Compounds based on a pyrazolyl-sulfonyl-phenyl skeleton structure, methods of preparation and use thereof, pharmaceutical compositions

Abstract

The application provides a kind of compound based on pyrazolyl-sulfonyl-phenyl skeleton structure and its preparation method and application, pharmaceutical composition, belong to the technical field of medicinal chemistry.The compound based on pyrazolyl-sulfonyl-phenyl skeleton structure provided in the application has specific pyrazolyl-sulfonyl-phenyl skeleton structure, can effectively inhibit glucagon receptor activity, has higher antagonism to glucagon receptor, and thus can be used as glucagon receptor antagonist or for treating metabolic diseases related to glucagon receptor, such as type II diabetes, atherosclerosis, hyperglycemia, obesity, insulin resistance, etc.

Description

Technical Field

[0001] This application relates to the field of medicinal chemistry, and more specifically, to a compound based on a pyrazolyl-sulfonyl-phenyl skeleton structure, its preparation method and application, and pharmaceutical compositions thereof. Background Technology

[0002] Type 2 diabetes is a chronic disease primarily characterized by abnormal blood glucose regulation. It has an extremely high incidence rate and is prevalent worldwide. The primary treatment for type 2 diabetes is lifestyle modification, a balanced diet, and weight control. However, some patients cannot control their condition through these methods and must resort to medication. Blood glucose regulation relies on the precise cooperation of multiple organs. Insulin, secreted by the pancreas, is the most important hormone for lowering blood glucose, and the main pathogenesis of type 2 diabetes is insufficient insulin secretion or insulin resistance. Therefore, supplementing with insulin can help control blood glucose. In addition, medication is also a common treatment method. These drugs mainly act on various aspects of blood glucose regulation; for example, metformin controls blood glucose by inhibiting glucose production in the liver.

[0003] Glucagon is also an important participant in the blood glucose regulation mechanism. Like insulin, it is secreted by the pancreas, but its functions are opposite; glucagon is primarily responsible for raising blood glucose levels. Therefore, inhibiting glucagon function can also achieve therapeutic goals. Glucagon binds to the glucagon receptor (GCGR) on cells, activating GCGR and transmitting signals to the cell to stimulate downstream gluconeogenesis, leading to elevated blood glucose.

[0004] Glucagon-glucose-restricted glucagon (GCGR) is an important glucose regulator in the human body and a promising target for the treatment of type 2 diabetes. GCGR is mainly distributed in the liver, with smaller amounts also found in other tissues such as the brain, heart, and pancreas. Activated by glucagon, GCGR increases hepatic gluconeogenesis and glycogenolysis to raise blood glucose levels and maintain glycemic homeostasis. Type 2 diabetes is a chronic metabolic disease caused by an imbalance between glucagon and insulin, primarily characterized by impaired glucagon inhibition and insulin resistance. Inhibiting glucagon function can effectively lower blood glucose; therefore, GCGR can serve as a good therapeutic target for type 2 diabetes.

[0005] This application is made in order to provide a compound that can effectively antagonize GCGR. Summary of the Invention

[0006] The purpose of this application is to provide a compound based on a pyrazolyl-sulfonyl-phenyl skeleton structure, its preparation method and application, and a pharmaceutical composition, which aims to effectively inhibit the activity of glucagon receptor.

[0007] In a first aspect, this application provides a compound based on a pyrazolyl-sulfonyl-phenyl skeleton structure, or its racemic mixture, R-isomer, S-isomer, pharmaceutically acceptable salt, or mixture thereof, the structural formula of which is as follows:

[0008]

[0009] R1 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted amino, substituted or unsubstituted amide, substituted or unsubstituted carbonyl, substituted or unsubstituted ester, halogen atom, hydroxyl, carboxyl, cyano or nitro.

[0010] p is 0, 1, 2, 3 or 4, and R2 is selected from hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen atom, hydroxyl, cyano or nitro.

[0011] R3 is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0012] R4 is selected from hydrogen atom, halogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cyano, nitro, substituted or unsubstituted amino, hydroxyl, carboxyl, mercapto, sulfonyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl.

[0013] R5 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic groups.

[0014] The compound provided in this application has a specific pyrazolyl-sulfonyl-phenyl skeleton structure, which can effectively inhibit the activity of glucagon receptor and has a high antagonistic effect on glucagon receptor. Therefore, it can be used as a glucagon receptor antagonist or to treat metabolic diseases related to glucagon receptor, such as type II diabetes, atherosclerosis, hyperglycemia, obesity, and insulin resistance.

[0015] In conjunction with the first aspect, in an optional embodiment of this application, in the structural formula of the above-mentioned compound, R1 is selected from C1-C6 alkyl groups with or without M1 substituted or unsubstituted, C1-C6 alkoxy groups with or without M2 substituted or unsubstituted, and C3-C6 alkyl groups with or without M3 substituted or unsubstituted. 10 Cycloalkyl, M4-substituted or unsubstituted 3-12-membered heterocyclic groups, M5-substituted or unsubstituted C6-C12 aryl, M6-substituted or unsubstituted heteroaryl, -NH2, -NR6R7, -C(O)NR8R9, -C(O)R 10 -C(O)OR 11 -NR 12 C(O)R 13 The halogen atom, hydroxyl group, cyano group, or nitro group; wherein M1 to M6 are each independently selected from halogen atom, hydroxyl group, cyano group, nitro group, -NR group ... 14 R 15 -C(O)NR 16 R 17 -C(O)R 18 -C(O)OR 19 and -NR 20 C(O)R 21 At least one of them; R6 to R 21 Each is independently selected from hydrogen atoms, M7-substituted or unsubstituted C1-C6 alkyl groups, and M8-substituted or unsubstituted C3-C groups. 10 Cycloalkyl, M9-substituted or unsubstituted 3-12 membered heterocyclic groups, M 10 Substituted or unsubstituted C6-C 12 aryl, M 11 Substituted or unsubstituted heteroaryl or carboxyl groups; M7 to M 11 Each group is independently selected from at least one of C1-C6 alkyl, hydroxyl, halogen, nitro, cyano, carboxyl, and ester groups. Or / and, p is 0, 1, 2, 3, or 4, and R2 is selected from hydrogen, M... 12 Substituted or unsubstituted C1-C6 alkyl groups, M 13 Substituted or unsubstituted C1-C6 alkoxy, halogen, hydroxyl, cyano, or nitro groups; wherein, M 12 and M 13 Each independently selected from -NR 22 R 23 -C(O)NR 24 R 25 -C(O)R 26 -C(O)OR 27 and -NR 28 C(O)R 29 At least one of them; R 22 To R 29 Each is independently selected from hydrogen atoms, M 14 Substituted or unsubstituted C1-C6 alkyl groups, M 15 Substituted or unsubstituted C3-C 10 cycloalkyl, M 16 Substituted or unsubstituted 3-12 membered heterocyclic groups, M 17 Substituted or unsubstituted C6-C12 aryl, M 18 Substituted or unsubstituted heteroaryl groups; M 14 To M 18 Each group is independently selected from at least one of hydroxyl, halogen atom, nitro, cyano, carboxyl and ester groups.

[0016] In the above technical solution, R1 and R2 in the structural formula of the above compound are selected from the above groups, which is beneficial to further improve the effect of inhibiting the activity of glucagon receptor and further improve the antagonistic effect on glucagon receptor.

[0017] In conjunction with the first aspect, in an optional embodiment of this application, R3 is selected from M. 19 Substituted or unsubstituted C3-C 10 cycloalkyl, M 20 Substituted or unsubstituted C3-C 10 Cycloalkenyl, M 21 Substituted or unsubstituted 3-12 membered heterocyclic groups, M 22 Substituted or unsubstituted C6-C 12 aryl, M 23 Substituted or unsubstituted heteroaryl groups; wherein, M 19 To M 23 Each group is independently selected from halogen atoms, C1-C6 alkyl groups, halogen-substituted C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkoxycarbonyl groups, halogen-substituted C1-C6 alkoxy groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, cyano groups, nitro groups, amino groups, hydroxyl groups, hydroxymethyl groups, carboxyl groups, mercapto groups, sulfonyl groups, and C6-C6 alkyl groups. 10 The aryl or 3-12 membered heterocyclic group. Or / and, R4 is selected from hydrogen atom, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, halogen atom, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxyl, mercapto, sulfonyl, C6-C 12 The aryl group and 3-12 membered heterocyclic groups. Or / and, R5 is selected from M 24 Substituted or unsubstituted C1-C6 alkyl groups, M 25 Substituted or unsubstituted C3-C 10 cycloalkyl, M 26 Substituted or unsubstituted C3-C 10 Cycloalkenyl, M 27 Substituted or unsubstituted C6-C 12 aryl, M 28 Substituted or unsubstituted 3-12 membered heterocyclic groups; wherein, M 24 To M 28Each group is independently selected from halogen atoms, C1-C6 alkyl groups, halogen-substituted C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkoxycarbonyl groups, halogen-substituted C1-C6 alkoxy groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, cyano groups, nitro groups, amino groups, hydroxyl groups, hydroxymethyl groups, carboxyl groups, mercapto groups, sulfonyl groups, and C6-C6 groups. 10 Aryl or 3-12 membered heterocyclic groups.

[0018] In the above technical solution, R3, R4 and R5 in the structural formula of the above compound are selected from the above groups, which is beneficial to further improve the effect of inhibiting the activity of glucagon receptor and further improve the antagonistic effect on glucagon receptor.

[0019] In conjunction with the first aspect, in an optional embodiment of this application, R1 is selected from -C(O)NR 16 R 17 Substituted C1-C6 alkyl groups, -C(O)NR8R9; wherein R8 and R 16 Each is independently selected from hydrogen atoms or C1-C6 alkyl groups; R9 and R 17 Each group is independently selected from carboxyl-substituted C1-C6 alkyl groups, carboxyl groups, C1-C6 alkyl-substituted 3-12-membered heterocyclic groups, or unsubstituted 3-12-membered heterocyclic groups. p is 4, R2 is selected from hydrogen atoms or C1-C6 alkyl groups. R3 is selected from M. 22 Substituted or unsubstituted C6-C 12 aryl; of which, M 22 R4 is selected from halogen atoms, C1-C6 alkyl groups, or C1-C6 alkyl groups substituted with halogen atoms. R5 is selected from M. 24 Substituted C1-C6 alkyl groups; wherein, M 24 Selected from C1-C6 alkyl groups with halogen atom or halogen atom substitution.

[0020] In the above technical solution, R1, R2, R3, R4 and R5 in the structural formula of the above compound are selected from the above groups, which is beneficial to further improve the effect of inhibiting the activity of glucagon receptor and further improve the antagonistic effect on glucagon receptor.

[0021] Optionally, R1 is selected from -C(O)NR 16 R 17 Substituted C1-C3 alkyl groups, -C(O)NR8R9, wherein R8 and R 16 Each is independently selected from hydrogen atoms or C1-C3 alkyl groups, R9, and R 17Each of the following is independently selected from carboxyl-substituted C1-C3 alkyl groups, carboxyl groups, C1-C3 alkyl-substituted 3-8 membered nitrogen-containing heterocyclic groups, or unsubstituted 3-8 membered nitrogen-containing heterocyclic groups; p is 4, R2 is selected from hydrogen atoms or C1-C3 alkyl groups; R3 is selected from M 22 Substituted or unsubstituted C6-C 12 aryl, of which M 22 R4 is selected from C1-C3 alkyl groups with halogen atoms or halogen-substituted atoms; R5 is selected from M. 24 Substituted C1-C3 alkyl groups, wherein M 24 Selected from C1-C3 alkyl groups with halogen atom or halogen atom substitution.

[0022] In conjunction with the first aspect, in an optional embodiment of this application, the compound has the following structural formula:

[0023]

[0024] Where p is 0, 1, 2, 3 or 4, and R2 is selected from hydrogen atoms or C1-C6 alkyl groups.

[0025] x is 0 or 1, R 30 It is a C1-C6 alkyl group.

[0026] y is 0 or 1, R 31 It is a C1-C6 alkyl group.

[0027] R 32 Selected from carboxyl, C1-C6 alkyl-substituted 3-12-membered heterocyclic groups or unsubstituted 3-12-membered heterocyclic groups.

[0028] m is 0 or 1, R 33 It is a C1-C6 alkyl group.

[0029] R 34 To R 38 Each is independently selected from hydrogen atoms, halogen atoms, C1-C6 alkyl groups, or C1-C6 alkyl groups substituted with halogen atoms, and R 34 To R 38 At least one of them contains a halogen atom.

[0030] n is 0 or 1, R 39 It is a C1-C6 alkyl group.

[0031] R 40 To R 42 Each is independently selected from hydrogen atoms, halogen atoms, C1-C6 alkyl groups, or C1-C6 alkyl groups substituted with halogen atoms, and R 40 To R 42 At least one of them contains a halogen atom.

[0032] The compounds provided in the above technical solutions have a specific pyrazolyl-sulfonyl-phenyl skeleton structure, and both the phenyl group and the pyrazolyl group are attached with specific groups, which can further effectively inhibit the activity of glucagon receptors and further enhance the antagonistic effect on glucagon receptors. Therefore, they can be used as highly effective glucagon receptor antagonists or for the effective treatment of metabolic diseases related to glucagon receptors, such as type II diabetes, atherosclerosis, hyperglycemia, obesity, and insulin resistance.

[0033] Optionally, p is 0, 1, 2, 3, or 4, and R2 is selected from hydrogen atoms or C1-C3 alkyl groups; x is 0 or 1, and R 30 It is a C1-C3 alkyl group; y is 0 or 1, R 31 It is a C1-C3 alkyl group; R 32 Selected from carboxyl, C1-C3 alkyl-substituted 3-12-membered heterocyclic groups or unsubstituted 3-12-membered heterocyclic groups; m is 0 or 1, R 33 It is a C1-C3 alkyl group; R 34 To R 38 Each is independently selected from hydrogen atoms, halogen atoms, C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with halogen atoms, and R 34 To R 38 At least one of them contains a halogen atom; n is 0 or 1, R 39 It is a C1-C3 alkyl group; R 40 To R 42 Each is independently selected from hydrogen atoms, halogen atoms, C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with halogen atoms, and R 40 To R 42 At least one of them contains a halogen atom.

[0034] Optionally, p is 0, 1, 2, 3, or 4, R2 is selected from hydrogen atoms or C1-C3 alkyl groups; x is 0; y is 0 or 1, R 31 It is a C1-C3 alkyl group; R 32 Selected from carboxyl, C1-C3 alkyl-substituted 3-8 membered nitrogen-containing heterocyclic groups or unsubstituted 3-8 membered nitrogen-containing heterocyclic groups; m is 0; R 34 To R 38 Each is independently selected from hydrogen atoms, halogen atoms, C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with halogen atoms, and R 34 To R 38 At least one of them contains a halogen atom; n is 1, R 39 It is a C1-C3 alkyl group; R 40 To R 42 Each is independently selected from hydrogen atoms, halogen atoms, C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with halogen atoms, and R40 To R 42 At least one of them contains a halogen atom.

[0035] Optionally, p is 4, R2 is a hydrogen atom; x is 0; y is 0 or 1, R 31 It is a C1-C3 alkyl group; R 32 Selected from carboxyl groups or 3-8 member nitrogen-containing heterocyclic groups; m is 0; R 34 To R 38 Each is independently selected from either hydrogen or halogen atoms, and R 34 To R 38 At least one of them is a halogen atom; n is 1, R 39 It is a C1-C3 alkyl group; R 40 To R 42 Each is independently selected from either hydrogen or halogen atoms, and R 40 To R 42 At least one of them contains a halogen atom.

[0036] Optionally, p is 4, R2 is a hydrogen atom; x is 0; y is 0 or 1, R 31 It is a C1-C3 alkyl group; R 32 Selected from carboxyl or m is 0; R 34 To R 38 Each is independently selected from either hydrogen or halogen atoms, and R 34 To R 38 At least one of them is a halogen atom; n is 1, R 39 It is a C1-C3 alkyl group; R 40 To R 42 Each is independently selected from either hydrogen or halogen atoms, and R 40 To R 42 At least one of them is a halogen atom.

[0037] Optionally, p is 4, R2 is a hydrogen atom; x is 0; y is 0 or 1, R 31 It is a C1-C3 alkyl group; R 32 Selected from carboxyl or m is 0; R 35 and R 37 All are halogen atoms, R 34 R 36 and R 38 All are hydrogen atoms; n is 1, R 39 It is a C1-C3 alkyl group; R 40 To R 42 Each is independently selected from either hydrogen or halogen atoms, and R 40 To R 42 At least one of them is a halogen atom.

[0038] Optionally, p is 4, R2 is a hydrogen atom; x is 0; y is 0 or 1, R 31 It is a C1-C3 alkyl group; R 32 Selected from carboxyl or m is 0; R 35 and R 37 All are halogen atoms, R 34 R 36 and R 38 All are hydrogen atoms; n is 1, R 39 It is a C1-C3 alkyl group; R 40 To R 42 All are halogen atoms.

[0039] In conjunction with the first aspect, in an optional embodiment of this application, the compound comprises:

[0040]

[0041] The two compounds described above have a highly effective antagonistic effect on glucagon receptors, and therefore can be used as highly effective glucagon receptor antagonists or for the effective treatment of metabolic diseases related to glucagon receptors, such as type II diabetes, atherosclerosis, hyperglycemia, obesity, and insulin resistance.

[0042] Secondly, this application provides a method for preparing a compound based on a pyrazolyl-sulfonyl-phenyl skeleton structure as provided in the first aspect above, the method comprising: reacting a mixed system containing NaH, a first substance and a second substance.

[0043] The structural formula of the first substance is as follows:

[0044]

[0045] The structural formula of the second substance is as follows:

[0046]

[0047] Wherein, R1' is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted amino, substituted or unsubstituted amide, substituted or unsubstituted carbonyl, substituted or unsubstituted ester, halogen atom, hydroxyl, carboxyl, cyano or nitro.

[0048] p is 0, 1, 2, 3 or 4, and R2 is selected from hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen atom, hydroxyl, cyano or nitro.

[0049] R3 is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0050] R4 is selected from hydrogen atom, halogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cyano, nitro, substituted or unsubstituted amino, hydroxyl, carboxyl, mercapto, sulfonyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl.

[0051] R5 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic groups.

[0052] R 43 For hydrogen atoms, R 44 For halogen atoms; or, R 43 For halogen atoms, R 44 It is a hydrogen atom.

[0053] In the above technical solution, reacting a mixed system containing NaH, a first substance, and a second substance can make the R of the first substance... 43 The group and the R of the second substance 44 The group is simultaneously removed, and the first substance and the second substance are connected to form the compound provided in the first aspect above. This compound can effectively inhibit the activity of glucagon receptors and has a high antagonistic effect on glucagon receptors. Therefore, it can be used as a glucagon receptor antagonist or to treat metabolic diseases related to glucagon receptors, such as type II diabetes, atherosclerosis, hyperglycemia, obesity, and insulin resistance.

[0054] In conjunction with the second aspect, in optional embodiments of this application, the mixed system further contains a solvent, including at least one of tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, acetone, diethyl ether, and dichloromethane; or / and, the reaction temperature is 20-30°C; or / and, the molar ratio of the first substance, the second substance, and NaH is 1:(2-5):(2-5).

[0055] The above technical solution facilitates a better reaction and increases the yield of the target product.

[0056] Thirdly, this application provides a pharmaceutical composition comprising: a compound based on a pyrazolyl-sulfonyl-phenyl skeleton structure as provided in the first aspect above, or a racemic mixture thereof, an R-isomer, an S-isomer, a pharmaceutically acceptable salt thereof, or a mixture thereof; and a pharmaceutically acceptable carrier.

[0057] The pharmaceutical composition provided in the third aspect of this application can effectively inhibit the activity of glucagon receptors and has a high antagonistic effect on glucagon receptors. Therefore, it can be used to treat metabolic diseases related to glucagon receptors, such as type II diabetes, atherosclerosis, hyperglycemia, obesity, and insulin resistance.

[0058] Fourthly, this application provides the use of a compound based on the pyrazolyl-sulfonyl-phenyl skeleton structure provided in the first aspect above, or its racemic mixture, R-isomer, S-isomer, pharmaceutically acceptable salt, or mixture thereof, in the preparation of a glucagon receptor antagonist or medicament; wherein the medicament is used to treat type II diabetes, hyperglycemia, atherosclerosis, obesity, and / or insulin resistance. Attached Figure Description

[0059] To more clearly illustrate the technical solutions of the embodiments of this application, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of this application and should not be regarded as a limitation of the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0060] Figure 1 Compound A1 prepared in Example 1 of this application 1 H NMR spectrum.

[0061] Figure 2 The image shows the MS spectrum of compound A1 prepared in Example 1 of this application.

[0062] Figure 3 Compound A2 prepared in Example 2 of this application 1 H NMR spectrum.

[0063] Figure 4 The MS spectrum of compound A2 prepared in Example 2 of this application is shown.

[0064] Figure 5 The IC50 of compound A1, prepared in Example 1 of this application, inhibits glucagon receptor activity. 50 Result image.

[0065] Figure 6 The IC50 of compound A2 prepared in Example 2 of this application inhibits glucagon receptor activity. 50 Result image. Detailed Implementation

[0066] In this application, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0067] In this application, the halogen atom is F, Cl, Br or I.

[0068] In this application, "substituted" means that one or more hydrogen atoms in a group are independently replaced by a corresponding number of substituents; for example, "M1-substituted alkyl" means that one or more hydrogen atoms in an alkyl group are independently replaced by a corresponding number of M1 substituents.

[0069] In this application, "C1-C6 alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, including, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl; "C1-C3 alkyl" has a similar meaning.

[0070] In this application, "C1-C6 alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, including, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy; "C1-C3 alkoxy" has a similar meaning.

[0071] In this application, "cycloalkyl" refers to a cyclic alkyl group. "C3-C" 10 "Cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms on a ring, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl; "C3-C8 cycloalkyl" has a similar meaning.

[0072] In this application, "heterocyclic group" refers to a non-aromatic cyclic group containing one or more heteroatoms, wherein the heteroatoms can be oxygen, nitrogen, sulfur, etc. "3-12 membered heterocyclic group" refers to a ring containing one or more heteroatoms, with a total number of atoms on the ring of 3-12, wherein the heteroatoms can be oxygen, nitrogen, sulfur, etc.; "3-8 membered heterocyclic group" has a similar meaning; "3-8 membered nitrogen-containing heterocyclic group" refers to a 3-8 membered heterocyclic group containing one or more nitrogen atoms on the ring.

[0073] In this application, “C6-C” 12 "Aryl" refers to an aromatic cyclic group with 6 to 12 carbon atoms that does not contain heteroatoms on the ring, such as phenyl, naphthyl, fluorenyl, or fused-ring aromatic compounds; "C6-C" 10 "Aryl" has a similar meaning. "Heteroaryl" refers to an aryl group in which one or more carbon atoms in the ring structure are replaced by heteroatoms, which can be oxygen, nitrogen, sulfur, etc.

[0074] In this application, "C2-C6 alkenyl" refers to a straight-chain or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, and non-limitingly includes vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl, etc. "Cyclic alkenyl" refers to a cyclic alkenyl group. "C3-C..." 10 "Cycloalkenyl" refers to a cyclic alkenyl group having 3 to 10 carbon atoms on the ring, including, without limitation, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and cyclodecylene; "C3-C8 cycloalkenyl" has a similar meaning.

[0075] In this application, "C2-C6 alkynyl" refers to a straight-chain or branched alkynyl group having 2 to 6 carbon atoms and containing a triple bond, and includes, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentylyl, and hexynyl.

[0076] In this application, "-C(O)" refers to the -C=O- group.

[0077] In this application, "medicinal salt" refers to certain salts that can maintain the biological activity of the original compound and are suitable for medicinal use; this application does not make any specific limitation.

[0078] This application provides a compound based on a pyrazolyl-sulfonyl-phenyl skeleton structure, or its racemic mixture, R-isomer, S-isomer, pharmaceutically acceptable salt, or mixture thereof, the structural formula of which is shown in Formula I:

[0079]

[0080] In Formula I, R1 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted amino, substituted or unsubstituted amide, substituted or unsubstituted carbonyl, substituted or unsubstituted ester, halogen atom, hydroxyl, carboxyl, cyano or nitro.

[0081] In Formula I, p is 0, 1, 2, 3 or 4, and R2 is selected from hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen atom, hydroxyl, cyano or nitro.

[0082] In Formula I, R3 is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0083] In Formula I, R4 is selected from hydrogen atom, halogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cyano, nitro, substituted or unsubstituted amino, hydroxyl, carboxyl, mercapto, sulfonyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl.

[0084] In Formula I, R5 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic groups.

[0085] The compound shown in Formula I has a specific pyrazolyl-sulfonyl-phenyl skeleton structure, which can effectively inhibit the activity of glucagon receptors and has a high antagonistic effect on glucagon receptors. Therefore, it can be used as a glucagon receptor antagonist or to treat metabolic diseases related to glucagon receptors, such as type II diabetes, atherosclerosis, hyperglycemia, obesity, and insulin resistance.

[0086] The inventors analyzed that the compound shown in Formula I can effectively inhibit the activity of glucagon receptors and has a high antagonistic effect on glucagon receptors. The reason may be that a sulfonyl group is introduced on the nitrogen atom of the pyrazole ring. The bond angle of the two single bonds of the sulfur atom in the sulfonyl group forms an angled structure of the molecular skeleton. This special configuration can have a high antagonistic effect on glucagon receptors.

[0087] In some optional embodiments of this application, in Formula I, R1 is selected from C1-C6 alkyl groups with or without M1 substituted or unsubstituted, C1-C6 alkoxy groups with or without M2 substituted or unsubstituted, and C3-C6 alkyl groups with or without M3 substituted or unsubstituted. 10 Cycloalkyl, M4-substituted or unsubstituted 3-12-membered heterocyclic groups, M5-substituted or unsubstituted C6-C 12 aryl, M6-substituted or unsubstituted heteroaryl, -NH2, -NR6R7, -C(O)NR8R9, -C(O)R 10 -C(O)OR 11 -NR 12 C(O)R 13 The halogen atom, hydroxyl group, cyano group, or nitro group; wherein M1 to M6 are each independently selected from halogen atom, hydroxyl group, cyano group, nitro group, -NR group ... 14 R 15 -C(O)NR 16 R 17 -C(O)R 18 -C(O)OR 19 and -NR 20 C(O)R 21At least one of them; R6 to R 21 Each is independently selected from hydrogen atoms, M7-substituted or unsubstituted C1-C6 alkyl groups, and M8-substituted or unsubstituted C3-C groups. 10 Cycloalkyl, M9-substituted or unsubstituted 3-12 membered heterocyclic groups, M 10 Substituted or unsubstituted C6-C 12 aryl, M 11 Substituted or unsubstituted heteroaryl or carboxyl groups; M7 to M 11 Each is independently selected from at least one of C1-C6 alkyl, hydroxyl, halogen atom, nitro, cyano, carboxyl and ester groups.

[0088] R1 in Formula I is selected from the above-mentioned groups, which is beneficial to further enhance the effect of inhibiting the activity of glucagon receptor and further enhance the antagonistic effect on glucagon receptor.

[0089] Furthermore, in some optional embodiments of this application, in Formula I, R1 is selected from -C(O)NR 16 R 17 Substituted C1-C6 alkyl groups, -C(O)NR8R9; wherein R8 and R 16 Each is independently selected from hydrogen atoms or C1-C6 alkyl groups; R9 and R 17 Each group is independently selected from carboxyl-substituted C1-C6 alkyl groups, carboxyl groups, C1-C6 alkyl-substituted 3-12-membered heterocyclic groups, or unsubstituted 3-12-membered heterocyclic groups. R1 in Formula I is selected from the above groups, which is beneficial for further enhancing the inhibitory effect on glucagon receptor activity and further improving the antagonistic effect on glucagon receptors.

[0090] Furthermore, in Equation I, R1 is selected from -C(O)NR 16 R 17 Substituted C1-C3 alkyl groups, -C(O)NR8R9, wherein R8 and R 16 Each is independently selected from hydrogen atoms or C1-C3 alkyl groups, R9, and R 17 Each group is independently selected from carboxyl-substituted C1-C3 alkyl groups, carboxyl groups, C1-C3 alkyl-substituted 3-8 membered nitrogen-containing heterocyclic groups, or unsubstituted 3-8 membered nitrogen-containing heterocyclic groups. R1 in Formula I is selected from the above groups, which is beneficial for further enhancing the inhibitory effect on glucagon receptor activity and further improving the antagonistic effect on glucagon receptors.

[0091] As an example, in Formula I, the substituent of "substituted 3-8 membered nitrogen-containing heterocyclic group" in R1 can be at least one of hydroxyl, halogen atom, nitro, cyano, C1-C3 alkyl and C1-C3 alkoxy.

[0092] In some optional embodiments of this application, in Formula I, p is 0, 1, 2, 3 or 4, and R2 is selected from hydrogen atoms, M 12 Substituted or unsubstituted C1-C6 alkyl groups, M 13 Substituted or unsubstituted C1-C6 alkoxy, halogen, hydroxyl, cyano, or nitro groups; wherein, M 12 and M 13 Each independently selected from -NR 22 R 23 -C(O)NR 24 R 25 -C(O)R 26 -C(O)OR 27 and -NR 28 C(O)R 29 At least one of them; R 22 To R 29 Each is independently selected from hydrogen atoms, M 14 Substituted or unsubstituted C1-C6 alkyl groups, M 15 Substituted or unsubstituted C3-C 10 cycloalkyl, M 16 Substituted or unsubstituted 3-12 membered heterocyclic groups, M 17 Substituted or unsubstituted C6-C 12 aryl, M 18 Substituted or unsubstituted heteroaryl groups; M 14 To M 18 Each group is independently selected from at least one of hydroxyl, halogen atom, nitro, cyano, carboxyl and ester groups.

[0093] R2 in Formula I is selected from the above-mentioned groups, which is beneficial to further enhance the effect of inhibiting the activity of glucagon receptor and further enhance the antagonistic effect on glucagon receptor.

[0094] Furthermore, in some optional embodiments of this application, in Formula I, p is 4, and R2 is selected from hydrogen atoms or C1-C6 alkyl groups. Selecting R2 from the aforementioned groups in Formula I is beneficial for further enhancing the effect of inhibiting glucagon receptor activity and further improving the antagonistic effect on glucagon receptors.

[0095] Furthermore, in Formula I, p is 4, and R2 is selected from hydrogen atoms or C1-C3 alkyl groups. Selecting R2 from the aforementioned groups in Formula I is beneficial for further enhancing the inhibitory effect on glucagon receptor activity and further improving the antagonistic effect on glucagon receptors.

[0096] In some optional embodiments of this application, in Formula I, R3 is selected from M 19 Substituted or unsubstituted C3-C 10 cycloalkyl, M20 Substituted or unsubstituted C3-C 10 Cycloalkenyl, M 21 Substituted or unsubstituted 3-12 membered heterocyclic groups, M 22 Substituted or unsubstituted C6-C 12 aryl, M 23 Substituted or unsubstituted heteroaryl groups; wherein, M 19 To M 23 Each group is independently selected from halogen atoms, C1-C6 alkyl groups, halogen-substituted C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkoxycarbonyl groups, halogen-substituted C1-C6 alkoxy groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, cyano groups, nitro groups, amino groups, hydroxyl groups, hydroxymethyl groups, carboxyl groups, mercapto groups, sulfonyl groups, and C6-C6 alkyl groups. 10 Aryl or 3-12 membered heterocyclic groups.

[0097] R3 in Formula I is selected from the above-mentioned groups, which is beneficial to further enhance the effect of inhibiting the activity of glucagon receptor and further enhance the antagonistic effect on glucagon receptor.

[0098] Furthermore, in some optional embodiments of this application, in Formula I, R3 is selected from M 22 Substituted or unsubstituted C6-C 12 aryl; of which, M 22 The group is selected from halogen atoms, C1-C6 alkyl groups, or C1-C6 alkyl groups substituted with halogen atoms. R3 in Formula I is selected from the above-mentioned groups, which is beneficial for further enhancing the effect of inhibiting glucagon receptor activity and further improving the antagonistic effect on glucagon receptors.

[0099] Furthermore, in Equation I, R3 is selected from M 22 Substituted or unsubstituted C6-C 12 aryl, of which M 22 The R3 group in Formula I is selected from the above-mentioned groups, which is beneficial to further enhance the effect of inhibiting glucagon receptor activity and further enhance the antagonistic effect on glucagon receptor.

[0100] As an example, in Formula I, when R3 is selected from a substituted or unsubstituted aryl group, the aryl group can be phenyl, naphthyl, fluorenyl, or a fused-ring aromatic compound, etc.; in Formula I, R3 is selected from M 22 Substituted or unsubstituted phenyl, wherein M 22 It is selected from C1-C3 alkyl groups with halogen atom or halogen atom substitution, and the substitution site can be ortho, meta or para.

[0101] In some optional embodiments of this application, in Formula I, R4 is selected from hydrogen atom, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, halogen atom, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxyl, mercapto, sulfonyl, C6-C 12 Aryl and 3-12 membered heterocyclic groups.

[0102] R4 in Formula I is selected from the above-mentioned groups, which is beneficial to further enhance the effect of inhibiting the activity of glucagon receptor and further enhance the antagonistic effect on glucagon receptor.

[0103] As an example, in Formula I, when R4 is selected from alkoxy groups, the alkoxy group can be -O[(CH2)] q O] r Y is selected from: hydrogen atom, halogen atom, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or hydroxymethyl; q is 1, 2, 3 or 4; r is 1, 2, 3 or 4.

[0104] Furthermore, in some optional embodiments of this application, in Formula I, R4 is selected from hydrogen atoms or C1-C6 alkyl groups. Selecting R4 from the aforementioned groups in Formula I is beneficial for further enhancing the effect of inhibiting glucagon receptor activity and further improving the antagonistic effect on glucagon receptors.

[0105] Furthermore, in Formula I, R4 is selected from hydrogen atoms or C1-C3 alkyl groups. Selecting R4 from the aforementioned groups in Formula I is beneficial for further enhancing the inhibitory effect on glucagon receptor activity and further improving the antagonistic effect on glucagon receptors.

[0106] In some optional embodiments of this application, in Formula I, R5 is selected from M. 24 Substituted or unsubstituted C1-C6 alkyl groups, M 25 Substituted or unsubstituted C3-C 10 cycloalkyl, M 26 Substituted or unsubstituted C3-C 10 Cycloalkenyl, M 27 Substituted or unsubstituted C6-C 12 aryl, M 28 Substituted or unsubstituted 3-12 membered heterocyclic groups; wherein, M 24 To M 28Each group is independently selected from halogen atoms, C1-C6 alkyl groups, halogen-substituted C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkoxycarbonyl groups, halogen-substituted C1-C6 alkoxy groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, cyano groups, nitro groups, amino groups, hydroxyl groups, hydroxymethyl groups, carboxyl groups, mercapto groups, sulfonyl groups, and C6-C6 groups. 10 Aryl or 3-12 membered heterocyclic groups.

[0107] R5 in Formula I is selected from the above-mentioned groups, which is beneficial to further enhance the effect of inhibiting the activity of glucagon receptor and further enhance the antagonistic effect on glucagon receptor.

[0108] Furthermore, in some optional embodiments of this application, in Formula I, R5 is selected from M 24 Substituted C1-C6 alkyl groups; wherein, M 24 The alkyl group is selected from C1-C6 alkyl groups with halogen atoms or halogen-substituted groups. R5 in Formula I is selected from the above-mentioned groups, which is beneficial for further enhancing the effect of inhibiting glucagon receptor activity and further enhancing the antagonistic effect on glucagon receptors.

[0109] Furthermore, in Equation I, R5 is selected from M 24 Substituted C1-C3 alkyl groups, wherein M 24 The R5 group in Formula I is selected from the above-mentioned groups, which is beneficial to further enhance the effect of inhibiting glucagon receptor activity and further enhance the antagonistic effect on glucagon receptor.

[0110] In some optional embodiments of this application, the structural formula of the compound based on the pyrazolyl-sulfonyl-phenyl skeleton structure is shown in Formula II:

[0111]

[0112] In Formula II, p is 0, 1, 2, 3, or 4, and R2 is selected from hydrogen atoms or C1-C6 alkyl groups. x is 0 or 1, R 30 It is a C1-C6 alkyl group. y is 0 or 1, R 31 It is a C1-C6 alkyl group. R 32 Selected from carboxyl, C1-C6 alkyl-substituted 3-12-membered heterocyclic groups, or unsubstituted 3-12-membered heterocyclic groups. m is 0 or 1, R 33 It is a C1-C6 alkyl group. R 34 To R 38 Each is independently selected from hydrogen atoms, halogen atoms, C1-C6 alkyl groups, or C1-C6 alkyl groups substituted with halogen atoms, and R 34 To R 38At least one of them contains a halogen atom. n is 0 or 1, R 39 It is a C1-C6 alkyl group. R 40 To R 42 Each is independently selected from hydrogen atoms, halogen atoms, C1-C6 alkyl groups, or C1-C6 alkyl groups substituted with halogen atoms, and R 40 To R 42 At least one of them contains a halogen atom.

[0113] Formula II has a specific pyrazolyl-sulfonyl-phenyl skeleton structure, and both the phenyl group and the pyrazolyl group are attached with specific groups, which can further effectively inhibit the activity of glucagon receptor and further enhance the antagonistic effect on glucagon receptor. Therefore, it can be used as a highly effective glucagon receptor antagonist or for the effective treatment of metabolic diseases related to glucagon receptor, such as type II diabetes, atherosclerosis, hyperglycemia, obesity, and insulin resistance.

[0114] In some optional embodiments of this application, in Formula II, p is 0, 1, 2, 3, or 4, and R2 is selected from hydrogen atoms or C1-C3 alkyl groups; x is 0 or 1, R 30 It is a C1-C3 alkyl group; y is 0 or 1, R 31 It is a C1-C3 alkyl group; R 32 Selected from carboxyl, C1-C3 alkyl-substituted 3-12-membered heterocyclic groups or unsubstituted 3-12-membered heterocyclic groups; m is 0 or 1, R 33 It is a C1-C3 alkyl group; R 34 To R 38 Each is independently selected from hydrogen atoms, halogen atoms, C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with halogen atoms, and R 34 To R 38 At least one of them contains a halogen atom; n is 0 or 1, R 39 It is a C1-C3 alkyl group; R 40 To R 42 Each is independently selected from hydrogen atoms, halogen atoms, C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with halogen atoms, and R 40 To R 42 At least one of them contains a halogen atom. The corresponding groups in Formula II are selected from the above groups. By coordinating each group with a specific pyrazolyl-sulfonyl-phenyl skeleton structure, it is beneficial to further enhance the effect of inhibiting glucagon receptor activity and further enhance the antagonistic effect on glucagon receptor.

[0115] In some optional embodiments of this application, in Formula II, p is 0, 1, 2, 3, or 4; R2 is selected from hydrogen atoms or C1-C3 alkyl groups; x is 0; y is 0 or 1; R 31It is a C1-C3 alkyl group; R 32 Selected from carboxyl, C1-C3 alkyl-substituted 3-8 membered nitrogen-containing heterocyclic groups or unsubstituted 3-8 membered nitrogen-containing heterocyclic groups; m is 0; R 34 To R 38 Each is independently selected from hydrogen atoms, halogen atoms, C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with halogen atoms, and R 34 To R 38 At least one of them contains a halogen atom; n is 1, R 39 It is a C1-C3 alkyl group; R 40 To R 42 Each is independently selected from hydrogen atoms, halogen atoms, C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with halogen atoms, and R 40 To R 42 At least one of them contains a halogen atom. The corresponding groups in Formula II are selected from the above groups. By coordinating each group with a specific pyrazolyl-sulfonyl-phenyl skeleton structure, it is beneficial to further enhance the effect of inhibiting glucagon receptor activity and further enhance the antagonistic effect on glucagon receptor.

[0116] In some optional embodiments of this application, in Formula II, p is 4, R2 is a hydrogen atom; x is 0; y is 0 or 1, R 31 It is a C1-C3 alkyl group; R 32 Selected from carboxyl groups or 3-8 member nitrogen-containing heterocyclic groups; m is 0; R 34 To R 38 Each is independently selected from either hydrogen or halogen atoms, and R 34 To R 38 At least one of them is a halogen atom; n is 1, R 39 It is a C1-C3 alkyl group; R 40 To R 42 Each is independently selected from either hydrogen or halogen atoms, and R 40 To R 42 At least one of them contains a halogen atom. The corresponding groups in Formula II are selected from the above groups. By coordinating each group with a specific pyrazolyl-sulfonyl-phenyl skeleton structure, it is beneficial to further enhance the effect of inhibiting glucagon receptor activity and further enhance the antagonistic effect on glucagon receptor.

[0117] Furthermore, in some optional embodiments of this application, in Formula II, p is 4, R2 is a hydrogen atom; x is 0; y is 0 or 1, R 31 It is a C1-C3 alkyl group; R 32 Selected from carboxyl or m is 0; R 34 To R 38 Each is independently selected from either hydrogen or halogen atoms, and R34 To R 38 At least one of them is a halogen atom; n is 1, R 39 It is a C1-C3 alkyl group; R 40 To R 42 Each is independently selected from either hydrogen or halogen atoms, and R 40 To R 42 At least one of them is a halogen atom. The corresponding groups in Formula II are selected from the above groups. By coordinating each group with a specific pyrazolyl-sulfonyl-phenyl skeleton structure, it is beneficial to further enhance the effect of inhibiting glucagon receptor activity and further enhance the antagonistic effect on glucagon receptor.

[0118] Furthermore, in some optional embodiments of this application, in Formula II, p is 4, R2 is a hydrogen atom; x is 0; y is 0 or 1, R 31 It is a C1-C3 alkyl group; R 32 Selected from carboxyl or m is 0; R 35 and R 37 All are halogen atoms, R 34 R 36 and R 38 All are hydrogen atoms; n is 1, R 39 It is a C1-C3 alkyl group; R 40 To R 42 Each is independently selected from either hydrogen or halogen atoms, and R 40 To R 42 At least one of them is a halogen atom. The corresponding groups in Formula II are selected from the above groups. By coordinating each group with a specific pyrazolyl-sulfonyl-phenyl skeleton structure, it is beneficial to further enhance the effect of inhibiting glucagon receptor activity and further enhance the antagonistic effect on glucagon receptor.

[0119] Furthermore, in some optional embodiments of this application, in Formula II, p is 4, R2 is a hydrogen atom; x is 0; y is 0 or 1, R 31 It is a C1-C3 alkyl group; R 32 Selected from carboxyl or m is 0; R 35 and R 37 All are halogen atoms, R 34 R 36 and R 38 All are hydrogen atoms; n is 1, R 39 It is a C1-C3 alkyl group; R 40 To R 42All are halogen atoms. The corresponding groups in Formula II are selected from the above groups. By coordinating each group with a specific pyrazolyl-sulfonyl-phenyl skeleton structure, it is beneficial to further enhance the effect of inhibiting glucagon receptor activity and further enhance the antagonistic effect on glucagon receptor.

[0120] As an example, the compound includes:

[0121]

[0122] The two compounds described above have a highly effective antagonistic effect on glucagon receptors, and therefore can be used as highly effective glucagon receptor antagonists or for the effective treatment of metabolic diseases related to glucagon receptors, such as type II diabetes, atherosclerosis, hyperglycemia, obesity, and insulin resistance.

[0123] This application provides a method for preparing the above-mentioned compound based on the pyrazolyl-sulfonyl-phenyl skeleton structure, the method comprising: reacting a mixed system containing NaH (sodium hydride), a first substance and a second substance.

[0124] The structural formula of the first substance is shown in Formula III:

[0125]

[0126] The structural formula of the second substance is shown in Formula IV:

[0127]

[0128] In Formula IV, R1' is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted amino, substituted or unsubstituted amide, substituted or unsubstituted carbonyl, substituted or unsubstituted ester, halogen atom, hydroxyl, carboxyl, cyano or nitro.

[0129] In Formula IV, p is 0, 1, 2, 3 or 4, and R2 is selected from hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen atom, hydroxyl, cyano or nitro.

[0130] In Formula III, R3 is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0131] In Formula III, R4 is selected from hydrogen atom, halogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cyano, nitro, substituted or unsubstituted amino, hydroxyl, carboxyl, mercapto, sulfonyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl.

[0132] In Formula III, R5 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic groups.

[0133] R in Formula III 43 For hydrogen atoms, R in formula IV 44 For halogen atoms; or, R in formula III 43 For halogen atoms, R in formula IV 44 It is a hydrogen atom.

[0134] It should be noted that R3, R4, and R5 in Formula III are referenced in the relevant content of compounds based on the pyrazolyl-sulfonyl-phenyl skeleton structure mentioned above, and will not be repeated here; R2 and p in Formula IV are referenced in the relevant content of compounds based on the pyrazolyl-sulfonyl-phenyl skeleton structure mentioned above, and will not be repeated here. R1' in Formula IV can be the same as or different from R1 in the compounds based on the pyrazolyl-sulfonyl-phenyl skeleton structure mentioned above. If R1' in Formula IV is the same as R1 in the compounds based on the pyrazolyl-sulfonyl-phenyl skeleton structure mentioned above, the reaction of the first and second substances yields the target compound (i.e., the compound based on the pyrazolyl-sulfonyl-phenyl skeleton structure); if R1' in Formula IV is different from R1 in the compounds based on the pyrazolyl-sulfonyl-phenyl skeleton structure mentioned above, the R1' group in the product obtained after the reaction of the first and second substances needs to undergo further reaction with other groups to form the R1 group.

[0135] In this application, the reaction pathways of the first and second substances are shown in the following equation:

[0136]

[0137] This application involves reacting a mixed system containing NaH, a first substance, and a second substance, which allows the R of the first substance to... 43 The group and the R of the second substance 44The group is simultaneously removed, and the first and second substances are linked to form the compound based on the pyrazolyl-sulfonyl-phenyl skeleton structure provided above. This compound can effectively inhibit the activity of glucagon receptors and has a high antagonistic effect on glucagon receptors. Therefore, it can be used as a glucagon receptor antagonist or to treat metabolic diseases related to glucagon receptors, such as type II diabetes, atherosclerosis, hyperglycemia, obesity, and insulin resistance.

[0138] In some optional embodiments of this application, the mixed system containing NaH, the first substance, and the second substance further contains a solvent, including at least one selected from tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, acetone, diethyl ether, and dichloromethane. The selection of the solvent from the above substances facilitates better dissolution of NaH, the first substance, and the second substance, and promotes a more efficient reaction.

[0139] In some optional embodiments of this application, the reaction temperature of the mixed system containing NaH, the first substance, and the second substance is 20-30°C; this is beneficial for the reaction to proceed better and for increasing the yield of the target product.

[0140] As an example, the reaction temperature can be any value among 20°C, 22°C, 25°C, 27°C, and 30°C, or a range between any two.

[0141] In some optional embodiments of this application, the molar ratio of the first substance, the second substance, and NaH is 1:(2-5):(2-5); the molar ratio of the first substance, the second substance, and NaH within the above range is beneficial for the reaction to proceed better and for improving the yield of the target product.

[0142] As an example, the molar ratio of the first substance to the second substance can be any one of 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 and 1:5 or any range between the two; the molar ratio of the first substance to NaH can be any one of 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 and 1:5 or any range between the two.

[0143] This application also provides a pharmaceutical composition comprising: a compound based on the pyrazolyl-sulfonyl-phenyl skeleton structure as described above, or a racemic, R-isomer, S-isomer, pharmaceutically acceptable salt, or mixture thereof; and a pharmaceutically acceptable carrier.

[0144] The pharmaceutical composition provided in this application, having the above-mentioned compound based on the pyrazolyl-sulfonyl-phenyl skeleton structure or its racemic, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, can effectively inhibit the activity of glucagon receptors and has a high antagonistic effect on glucagon receptors. Therefore, it can be used to treat metabolic diseases related to glucagon receptors, such as type II diabetes, atherosclerosis, hyperglycemia, obesity, insulin resistance, etc.

[0145] This application also provides the use of the above-mentioned compound based on the pyrazolyl-sulfonyl-phenyl skeleton structure or its racemic mixture, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof in the preparation of a glucagon receptor antagonist or medicament; wherein the medicament is used to treat type II diabetes, hyperglycemia, atherosclerosis, obesity and / or insulin resistance.

[0146] To make the objectives, technical solutions, and advantages of the embodiments of this application clearer, the technical solutions in the embodiments of this application will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0147] Example 1

[0148] This embodiment provides a compound A1, and the synthetic route of compound A1 is as follows:

[0149]

[0150] The preparation steps of compounds 1-2 were as follows: 1-(3,5-dichlorophenyl)-6,6,6-trifluorohexane-1,3-dione (compound 1-1, 4.3 g, 22.87 mmol) was dissolved in tetrahydrofuran (40 mL), and sodium methoxide (12 g, 68.61 mmol) was added under nitrogen protection. A solution of ethyl 4,4,4-trifluorobutyrate (5.8 g, 34.3 mmol) in tetrahydrofuran (5 mL) was added in portions, and the mixture was stirred at 50 °C for 16 h. After the reaction was complete, the mixture was diluted with water (20 mL), extracted with ethyl acetate (3 × 50 mL), dried, concentrated, and separated by silica gel column chromatography to obtain a white solid (denoted as compound 1-2, 2.9 g, yield 42%), MS (ESI, m / z): 311.1 [MH]-.

[0151] The preparation steps of compounds 1-3 were as follows: hydrazine hydrate (N2H4·H2O, 15mL) was added to an ethanol (15mL) solution of compound 1-2 (1.5g, 5mmol), and the mixture was heated to 80℃ and stirred for 4h. After the reaction was complete, the reaction solution was concentrated, and silica gel column chromatography was used to obtain a white solid (denoted as compound 1-3, 1.1g, yield 73%), MS (ESI, m / z): 308.7 [M+H]+.

[0152] The preparation steps of compounds 1-4 were as follows: Compound 1-3 (500 mg, 1.6 mmol) was added to a 10 mL solution of NaH (192.8 mg, 4.82 mmol) in tetrahydrofuran under nitrogen protection in an ice bath. After stirring for 30 min, 4-(chlorosulfonyl)benzoic acid (1.06 g, 4.82 mmol) was added, and the mixture was reacted at room temperature for 16 h. After the reaction was complete, the reaction solution was poured into 30 mL of 1 N HCl ice water and stirred. Extraction was performed with ethyl acetate (3 × 50 mL), and the solution was dried, concentrated, and separated by silica gel column chromatography to obtain a yellow solid (denoted as compound 1-4, 400 mg, 0.8 mmol, yield 50%). MS (ESI, m / z): 491.2 [MH]-.

[0153] The preparation steps of compound A1 were as follows: Compounds 1-4 (200 mg, 0.4 mmol) were dissolved in dichloromethane (20 mL) at room temperature. 5-Aminotetrazole (34.7 mg, 0.4 mmol), carbodiimide (EDC, 68.1 mg, 0.44 mmol), and 4-dimethylaminopyridine (DMAP, 4.8 mg, 0.04 mmol) were added slowly in dichloromethane under nitrogen protection. The reaction was then carried out at room temperature for 16 h. After the reaction was complete, the solution was concentrated under reduced pressure, and 30 mg of crude product was obtained by chromatography. This crude product was then purified by high pressure to obtain a white solid (denoted as A1, 10 mg, yield 4%).

[0154] in, Figure 1 Compound A1 prepared in Example 1 of this application 1 H NMR spectrum 1 H NMR (400MHz, DMSO-d6) δ8.24 (s, 4H), 7.865 (d, J = 2, 2H), 7.69 (t, J = 2, 1H), 7.30 (s, 1H), 3.28-3.26 (m, 2H), 2.85-2.76 (m, 2H). Figure 2 The MS spectrum of compound A1 prepared in Example 1 of this application is shown. MS (ESI, m / z): 560.1 [M+H]+.

[0155] from Figure 1 and Figure 2 It can be seen that the compound A1 prepared in Example 1 conforms to the expected structure.

[0156] Example 2

[0157] This embodiment provides a compound A2, and the synthetic route of compound A2 is as follows:

[0158]

[0159] The preparation steps of compounds 1-2, 1-3 and 1-4 are the same as those in Example 1.

[0160] The preparation steps of compound A2 were as follows: Dicyclohexylcarbodiimide (DCC, 75 mg, 0.33 mmol) and 1-hydroxybenzotriazole (HOBT, 48 mg, 0.33 mmol) were added to a solution of compounds 1-4 (150 mg, 0.3 mmol) in N,N-dimethylformamide (5 mL) at 0 °C. After stirring at room temperature for 10 h, 3-aminopropionic acid (27 mg, 0.3 mmol) was added, and the mixture was stirred at room temperature for 16 h. After the reaction was complete, the mixture was diluted with water (10 mL), extracted with ethyl acetate (3 × 20 mL), dried, concentrated, and separated by reverse column chromatography to obtain a white solid (denoted as compound A2, 40 mg, yield 23%).

[0161] in, Figure 3 Compound A2 prepared in Example 2 of this application 1 H NMR spectrum 1 HNMR (400MHz, DMSO-d6) δ8.83(t,J=5,1H),8.17(d,J=8.4,2H),8.03(d,J=8.4,2H),7.85(d,J=2,2H),7.6 9(d,J=0.8,1H),7.27(s,1H),3.46-3.42(m,2H),3.28-3.24(m,2H),2.81-2.74(m,2H),2.49-2.47(m,2H). Figure 4 The MS spectrum of compound A2 prepared in Example 2 of this application is shown. MS (ESI, m / z): 564.1 [M+H]+.

[0162] from Figure 3 and Figure 4 It can be seen that the compound A2 prepared in Example 2 conforms to the expected structure.

[0163] Experimental Example

[0164] The inhibitory activity of compound A1 prepared in Example 1 and compound A2 prepared in Example 2 on glucagon-induced intracellular c-AMP (cyclic adenosine monophosphate) production was determined by experiments.

[0165] After receiving extracellular signals, GPCR receptors regulate intracellular adenylate cyclase activity through signal-responsive G proteins, thereby affecting intracellular c-AMP concentration and producing corresponding biological consequences. The increase or decrease in c-AMP concentration depends on the type of G protein responding to the signal. When glucagon receptors are activated, intracellular Gs proteins respond to the signal, leading to an increase in c-AMP concentration. Therefore, by testing the c-AMP concentration in cells treated with a compound, it is possible to determine whether the compound affects glucagon receptor function, i.e., whether the compound antagonizes glucagon. The cAMP assay is a commonly used method to detect the c-AMP production in cells after a compound has affected GPCRs.

[0166] The experimental procedure was as follows: Using 1X HBSS (balanced salt solution, purchased from Gibco, model: 14-025), 20mM HEPES (4-hydroxyethylpiperazine ethanesulfonic acid, purchased from Gibco, model: 15630080), 0.1wt% BSA (bovine serum albumin, purchased from Perkin Elmer, model: CR84-100), and 500μM IBMX (3-isobutyl-1-methylxanthine, purchased from Sigma, model: I5879) as the assay buffer, Flp-In-CHO-GCGR cells were added to a 384-well plate (purchased from Perkin Elmer, model: 6007680-50) at a density of 2000 cells / well; the working solution of the 8X compound was prepared using the assay buffer; and 2.5μL of the solution was added. 8X compound working solution was added to cell plates and incubated at 37°C for 10 min. 2.5 μL of 120 pM glucagon was added to the cell plates and incubated at 37°C for 30 min. Eu-cAMP tracer (1 / 50, Perkin Elmer, TRF0263) was diluted with lysis buffer (Perkin Elmer, TRF0263) and added to each well of the cell plate (10 μL). Ulight-anti-cAMP (1 / 150, Perkin Elmer, TRF0263) was diluted with lysis buffer and added to each well of the cell plate (10 μL). The cells were incubated at room temperature for 1 h. Cell plate data were detected using an Envision 2105 (Perkin Elmer HTS) at 665 nm and 615 nm wavelengths. The lysis buffer, Eu-cAMP tracer, and Ulight-anti-cAMP were all Perkin Elmer products. Reagents in Elmer's kit, model number TRF0263.

[0167] Figure 5 The IC50 of compound A1, prepared in Example 1 of this application, inhibits glucagon receptor activity. 50 Resulting image; Figure 5 In China, "IC" 50 "5733" means that the concentration of compound A1 when it reaches half the level of glucagon receptor inhibition is 2394 nM. The horizontal axis "Log A1[nM]" represents the logarithm of the concentration of compound A1, and the vertical axis "%inhibition" represents the degree of inhibition of glucagon receptor by compound A1.

[0168] from Figure 5 It can be seen that compound A1 prepared in Example 1 can inhibit glucagon receptor activity.

[0169] Figure 6 The IC50 of compound A2 prepared in Example 2 of this application inhibits glucagon receptor activity. 50 Resulting image; Figure 6 In China, "IC" 50 "2394" means that the concentration of compound A2 when it reaches half the level of inhibition of glucagon receptor is 2394 nM. The horizontal axis "Log A2 [nM]" represents the logarithm of the concentration of compound A2, and the vertical axis "%inhibition" represents the degree of inhibition of glucagon receptor by compound A2.

[0170] from Figure 6 It can be seen that compound A2 prepared in Example 2 can inhibit glucagon receptor activity.

[0171] In summary, the compounds based on the pyrazolyl-sulfonyl-phenyl skeleton structure provided in this application have a specific pyrazolyl-sulfonyl-phenyl skeleton structure, which can effectively inhibit the activity of glucagon receptors and has a high antagonistic effect on glucagon receptors. Therefore, they can be used as glucagon receptor antagonists or to treat metabolic diseases related to glucagon receptors, such as type II diabetes, atherosclerosis, hyperglycemia, obesity, and insulin resistance.

[0172] The embodiments described above are some, but not all, of the embodiments of this application. The detailed description of the embodiments of this application is not intended to limit the scope of the claimed application, but merely to illustrate selected embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of this application without inventive effort are within the scope of protection of this application.

Claims

1. A compound or pharmaceutically acceptable salt or mixture thereof based on a pyrazolyl-sulfonyl-phenyl skeleton structure, characterized in that, The structural formula of the compound is as follows: p is 4, R2 and R4 are both hydrogen atoms; x is 0; y is 0 or 1, R 31 It is a C1-C3 alkyl group; R 32 Selected from carboxyl or m is 0; R 34 To R 38 Each is independently selected from either hydrogen or halogen atoms, and R 34 To R 38 At least one of them is a halogen atom; n is 1, R 39 It is a C1-C3 alkyl group; R 40 To R 42 Each is independently selected from either hydrogen or halogen atoms, and R 40 To R 42 At least one of them is a halogen atom.

2. The compound or pharmaceutically acceptable salt or mixture thereof based on the pyrazolyl-sulfonyl-phenyl skeleton structure according to claim 1, characterized in that, p is 4, R2 and R4 are both hydrogen atoms; x is 0; y is 0 or 1, R 31 It is a C1-C3 alkyl group; R 32 Selected from carboxyl or m is 0; R 35 and R 37 All are halogen atoms, R 34 R 36 and R 38 All are hydrogen atoms; n is 1, R 39 It is a C1-C3 alkyl group; R 40 To R 42 Each is independently selected from either hydrogen or halogen atoms, and R 40 To R 42 At least one of them is a halogen atom.

3. The compound or pharmaceutically acceptable salt or mixture thereof based on the pyrazolyl-sulfonyl-phenyl skeleton structure according to claim 2, characterized in that, p is 4, R2 and R4 are both hydrogen atoms; x is 0; y is 0 or 1, R 31 It is a C1-C3 alkyl group; R 32 Selected from carboxyl or m is 0; R 35 and R 37 All are halogen atoms, R 34 R 36 and R 38 All are hydrogen atoms; n is 1, R 39 It is a C1-C3 alkyl group; R 40 To R 42 All are halogen atoms.

4. The compound or pharmaceutically acceptable salt or mixture thereof based on the pyrazolyl-sulfonyl-phenyl skeleton structure according to claim 3, characterized in that, The compound includes: or / and .

5. A compound A1, the synthetic route of compound A1 is as follows: The preparation steps of compounds 1-2 are as follows: 22.87 mmol of 3,5-dichloroacetophenone was dissolved in 40 mL of tetrahydrofuran, 68.61 mmol of sodium methoxide was added under nitrogen protection, and 5 mL of tetrahydrofuran solution containing 34.3 mmol of ethyl 4,4,4-trifluorobutyrate was added in portions. The mixture was stirred at 50 °C for 16 h. After the reaction was completed, the mixture was diluted with 20 mL of water, extracted with 50 mL of ethyl acetate, dried, concentrated, and separated by silica gel column chromatography to obtain 2.9 g of white solid. The preparation steps of compounds 1-3 are as follows: 15 mL of hydrazine hydrate was added to 15 mL of ethanol solution containing 5 mmol of compounds 1-2, and the mixture was heated to 80 °C and stirred for 4 h. After the reaction was completed, the reaction solution was concentrated and separated by silica gel column chromatography to obtain 1.1 g of white solid. The preparation steps of compounds 1-4 are as follows: under ice bath, 1.6 mmol of compounds 1-3 were added to 10 mL of tetrahydrofuran solution containing 4.82 mmol NaH under nitrogen protection. After stirring for 30 min, 4.82 mmol of 4-(chlorosulfonyl)benzoic acid was added, and the mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was poured into 30 mL of 1N HCl ice water and stirred. The solution was extracted with 50 mL of ethyl acetate, dried, concentrated, and separated by silica gel column chromatography to obtain 400 mg of yellow solid. The preparation steps of compound A1 are as follows: At room temperature, 0.4 mmol of compounds 1-4 were dissolved in 20 mL of dichloromethane, and 0.4 mmol of 5-aminotetrazolium, 0.44 mmol of carbodiimide, and 0.04 mmol of 4-dimethylaminopyridine were added. Under nitrogen protection, a dichloromethane solution of 0.32 mmol of N,N-diisopropylethylamine was slowly added, and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the solution was concentrated under reduced pressure, and 30 mg of crude product was obtained by chromatography. 10 mg of white solid was obtained by high pressure preparation.

6. A compound A2, the synthetic route of compound A2 is as follows: The preparation steps of compounds 1-2 are as follows: 22.87 mmol of 3,5-dichloroacetophenone was dissolved in 40 mL of tetrahydrofuran, 68.61 mmol of sodium methoxide was added under nitrogen protection, and 5 mL of tetrahydrofuran solution containing 34.3 mmol of ethyl 4,4,4-trifluorobutyrate was added in portions. The mixture was stirred at 50 °C for 16 h. After the reaction was completed, the mixture was diluted with 20 mL of water, extracted with 50 mL of ethyl acetate, dried, concentrated, and separated by silica gel column chromatography to obtain 2.9 g of white solid. The preparation steps of compounds 1-3 are as follows: 15 mL of hydrazine hydrate was added to 15 mL of ethanol solution containing 5 mmol of compounds 1-2, and the mixture was heated to 80 °C and stirred for 4 h. After the reaction was completed, the reaction solution was concentrated and separated by silica gel column chromatography to obtain 1.1 g of white solid. The preparation steps of compounds 1-4 are as follows: under ice bath, 1.6 mmol of compounds 1-3 were added to 10 mL of tetrahydrofuran solution containing 4.82 mmol NaH under nitrogen protection. After stirring for 30 min, 4.82 mmol of 4-(chlorosulfonyl)benzoic acid was added, and the mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was poured into 30 mL of 1N HCl ice water and stirred. The solution was extracted with 50 mL of ethyl acetate, dried, concentrated, and separated by silica gel column chromatography to obtain 400 mg of yellow solid. The preparation steps of compound A2 are as follows: At 0℃, 0.33 mmol of dicyclohexylcarbodiimide and 0.33 mmol of 1-hydroxybenzotriazole were added to 5 mL of N,N-dimethylformamide solution containing 0.3 mmol of compounds 1-4 and stirred at room temperature for 10 h. Then, 0.3 mmol of 3-aminopropionic acid was added and stirred at room temperature for 16 h. After the reaction was completed, 10 mL of water was added for dilution, 20 mL of ethyl acetate was added for extraction, dried, concentrated, and separated by reverse column chromatography to obtain 40 mg of white solid.

7. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: The compound or pharmaceutically acceptable salt or mixture thereof based on the pyrazolyl-sulfonyl-phenyl skeleton structure according to any one of claims 1-4; and the pharmaceutically acceptable carrier.

8. The use of any compound or pharmaceutically acceptable salt or mixture thereof based on the pyrazolyl-sulfonyl-phenyl skeleton structure as described in any one of claims 1-4 in the preparation of a glucagon receptor antagonist or medicament; in, The drug is used to treat type II diabetes, atherosclerosis, hyperglycemia, obesity, and / or insulin resistance.

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