacted at 90 ℃ for 3 hours. Cooled to room temperature, filtered, concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 2d (370mg, yield: 95.9%).
MS m/z(ESI):404.1[M-55]。
The fourth step
4- (2- (4-chloro-2-fluorobenzyl) -2-methylbenzo [ d ] [1,3] dioxan-4-yl) piperidine-1-carboxylic acid tert-butyl ester 2e
Compound 2d (370mg, 0.8mmol) was dissolved in 21mL of a mixed solution of ethyl acetate and 1, 2-dichlorobenzene (V: V ═ 20:1), 10% palladium on carbon (43mg, 0.4mmol) was added, hydrogen gas was substituted three times, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. Filtration and concentration of the filtrate under reduced pressure were carried out to remove the solvent, whereby the title compound 2e (370mg, yield: 99%) was obtained.
MS m/z(ESI):406.1[M-55]。
The fifth step
4- (2- (4-chloro-2-fluorobenzyl) -2-methylbenzo [ d ] [1,3] dioxalan-4-yl) piperidine 2f
Compound 2e was dissolved in 3mL ethyl acetate, p-toluenesulfonic acid monohydrate (335mg, 1.76mmol) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, 5mL of a saturated sodium bicarbonate solution was added to the reaction system, followed by extraction with 50mL of ethyl acetate, washing with saturated sodium chloride, drying the organic phase over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure to remove the solvent, whereby the title compound 2f (289mg, yield: 99%) was obtained.
MS m/z(ESI):362.1[M+1]。
The sixth step
2g of methyl 2- ((4- (2- (4-chloro-2-fluorobenzyl) -2-methylbenzo [ d ] [1,3] dioxolan-4-yl) piperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylate
Compound 2f (289mg, 0.8mmol) and compound 1g (235mg, 0.8mmol) were combined and dissolved in 20mL acetonitrile, followed by the addition of potassium carbonate (552mg, 4.0mmol) and reaction at 60 ℃ for 3 hours. Cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain 2g (460mg, yield: 93%) of the title compound.
MS m/z(ESI):620.2[M+1]。
Seventh step
2- ((4- (2- (4-chloro-2-fluorobenzyl) -2-methylbenzo [ d ] [1,3] dioxolan-4-yl) piperidin-1-yl) methyl) -1- (((S) -oxetan-2-yl) methyl) -1H-benzo [ d ] imidazole-6-carboxylic acid 2
2g (60mg, 96.7. mu. mol) of the compound was dissolved in 5mL of acetonitrile, 1mL of water and lithium hydroxide monohydrate (41mg, 967. mu. mol, Shaoshima technologies Ltd.) were added, and the mixture was heated to 40 ℃ for reaction for 6 hours. After cooling, 2.5M citric acid was added to adjust the pH to 5 to 6, a white solid precipitated, which was filtered, and the filter cake was washed with water and dried to obtain the title product 2(32mg, yield: 54%).
MS m/z(ESI):606.2[M+1]。
1 H NMR(500MHz,DMSO-d 6 )δ8.22(s,1H),7.81(d,1H),7.58(d,1H),7.35(q,2H),7.17(dd,1H),6.74–6.53(m,3H),5.15-5.07(m,1H),4.82-4.73(m,1H),4.68-4.60(m,1H),4.51(q,1H),4.44-4.36(m,1H),3.94(dd,1H),3.77(dd,1H),3.24(s,2H),3.01(d,1H),2.93-2.70(m,3H),2.59-2.53(m,1H),2.48-2.42(m,1H),2.27-2.11(m,2H),1.82-1.55(m,6H)。
Biological evaluation
Test example 1 evaluation of GLP-1 receptor agonistic Activity
First, test purpose
The purpose of this experiment was to test the agonistic activity of the compound molecule at the GLP-1 receptor, according to EC 50 Size the molecules were evaluated for in vitro activity. ONE-Glo was used in this experiment TM Luciferase assay System (ONE-Glo) TM Luciferase Assay System, Promega, E6110) under the action of compound molecules, GLP-1R downstream signal pathways are activated to cause cAMP level to rise, cAMP is combined with CRE to start transcription expression of CRE downstream Luciferase genes, Luciferase can emit fluorescence through reaction with substrates thereof, and ONE-Glo Luciferase can emit fluorescence through ONE-Glo reaction TM The reagent measures the fluorescence signal reflecting the activity of the compound for stimulating the GLP-1 receptor.
Second, Experimental methods
CHO-K1/CRE-luc/GLP-1 receptor stable cell strain (GLP-1 receptor plasmid self-construction; CRE-luc plasmid Promega E8471) was constructed. CHO-K1/CRE-luc/GLP-1 receptor cells were digested, centrifuged, resuspended, single cell suspension was mixed well, viable cell density was adjusted to 2.5X 10 with cell culture medium (DME/F-12+ 10% FBS) 5 cells/mL were added at 90. mu.L/well to a 96-well cell culture plate (Corning, # 3903). The plates were incubated in an incubator for 16 hours (37 ℃, 5% CO) 2 )。
Compounds were dissolved in DMSO to prepare stock solutions with an initial concentration of 20 mM. The starting concentration of the small molecule compound was 0.2mM, 3-fold dilution, 10 points of dilution, and DMSO at 11 points. Another 96-well plate is taken, 95 mu L of cell culture solution (DME/F-12+ 10% FBS) is added into each well, 5 mu L of samples to be detected with different concentrations are added into each well and mixed evenly, and then 10 mu L of samples to be detected with different concentrations are added into the cell culture plate, and each sample has two wells. The plates were incubated in an incubator for 6 hours (37 ℃, 5% CO) 2 ). The 96-well cell culture plate was removed and 100. mu.L of ONE-Glo was added to each well TM Reagents, incubated for 10 minutes at room temperature. Chemiluminescence was measured in a microplate reader (EnVision 2105, PE).
Third, data analysis
Data were processed using Microsoft Excel, Graphpad Prism 5And (6) physical analysis. EC to give Compounds of the disclosure 50 See table 1 below for values, results.
TABLE 1 EC of agonistic activity of the presently disclosed compounds at GLP-1 receptor 50
Example numbering | EC 50 (nM) | Emax% |
1 | 0.15 | 105 |
2 | 0.75 | 108 |
And (4) conclusion: the disclosed compounds have high agonistic activity at the GLP-1 receptor.
Claims (23)
1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
q is Q1 or Q2,
ring B is phenyl or 5 or 6 membered heteroaryl;
ring C is 5 or 6 membered heterocyclyl;
ring a is 6-to 10-membered aryl or 5-to 10-membered heteroaryl;
when in useWhen it is a single bond, M is a nitrogen atom or CR 9 (ii) a When in useWhen it is a double bond, M is a carbon atom;
Z 1 、Z 2 、Z 3 and Z 4 Are the same or different and are each independently CR 10 Or a nitrogen atom;
each R is 1 The same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R 2 selected from the group consisting of hydrogen atoms, alkyl groups, cycloalkyl groups, and heterocyclic groups; wherein said alkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
each R is 3 The same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, oxo, cyano, amino, nitro, hydroxy, cycloalkyl, and heterocyclyl;
each R is 4 The same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, and heterocyclyl;
each R is 5 The same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, and heterocyclyl;
each R is 6 The same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, and heterocyclyl;
R 7 and R 8 The same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, and heterocyclyl;
R 9 selected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, amino groups, hydroxyl groups, and hydroxyalkyl groups;
R 10 the same or different at each occurrence and are each independently selected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, and heterocyclic groups;
n is 0, 1,2 or 3;
m is 0, 1,2,3, 4 or 5;
p is 0, 1,2 or 3;
q is 0, 1 or 2; and is
g is 0, 1,2,3, 4 or 5.
2. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, wherein ring B is phenyl or pyridyl; preferably phenyl.
4. A compound of general formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, whereinSelected from the group consisting of:
R 5a 、R 5b 、R 5c and R 5d The same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, and heterocyclyl; preferably, R 5a 、R 5b 、R 5c And R 5d Are the same or different and are each independently a hydrogen atom or C 1-6 An alkyl group;
ring A, R 4 、R 6 P and g are as defined in claim 1.
5. The compound of the general formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 or2, which is a compound of the general formula (III), or a pharmaceutically acceptable salt thereof:
wherein:
ring A, Z 1 、Z 2 、Z 3 、Z 4 、M、R 1 、R 2 、R 3 、R 6 To R 8 N, m and g are as defined in claim 1.
6. A compound of general formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 5, wherein: m is CR 9 ;R 9 Selected from hydrogen atoms, C 1-6 Alkyl groups and hydroxyl groups.
8. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1,2 and 5 to 7, wherein: z 1 、Z 2 、Z 3 And Z 4 Are the same or different and are each independently CR 10 ,R 10 As defined in claim 1; or Z 1 Is a nitrogen atom, Z 2 、Z 3 And Z 4 Are the same or different and are each independently CR 10 ,R 10 As defined in claim 1; preferably, Z 1 、Z 2 、Z 3 And Z 4 Are the same or different and are each independently CR 10 ,R 10 Is the same or different at each occurrence and is each independently selected from the group consisting of hydrogen, halogen and C 1-6 An alkyl group; or Z 1 Is a nitrogen atom, Z 2 、Z 3 And Z 4 Are the same or different and are each independently CR 10 ,R 10 Is the same or different at each occurrence and is each independently selected from the group consisting of hydrogen, halogen and C 1-6 An alkyl group.
9. The compound of the general formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 8Wherein: r 1 Is a hydrogen atom.
10. A compound of general formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9, wherein: r 2 Is C 1-6 An alkyl group; wherein said C 1-6 Alkyl is optionally selected from halogen, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, cyano, amino, hydroxy, 3-to 6-membered cycloalkyl and 3-to 6-membered heterocyclyl; preferably, R 2 Is C 1-6 An alkyl group; wherein said C 1-6 Alkyl is optionally substituted with one 3-to 6-membered heterocyclyl.
11. A compound of general formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 10, wherein: each R is 3 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl and oxo.
12. A compound of general formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 11, wherein: each R is 4 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C 1-6 An alkyl group.
13. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3 and 6 to 12, wherein: each R is 5 Are the same or different and are each independently a hydrogen atom or C 1-6 An alkyl group.
14. A compound of general formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 13, wherein: each R is 6 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C 1-6 An alkyl group.
15. A compound of general formula (I) according to any one of claims 1,2 and 5 to 14, or a pharmaceutically acceptable salt thereof, whichThe method comprises the following steps: r 7 And R 8 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C 1-6 An alkyl group.
19. a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, which comprises:
carrying out hydrolysis reaction on the compound of the general formula (IA) to obtain a compound of a general formula (I) or a pharmaceutically acceptable salt thereof;
wherein:
R w is C 1-6 An alkyl group;
20. A pharmaceutical composition comprising a compound of general formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 16, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
21. Use of a compound of general formula (I) according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 20 for the preparation of a medicament for agonizing a GLP-1 receptor.
22. Use of a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16 or a pharmaceutical composition according to claim 20 for the preparation of a medicament for the treatment and/or prevention of type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic steatohepatitis, parkinson's disease, dementia, insulin resistance and hepatic insulin resistance; preferably in the manufacture of a medicament for the treatment and/or prevention of type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis and cardiovascular disease.
23. Use of a compound of general formula (I) according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 20 for the preparation of a medicament for the treatment and/or prevention of idiopathic type I diabetes, latent immune diabetes in adults (LADA), juvenile adult onset diabetes (MODY), gestational diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension and coronary heart disease.
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WO2023011539A1 (en) * | 2021-08-04 | 2023-02-09 | 上海翰森生物医药科技有限公司 | Cycloalkene derivative regulator, preparation method therefor, and application thereof |
WO2023057429A1 (en) | 2021-10-05 | 2023-04-13 | Astrazeneca Ab | Certain 2,5-diazabicyclo[4.2.0]octanes and octahydrofuro[3,4- b]pyrazines as glp-1 receptor modulators |
WO2023057414A1 (en) | 2021-10-05 | 2023-04-13 | Astrazeneca Ab | Certain octahydrofuro[3,4- b]pyrazines as glp-1 receptor modulators |
WO2023057427A1 (en) | 2021-10-05 | 2023-04-13 | Astrazeneca Ab | Certain 2,5-diazabicyclo[4.2.0]octanes as glp-1 receptor modulators |
WO2023111145A1 (en) | 2021-12-16 | 2023-06-22 | Astrazeneca Ab | Certain 3-azabicyclo[3.1.0]hexanes as glp-1 receptor modulators |
WO2023111144A1 (en) | 2021-12-16 | 2023-06-22 | Astrazeneca Ab | Certain 3-azabicyclo[3.1.0]hexanes as glp-1 receptor modulators |
WO2024107781A1 (en) | 2022-11-16 | 2024-05-23 | Eli Lilly And Company | Glucagon-like peptide 1 receptor agonists |
WO2024160271A1 (en) * | 2023-02-02 | 2024-08-08 | 江苏豪森药业集团有限公司 | Salt and crystal form of cycloalkene compound, and preparation method therefor and use thereof |
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2022
- 2022-01-19 CN CN202210061595.6A patent/CN114805336A/en active Pending
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Publication number | Priority date | Publication date | Assignee | Title |
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WO2023011539A1 (en) * | 2021-08-04 | 2023-02-09 | 上海翰森生物医药科技有限公司 | Cycloalkene derivative regulator, preparation method therefor, and application thereof |
WO2023057429A1 (en) | 2021-10-05 | 2023-04-13 | Astrazeneca Ab | Certain 2,5-diazabicyclo[4.2.0]octanes and octahydrofuro[3,4- b]pyrazines as glp-1 receptor modulators |
WO2023057414A1 (en) | 2021-10-05 | 2023-04-13 | Astrazeneca Ab | Certain octahydrofuro[3,4- b]pyrazines as glp-1 receptor modulators |
WO2023057427A1 (en) | 2021-10-05 | 2023-04-13 | Astrazeneca Ab | Certain 2,5-diazabicyclo[4.2.0]octanes as glp-1 receptor modulators |
WO2023111145A1 (en) | 2021-12-16 | 2023-06-22 | Astrazeneca Ab | Certain 3-azabicyclo[3.1.0]hexanes as glp-1 receptor modulators |
WO2023111144A1 (en) | 2021-12-16 | 2023-06-22 | Astrazeneca Ab | Certain 3-azabicyclo[3.1.0]hexanes as glp-1 receptor modulators |
WO2024107781A1 (en) | 2022-11-16 | 2024-05-23 | Eli Lilly And Company | Glucagon-like peptide 1 receptor agonists |
WO2024160271A1 (en) * | 2023-02-02 | 2024-08-08 | 江苏豪森药业集团有限公司 | Salt and crystal form of cycloalkene compound, and preparation method therefor and use thereof |
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