Sulfonylurea derivative and medical application thereof

Abstract

The invention relates to sulfonylurea derivatives and medical application thereof. Specifically, the invention relates to a sulfonylurea derivative shown in a general formula (I), a preparation method of the sulfonylurea derivative, a pharmaceutical composition containing the sulfonylurea derivative and application of the sulfonylurea derivative in treatment of diseases and symptoms affected by neuronal injury, such as cerebral apoplexy, cerebral injury, neuropathic pain, migraine, inflammatory pain, chronic pain or depression. The definition of each group in the general formula (I) is the same as that in the specification. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202180042983.3, application date July 16, 2021, and invention name “Sulfonylurea derivatives and their medical uses”. Technical Field

[0002] The present invention belongs to the field of medicine, and specifically relates to a class of sulfonylurea derivatives, a preparation method thereof, and use thereof as medicine. Background Art

[0003] Cerebral stroke, also known as "stroke" or "cerebral vascular accident" (CVA), is an acute cerebrovascular disease. It is a group of diseases that cause brain tissue damage due to sudden rupture of brain blood vessels or blockage of blood vessels, which prevents blood from flowing into the brain. It includes ischemic and hemorrhagic strokes. The incidence of ischemic stroke is higher than that of hemorrhagic stroke, accounting for 60% to 70% of the total number of strokes. Occlusion and stenosis of the internal carotid artery and vertebral artery can cause ischemic stroke, which mostly occurs in people over 40 years old, more often in men than in women, and can cause death in severe cases. The mortality rate of hemorrhagic stroke is relatively high. Surveys show that stroke has become the leading cause of death in my country in both urban and rural areas, and is also the leading cause of disability among Chinese adults. Stroke is characterized by high incidence, high mortality and high disability rate.

[0004] The most common cause of stroke is small emboli on the inner wall of the blood vessels supplying the brain, which can cause arterial embolism after detachment, i.e. ischemic stroke. It can also be caused by bleeding from cerebral blood vessels or thrombus, which is hemorrhagic stroke. The heart valves of patients with coronary heart disease and atrial fibrillation are prone to mural thrombi, which can block cerebral blood vessels after detachment and can also cause ischemic stroke. Other factors include hypertension, diabetes, hyperlipidemia, etc.

[0005] In 2018, the biopharmaceutical company Biogen evaluated BIIB093 (intravenous glibenclamide) for the prevention and treatment of severe cerebral edema in patients with massive cerebral infarction (LHI) in a Phase III clinical study (CN103108637B). LHI is one of the most serious types of stroke. In the three major pharmaceutical markets of the United States, the European Union, and Japan, it is estimated that approximately 1.7 million ischemic strokes occur each year, of which approximately 15% are classified as LHI. Glibenclamide is a sulfonylurea hypoglycemic drug that acts on the ATP-sensitive potassium channels of beta cells, directly stimulating the secretion of insulin by pancreatic beta cells, and has a strong hypoglycemic effect. It is one of the most widely used oral hypoglycemic drugs in clinical practice. BIIB093 is a high affinity inhibitor of the SUR1-TRPM4 (sulfonylurea receptor 1-transient receptor potential ion channel protein 4) channel, which is upregulated after ischemia and trauma. The opening of these channels can lead to brain edema, midline shift, increased intracranial pressure and brain herniation, leading to permanent disability or death (Drug Des Devel Ther. 2018, 15, 2539-2552.). BIIB093 is an experimental drug currently being developed for the prevention and treatment of severe brain edema caused by LHI.

[0006] The purpose of the present disclosure is to provide a class of sulfonylurea derivatives, which have a high brain-penetration rate and can produce inhibitory or therapeutic effects on central nervous system diseases such as stroke. Summary of the invention

[0007] The present disclosure provides a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, or an isomer thereof,

[0008]

[0009] in,

[0010] Every R 1 are each independently selected from deuterium, alkyl optionally substituted by halogen, halogen, hydroxyl, thiol, -NR i R j 、-C(O)R k 、-C(O)OR k , nitro, cyano, alkoxy optionally substituted by halogen, alkylthio;

[0011] R 2 is selected from alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl is optionally further selected from deuterium, alkyl, haloalkyl, halogen, hydroxy, oxo, thiol, -NR i R j 、-C(O)R k 、-C(O)OR k、-SR i 、-S(O)R i 、-SO 2 R i , nitro, cyano, aryl optionally substituted by hydroxy or alkoxy, heteroaryl optionally substituted by oxo or alkyl, heterocyclyl optionally substituted by oxo or alkyl, cycloalkyl optionally substituted by oxo or alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkoxy, alkylthio;

[0012] R 3 are each independently selected from deuterium, alkyl optionally substituted by halogen, halogen, hydroxyl, thiol, -NR i R j 、-C(O)R k 、-C(O)OR k , nitro, cyano, alkoxy, alkylthio;

[0013] R i and R j are independently selected from hydrogen, hydroxy, alkyl, cycloalkyl, alkoxy, -C(=NH)-NH 2 ;

[0014] R k is selected from alkyl, alkoxy, aryl, alkenyl, alkynyl, wherein the alkyl, alkoxy, aryl, alkenyl, alkynyl is optionally further substituted by one or more groups selected from aryl, heteroaryl, heterocyclyl, cycloalkyl, alkyl, alkoxy;

[0015] m is an integer selected from 0 to 5;

[0016] n is an integer selected from 0 to 10;

[0017] And R 2 no

[0018] In some embodiments, in the compound of formula (I),

[0019] Each R 1 are each independently selected from deuterium, C optionally substituted by halogen 1-6 Alkyl, halogen, hydroxyl, mercapto, -NR i R j 、-C(O)R k 、-C(O)OR k , nitro, cyano, C 1-6 Alkoxy, C 1-6 Alkylthio;

[0020] R 2 Selected from C 1-20 Alkyl, C 1-20 Alkoxy, C2-12 Alkenyl, C 2-12 Alkynyl, 6-14 membered aryl, 5-14 membered heteroaryl, 3-15 membered cycloalkyl, 3-20 membered heterocyclyl:

[0021] The C 1-20 The alkyl group is preferably C 1-12 Alkyl, more preferably C 1-6 alkyl,

[0022] The C 1-20 Alkoxy is preferably C 1-12 Alkoxy, more preferably C 1-6 Alkoxy,

[0023] The C 2-12 The alkenyl group is preferably C 2-6 Alkenyl,

[0024] The 6-14-membered aryl group is preferably a 6-12-membered aryl group, more preferably a phenyl group or a naphthyl group.

[0025] The 5-14-membered heteroaryl group is preferably a 6-12-membered heteroaryl group, more preferably a 5-membered or 6-membered heteroaryl group.

[0026] The 3-15-membered cycloalkyl is preferably a 3-10-membered cycloalkyl, more preferably a 5-7-membered cycloalkyl.

[0027] The 3-20-membered heterocyclic group is preferably a 3-12-membered heterocyclic group, and more preferably a 3-8-membered heterocyclic group.

[0028] The C 1-20 Alkyl, C 1-20 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, 6-14 membered aryl, 5-14 membered heteroaryl, 3-15 membered cycloalkyl, 3-20 membered heterocyclyl are optionally further selected from deuterium, alkyl, haloalkyl, halogen, hydroxy, oxo, mercapto, -NR i R j 、-C(O)R k 、-C(O)OR k 、-SR i 、-S(O)R i 、-SO 2 R i , nitro, cyano, aryl optionally substituted by hydroxy or alkoxy, heteroaryl optionally substituted by oxo or alkyl, heterocyclyl optionally substituted by oxo or alkyl, cycloalkyl optionally substituted by oxo or alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkoxy, alkylthio;

[0029] R 3 are each independently selected from deuterium, C optionally substituted by halogen 1-6Alkyl, halogen, hydroxyl, mercapto, -NR i R j 、-C(O)R k 、-C(O)OR k , nitro, cyano, C 1-6 Alkoxy, C 1-6 Alkylthio;

[0030] R i and R j are independently selected from hydrogen, hydroxy, alkyl, cycloalkyl, alkoxy, -C(=NH)-NH 2 ;

[0031] R k is selected from alkyl, alkoxy, aryl, alkenyl, alkynyl, wherein the alkyl, alkoxy, aryl, alkenyl, alkynyl is optionally further substituted by one or more groups selected from aryl, heteroaryl, heterocyclyl, cycloalkyl, alkyl, alkoxy;

[0032] m is an integer selected from 0 to 5;

[0033] n is an integer selected from 0 to 10;

[0034] And R 2 no

[0035] In some embodiments, in the compound of formula (I), R 1 Selected from halogen, C 1-6 Alkoxy, optionally substituted by halogen, C 1-6 Alkyl or cyano, R 2 , R 3 The definitions of , m, and n are as described above.

[0036] In some embodiments, in the compound of formula (I), R 1 Selected from Cl, OCH 3 , OCD 3 、CN、OH、OCF 3 , R 2 , R 3 The definitions of , m, and n are as described above.

[0037] In some embodiments, in the compound of formula (I),

[0038] Each R 1 are each independently selected from deuterium, C optionally substituted by halogen 1-6 Alkyl, halogen, hydroxyl, mercapto, -NR i R j 、-C(O)R k 、-C(O)OR k , nitro, cyano, C1-6 Alkoxy, C 1-6 Alkylthio;

[0039] R 2 Selected from C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 6 -C 10 Aryl:

[0040] The alkyl group is optionally C 6 -C 10 Aryl or -NR i R j Replacement, R i and R j may be independently selected from hydrogen or -C(=NH)-NH 2 ,

[0041] The C 6 -C 10 The aryl group is optionally substituted with hydroxyl and / or C 1 -C 6 The aryl group is optionally substituted by an alkoxy group, or the aryl group is optionally substituted by a 5-7 membered heterocyclic group, and the 5-7 membered heterocyclic group is optionally substituted by an oxo group and / or a C 1 -C 6 Alkyl substitution;

[0042] The C 2 -C 6 The alkenyl group is optionally substituted with C 6 -C 10 Aryl substituted, the C 6 -C 10 The aryl group is optionally substituted with hydroxyl and / or C 1 -C 6 Alkoxy substitution;

[0043] R 3 are each independently selected from deuterium, C optionally substituted by halogen 1-6 Alkyl, halogen, hydroxyl, mercapto, -NR i R j 、-C(O)R k 、-C(O)OR k , nitro, cyano, C 1-6 Alkoxy, alkylthio;

[0044] R i and R j may be independently selected from hydrogen, hydroxy, alkyl, cycloalkyl, alkoxy, -C(=NH)-NH 2 ;

[0045] R kis selected from alkyl, alkoxy, aryl, alkenyl, and alkynyl, wherein the alkyl, alkoxy, aryl, alkenyl, and alkynyl may be further substituted by aryl, heteroaryl, heterocyclic, cycloalkyl, alkyl, and alkoxy;

[0046] m is an integer selected from 0 to 5;

[0047] n is selected from an integer of 0-10.

[0048] In some embodiments, in the compound of formula (I),

[0049] R 1 Selected from halogen, C 1-6 Alkoxy, optionally substituted by halogen, C 1-6 Alkyl or cyano,

[0050] R 2 Selected from C 1-6 Alkyl, C 2 -C 6 Alkenyl, C 6 -C 10 Aryl:

[0051] The alkyl group is optionally substituted with an aryl group or a -NR i R j Replacement, R i and R j may be independently selected from hydrogen or -C(=NH)-NH 2 , the aryl group is optionally substituted by hydroxyl and / or alkoxy,

[0052] The alkenyl group is optionally substituted by an aryl group, and the aryl group is optionally substituted by a hydroxyl group and / or an alkoxy group,

[0053] The aryl group is optionally substituted by a heterocyclic group, and the heterocyclic group is optionally substituted by an oxo group and / or an alkyl group;

[0054] n is 0;

[0055] m is selected from an integer of 0-5.

[0056] In some embodiments, in the compound of formula (I),

[0057] Each R 1 are each independently selected from deuterium, alkyl optionally substituted by halogen, halogen, hydroxyl, thiol, -NR i R j 、-C(O)R k 、-C(O)OR k , nitro, cyano, alkoxy, alkylthio;

[0058] R 3 are each independently selected from deuterium, alkyl optionally substituted by halogen, halogen, hydroxyl, thiol, -NRi R j 、-C(O)R k 、-C(O)OR k , nitro, cyano, alkoxy, alkylthio;

[0059] R i and R j may be independently selected from hydrogen, hydroxy, alkyl, cycloalkyl, alkoxy, -C(=NH)-NH 2 ;

[0060] R k is selected from alkyl, alkoxy, aryl, alkenyl, and alkynyl, wherein the alkyl, alkoxy, aryl, alkenyl, and alkynyl may be further substituted by aryl, heteroaryl, heterocyclic, cycloalkyl, alkyl, and alkoxy;

[0061] m is an integer selected from 0 to 5;

[0062] n is an integer selected from 0 to 10;

[0063] R 2 Selected from

[0064] In some embodiments, in the compound of formula (I), n is 0,

[0065] R 1 are each independently selected from deuterium, alkyl optionally substituted by halogen, halogen, hydroxyl, thiol, -NR i R j 、-C(O)R k 、-C(O)OR k , nitro, cyano, alkoxy, alkylthio;

[0066] R 2 is selected from alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl is optionally further selected from deuterium, alkyl, haloalkyl, halogen, hydroxy, oxo, thiol, -NR i R j 、-C(O)R k 、-C(O)OR k 、-SR i 、-S(O)R i 、-SO 2 R i , nitro, cyano, aryl optionally substituted by hydroxy or alkoxy, heteroaryl optionally substituted by oxo or alkyl, heterocyclyl optionally substituted by oxo or alkyl, cycloalkyl optionally substituted by oxo or alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkoxy, alkylthio;

[0067] R i and R j may be independently selected from hydrogen, hydroxy, alkyl, cycloalkyl, alkoxy, -C(=NH)-NH 2 ;

[0068] R k is selected from alkyl, alkoxy, aryl, alkenyl, and alkynyl, wherein the alkyl, alkoxy, aryl, alkenyl, and alkynyl may be further substituted by one or more groups selected from aryl, heteroaryl, heterocyclic group, cycloalkyl, alkyl, and alkoxy;

[0069] m is an integer selected from 0 to 5;

[0070] And R 2 no

[0071] In some embodiments, in the compound of formula (I),

[0072] n is 0,

[0073] R 1 is selected from halogen, alkoxy, alkyl optionally substituted by halogen, or cyano,

[0074] R 2 is selected from alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl is optionally further selected from deuterium, alkyl, haloalkyl, halogen, hydroxy, oxo, thiol, -NR i R j 、-C(O)R k 、-C(O)OR k 、-SR i 、-S(O)R i 、-SO 2 R i , nitro, cyano, aryl optionally substituted by hydroxy or alkoxy, heteroaryl optionally substituted by oxo or alkyl, heterocyclyl optionally substituted by oxo or alkyl, cycloalkyl optionally substituted by oxo or alkyl, optionally substituted alkenylene, optionally substituted alkynylene, alkoxy, alkylthio;

[0075] R i and R j may be independently selected from hydrogen, hydroxy, alkyl, cycloalkyl, alkoxy, -C(=NH)-NH 2 ;

[0076] R kis selected from alkyl, alkoxy, aryl, alkenyl, and alkynyl, wherein the alkyl, alkoxy, aryl, alkenyl, and alkynyl may be further substituted by one or more groups selected from aryl, heteroaryl, heterocyclic group, cycloalkyl, alkyl, and alkoxy;

[0077] m is an integer selected from 0 to 5;

[0078] And R 2 no

[0079] In some embodiments, in the compound of formula (I),

[0080] n is 0,

[0081] R 1 Selected from Cl, OCH 3 、CN、OH、OCF 3 ,

[0082] R 2 is selected from alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl is optionally further selected from deuterium, alkyl, haloalkyl, halogen, hydroxy, oxo, thiol, -NR i R j 、-C(O)R k 、-C(O)OR k 、-SR i 、-S(O)R i 、-SO 2 R i , nitro, cyano, aryl optionally substituted by hydroxy or alkoxy, heteroaryl optionally substituted by oxo or alkyl, heterocyclyl optionally substituted by oxo or alkyl, cycloalkyl optionally substituted by oxo or alkyl, optionally substituted alkenylene, optionally substituted alkynylene, alkoxy, alkylthio;

[0083] R i and R j may be independently selected from hydrogen, hydroxy, alkyl, cycloalkyl, alkoxy, -C(=NH)-NH 2 ;

[0084] R k is selected from alkyl, alkoxy, aryl, alkenyl, and alkynyl, wherein the alkyl, alkoxy, aryl, alkenyl, and alkynyl may be further substituted by aryl, heteroaryl, heterocyclic, cycloalkyl, alkyl, and alkoxy;

[0085] m is an integer selected from 0 to 5;

[0086] And R 2 no

[0087] In some embodiments, in the compound of formula (I),

[0088] n is 0,

[0089] Every R 1 are each independently selected from deuterium, alkyl optionally substituted by halogen, halogen, hydroxyl, thiol, -NR i R j 、-C(O)R k 、-C(O)OR k , nitro, cyano, alkoxy, alkylthio;

[0090] R 2 Selected from

[0091] R i and R j may be independently selected from hydrogen, hydroxy, alkyl, cycloalkyl, alkoxy, -C(=NH)-NH 2 ;

[0092] R k is selected from alkyl, alkoxy, aryl, alkenyl, and alkynyl, wherein the alkyl, alkoxy, aryl, alkenyl, and alkynyl may be further substituted by one or more groups selected from aryl, heteroaryl, heterocyclic group, cycloalkyl, alkyl, and alkoxy;

[0093] m is selected from an integer of 0-5.

[0094] In some embodiments, in the compound of formula (I),

[0095] R 1 is selected from halogen, alkoxy, alkyl optionally substituted by halogen or cyano,

[0096] R 2 Selected from

[0097] n is 0;

[0098] m is selected from an integer of 0-5.

[0099] In some embodiments, in the compound of formula (I),

[0100] R 1 Selected from Cl, OCH 3 、CN、OH、OCF 3 ,

[0101] R 2 Selected from

[0102] n is 0,

[0103] m is selected from an integer of 0-5.

[0104] A compound of formula (I-1), or a pharmaceutically acceptable salt thereof, or an isomer thereof,

[0105]

[0106] in,

[0107] R 2 is selected from alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl is optionally further selected from deuterium, alkyl, haloalkyl, halogen, hydroxy, oxo, thiol, -NR i R j 、-C(O)R k 、-C(O)OR k 、-SR i 、-S(O)R i 、-SO 2 R i , nitro, cyano, aryl optionally substituted by hydroxy and / or alkoxy, heteroaryl optionally substituted by oxo and / or alkyl, heterocyclyl optionally substituted by oxo and / or alkyl, cycloalkyl optionally substituted by oxo and / or alkyl, optionally substituted alkenylene, optionally substituted alkynylene, alkoxy, alkylthio;

[0108] R i and R j may be independently selected from hydrogen, hydroxy, alkyl, cycloalkyl, alkoxy, -C(=NH)-NH 2 ;

[0109] R k is selected from alkyl, alkoxy, aryl, alkenyl, and alkynyl, wherein the alkyl, alkoxy, aryl, alkenyl, and alkynyl may be further substituted by one or more groups selected from aryl, heteroaryl, heterocyclic group, cycloalkyl, alkyl, and alkoxy;

[0110] And R 2 no

[0111] In some embodiments, in the compound of formula (I-1), R 2 is selected from alkyl, alkenyl, aryl,

[0112] The alkyl group is optionally substituted with an aryl group or a -NR i R j Replacement, R i and R j may be independently selected from hydrogen or -C(=NH)-NH 2 ,

[0113] The aryl group is optionally substituted by hydroxyl and / or alkoxy; or the aryl group is optionally substituted by a heterocyclic group, and the heterocyclic group is optionally substituted by oxo and / or alkyl,

[0114] The alkenyl group is optionally substituted with an aryl group, and the aryl group is optionally substituted with a hydroxyl group and / or an alkoxy group.

[0115] In some embodiments, in the compound of formula (I-1), R 2 Selected from C 1-20 Alkyl, C 1-20 Alkoxy, C 2-12 Alkenyl, C 2-12 alkynyl, 6-14 membered aryl, 5-14 membered heteroaryl, 3-15 membered cycloalkyl, 3-20 membered heterocyclyl,

[0116] The C 1-20 The alkyl group is preferably C 1-12 Alkyl, more preferably C 1-6 alkyl,

[0117] The C 1-20 Alkoxy is preferably C 1-12 Alkoxy, more preferably C 1-6 Alkoxy,

[0118] The C 2-12 The alkenyl group is preferably C 2-6 Alkenyl,

[0119] The 6-14-membered aryl group is preferably a 6-12-membered aryl group, more preferably a phenyl group or a naphthyl group.

[0120] The 5-14-membered heteroaryl group is preferably a 6-12-membered heteroaryl group, more preferably a 5-membered or 6-membered heteroaryl group.

[0121] The 3-15-membered cycloalkyl is preferably a 3-10-membered cycloalkyl, more preferably a 5-7-membered cycloalkyl.

[0122] The 3-20-membered heterocyclic group is preferably a 3-12-membered heterocyclic group, and more preferably a 3-8-membered heterocyclic group.

[0123] The C 1-20 Alkyl, C 1-20 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, 6-14 membered aryl, 5-14 membered heteroaryl, 3-15 membered cycloalkyl, 3-20 membered heterocyclyl are optionally further selected from deuterium, alkyl, haloalkyl, halogen, hydroxy, oxo, mercapto, -NR i R j 、-C(O)R k 、-C(O)OR k 、-SRi 、-S(O)R i 、-SO 2 R i , nitro, cyano, aryl optionally substituted by hydroxy or alkoxy, heteroaryl optionally substituted by oxo or alkyl, heterocyclyl optionally substituted by oxo or alkyl, cycloalkyl optionally substituted by oxo or alkyl, optionally substituted alkenylene, optionally substituted alkynylene, alkoxy, alkylthio;

[0124] R i and R j may be independently selected from hydrogen, hydroxy, alkyl, cycloalkyl, alkoxy, -C(=NH)-NH 2 ;

[0125] R k is selected from alkyl, alkoxy, aryl, alkenyl, and alkynyl, wherein the alkyl, alkoxy, aryl, alkenyl, and alkynyl may be further substituted by one or more groups selected from aryl, heteroaryl, heterocyclic group, cycloalkyl, alkyl, and alkoxy;

[0126] And R 2 no

[0127] The present disclosure also provides the following compounds, or pharmaceutically acceptable salts thereof, or isomers thereof,

[0128]

[0129] The present disclosure also provides the use of the following compounds, or pharmaceutically acceptable salts thereof, or isomers thereof in the preparation of drugs for preventing or treating diseases and disorders affected by neuronal damage,

[0130]

[0131]

[0132] The present disclosure also provides the use of the following compounds, or pharmaceutically acceptable salts thereof, or isomers thereof in the preparation of drugs for treating acute stroke, traumatic brain injury, spinal cord injury, myocardial infarction, shock, organ ischemia, ventricular arrhythmia, ischemic injury, hypoxia / ischemia or other injury conditions and disorders in patients:

[0133]

[0134]

[0135] The present disclosure also provides a method for preparing the following compound or a pharmaceutically acceptable salt thereof, comprising:

[0136]

[0137] The present disclosure also provides a method for preparing the following compound or a pharmaceutically acceptable salt thereof, comprising:

[0138]

[0139] The present disclosure also provides a method for preparing a compound of formula (I-1), or a pharmaceutically acceptable salt thereof, or an isomer thereof, comprising:

[0140]

[0141] Where R 2 The definition of is the same as described in formula (I-1).

[0142] The present disclosure also relates to a pharmaceutical composition comprising the compound described in the present disclosure or a pharmaceutically acceptable salt thereof, or an isomer thereof. Generally, the composition further comprises at least one pharmaceutically acceptable carrier, diluent or excipient.

[0143] In certain embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0144] In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of the aforementioned compound based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of the aforementioned compound. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound.

[0145] In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable carrier, diluent or excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable carrier, diluent or excipient.

[0146] The present disclosure also provides use of the compound or its pharmaceutically acceptable salt, or its isomer, or a pharmaceutical composition comprising the same in the preparation of a drug for preventing or treating diseases and disorders affected by neuronal damage.

[0147] In some embodiments, the diseases and conditions affected by neuronal damage are selected from stroke, brain injury, neuropathic pain, migraine, inflammatory pain, chronic pain or depression. In some embodiments, the diseases and conditions affected by neuronal damage are ischemic stroke. In some embodiments, the diseases and conditions affected by neuronal damage are cerebral hemisphere infarction. In some embodiments, the diseases and conditions affected by neuronal damage are acute subarachnoid hemorrhage.

[0148] The present disclosure also provides use of the compound or its pharmaceutically acceptable salt, or its isomer, or a pharmaceutical composition comprising the same in the preparation of a medicament for treating acute stroke, traumatic brain injury, spinal cord injury, myocardial infarction, shock, organ ischemia, ventricular arrhythmia, ischemic injury, hypoxia / ischemia or other injury conditions and disorders in patients.

[0149] The present disclosure also provides use of the compound or its pharmaceutically acceptable salt, or its isomer, or a pharmaceutical composition comprising the compound in preparing a drug for treating central nervous system diseases such as stroke.

[0150] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, or isomers thereof, can be formulated for administration orally, buccally, vaginally, rectally, via inhalation, via insufflation, intranasally, sublingually, topically, or parenterally (e.g., intramuscularly, subcutaneously, intraperitoneally, intrathoracically, intravenously, epidurally, intrathecally, intracerebroventricularly, or by injection into a joint).

[0151] The term "treating" refers to administering a pharmaceutical composition for preventive and / or therapeutic purposes. For "preventing a disease" it refers to prophylactic treatment of a subject who does not yet have the disease, but is susceptible to or at risk for a particular disease. For "treating a disease" it refers to treating a patient who already has the disease to improve or stabilize the patient's condition.

[0152] Any isotopically labeled (or "radiolabeled") derivative of the compounds of the present disclosure or their pharmaceutically acceptable salts, or their isomers, is covered by the present disclosure. Such derivatives are those in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of radionuclides that may be incorporated include 2 H (also written as "D" for deuterium), 3 H (also written as "T" for tritium), 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 18 F. 36 Cl,82 Br, 75 Br, 76 Br, 77 Br, 123 I. 124 I. 125 I. 31 P. 32 P. 35 S. and 131 I. The radionuclide used will depend on the specific application of the radiolabeled derivative. For example, for in vitro receptor labeling and competition assays, 3 H or 14 C is often useful. For radiographic applications, 11 C or 18 F is often useful. In some embodiments, the radionuclide is 3 H. In some embodiments, the radionuclide is 14 C. In some embodiments, the radionuclide is 11 C. And in some embodiments, the radionuclide is 18 F.

[0153] Unless stated otherwise, the following terms used in the specification and claims have the following meanings.

[0154] "Acceptable carriers, diluents or excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration for use by humans or domestic animals.

[0155] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched groups of 1 to 20 carbon atoms. Preferably, the alkyl group contains 1 to 12 carbon atoms, and more preferably, the alkyl group contains 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, and various branched isomers thereof. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from aryl, heteroaryl, halogen substituted.

[0156] The term "alkenyl" includes branched and straight chain alkenes having 2 to 12 carbon atoms or alkenes containing aliphatic hydrocarbon groups. 2-6The term "alkenyl" refers to an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl.

[0157] The term "alkynyl" includes branched and straight chain alkynyl or aliphatic hydrocarbon-containing olefins having 2 to 12 carbon atoms, or if a specific number of carbon atoms is specified, that specific number is intended, for example, ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl, and 1-methylpent-2-ynyl.

[0158] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spirocyclic, fused and bridged rings. The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0159] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O). m (wherein m is an integer from 0 to 2) heteroatoms, but does not include the ring parts of "O-O-", "O-S-" or "S-S-", and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged ring heterocyclic groups. Non-limiting examples of "heterocyclic group" include:

[0160]

[0161]

[0162] wait.

[0163] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0164] wait.

[0165] The ring carbon atoms of the heterocycloalkyl group may be oxo-substituted (functionalized as a carbonyl group). Illustrative examples of such heterocycloalkyl groups are:

[0166] The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0167] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:

[0168]

[0169] The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate, preferably phenyl.

[0170] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 6 to 12 members, more preferably 5 or 6 members. For example. Non-limiting examples include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazine, thiadiazole etc.

[0171] The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0172]

[0173] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, oxo, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0174] The term "alkoxy" refers to "O" (alkyl) and "O" (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0175] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0176] The term "haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.

[0177] The term "haloaryl" refers to an aryl group substituted with a halogen, wherein aryl is as defined above.

[0178] The term "haloheteroaryl" refers to a heteroaryl group substituted with a halogen, wherein heteroaryl is as defined above.

[0179] The term "haloheterocyclyl" refers to a heterocyclyl group substituted with a halogen, wherein the heterocyclyl group is as defined above.

[0180] The term "halocycloalkyl" refers to a ring radical substituted with halogen, wherein cycloalkyl is as defined above.

[0181] The term "hydroxy" refers to an -OH group.

[0182] The term "mercapto" refers to a -SH group.

[0183] The term "alkylthio" refers to an -S-alkyl group, such as -S-CH 3 、-S-CH 2 -CH 3 wait.

[0184] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0185] The term "amino" refers to -NH 2 .

[0186] The term "cyano" refers to -CN.

[0187] The term "nitro" refers to -NO 2 .

[0188] The term "oxo" refers to a =0 substituent.

[0189] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "C 1 -C 6 "Alkyl" means that halogen or cyano may but need not be present, and the description includes the case where the alkyl is substituted with halogen or cyano and the case where the alkyl is not substituted with halogen and cyano.

[0190] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort.

[0191] In the chemical structures of the compounds disclosed herein, the bond “ / ” does not specify a configuration, i.e., the bond “ / ” can be or or include both and In the chemical structure of the compounds disclosed in the present invention, the bond The configuration is not specified, that is, it can be Z configuration or E configuration, or contain both configurations.

[0192] Although all of the above formulae are drawn in certain isomeric forms for simplicity, the present disclosure may include all isomers, such as tautomers, rotational isomers, geometric isomers, diastereomers, racemates, and enantiomers.

[0193] Tautomers are structural isomers of organic compounds that are easily interconvertible through a chemical reaction known as tautomerization. This reaction often results in the formal migration of hydrogen atoms or protons, accompanied by the conversion of single bonds and adjacent double bonds. Some common tautomeric pairs are: keto-enol, lactam-lactim. An example of a lactam-lactim equilibrium is between A and B as shown below.

[0194]

[0195] All compounds in the present disclosure can be drawn as either Form A or Form B. All tautomeric forms are within the scope of the present disclosure. The naming of the compounds does not exclude any tautomers.

[0196] Any isotope-labeled derivatives of the compounds or pharmaceutically acceptable salts thereof, or isomers thereof described in the present disclosure are covered by the present disclosure. Atoms that can be isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, etc. They can be labeled with isotopes. 2 H(D), 3 H. 11 C. 13 C. 14 C. 15 N. 18 F. 31 P. 32 P. 35 S. 36 Cl and 125 Unless otherwise indicated, when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (ie, at least 45% deuterium incorporation). BRIEF DESCRIPTION OF THE DRAWINGS

[0197] Figure 1 : Concentration distribution of the disclosed compounds in brain tissue 10 minutes after intravenous injection.

[0198] Figure 2 : The concentration distribution of the disclosed compound in cerebrospinal fluid 10 minutes after intravenous injection.

[0199] Figure 3 : Brain-to-plasma ratio of the disclosed compound 10 min after intravenous injection.

[0200] Figure 4 : Cerebrospinal fluid-to-plasma ratio of the disclosed compound 10 min after intravenous injection. DETAILED DESCRIPTION

[0201] The present disclosure is further described below in conjunction with embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0202] The experimental methods without specific conditions in the examples disclosed herein are usually carried out under conventional conditions or under conditions recommended by raw material or product manufacturers. Reagents without specific sources are conventional reagents purchased from the market.

[0203] NMR shift (δ) was 10 -6 The NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer and the solvent used was deuterated dimethyl sulfoxide (DMSO-d6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethylsilane (TMS).

[0204] MS was measured using a Shimadzu 2010 Mass Spectrometer or an Agilent 6110A MSD mass spectrometer.

[0205] High performance liquid chromatography (HPLC) was performed using a Shimadzu LC-20A systems, Shimadzu LC-2010HT series, or Agilent 1200LC high pressure liquid chromatograph (Ultimate XB-C18 3.0*150 mm column or Xtimate C18 2.1*30 mm column).

[0206] Chromatographic columns used for chiral HPLC analysis: Chiralpak IC-3 100×4.6mm ID, 3um, Chiralpak AD-3 150×4.6mm ID, 3um, Chiralpak AD-3 50×4.6mm ID, 3um, Chiralpak AS-3 150×4.6mm ID, 3um, Chiralpak AS-3 100×4.6mm ID, 3μm, ChiralCel OD-3 150×4.6mm ID, 3um, Chiralcel OD-3 100×4.6mm ID, 3μm, ChiralCel OJ-H 150×4.6mm ID, 5um, Chiralcel OJ-3 150×4.6mm ID, 3um.

[0207] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0208] Column chromatography generally uses Yantai Huanghai silica gel 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel as the carrier.

[0209] The chiral preparative column used was DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um) or Phenomenex-Amylose-1 (250 mm*30 mm, 5 um).

[0210] The CombiFlash rapid preparation instrument used was Combiflash Rf150 (TELEDYNE ISCO).

[0211] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0212] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, and other companies.

[0213] Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0214] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0215] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0216] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0217] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0218] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0219] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0220] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0221] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of thin layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, D: petroleum ether / ethyl acetate / methanol, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0222] The abbreviations used in the following experiments have the following meanings:

[0223] EtOAc: ethyl acetate; DCM: dichloromethane; DIPEA: N,N-diisopropylethylamine; PPTS: pyridinium p-toluenesulfonate; Boc: tert-butyloxycarbonyl, MeOH: methanol.

[0224] Example 1: Preparation of 5-chloro-N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-hydroxybenzamide

[0225]

[0226] In a 50mL reaction bottle, compound 1-1 (986mg, 2mmol, purchased from Cadilapharmaceuticals limited) and DCM (10mL) were added under nitrogen atmosphere. The mixture was stirred and cooled to 0°C in an ice bath, and a solution of BBr3 in DCM (3mL, 3mmol) was slowly added dropwise for about 10 minutes. Stirring was continued under ice bath for 30 minutes. The ice bath was removed, the mixture was naturally warmed to room temperature, and stirred overnight. Methanol (2mL) was added dropwise under ice bath to quench the reaction. The solvent was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 1 (560mg, purity 99.08%) with a yield of 58.4%.

[0227] 1 HNMR (d 6 -DMSO, 400MHz) δ1.06~1.30(m,5H),1.47~1.65(m,5H),2.96(t,J=6.4Hz,2H),3.32(bs,1H),3.55~3.58(m,2H),6.33(d, J=7.6Hz,1H),6.93(d,J=8.8Hz,1H),7.42~7.49(m,3H),7.81~7.89(m,3H),8.96(s,1H),10.31(bs,1H),12.46(bs,1H).

[0228] Example 2: Preparation of 5-chloro-N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-(methoxy-d3)benzamide (2)

[0229]

[0230] Step 1: Preparation of methyl-d3 5-chloro-2-(methoxy-d3)benzoate (2-2)

[0231] At room temperature and under nitrogen atmosphere, in a 100 mL reaction bottle, add 5-chloro-2-hydroxybenzoic acid (2-1) (5.18 g, 30.0 mmol), iodomethane (7.5 mL, 75.0 mmol), potassium carbonate (8.4 g, 61.0 mmol), and DMF (15 mL). Heat to 60 ° C and stir for about 20 hours. LCMS monitoring shows that the reaction is complete. Water (50 mL) and methyl tert-butyl ether (100 mL) are added to the reaction solution, the aqueous phase is extracted with methyl tert-butyl ether (2×100 mL), the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is dissolved in toluene (50 mL), washed with 5% sodium hydroxide solution (30 mL), the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6.20 g of crude product 2-2, which is directly used in the next step reaction.

[0232] Step 2: Preparation of 5-chloro-2-(methoxy-d3)benzoic acid (2-3)

[0233] At room temperature, in a 100 mL flask, add compound 2-2 (6.20 g, 30 mmol), ethanol (30 mL) and 30 mL of 10% sodium hydroxide solution. The mixture was heated to reflux and stirred for 2 hours. The reaction was monitored to be substantially complete and cooled to room temperature. The ethanol was removed by concentration under reduced pressure. 5% dilute hydrochloric acid (60 mL) was added to the resulting aqueous solution to form a suspension, stirred for 1 hour, filtered, and the solid was vacuum dried to obtain 5.5 g of off-white solid crude product 2-3, with a two-step yield of 96.7% and a purity of 97%.

[0234] Step 3: Preparation of 5-chloro-2-(methoxy-d3)-N-(4-sulfamoylphenethyl)benzamide (2-5)

[0235] In a 50mL reaction bottle, under nitrogen atmosphere, compound 2-3 (3.79g, 20.0mmol), 4-(2-aminoethyl)benzenesulfonamide (2-4) (4.01g, 20.0mmol), and MeCN (15mL) were added. The mixture was stirred and cooled with an ice bath. Pyridine (2.5mL, 40.0mmol) and EDCI (3.84g, 20.0mmol) were added, and the mixture was stirred for 30 minutes under an ice bath. The ice bath was removed, and the mixture was naturally warmed to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, and water (400mL) was added at room temperature and stirred for 15 minutes. Filter, collect the solid, and dry to obtain an off-white solid 2-5 (6.2g), which was directly used in the next step without purification, with a yield of 83% and a purity of 99%.

[0236] Step 4: Preparation of 5-chloro-N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-(methoxy-d3)benzamide (2)

[0237] Compound 2-5 (2.23 g, 6.0 mmol) and cyclohexyl isocyanate (2-6) (1.28 g, 10.2 mmol) were added to 16 mL of DMF to dissolve. The mixture was then cooled in an ice-water bath and potassium tert-butoxide solution (7.8 mL, 7.8 mmol, 1 M in THF) was slowly added dropwise for about 5 minutes. After the addition was complete, the mixture was warmed to room temperature and stirred overnight. Water (50 mL) was added and the suspension was stirred for about 10 minutes. The resulting material was collected and prepared by HPLC to obtain 1.9 g of compound 2 with a yield of 63.8% and a purity of 99.6%.

[0238] 1 HNMR (d 6 -DMSO, 400MHz) δ1.07~1.23(m,5H),1.46~1.65(m,5H),2.93(t,J=6.4Hz,2H),3.28(bs,1H),3.54~3.57(m,2H),6. 33(d,J=7.6Hz,1H),7.14(d,J=8.8Hz,1H),7.45~7.64(m,4H),7.84(d,J=8.0Hz,2H),8.27(s,1H),10.31(bs,1H).

[0239] Example 3: Preparation of 5-chloro-N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-(trifluoromethoxy)benzamide (3)

[0240]

[0241] Step 1: Preparation of 5-chloro-N-(4-sulfamoylphenethyl)-2-(trifluoromethoxy)benzamide (3-2)

[0242] In a 50 mL reaction bottle, under nitrogen atmosphere, 5-chloro-2-(trifluoromethoxy)benzoic acid (3-1) (288.7 mg, 1.2 mmol), 4-(2-aminoethyl)benzenesulfonamide (2-4) (240.3 mg, 1.2 mmol), and MeCN (2 mL) were added. The mixture was stirred and cooled with an ice bath; pyridine (0.2 mL, 2.4 mmol) and EDCI (230 mg, 1.2 mmol) were added, and the mixture was stirred for 30 minutes under an ice bath, and the ice bath was removed, and the mixture was naturally warmed to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain an off-white solid compound 3-2 (280 mg) with a yield of 55% and a purity of 98.8%.

[0243] Step 2: Preparation of 5-chloro-N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-(trifluoromethoxy)benzamide (3)

[0244] Compound 3-2 (280 mg, 6.0 mmol) and cyclohexyl isocyanate (2-6) (140 mg, 1.12 mmol) were added to 2.5 mL of DMF to dissolve. The mixture was then cooled in an ice-water bath, and potassium tert-butoxide solution (0.86 mL, 0.86 mmol, 1 M in THF) was slowly added dropwise for about 5 minutes. After the addition was complete, the mixture was warmed to room temperature and stirred overnight. Water (5 mL) was added, and no solid was precipitated. The mixture was extracted with ethyl acetate (3×10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was prepared by HPLC to obtain 240 mg of compound 3, with a yield of 66.4% and a purity of 99.69%.

[0245] 1 HNMR (d 6 -DMSO, 400MHz) δ1.05~1.25(m,5H),1.46~1.66(m,5H),2.91(t,J=6.4Hz,2H),3.32(bs,1H),3.48~3.52(m,2H),6. 33(d,J=7.6Hz,1H),7.46~7.55(m,4H),7.64(d,J=8.8Hz,1H),7.82(d,J=8.0Hz,2H),8.67(s,1H),10.31(bs,1H).

[0246] Example 4: Preparation of 5-chloro-N-(4-(N-(((1r,4r)-4-hydroxycyclohexyl)carbamoyl)sulfamoyl)phenethyl)-2-methoxybenzamide (4)

[0247]

[0248] (1r, 4r)-4-aminocyclohexan-1-ol (4-2) (250 mg, 2.2 mmol) and ethyl ((4-(2-(5-chloro-2-methoxybenzamido)ethyl)phenyl)sulfonyl)carbamate (4-1) (880 mg, 2.0 mmol, synthesized according to the literature method (Bioorganic & Medicinal Chemistry, 2003, 11, 2099-2113)) were added to 30 mL of toluene, and then the mixture was heated to reflux and stirred for about 3 hours. Cooled to room temperature and concentrated under reduced pressure. The residue was prepared by HPLC to obtain 420 mg of compound 4 with a yield of 41.2% and a purity of 98.85%.

[0249] 1 HNMR (d 6-DMSO, 400MHz) δ1.02~1.24(m,4H),1.66~1.76(m,4H),2.08(s,1H),2.94(t,J=6.4Hz,2H),3.22(bs,1H),3.54~3.57(m,2H),3.80(s,3H),4. 52(bs,1H),6.30(d,J=6.0Hz,1H),7.15(d,J=8.4Hz,1H),7.47~7.51(m,3H),7.65(s,1H),7.85(d,J=7.2Hz,2H),8.28(s,1H),10.35(bs,1H).

[0250] Example 5: Preparation of 5-chloro-N-(4-(N-((cyclohexyl-4,4-d2)carbamoyl)sulfamoyl)phenethyl)-2-methoxybenzamide (5)

[0251]

[0252]

[0253] Ethyl ((4-(2-(5-chloro-2-methoxybenzamido)ethyl)phenyl)sulfonyl)carbamate (4-1) (137 mg, 1.36 mmol) and cyclohexane-4,4-d2-1-amine (5-1) (500 mg, 1.13 mmol) were added to 30 mL of toluene, and then the mixture was heated to reflux and stirred for about 6 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was prepared by HPLC to obtain 380 mg of compound 5 with a yield of 67.9% and HPLC purity of 100%.

[0254] 1 HNMR (d 6 -DMSO, 400MHz) δ1.04~1.23(m,4H),1.54~1.66(m,4H),2.93(t,J=6.4Hz,2H),3.28(bs,1H),3.53~3.56(m,2H),3.79(s,3H),6. 33(d,J=6.4Hz,1H),7.15(d,J=8.8Hz,1H),7.46~7.50(m,3H),7.63(s,1H),7.84(d,J=7.6Hz,2H),8.27(bs,1H),10.31(bs,1H).

[0255] Example 6: Preparation of 5-chloro-N-(4-(N-(((1R,2R)-2-cyanocyclohexyl)carbamoyl)sulfamoyl)phenethyl)-2-methoxybenzamide (6)

[0256]

[0257] (1R,2R)-2-aminocyclohexane-1-carbonitrile (6-1) (0.1 g, 0.80 mmol) was dissolved in dry toluene (4 mL), and ethyl ((4-(2-(5-chloro-2-methoxybenzamido)ethyl)phenyl)sulfonyl)carbamate (4-1) (0.44 g, 0.96 mmol) was added, and the mixture was refluxed at 120°C for 4 hours. The reaction solution was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was subjected to pre-HPLC to obtain 43 mg of compound 6, with HPLC purity of 96.6% and a yield of 10%.

[0258] 1 HNMR (d6-DMSO, 400MHz) δ1.03~1.24(m,3H),1.45~1.58(m,4H),1.95~1.99(m,1H),2.80(t,J=6.4Hz,1H),2.92(t,J=6.4Hz,2H),3.52~3.56(m,3H ),3.79(s,3H),6.79(d,J=7.6Hz,1H),7.15(d,J=8.8Hz,1H),7.44~7.51( m, 3H), 7.64 (s, 1H), 7.84 (d, J = 7.2Hz, 2H), 8.26 (bs, 1H), 10.93 (bs, 1H).

[0259] Example 7: Preparation of 5-cyano-N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-methoxybenzamide (7)

[0260]

[0261] Step 1: Preparation of 5-cyano-2-methoxy-N-(4-sulfamoylphenethyl)benzamide (7-2)

[0262] In a 25mL reaction bottle, under nitrogen atmosphere, add 5-cyano-2-methoxybenzoic acid (7-1) (500mg, 2.82mmol), 4-(2-aminoethyl)benzenesulfonamide (2-4) (565.8mg, 2.82mmol), MeCN (2.8mL). Stir the mixture and cool it with an ice bath, add pyridine (697mg, 8.81mmol), EDCI (541mg, 2.82mmol), and keep stirring for 30 minutes in an ice bath. Remove the ice bath, naturally warm to room temperature, and stir overnight. The reaction solution is concentrated under reduced pressure, water (2.5mL) is added, stirred for 30 minutes, filtered, the solid is collected, and dried to obtain an off-white solid compound 7-2 (934mg), which is directly used in the next step without purification, and the reaction yield is 92%.

[0263] Step 2: Preparation of 5-cyano-N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-methoxybenzamide (7)

[0264] At room temperature, in a 25 mL flask, under nitrogen atmosphere, compound 7-2 (567 mg, 1.578 mmol), cyclohexyl isocyanate (2-6) (316 mg, 2.525 mmol), and DMF (5 mL) were added. The mixture was stirred to dissolve and cooled with an ice bath, and a solution of KOtBu in THF (2.4 mL, 2.4 mmol) was added dropwise, and stirred for 10 minutes under an ice bath. The ice bath was removed, and the mixture was naturally warmed to room temperature and stirred overnight. Water (15 mL) was added to the reaction system for dilution, stirred for 5 minutes, filtered, and the residue was diluted with ethyl acetate, stirred for 30 minutes, filtered, and the solid was washed once with a small amount of ethyl acetate, and the solid was collected. The mixture was slurried and stirred with DCM:MeOH = 10:1 (4 mL) at room temperature for 30 minutes, filtered, and the solid was collected to obtain compound 7 (220 mg, purity 95.9%), with a yield of 28.8%.

[0265] 1 HNMR (d 6 -DMSO, 400MHz) δ1.05~1.23(m,5H),1.46~1.65(m,5H),2.93(t,J=6.4Hz,2H),3.28(bs,1H),3.52~3.56(m,2H),3.87(s,3H),6.34(d ,J=7.6Hz,1H),7.30(d,J=8.0Hz,1H),7.49(d,J=7.6Hz,2H),7.84(d,J=8.0Hz,2H),7.92~7.97(m,2H),8.32(bs,1H),10.32(bs,1H).

[0266] Biological tests

[0267] Test Example 1: SUR1 receptor binding activity of the disclosed compounds

[0268]

[0269]

[0270] Experimental instruments Provider model Vortex mixer IKA MS3 BASIC Electric constant temperature incubator Shanghai Yiheng DHP-9032 Microplate vibrating screen VWR 12620-928 TopCount PerkinElmer NTX Universal Harvester PerkinElmer UNIFILTER-96

[0271] Reaction buffer

[0272]

[0273] Lotion

[0274]

[0275] Steps:

[0276] a) Add 100 μL of reaction buffer to each well of a 96-deep well plate.

[0277] b) Add 5 μL of diluted test compound (1% DMSO) to each well of a 96-deep-well plate.

[0278] c) Add 30 μL SUR1 membrane protein and 270 μL reaction mixture to each well and shake at 600 rpm for 5 minutes.

[0279] d) Add 100 μL of a mixture of reaction buffer and [3H]-Glibenclamide (final concentration: 2 nM) to the reaction system, shake at 600 rpm for 5 minutes, and incubate at 37° C. for 1 hour.

[0280] e) Pre-treat UNIFILTER-96GF / B plates with 0.5% PEI, add 150 μL of 0.5% PEI to each well, and incubate at 4° C. for 1 hour.

[0281] f) Wash UNIFILTER-96GF / C and UNIFILTER-96GF / B plates twice with Universal Harvester, using 50 mL of wash solution each time.

[0282] g) Transfer the SUR1 receptor reaction system to a UNIFILTER-96GF / B plate using Universal Harvester, add 900 μL of washing solution to each well and wash the GF / B plate 4 times. Place the washed UNIFILTER-96GF / B plate in a 55°C oven for 10 min to dry.

[0283] h) Add 40 μL of ULTIMA GOLD scintillation fluid to each well and read using Microbeta.

[0284] Results: The SUR1 receptor binding activities of the disclosed compounds are shown in Table 1 below.

[0285] Table 1 SUR1 receptor binding activity of the disclosed compounds

[0286]

[0287] Test Example 2: In vivo pharmacokinetics and brain tissue distribution study of different compounds given intravenously to SD rats

[0288] Test sample preparation

[0289] 1. Accurately weigh an appropriate amount of Compound 1, Compound 4, Compound 7 or glibenclamide, add an appropriate volume of 5% DMSO + 10% Solutol + 85% saline, stir or sonicate until completely dissolved to obtain a clear solution with a concentration of 1 mg / mL for intravenous injection.

[0290] 2. Accurately weigh an appropriate amount of compound 3 or compound 6, add an appropriate volume of 5% DMSO + 20% PG + 20% PEG400 + 55% PBS (pH 8.0), stir or sonicate until completely dissolved to obtain a clear solution with a concentration of 1 mg / mL for intravenous injection.

[0291] Experimental animals

[0292] SPF grade SD rats, source: animals transferred from the experimental institution animal reserve bank (999M-017), Shanghai Xipul-Bikai Experimental Animal Co., Ltd.

[0293] Experimental design

[0294]

[0295]

[0296] Collection time point

[0297] 3 mice / time point, blood samples were collected from the first 3 mice in each group, and cerebrospinal fluid and brain tissue were collected from the last 3 mice in each group. Blood samples: before administration and 5min, 0.25h, 0.5h, 1h, 1.5h, 2h, 4h, 6h, 8h, 12h, 24h after administration. Tissue: Cerebrospinal fluid and brain tissue were collected 10min after administration.

[0298] Sample collection and handling

[0299] Blood samples: Blood is collected through the jugular vein or other appropriate methods. Each sample is about 0.20 mL, anticoagulated with EDTA-K2, placed on ice after collection, and centrifuged within 2 hours to separate plasma (centrifugation conditions: centrifugal force 6800g, 6 minutes, 2-8°C). The collected plasma samples are stored in a -70°C refrigerator before analysis. After analysis, the remaining plasma samples continue to be stored in a -70°C refrigerator and will be processed according to the client's requirements.

[0300] Tissue samples: Cerebrospinal fluid and brain tissue were collected from animals for tissue collection 10 minutes after administration. The brain tissue was rinsed with physiological saline to avoid cross contamination, blotted with filter paper, and weighed. Then, the samples were placed in labeled tubes (one tube for each tissue), and the samples were temporarily placed on ice before being stored in a -70°C refrigerator.

[0301] The collected plasma samples and tissue samples were stored in a -70°C refrigerator before analysis. After analysis, the remaining plasma samples and tissue samples continued to be stored in a -70°C refrigerator and will be subsequently processed according to the client's requirements.

[0302] Bioanalysis and data processing

[0303] The concentration of each test substance in plasma and tissue samples is detected, and the accuracy of quality control samples is evaluated while analyzing the samples, and it is required that more than 66% of the quality control samples have an accuracy between 80-120%.

[0304] WinNonlin was used to calculate pharmacokinetic parameters such as AUC(0-t), T1 / 2, Cmax, Tmax and MRT based on the blood drug concentration data at different time points.

[0305] When plotting the plasma drug concentration-time curve, BLQ is recorded as 0. When calculating pharmacokinetic parameters, the concentration before administration is calculated as 0; the BLQ before Cmax (including "No peak") is calculated as 0; and the BLQ after Cmax (including "No peak") is not included in the calculation.

[0306] Table 2 Changes in plasma concentrations of compounds after a single intravenous injection

[0307]

[0308]

[0309] Note: The dosage is 5 mg / kg;

[0310] The detection limit ranged from 5 to 30 ng / mL.

Claims

1. A compound as shown below or a pharmaceutically acceptable salt thereof, or an isomer thereof, 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, or an isotope substituted isomer thereof. The isotope substitution according to claim 2 , wherein the isotope substitution is deuterium atom substitution.

4. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, or an isomer thereof, or the isotope substitution according to claim 2 or 3, and at least one pharmaceutically acceptable carrier, diluent or excipient.

5. Use of the compound according to claim 1 or its pharmaceutically acceptable salt, or its isomer, or the isotope-substituted product according to claim 2 or 3, or the pharmaceutical composition according to claim 4 in the preparation of a medicament for preventing or treating diseases and disorders affected by neuronal damage.

6. Use of the compound according to claim 1 or its pharmaceutically acceptable salt, or its isomer, or the isotope substitution according to claim 2 or 3, or the pharmaceutical composition according to claim 4 in the preparation of a medicament for treating acute cerebral stroke, traumatic brain injury, spinal cord injury, myocardial infarction, shock, organ ischemia, ventricular arrhythmia, ischemic injury, hypoxia / ischemia or other injury conditions and disorders.

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