JPWO2021047622A5 - - Google Patents

Description

[Cross reference to related applications]
This application is filed with application number CN201910863718.6 filed on September 12, 2019, application number CN201911094782.9 filed on November 11, 2019, and application number CN202010531381.1 filed on June 11, 2020. , is based on application number CN202010923311.0 filed on September 4, 2020, and claims priority thereto.

[Technical field]
The present invention belongs to the field of medicinal chemistry. Specifically, the present invention provides novel compounds or stereoisomers, racemates, geometric isomers, tautomers, prodrugs, hydrates, solvates or pharmaceutically acceptable salts thereof; and pharmaceutical compositions containing them, they are voltage-gated sodium ion channels (NaV) blockers with a completely new structure.

Pain is one of the most common clinical symptoms, and as the fifth vital sign after breathing, pulse, blood pressure and body temperature, it severely affects the quality of life of patients. According to statistics, the global market for painkillers reached approximately $36 billion in 2018 and is expected to reach $56 billion by 2023. Among them, acute moderate to severe pain is mainly dependent on opioid drugs, accounting for around two-thirds of the analgesic market share, and is expected to grow steadily at a compound annual growth rate of 2.5% in the future. Ru. The number of chronic pain patients, mainly neuropathic pain and arthritic pain, is increasing year by year, and it is expected that the market will exhibit a compound annual growth rate of around 18%. is the main driving force driving sustainable growth.

Neuropathic pain is chronic pain due to injury or disease of the peripheral somatosensory nervous system, and its symptoms include spontaneous pain and allodynia to normal innocuous stimuli. Common etiologies that induce neuropathic pain include diabetes, shingles, spinal cord injury, stroke, multiple sclerosis, cancer, HIV infection, lumbar or cervical radicular nerve lesions and wounds, or postoperative nerve damage. included. Osteoarthritis, also called degenerative arthritis, is the degeneration of bone and articular cartilage caused by various factors, which can lead to unevenness of the joint bone surface, and may form osteophytes. It manifests as pain and joint stiffness. Long-term pain not only affects patients' ability to sleep, work and live, but also increases the incidence of emotional disorders such as depression or anxiety, resulting in a heavy economic burden on patients' families and society.

According to data published by the International Pain Society Neuropathic Pain Special Group (NeuPSIG), the prevalence of neuropathic pain is approximately 3.3% to 8.2%. According to this, it is estimated that there are at least 50 million patients in China alone. In 2017, there were a total of 30.5 million neuropathic pain patients in the five major markets of the United States, Japan, and the EU (France, Germany, Italy, Spain, and the United Kingdom), and the number is increasing year by year. Neuropathic pain is one of the most difficult diseases to treat, and many current treatment strategies still fail to achieve satisfactory effects. According to one report, only 14.9% of outpatients are able to quickly stop their pain through drug treatment, which means that about 85% of pain patients do not receive effective drug treatment quickly. Some patients are forced to seek surgical interventional treatment. Currently, the first-line drugs used clinically to treat neuropathic pain are mainly calcium ion channel modulators (e.g. pregabalin, gabapentin), tricyclic antidepressants and 5-hydroxytryptamine, and noradrenaline reuptake inhibitors ( For example, anticonvulsant and antidepressant drugs such as duloxetine and venlafaxine). The therapeutic efficacy of these drugs is limited and they are associated with various side effects. Duloxetine is one of the first-line drugs for the treatment of neuropathic pain, and its main side effects include gastrointestinal reactions, nausea, somnolence, dry mouth, hyperhidrosis, and dizziness, resulting in a drug discontinuation rate of 15% to 20%. reach %. The anti-epileptic drugs gabapentin and pregabalin are the main drugs to treat neuropathic pain and cause many side effects such as dizziness, somnolence, peripheral edema, weight gain, weakness, headache and dry mouth. In recent years, pregabalin has been found to cause suicidal ideation and self-harm behaviors associated with drug use in a small minority of patients.

The number of osteoarthritis patients is enormous; currently, the number of osteoarthritis patients worldwide is expected to exceed 400 million, and the number of patients in China has already exceeded 100 million. There is currently no effective treatment for osteoarthritis pain. Clinically, there are physical therapy, drug therapy and surgical treatment. Physiotherapy includes heat therapy, hydrotherapy, ultrasound and massage, and assistive devices reduce joint pressure and relieve pain, but the effectiveness is limited and most remain drug-dependent. treatment is required. All of these drugs have different degrees of side effects. Nonsteroidal anti-inflammatory drugs are indicated only for mild to moderate pain and have gastrointestinal side effects and cardiovascular risks. Opioid analgesics are used to treat severe pain, but they have side effects such as significant nausea and vomiting, constipation, and drug dependence, making them unsuitable for long-term use. Therefore, researching and developing novel mechanisms and safe and effective analgesic drugs targeting novel targets to meet unmet clinical needs has important economic and social significance.

Recent research results have increasingly shown that sodium ion channel subtype 1.8 (NaV1.8) plays an important role in the generation and transmission of pain sensation. NaV1.8 is a voltage-gated sodium ion channel that is mainly expressed in afferent sensory neurons, including sensory neurons, and controls the entry and exit of sodium ions into cells, thereby increasing the excitability and operating potential of injured sensory neurons. It plays an important role in maintaining the release and duration of pain and regulating pain sensitivity. Patients with the NaV1.8 activation mutation developed paroxysmal pain due to small fiber nerve lesions (damage to Aδ fibers and unmyelinated type C fibers, which are mainly responsible for pain transmission). Chronic inflammation and diseases such as diabetes cause increased expression or property changes of NaV1.8, thereby sensitizing sensory neurons and causing various pains. However, NaV1.8 knockout mice are not sensitive to pain.

With the establishment of Nav1.8 in chronic pain, drug research based on this target is also intensifying, with small molecule blockers currently in Phase II trials internationally, and several other small molecule blockers in progress. Molecular blockers and antibodies have been developed preclinically, and there is still no new drug research and development for this target in Japan. At the forefront of research and development is Vertex's small molecule NaV1.8 blocker VX-150, which is currently in Phase II treatment in patients with osteoarthritis, acute pain and pain caused by small fiber nerve lesions. Tests were conducted and all three studies obtained positive results, demonstrating that inhibiting NaV1.8 activity can alleviate various pains, including neuropathic pain. VX-150 has now been approved as a breakthrough therapy by the US FDA and is used to treat moderate to severe pain, re-proving NaV1.8 as a potential target for analgesia. Ta. Furthermore, as can be seen from the mechanism of action and phase II studies of NaV1.8 blockers, their indications are wide, including various types of pain such as neuropathic pain, osteoarthritis pain, and acute injury pain, and their safety is poor. Relatively high, non-addictive, has no gastrointestinal side effects or cardiovascular side effects of nonsteroidal anti-inflammatory drugs, and can be used in combination with other analgesics to enhance therapeutic effects and reduce side effects. .

Recently, studies have shown that sodium ion channel subtype 1.8 (NaV1.8) has a certain regulatory effect on cough, making NaV1.8 blockers a potential drug to treat cough. there is a possibility.

Through repeated experimental studies, the present inventors have rationalized a series of novel structural small molecule compounds represented by the following general formula (I) that have very high sodium ion channel 1.8 (NaV1.8) blocking activity. was designed and synthesized. These compounds or their stereoisomers, racemates, geometric isomers, tautomers, prodrugs, hydrates, solvates or pharmaceutically acceptable salts and pharmaceutical compositions thereof may be It can be used for the treatment and/or prevention of mediated related diseases.

The compounds of the invention have high NaV1.8 blocking activity and provide new therapeutic options for the treatment of diseases such as pain.

The present invention provides a compound represented by formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof,
here,
T ₁ is selected from N or C (R ₇ ),
T ₂ is selected from N or C (R ₈ ),
T ₃ is selected from N or C (R ₉ ),
T ₄ is selected from N or C (R ₁₀ ),
R ₁ , R ₂ , R ₈ , and R ₉ each independently represent H, halogen, OH, NH ₂ , CN, SF ₅ , C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 alkylamino group, vinyl-C _1-6 alkyl-, C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C _3-6 cycloalkyl-C _1-6 alkyl-, 3-6 membered heterocycloalkyl- C _1-6 alkyl-, 3-6 membered heterocycloalkyl-C _1-6 alkyl-O-, phenyl-C _1-3 alkyl-, C _3-6 cycloalkyl-C _1-3 alkyl-O-, 3 ~6-membered heterocycloalkyl-C _1-3 alkyl-O-, phenyl-C _1-3 alkyl-O-, phenyl-C _1-3 alkyl-NH-, 5- to 6-membered heteroaryl-C _1-3 alkyl -, 5- to 6-membered heteroaryl-C _1-3 alkyl-O-, and 5- to 6-membered heteroaryl-C _1-3 alkyl-NH-, and the C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 alkylamino group, vinyl-C _1-6 alkyl-, C _3-6 cycloalkyl group, 3- to 6-membered heterocycloalkyl group, C _3-6 cycloalkyl-C _1-6 alkyl-, 3-6 membered heterocycloalkyl-C _1-6 alkyl-, 3-6 membered heterocycloalkyl-C _1-6 alkyl-O-, phenyl-C _1-3 alkyl-, C _3-6 cycloalkyl-C _{1 -3} alkyl-O-, 3-6 membered heterocycloalkyl-C _1-3 alkyl-O-, phenyl-C _1-3 alkyl-O-, phenyl-C _1-3 alkyl-NH-, 5-6 members Heteroaryl-C _1-3 alkyl-, 5- to 6-membered heteroaryl-C _1-3 alkyl-O-, or 5- to 6-membered heteroaryl-C _1-3 alkyl-NH- is optionally 1, 2 or 3 is replaced by R,
And if T ₃ is selected from N, R ₁ is not selected from H,
R ₃ , R ₄ , R ₅ , R ₆ and R ₁₀ each independently represent H, halogen, OH, NH ₂ , SF ₅ , CN, C _1-6 alkyl group, C _1-6 alkylamino group, C _{1 -6} alkoxy group, C _3-6 cycloalkyl group, -O-C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C _3-6 cycloalkyl-C _1-6 alkyl-, and 3-6 member heterocycloalkyl -C _1-6 alkyl-, the above-mentioned C _1-6 alkyl group, C _1-6 alkylamino group, C _1-6 alkoxy group, C _3-6 cycloalkyl group, -O-C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C _3-6 cycloalkyl-C _1-6 alkyl- or 3-6 membered heterocycloalkyl-C _1-6 alkyl- is optionally 1, 2 or substituted by 3 R,
R ₇ is selected from H, F, Cl, Br, I, a C _1-6 alkyl group, a C _1-6 alkoxy group, and a C _1-6 alkylamino group, and the above C _1-6 alkyl group, C _1-6 an alkoxy group or a C _1-6 alkylamino group optionally substituted with 1, 2 or 3 R;
L ₁ is C (=O), NH and
selected from
_L2 is selected from O, S, NH and _CH2 , said CH is optionally substituted by 1 or 2 R, NH is optionally substituted by R,
R ₁₁ and R ₁₂ are each independently selected from H, halogen, OH, NH ₂ and a C _1-6 alkyl group, and the C _1-6 alkyl group is optionally substituted with 1, 2 or 3 R. , or R ₁₁ and R ₁₂ are joined together to form a 3- to 6-membered ring,
each R ₁₃ is independently selected from H, halogen and a C _1-6 alkyl group, said C _1-6 alkyl group being optionally substituted with 1, 2 or 3 R;
n is selected from 1, 2 or 3,
R each independently represents H, D, halogen, OH, NH ₂ , CN,
selected _from a C _1-6 alkyl group, a _{C 1-6} alkoxy group, a C _1-6 alkylthio group, and a C _1-6 alkylamino group _{; 6} alkylthio group or C _1-6 alkylamino group optionally substituted with 1, 2 or 3 R',
R' is selected from F, Cl, Br, I, OH, _NH2 and _CH3 ,
The above 3- to 6-membered heterocycloalkyl group or 5- to 6-membered heteroaryl group is -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S( 1, 2 or 3 heteroatoms or heteroatoms independently selected from =O)-, -S(=O) ₂ - and N.

In some embodiments of the invention, R is H, D, F, Cl, Br, I, OH, _NH2 ,
Me, CF ₃ , CHF ₂ , CH ₂ F,
, with other variables as defined herein.

In some embodiments of the present invention, R ₁ , R ₂ , R ₈ , and R ₉ each independently represent H, halogen, OH, NH ₂ , CN, SF ₅ , C _1-3 alkyl group, C _{1- 3} alkoxy group, C _1-3 alkylamino group, vinyl-C _1-3 alkyl-, C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C _3-6 cycloalkyl-C _1-3 alkyl -, 3- to 6-membered heterocycloalkyl-C _1-3 alkyl-, 3- to 6-membered heterocycloalkyl-C _1-3 alkyl-O-, phenyl-C _1-3 alkyl-, phenyl-C _1-3 alkyl -O-, phenyl-C _1-3 alkyl-NH-, pyridyl-C _1-3 alkyl-, pyrimidinyl-C _1-3 alkyl-, thienyl-C _1-3 alkyl-, thiazolyl -C _1-3 Alkyl-, pyrazolyl -C _1-3 alkyl-, imidazolyl -C _1-3 alkyl-, pyridyl-C _1-3 alkyl-O-, pyrimidinyl-C _1-3 alkyl-O-, thienyl-C _1-3 alkyl-O-, thiazolyl -C _1-3 alkyl-O-, pyrazolyl -C _1-3 alkyl-O-, imidazolyl -C _1-3 alkyl-O-, pyridyl-C _1-3 alkyl-NH-, pyrimidinyl-C _1-3 alkyl-NH-, thienyl-C _1-3 alkyl-NH-, thiazolyl -C _1-3 alkyl-NH-, pyrazolyl -C _{1- 3} alkyl- _{NH- and} imidazolyl -C _1-3 alkyl- _{NH- ; 3} alkyl-, C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C _3-6 cycloalkyl-C _1-3 alkyl-, 3-6 membered heterocycloalkyl-C _1-3 alkyl-, 3- to 6-membered heterocycloalkyl-C _1-3 alkyl-O-, phenyl-C _1-3 alkyl-, phenyl-C _1-3 alkyl-O-, phenyl-C _1-3 alkyl-NH-, pyridyl- C _1-3 alkyl-, pyrimidinyl-C _1-3 alkyl-, thienyl-C _1-3 alkyl-, thiazolyl -C _1-3 alkyl-, pyrazolyl -C _1-3 alkyl-, imidazolyl -C _1-3 alkyl-, pyridyl-C _1-3 alkyl-O-, pyrimidinyl-C _1-3 alkyl-O-, thienyl-C _1-3 alkyl-O-, thiazolyl -C _1-3 alkyl -O-, pyrazolyl -C _1-3 alkyl-O-, imidazolyl -C _1-3 alkyl-O-, pyridyl-C _1-3 alkyl-NH-, pyrimidinyl-C _1-3 alkyl-NH -, thienyl-C _1-3 alkyl-NH-, thiazolyl -C _1-3 alkyl-NH-, pyrazolyl -C _1-3 alkyl-NH- or imidazolyl -C _1-3 alkyl-NH - is optionally replaced by 1, 2 or 3 R, and other variables are as defined herein.

In some embodiments of the present invention, R ₁ , R ₂ , R ₈ , and R ₉ each independently represent H, F, Cl, Br, I, OH, NH ₂ , CN, SF ₅ , Me, CF _{3 , CHF2 , CH2F , CF3CF2 , OCF3 , HOCH2CH2O , CH3NHCH2CH2O} , ( _CH3 ) _2NCH2CH2O ,
, with other variables as defined herein.

In some aspects of the present invention, the above structural unit
, with other variables as defined herein.

In some embodiments of the present invention, R ₃ , R ₄ , R ₅ , R ₆ and R ₁₀ are each independently H, halogen, OH, NH ₂ , SF ₅ , CN, C _1-3 alkyl group, C _1-3 alkylamino group, C _1-3 alkoxy group, C _3-6 cycloalkyl group, -O-C _3-6 cycloalkyl group, 3- to 6-membered heterocycloalkyl group, C _3-6 cycloalkyl- selected from C _1-3 alkyl- and 3- to 6-membered heterocycloalkyl-C _1-3 alkyl-, the C _1-3 alkyl group, C _1-3 alkylamino group, C _1-3 alkoxy group, C _{3 -6} cycloalkyl group, -O-C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C _3-6 cycloalkyl-C _1-3 alkyl- or 3-6 membered heterocycloalkyl-C _{1 -3alkyl-} is optionally substituted with 1, 2 or 3 R, other variables as defined herein.

In some embodiments of the present invention, R ₃ , R ₄ , R ₅ , R ₆ and R ₁₀ are each independently H, F, Cl, Br, I, OH, NH ₂ , SF ₅ , Me, CF ₃ , _CHF2 , _CH2F , CN, CH( _F2 ) _CH3 , _CD3 , _OCD3 ,
, with other variables as defined herein.

In some aspects of the present invention, the above structural unit
, with other variables as defined herein.

In some aspects of the present invention, the above structural unit
, with other variables as defined herein.

In some embodiments of the present invention, R ₁₁ and R ₁₂ each independently represent H, F, Cl, Br, I, OH, NH ₂ , Me, CHF ₂ , CF ₃ ,
, with other variables as defined herein.

In some embodiments of the invention, R ₁₁ and R ₁₂ are joined together to form a cyclopropyl, oxetanyl, azetidinyl, and cyclopentanonyl group, and other variables are defined herein. That's right.

In some embodiments of the present invention, L ₁ is C(=O), CH ₂ , NH, CH(CH ₃ ), CHF, CF ₂ , CHCHF ₂ , CHCF ₃ ,
, with other variables as defined herein.

In some embodiments of the invention, the compound, its optical isomer and its pharmaceutically acceptable salts are:
selected from
here,
T ₁ , R ₁ , R ₂ , T ₂ , T ₃ , R ₃ , R ₄ , R ₅ , R ₆ , T ₄ , L ₁ , L ₂ , R are as defined above;
R _13a and R _13b are each independently selected from H, halogen and C _1-6 alkyl group, and said C _1-6 alkyl group is optionally substituted with 1, 2 or 3 R.

In some embodiments of the invention, R _13a , R _13b are each independently selected from H, F, Cl, Br, I, and Me, and the other variables are as defined herein.

The present invention






Further provided are compounds selected from the following, optical isomers thereof, and pharmaceutically acceptable salts thereof.

In a further aspect of the invention, the invention further discloses pharmaceutical compositions. In some embodiments of the invention, the pharmaceutical compositions include the compounds described above, optical isomers thereof, and pharmaceutically acceptable salts thereof.

In some embodiments of the invention, the pharmaceutical composition further comprises a pharmaceutically acceptable vector or excipient.

In a further aspect of the invention, the invention provides a compound as defined above, an optical isomer thereof and a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined above, in the manufacture of a medicament for inhibiting voltage-gated sodium channels in an individual. further disclosing the use of the object;

In some aspects of the invention, the voltage-gated sodium channel is Nav 1 . It is 8.

In a further aspect of the invention, the present invention provides the use of the above-mentioned compounds , their optical isomers and their Further disclosed are uses of pharmaceutically acceptable salts or pharmaceutical compositions as described above.

In some aspects of the invention, the pain is chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, post-surgical pain, visceral pain, multiple Selected from sexual sclerosis, Charcot-Marie-Tooth disease, incontinence, and arrhythmia.

In some embodiments of the invention, the intestinal pain is selected from inflammatory bowel disease pain, Crohn's disease pain, and interstitial cystitis pain.

In some aspects of the invention, the neuropathic pain is postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory nerve lesions, trigeminal neuralgia, mouth burn syndrome, post-amputation pain, phantom pain, painful Neuroma, traumatic neuroma, Morto neuroma, nerve crush injury, spinal canal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion injury, arm avulsion injury, complex regional pain syndrome, neuralgia due to drug therapy , neuralgia due to cancer chemotherapy, neuralgia due to antiretroviral therapy, pain after spinal cord injury, primary small fiber nerve lesion, primary sensory nerve lesion, and trigeminal autonomic headache.

In some embodiments of the invention, the musculoskeletal pain is selected from osteoarthritis pain, back pain, cold pain, burn pain, and tooth pain.

In some embodiments of the invention, the inflammatory pain is selected from rheumatoid arthritis pain and vulvodynia.

In some embodiments of the invention, the primary pain is selected from fibromyalgia.

In some embodiments of the invention, one or more other therapeutic agents are administered simultaneously with, before, or after administration of said compound, its optical isomer, and its pharmaceutically acceptable salts or said pharmaceutical composition. administered.

In a further aspect of the invention, the invention further proposes a method of treating or alleviating pain in a subject. In some embodiments of the invention, the method comprises administering to the subject a therapeutically effective amount of a compound as described above, an optical isomer thereof and a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above. In some embodiments of the invention, the subject's pain is as defined herein.

In a further aspect of the invention, the invention further proposes a method of inhibiting voltage-gated sodium channels in a subject. In some embodiments of the invention, the method comprises administering to the subject a therapeutically effective amount of a compound as described above, an optical isomer thereof and a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above. In some aspects of the invention, the voltage-gated sodium channel is Nav 1 . It is 8.

[Definition]
Unless the context clearly dictates otherwise, the following terms and symbols used herein have the meanings explained below.

A dash (“-”) not between two letters or symbols represents the site of attachment of a substituent. For example, a C _1-6 alkyl group carbonyl group refers to a C _1-6 alkyl group attached to the remainder of the molecule through a carbonyl group. However, if the site of attachment of the substituent is obvious to a person skilled in the art, for example, a halogen substituent, "-" may be omitted.

Dashed line on group valence bond
For example, if
, the dashed line represents the point of attachment of that group to the rest of the molecule.

The term "hydrogen" as used herein refers to the group -H.

The term "deuterium" as used herein refers to the group -D.

The term "hydroxy group" as described herein refers to the group -OH.

The term "halo" or "halogen" as used herein refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

The term "cyano group" as used herein refers to the group -CN.

Unless otherwise specified, C _n-n+m or C _n -C _n+m includes any specific case of n to n+m carbons, for example C _1-12 is C ₁ , including C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , and C ₁₂ , and also includes any one range from n to n+m; For example, C _1-12 is C _1-3 , C _1-6 , C 1-9 , C _{3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 and} C _9- Including ₁₂ and more. Similarly, n-member to n+m-member represents that the number of atoms on the ring is n to n+m, for example, a 3- to 12-membered ring is a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, It includes a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any one of n to n+m, for example, a 3 to 12-membered ring is 3 ~ Including 6-membered rings, 3- to 9-membered rings, 5- to 6-membered rings, 5- to 7-membered rings, 6- to 7-membered rings, 6- to 8-membered rings, and 6- to 10-membered rings.

Unless otherwise specified, the number of atoms on a ring is generally defined as the number of members in the ring; for example, a "3- to 6-membered ring" refers to a "ring" having 3 to 6 atoms arranged around it. .

Unless otherwise specified, the term "C _1-6 alkyl group" is used to represent a straight or side chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C _1-6 alkyl group includes C _1-5 , C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ and C ₅ alkyl groups, Monovalent (e.g. CH ₃ ), divalent (-CH ₂ -) or polyvalent (e.g.
). Examples of C _1-6 alkyl groups are CH ₃ ,
including but not limited to.

Unless otherwise specified, the term "C _1-3 alkyl group" is used to represent a straight or side chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C _1-3 alkyl group includes C _1-2 and C _2-3 alkyl groups, and is monovalent (e.g., CH ₃ ), divalent (-CH ₂ -), or polyvalent (e.g.,
). Examples of C _1-3 alkyl groups are CH ₃ ,
including but not limited to.

Unless otherwise specified, the term "C _1-6 alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms attached through one oxygen atom to the remainder of the molecule. The C _1-6 alkoxy group includes C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ , C ₅ , C ₄ and C ₃ alkoxy groups, etc. . Examples of C _1-6 alkoxy groups include methoxy group, ethoxy group, propoxy group (including normal propoxy group and isopropoxy group), butoxy group (n-butoxy group, isobutoxy group, s-butoxy group and t-butoxy group). ), pentoxy groups (including n-pentoxy groups, isopentoxy groups and neopentyloxy groups), hexyloxy groups, etc., but are not limited thereto.

Unless otherwise specified, the term "C _1-3 alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms attached through one oxygen atom to the remainder of the molecule. The C _1-3 alkoxy group includes C _1-2 , C _2-3 , C ₃ and C ₂ alkoxy groups. Examples of C _1-3 alkoxy groups include, but are not limited to, methoxy groups, ethoxy groups, propoxy groups (including normal propoxy groups and isopropoxy groups), and the like.

Unless otherwise specified, the term "C _1-6 alkylamino group" refers to an alkyl group containing 1 to 6 carbon atoms attached to the remainder of the molecule through an amino group. The C _1-6 alkylamino group is C _1-4 , C _{1-3 ,} C 1-2 , C _2-6 , C _2-4 , C ₆ , C ₅ , C ₄ , C ₃ and C ₂ alkyl Contains amino groups, etc. Examples of C _1-6 alkylamino groups are -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ , -N(CH ₃ )CH ₂ CH ₃ , -N(CH ₂ CH ₃ )(CH ₂ CH ₃ ), -NHCH ₂ CH ₂ CH ₃ , -NHCH ₂ (CH ₃ ) ₂ , -NHCH ₂ CH ₂ CH ₂ CH ₃ and the like.

Unless otherwise specified, the term "C _1-3 alkylamino group" refers to an alkyl group containing 1 to 3 carbon atoms attached to the remainder of the molecule through an amino group. The C _1-3 alkylamino group includes C _1-2 , C ₃ and C ₂ alkylamino groups. Examples of C _1-3 alkylamino groups are -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ , -N(CH ₃ )CH ₂ CH ₃ , -NHCH ₂ CH ₂ CH ₃ , -NHCH ₂ (CH ₃ ) _2, etc., but not limited to them.

Unless otherwise specified, the term "C _1-6 alkylthio group" refers to an alkyl group containing 1 to 6 carbon atoms attached to the remainder of the molecule through a sulfur atom. The C _1-6 alkylthio group is a C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ , C ₅ , C ₄ , C ₃ and C ₂ alkylthio group. Including. Examples of C _1-6 alkylthio groups include, but are not limited to, -SCH ₃ , -SCH ₂ CH ₃ , -SCH ₂ CH ₂ CH ₃ , -SCH ₂ (CH ₃ ) ₂ , and the like.

Unless otherwise specified, the term "C _1-3 alkylthio group" refers to an alkyl group containing 1 to 3 carbon atoms attached to the remainder of the molecule through a sulfur atom. The C _1-3 alkylthio group includes C _1-3 , C _1-2 and C ₃ alkylthio groups. Examples of C _1-3 alkylthio groups include, but are not limited to, -SCH ₃ , -SCH ₂ CH ₃ , -SCH ₂ CH ₂ CH ₃ , -SCH ₂ (CH ₃ ) ₂ , and the like.

Unless otherwise specified, "C _3-6 cycloalkyl group" refers to a saturated cyclic hydrocarbon group that is a monocyclic or bicyclic ring system consisting of 3 to 6 carbon atoms, and the C _3-6 cycloalkyl Groups include _C3-5 , _C4-5 and _C5-6 cycloalkyl groups, and may be monovalent, divalent or polyvalent. Examples of C _3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

Unless otherwise specified, the term "3- to 6-membered heterocycloalkyl group" by itself or in combination with other terms represents a saturated cyclic group consisting of 3 to 6 ring atoms, of which 1, 2, The 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms, where the nitrogen atom is optionally quaternary ammoniated and nitrogen and The sulfur heteroatoms may optionally be oxidized (ie NO and S(O) _p , where p is 1 or 2). Includes monocyclic and bicyclic ring systems, where bicyclic systems include spirocycles, parallel rings and bridged rings. In addition, in the case of a "3- to 6-membered heterocycloalkyl group", the heteroatom can occupy the bonding position between the heterocycloalkyl group and the rest of the molecule. The 3- to 6-membered heterocycloalkyl group includes 4- to 6-membered, 5- to 6-membered, 4-, 5-, and 6-membered heterocycloalkyl groups. Examples of 3- to 6-membered heterocycloalkyl groups are azetidinyl group, oxetanyl group, thietanyl group, pyrrolidinyl group, pyrazolidinyl group, imidazolidinyl group, tetrahydrothienyl group (tetrahydrothiophen-2-yl group and tetrahydrothiophen-3-yl group). ), tetrahydrofuranyl group (including tetrahydrofuran-2-yl group, etc.), tetrahydropyranyl group, piperidinyl group (including 1- piperidinyl group, 2- piperidinyl group, 3- piperidinyl group, etc.) ), piperazinyl group (including 1- piperazinyl group and 2- piperazinyl group), morpholinyl group (including 3-morpholinyl group and 4-morpholinyl group), dioxanyl group, dithianyl group, isoxazolidinyl group, It includes, but is not limited to, isothiazolidinyl group, 1,2- oxazinyl group, 1,2-thiazinyl group, hexahydropyridazinyl group, homopiperazinyl group, or homopiperidinyl group.

Unless otherwise specified, the term "3- to 6-membered ring" by itself or in combination with other terms represents a saturated monocyclic group or an unsaturated monocyclic group consisting of 3 to 6 ring atoms, respectively; That is, it may contain a pure carbocyclic ring or a ring having a heteroatom. Here, 3 to 6 refer to the number of atoms forming the ring. Examples of "3- to 6-membered ring" include, but are not limited to, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, azetidinyl group, oxetanyl group, thietanyl group, cyclopentanonyl group, cyclohexanonyl group, etc. do not have.

Unless otherwise specified, the terms "5- to 6-membered heteroaryl ring" and the terms "5- to 6-membered heteroaryl group" of the present invention can be used interchangeably, and the term "5- to 6-membered heteroaryl group" can be used interchangeably. "Aryl group" refers to a monocyclic group having a conjugated π-electron system consisting of 5 to 6 ring atoms , of which 1, 2, 3 or 4 ring atoms are independent of O, S and N. The remaining are carbon atoms. Here, the nitrogen atom is optionally quaternary ammoniated and the nitrogen and sulfur heteroatoms are optionally oxidized (ie NO and S(O) _p , p is 1 or 2). A 5- to 6-membered heteroaryl group may be attached to other parts of the molecule through a heteroatom or a carbon atom. The 5- to 6-membered heteroaryl group includes 5- and 6-membered heteroaryl groups. Examples of the 5- to 6-membered heteroaryl group include pyrrolyl group (including N-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, etc.), pyrazolyl group (2- pyrazolyl group and 3- pyrazolyl group ), imidazolyl group (including N- imidazolyl group, 2- imidazolyl group, 4-imidazolyl group, 5- imidazolyl group, etc.), oxazolyl group (2-oxazolyl group , etc.) group, 4-oxazolyl group, 5-oxazolyl group, etc.), triazolyl group (1H-1,2,3-triazolyl group, 2H-1,2,3-triazolyl group, 1H-1,2,4-triazolyl group) 4H-1,2,4-triazolyl group, etc.), tetrazolyl group, isoxazolyl group (including 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, etc.), thiazolyl group (2-thiazolyl group), (including lyl group, 4- thiazolyl group, 5- thiazolyl group, etc.), furanyl group (including 2- furanyl group, 3- furanyl group, etc.), thienyl group (2-thienyl group and 3-thienyl group, etc.), pyridyl group (including 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, etc.), pyrazinyl group or pyrimidinyl group (including 2-pyrimidinyl group, 4-pyrimidinyl group, etc.) including but not limited to.

Accordingly, the term "heteroaryl ring" as used herein refers to a ring of a heteroaryl group as defined above.

As used herein, "aryl group", "aromatic" means Huckel's rule (Huckel's rule) where the number of π electrons is equal to 4n+2 and n is zero or any positive integer up to 6. 's rules).

The term "carbonyl group" as used herein refers to the group -C(O)-, which can be represented as -CO-.

The term "amino group" as used herein refers to the group _-NH2 .

As used herein, the term "optional" means that an event described below may or may not occur, and the description is applicable both when said event occurs and when said event does not occur. including. For example, "optionally substituted alkyl group" means unsubstituted alkyl groups and substituted alkyl groups, where alkyl group is defined herein. Those skilled in the art will appreciate that for any group containing one or more substituents, said group is spatially impractical, chemically imprecise, synthetically impossible, and It should be understood that this does not include substitutions that are/or inherently unstable.

As used herein, the term "substituted" or "substituted by" means one or more hydrogen atoms on a given atom or group are substituted, e.g., a group consisting of a given substituent. is substituted with one or more substituents selected from the following, provided that the normal valence of the given atom is not exceeded. When a substituent is oxo (ie =O), two hydrogen atoms on a single atom are replaced by oxygen. Such combinations are permissible only if the combinations of substituents and/or variables result in chemically precise and stable compounds. A chemically precise and stable compound is one that is sufficiently stable so that the compound can be separated from a reaction mixture, the chemical structure of the compound can be determined, and it can be formulated into a drug that has at least practical utility. It means doing. For example, when a substituent is not explicitly recited, the terms "substituted by" or "substituted" as used herein mean that one or more hydrogen atoms on a given atom or group are independently is substituted with one or more, for example 1, 2, 3 or 4 substituents, said substituents being independently deuterium (D), halogen, -OH, thiol group, cyano group, - CD ₃ , an alkyl group (preferably a C _1-6 alkyl group), an alkoxy group (preferably a C _1-6 alkoxy group), a haloalkyl group (preferably a halo C _1-6 alkyl group), a haloalkoxy group (preferably a halo C 1-6 alkyl group), C _1-6 alkoxy group), -C(O)NR _a R _b and -N(R _a )C(O)R _b and -C(O)OC _1-4 alkyl group (where R _a and R _b is each independently selected from hydrogen, a C _1-4 alkyl group, a haloC _1-4 alkyl group), a carboxyl group (-COOH), a cycloalkyl group (preferably a 3- to 8-membered cycloalkyl group) , heterocyclyl group (preferably 3- to 8-membered heterocyclyl group), aryl group, heteroaryl group, aryl-C _1-6 alkyl-, heteroaryl-C _1-6 alkyl-, -OC _1-6 alkylphenyl, -C _1-6 alkyl-OH (preferably -C _1-4 alkyl-OH), -C _1-6 alkyl-SH, -C _1-6 alkyl-O-C _1-2 , -C _1-6 alkyl -NH ₂ (preferably -C _1-3 alkyl-NH ₂ ), -N (C _1-6 alkyl group) ₂ (preferably -N (C _1-3 alkyl group) ₂ ), -NH (C _{1- 6} alkyl group) (preferably -NH (C _1-3 alkyl group)), -N (C _1-6 alkyl group) (C _1-6 alkyl group phenyl group), -NH (C _1-6 alkyl group phenyl group) group), nitro group, -C(O)OC _1-6 alkyl group (preferably -C(O)OC _1-3 alkyl group), -NHC(O) (C _1-6 alkyl group), -NHC( O) (phenyl group), -N (C _1-6 alkyl group) C (O) (C _1-6 alkyl group), -N (C _1-6 alkyl group) C (O) (phenyl group), - C(O)C _1-6 alkyl group, -C(O)heteroaryl group (preferably -C(O)-5- to 7-membered heteroaryl group), -C(O)C _1-6 alkyl group, phenyl group , -C(O)C _1-6 haloalkyl group, -OC(O)C _1-6 alkyl group (preferably -OC(O)C _1-3 alkyl group), alkyl group sulfonyl group (e.g. -S(O) ) ₂ -C _1-6 alkyl group), alkyl group sulfinyl group (-S(O)-C _1-6 alkyl group), -S(O) ₂ -phenyl group, -S(O) ₂ -C _{1- 6} haloalkyl group, -S(O) ₂ NH ₂ , -S(O) ₂ NH (C _1-6 alkyl group), -S(O) ₂ NH (phenyl group), -NHS(O) ₂ (C _{1 -6} alkyl group), -NHS(O) ₂ (phenyl group) and -NHS(O) ₂ (C _1-6 haloalkyl group), where the above-mentioned alkyl group, cycloalkyl group, phenyl group, The aryl group, heterocyclyl group and heteroaryl group each optionally include halogen, -OH, -NH ₂ , cycloalkyl group, 3- to 8-membered heterocyclyl group, C _1-4 alkyl group, C _1-4 haloalkyl group , -OC _1-4 alkyl group, -C _1-4 alkyl- OH, -C _1-4 alkyl- OC _1-4 alkyl group, -OC _1-4 haloalkyl group, cyano group, nitro group, -C(O)-OH, -C(O)OC _1-6 alkyl group, -CON(C _1-6 alkyl group) ₂ , -CONH(C _1-6 alkyl group), -CONH ₂ , -NHC( O) (C _1-6 alkyl group), -NH (C _1-6 alkyl group) C(O) (C _1-6 alkyl group), -SO ₂ (C _1-6 alkyl group), -SO ₂ ( phenyl group), -SO ₂ (C _1-6 haloalkyl group), -SO ₂ NH ₂ , -SO ₂ NH (C _1-6 alkyl group), -SO ₂ NH (phenyl group), -NHSO ₂ (C _{1 -6} alkyl group), -NHSO ₂ (phenyl group) and -NHSO ₂ (C _1-6 haloalkyl group). When one atom or group is substituted by multiple substituents, the substituents may be the same or different.

When any variable (eg, R) occurs more than one time in the composition or structure of a compound, its definition at each occurrence is independent. Thus, for example, if one group is substituted by 0 to 2 R, said group can be optionally substituted by up to 2 R, and R in each case is an independent option. has. It should be noted that combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.

The term "pharmaceutically acceptable" as used herein refers to non-toxic, biologically acceptable, and suitable for administration to an individual.

As used herein, the term "pharmaceutically acceptable salts" refers to non-toxic, biologically acceptable acid or base addition salts of compounds of formula (I) that are suitable for administration to an individual. refers to acid addition salts of compounds of formula (I) with inorganic acids, such as hydrochlorides, hydrobromides, carbonates, bicarbonates, phosphates, sulfates, sulfites, nitrates, and the like; I) Acid addition salts of compounds with organic acids, such as formates, acetates, malates, maleates, fumarates, tartrates, succinates, citrates, lactates, mesylates, para Toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate and alkanedicarboxylic acids of the formula HOOC-(CH ₂ ) _n -COOH, where n is from 0 to 4. This includes, but is not limited to, salt and the like. "Pharmaceutically acceptable salts" also include base addition salts of compounds of formula (I) having acidic groups with pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium and ammonium.

Note that when the compound described herein is obtained in the form of an acid addition salt, its free base form can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is in the free base form, its acid addition salts, particularly pharmaceutically acceptable acid addition salts, can be prepared by converting the free base into a suitable solvent according to conventional procedures for preparing acid addition salts from alkaline compounds. and by treating the solution with an acid. Those skilled in the art can determine, without undue experimentation, the various synthetic methods available for producing non-toxic pharmaceutically acceptable acid addition salts.

Those skilled in the art will appreciate that some compounds of formula (I) may contain one or more chiral centers and therefore exist in two or more stereoisomers. . Therefore, the compounds of the invention may exist in the form of single stereoisomers (e.g. enantiomers , diastereomers ) and mixtures thereof in any proportion, e.g. racemates, and, where appropriate, their It may exist in the form of tautomers and geometric isomers.

The term "stereoisomer" as used herein refers to compounds that have the same chemical composition but differ in the arrangement of their atoms or groups in space. Stereoisomers include enantiomers , diastereomers , conformers, and the like.

The term " enantiomer " as used herein refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.

The term " diastereomer " as used herein refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, or biological activities. Mixtures of diastereomers can be separated by high resolution analytical methods, such as electrophoresis and chromatography, such as HPLC.

Stereochemical definitions and conventions are provided by S. P. (McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereoche "Mistry of Organic Compounds", John Wiley & Sons, Inc. , New York, 1994). Many organic compounds exist in optically active forms, ie, have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center. The prefixes d and l or (+) and (-) are used to represent the rotating plane- polarized symbol of a compound, where (-) or l indicates that the compound is left-handed. represent. Compounds with a (+) or d prefix are right-handed. For a given chemical structure, these stereoisomers are the same except that they are mirror images of each other. A particular stereoisomer is sometimes referred to as an enantiomer , and a mixture of such isomers is commonly referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers without optical activity.

Racemic mixtures may be used in their original form or separated into single isomers. By resolution, stereochemically pure compounds can be obtained or mixtures enriched in one or more isomers can be obtained. Methods for separating isomers are known methods (see Allinger N.L. and Eliel E.L., "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), and physical methods, such as chiral adsorbents. including chromatographic methods using A single isomer in chiral form can be obtained from a chiral precursor. or salts of diastereomers with chiral acids (e.g., single enantiomers such as 10-camphorsulfonic acid, camphoric acid, α-brominated camphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.) A single isomer can be chemically separated from the mixture by forming a single isomer, and the salt described above can be fractionally crystallized, followed by liberating one or two of the resolved bases. , optionally repeating this process. Thereby one or two isomers substantially free of another isomer, i.e. optical purity calculated by weight, e.g. at least 91%, 92%, 93%, 94%, 95%, 96%. , 97%, 98%, 99% or 99.5% of the desired stereoisomer. Alternatively, the racemate can be covalently linked to a chiral compound (auxiliary substance) to obtain diastereomers , as is known to those skilled in the art.

The term "tautomer" or "tautomeric form" as used herein refers to structural isomers of different energies that are interconvertible by low energy inhibition. For example, proton tautomers (also called prototropic tautomers) include interconversions that occur via proton transfer, such as ketone-enol and imine-enamine isomerizations. Valence tautomers include interconversions that occur through recombination of some bonding electrons.

As used herein, the term "treatment" means treating an individual with a disease or symptoms of said disease with one or more pharmaceutical substances, in particular compounds of formula (I) as described herein and/or their pharmaceutical refers to administering a salt acceptable to a person to cure, alleviate, alleviate, change, treat, ameliorate, ameliorate, or influence the disease or the symptoms of the disease. As used herein, the term "prophylaxis" refers to the administration of one or more pharmaceutical substances, in particular the compounds of formula (I) and/or their pharmaceutically acceptable salts described herein, to the prevention of said disease. It refers to administering to individuals who are predisposed to the disease to prevent them from contracting the disease. When referring to chemical reactions, the terms "processing", "contacting" and "reacting" refer to the bringing together of two or more reagents under appropriate conditions to produce the indicated product and/or the desired product. Refers to adding or mixing. It is possible that the reaction producing the indicated product and/or the desired product does not necessarily result directly from the combination of the two reagents initially added, i.e. the mixture contains the 1 It should be understood that one or more intermediates may be present which ultimately result in the formation of the indicated product and/or the desired product.

The term "effective amount" as used herein generally refers to an amount sufficient to produce a beneficial effect on an individual. Effective amounts of the compounds of the invention are determined by conventional methods (e.g., modeling, dose escalation studies, or clinical trials) and by conventional influencing factors (e.g., method of administration, pharmacokinetics of the compound, disease severity and disease course, individual medical history, the individual's health condition, the individual's response to drugs, etc.).

All technical and scientific terms used herein that are not specifically defined have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to specific examples. It should be understood that these specific examples are merely for the purpose of interpreting the invention and are not intended to limit the scope of the invention. In the following examples, eg, experimental procedures where specific conditions are not specified, the general conditions for such reactions are generally followed or the conditions suggested by the manufacturer are followed. Unless otherwise specified, percentages and parts are by weight. Unless otherwise specified, liquid ratios are by volume.

All experimental materials and reagents used in the following examples are commercially available unless otherwise specified.

In the following examples, ¹ H-NMR spectra were recorded using a Bluker AVANCE III HD 400 MHz nuclear magnetic resonance instrument, and ¹³ C-NMR spectra were recorded using a Bluker AVANCE III HD 400 MHz nuclear magnetic resonance instrument. Chemical shifts are expressed in δ (ppm), and mass spectra were recorded using an Agilent 1260 (ESI) or Shimadzu LCMS-2020 (ESI) or Agilent 6215 (ESI) mass spectrometer. Reversed-phase preparative HPLC separations were recorded using an Agilent 1290 UV-induced fully automated purification system (Xtimate® Prep C18 OBDTM 21.2*250 mm 10 μm column) or a Gilson GX281 UV-induced fully automated purification system. be performed using an automated purification system (xBridge® Prep C18 OBDTM 19*250 mm 10 μm column) or a Waters QDa-induced fully automated purification system (SunFire® Prep C18 OBD 29*250 mm 10 μm column) .

Here, the Japanese names of the reagents expressed by chemical formulas or English abbreviations are as follows.
Aq represents aqueous solution, Ar represents argon gas, BH ₃ represents borane, br represents broad peak, B ₂ Pin ₂ represents bis( pinacolato ) diboron, °C represents temperature in degrees Celsius, CD ₃ OD represents deuterated methanol, CDCl ₃ represents deuterated chloroform, conc. (COCl) ₂ represents oxalyl chloride, Cs ₂ CO ₃ represents cesium carbonate, CuI represents copper iodide, d represents double peak, DCM represents dichloromethane, Dioxane or 1 ,4-dioxane stands for dioxane, DIPEA or DIEA stands for N,N-diisopropylethylamine, DMF stands for dimethylformamide , DMSO stands for dimethyl sulfoxide, EA or EtOAc stands for ethyl acetate, and ESI stands for electrospray. - represents ionization , g represents grams, h represents time, H ₂ O represents water, HATU represents 1-[bis(dimethylamino ) methylene] -1H-1,2,3-triazolo[4 , 5-b] represents pyridinium 3- oxide hexafluorophosphate , HOBt represents 1-hydroxybenzotriazole, HPLC represents high performance liquid chromatography method, K ₂ CO ₃ represents potassium carbonate, KOAc represents potassium acetate. , LCMS stands for liquid chromatography mass spectrometry, LiOH stands for lithium hydroxide, m stands for multiple peaks, m/z stands for mass-to-charge ratio, MeCN, ACN or CH ₃ CN stands for acetonitrile, m -CPBA stands for metachloroperbenzoic acid, MeOH stands for methanol, min stands for minutes, mg stands for milligrams, mL stands for milliliters, mmol stands for millimoles, _N2 stands for nitrogen gas, _Na2 CO ₃ represents sodium carbonate, NaCl represents sodium chloride, NaHCO ₃ represents sodium bicarbonate, NaOH represents sodium hydroxide, Na ₂ SO ₄ represents sodium sulfate, NMP represents N-methyl-2- pyrrolidone, PBr ₃ represents phosphorous tribromide, Pd(dppf)Cl ₂ or PdCl ₂ (dppf) represents 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride, PE represents petroleum ether represents r. t. or RT stands for room temperature, s stands for single peak, SOCl ₂ stands for dichlorosulfoxide, t stands for triple peak, TLC stands for thin layer chromatography, THF stands for tetrahydrofuran, Toluene or tol. represents toluene.

Synthesis of Example A1

Step 1, Synthesis of Intermediate 3 Compound 1 (2.2 g, 10.57 mmol) was added to DMF (10 mL), HATU (5.23 g, 13.75 mmol) was added at 0°C, and after stirring for 10 min, the compound 2 (1.09 g, 11.62 mmol) was added, DIEA (1.78 g, 13.79 mmol) was gradually added dropwise, and the reaction solution was stirred at room temperature for 2 h. LC-MS indicated that the reaction was complete. H ₂ O (20 mL) was added to the liquid to precipitate a solid, which was filtered. The filter cake was used as the target compound and dried to obtain 2.2 g of Compound 3 as a white solid. Yield was 73%.

LCMS: m/z 285.0 (M+H) ⁺ .

Step 2, Synthesis of Intermediate 5 Compound 3 (500 mg, 1.76 mmol) was dissolved in NMP (5 mL), and compound 4 (333 mg, 2.64 mmol) and K ₂ CO ₃ (730 mg, 5.28 mmol) were added to the solution. Then, the reaction solution was stirred at 100° C. overnight, the reaction was indicated to be complete by LC-MS, H ₂ O (20 mL) was added to the reaction solution, extracted with EA (15 mL*3), and the organic phases were combined . After drying over anhydrous Na ₂ SO ₄ and concentration, the crude product was purified on a normal phase column (PE/EA=0-100%) to yield 500 mg of compound 5 as a yellow solid. The yield was 72.8%.

LCMS: m/z 391.1 (M+H) ⁺ .

Step 3, Synthesis of Example A1 Compound 5 (200 mg, 0.51 mmol) was dissolved in DCM (2 mL), m-CPBA (133 mg, 0.77 mmol) was added, the reaction was stirred at room temperature for 1 h, and LC - MS indicated the reaction was complete. The pH was adjusted to weak basicity by adding saturated NaHCO ₃ , extracted with EA (20 mL*2), and the combined organic phases were washed with saturated NaCl (20 mL) and dried over anhydrous Na ₂ SO ₄ . , concentration to obtain the crude product (acetonitrile is 5-95% in water (containing 0.05% NH ₄ HCO ₃ )) was prepared to obtain compound A1.

LCMS: m/z 407.2(M+H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.93 (s, 1H), 8.68 (s, 1H), 8.01 (ddd, J = 6.4, 1.7, 0.9 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.62 (dd, J = 7.9, 0.8 Hz, 1H), 7.51 (d, J = 9.2 Hz, 1H), 7.39 (dd, J = 8.4, 6.4 Hz, 1H), 7.22 (dd, J = 9.2, 2.5 Hz, 1H), 7.13 - 7.05 (m, 2H), 7.01 (s, 1H), 2.17 (s, 3H).

Similar to the synthesis of Example A1, the following Examples A2 to A40 were synthesized as shown in Table 1 below.

Synthesis of Example A41

Step 1, Synthesis of Intermediate 8 Compound 6 (450 mg, 1.6 mmol) was added to toluene (10 mL), Cs ₂ CO ₃ (1.25 g, 3.84 mmol), and compound 7 (391 mg, 1.9 mmol) were added. , stirred for 1.5 h at 100°C in a nitrogen gas atmosphere, showed completion of raw material reaction by LC-MS, cooled to room temperature, filtered with suction, washed the filter cake with EA (30 mL * 3), and removed the organic phase. The combined materials were spin-dried and purified on a normal phase column (PE/EA=0-100%) to yield 300 mg of compound 8 as a white solid. Yield was 45%.

LCMS: m/z 415.2 (M+H) ⁺ .

Step 2, Synthesis of Intermediate 9 Compound 8 (200 mg, 0.48 mmol) was dissolved in DCM (8 mL), cooled in an ice bath to 0°C, 3 drops of DMF were added, and oxalyl chloride (245 mg, 1.93 mmol) was dissolved in DCM (8 mL). After the dropwise addition, the mixture was stirred at room temperature for 1 h, sampled, and quenched by adding methanol. Completion of the raw material reaction was confirmed by TLC detection, and the reaction solution was spin-dried. Add DCM (10 mL), cool in ice bath to 0 °C, add DIPEA (250 mg, 1.93 mmol), add compound 2 (68 mg, 0.72 mmol), stir at room temperature for 2 h, add methanol (10 mL). quenched , spin dried and purified on a normal phase column (PE/EA=0-100%) to yield 70 mg of compound 9 as a white solid. Yield was 30%.

LCMS: m/z 491.0 (M+H) ⁺ .

Step 3, Synthesis of Example A41 Compound 9 (70 mg, 0.14 mmol) was dissolved in DCM (10 mL), m-CPBA (50 mg, 0.29 mmol) was added, stirred at room temperature for 4 h, and raw material reaction was detected by LCMS detection. After confirming completion, add saturated NaHCO ₃ (20 mL), stir for 30 min, separate the layers, extract the aqueous phase with DCM (20 mL*2), combine the organic phases, and add the organic phase to saturated NaCl (30 mL). ), dried with anhydrous Na ₂ SO ₄ and spin dried (acetonitrile 5-95% in water (containing 0.05% NH ₄ HCO ₃ )) to give compound A41.

LCMS: m/z 507.2(M+H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.28 (s, 1H), 8.69 - 8.68 (t, J = 1.2 Hz, 1H), 8.05 - 8.03 (d, J = 7.2 Hz, 1H), 7.83 - 7.79 (t, J = 8.4 Hz, 1H), 7.54 - 7.52 (d, J = 9.2 Hz, 1H), 7.43 - 7.36 (m, 2H), 7.27 - 7.26 (d, J = 2.4 Hz, 1H), 7.06 -7.04 (m, 1H), 6.69 - 6.67 (d, J = 8.8 Hz, 1H), 3.79 (s, 3H).

Similar to the synthesis of Examples A1 and A41, the following Examples A42 to A114 were synthesized as shown in Table 2 below.

Synthesis of Example A114

Step 1, synthesis of intermediate 11
Compound 10 (5 g, 32.4 mmol) was added to anhydrous THF (20 mL), and 1M tetrahydrofuran borane complex compound (65 mL) was added dropwise in an ice water bath in a nitrogen gas atmosphere. The reaction was carried out at room temperature for 3 h, and the reaction was determined by TLC. After indicating completion, methanol (5 mL) was added to quench the reaction , the reaction was concentrated, EA (100 mL) was added, washed with water (50 mL), saturated NaCl (50 mL), anhydrous _Na2 After drying with SO ₄ and filtering and concentration, 4.46 g of compound 11 was obtained as a white solid. Yield was 98%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.40 - 7.29 (m, 1H), 7.03 - 6.90 (m, 2H), 5.10 (t, J = 5.4 Hz, 1H), 4.45 (d, J = 5.4 Hz, 2H), 2.25 (s, 3H).

Step 2, Synthesis of Intermediate 12 Compound 11 (4.4 g, 31.4 mmol) was added to dichloromethane (40 mL), PBr ₃ (3.6 mL) was added dropwise under an ice water bath in a nitrogen gas atmosphere, and the reaction was carried out for 2 h at room temperature. After the reaction was indicated to be complete by TLC, the reaction was poured into ice water, extracted with DCM (50 mL x 2), the organic phases were combined , dried over anhydrous Na ₂ SO ₄ and loaded onto a normal phase column (PE/EA). =0-100%) to obtain 5.6 g of Compound 12 as a colorless liquid. Yield was 88%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.51 - 7.40 (m, 1H), 7.15 - 6.95 (m, 2H), 4.72 (s, 2H), 2.36 (s, 3H).

Step 3, Synthesis of Intermediate 14 Compound 13 (2 g, 7.09 mmol), bis(pinacolato)diboron (1.98 g, 7.80 mmol), KOAc (2.09 g, 21.3 mmol) and Pd(dppf)(Cl ) ₂ (0.26 g, 0.35 mmol) was placed in a 50 mL three-necked flask, the atmosphere was replaced with nitrogen gas three times, 1,4-dioxane (20 mL) was added as a solvent, and the mixture was reacted in an oil bath at 85 °C for 4 h. , after the completion of the reaction was indicated by LC-MS, the reaction solution was poured into ice water, extracted with EA (50 mL x 2), the organic phases were combined , dried over anhydrous Na ₂ SO ₄ and loaded onto a normal phase column (PE/ EA=0-100%) to obtain 1.8 g of Compound 14. Yield was 77%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (d, J = 8.2 Hz, 1H), 7.74 (s, 1H), 7.68 (d, J = 8.2 Hz, 1H), 3.95 (s, 3H), 1.43 (s, 12H).

Step 4, Synthesis of Intermediate 15 Compound 14 (359 mg, 1.1 mmol), Compound 12 (200 mg, 1 mmol), K ₂ CO ₃ (273 mg, 1.98 mmol) and Pd(dppf)(Cl) ₂ (36 mg, 0 .05 mmol) was placed in a 25 mL three-necked flask, the atmosphere was replaced with nitrogen gas three times, a mixed solvent of 1,4-dioxane (10 mL) and water (3 mL) was added, and the mixture was reacted in an oil bath at 100°C for 2 hours. After the completion of the reaction was indicated by LC-MS, the reaction solution was poured into ice water, extracted with EA (20 mL x 2), the organic phases were combined , dried over anhydrous Na ₂ SO ₄ and loaded onto a normal phase column (PE/EA =0-100%) to obtain 200 mg of Compound 15 as a colorless oil. Yield was 62%.

LC-MS: m/z 327 (M+H) ⁺ .

Step 5, Synthesis of Intermediate 16 Compound 15 (160 mg, 0.49 mmol) was added to a mixed solvent of tetrahydrofuran (6 mL) and methanol (3 mL), and monohydrated lithium hydroxide (82 mg, 1.96 mmol) was added to a mixed solvent of tetrahydrofuran (6 mL) and methanol (3 mL). ) was added followed by water (2 mL). After reacting at room temperature for 2 h and showing completion of the reaction by TLC, the reaction solution was poured into ice water, the pH value was adjusted to 3-4 with diluted hydrochloric acid, extracted with EA (10 mL x 2), and the organic phases were combined . After drying with anhydrous Na ₂ SO ₄ , filtering and concentration, 150 mg of product 16 was obtained as a white solid. Yield was 98%.

LCMS: m/z 311 (MH) ^- .

Step 6, Synthesis of Intermediate 17 Compound 16 (150 mg, 0.48 mmol) was added to DCM (5 mL) and 0.2 mL oxalyl chloride was added dropwise under an ice-water bath, followed by 2 drops of DMF to catalyze the catalyst. The reaction solution was reacted at room temperature for 2 h, and after TLC indicated the completion of the reaction, the reaction solution was directly concentrated to dryness to obtain 160 mg of product. In addition to dichloromethane (20 mL), DIPEA (0.24 mL, 1.45 mmol) was added dropwise under an ice-water bath, and then compound 2 (160 mg, 0.48 mmol) was gradually added dropwise and reacted at room temperature for 2 h. After completion of the reaction by LC-MS, the reaction was poured into ice water and extracted with DCM (20 mL x 2), the organic phases were combined , dried over anhydrous Na ₂ SO ₄ and concentrated to yield the crude product. was purified using a normal phase column (PE/EA=0-100%) to obtain 63 mg of Compound 17 as a white solid. Yield was 33%.

LCMS: m/z 389 (M+H) ⁺ .

Step 7, Synthesis of Example A114 Compound 17 (63 mg, 0.16 mmol) was added to DCM (5 mL), m-CPBA (56 mg, 0.32 mmol) was added at 0°C, reacted for 2 h at room temperature, and LC -After the reaction was indicated to be complete by MS, the reaction solution was poured into ice water, the pH was adjusted to weakly basic by adding saturated NaHCO ₃ , extracted with DCM (20 mL x 2), and the organic phases were combined . After drying with anhydrous Na ₂ SO ₄ , filtering and concentration, the crude product was obtained (acetonitrile is 5-95% in water (containing 0.05% NH ₄ HCO ₃ )). Product A114 was obtained.

LCMS: m/z 405.2(M+H) ⁺ ;1H NMR (400 MHz, DMSO-d ₆ ) δ 10.83 (s, 1H), 8.65 (s, 1H), 8.06 - 7.96 (m, 1H), 7.78 ( s, 2H), 7.47 (d, J = 10.7 Hz, 2H), 7.38 (dd, J = 8.4, 6.3 Hz, 1H), 7.03 - 6.94 (m, 2H), 6.88 (td, J = 8.6, 2.7 Hz , 1H), 4.18 (s, 2H), 2.16 (s, 3H).

Effect example:
1. Blocking activity of the compound of the present invention against sodium ion channel 1.8 (NaV1.8) 1. Test method: The effects of compounds on voltage-gated sodium ion channel (NaV) 1.1-1.8 subtype currents were determined by patch-clamp analysis technique.

2. Preparation and Analysis of Dosage Formulation 2.1 Method for Preparing Dosage Formulation Stock Solution Control: An appropriate volume of DMSO was weighed out as a stock solution.

Test compound: An appropriate mass of the compound (actual amount=theoretical concentration*volume*molecular weight/purity) was weighed, the required volume of DMSO was calculated using the formula, and finally converted to the required mass of DMSO. The powder was then dissolved in a weighed amount of DMSO. Based on the final DMSO usage, the actual stock solution concentration is calculated, and the actual stock solution concentration is generally slightly different from the theoretical concentration.

2.2 Preparation method and concentration of diluted standard solutions for administration preparations Before the NaV channel current test, the control and test compound stock solutions were diluted in 10 mL of extracellular fluid to prepare diluted standard solutions, and ultrasound was performed for 20 min.

3. Experimental system 3.1. Cell Culture 1) Detailed information on the CHO cell line stably expressing Nav1.8 channel is SCN10A:NM_006514.

2) Cells were grown in HAM'S/F- containing 10 % fetal bovine serum and 10 μg/mL Blasticidin , 200 μg/mL Hygromycin B, and 100 μg /mL Zeocin. 12 medium, the culture temperature was 37° C., and the carbon dioxide concentration was 5%.

3) Cell passaging: The old medium was removed and washed once with PBS, then 1 mL of 0.25% Trypsin - EDTA solution was added and incubated at 37°C for 1.5 min. Once the cells were detached from the bottom of the dish, 5 mL of complete medium preheated at 37°C was added. The cell suspension was lightly sprayed with a suction tube to separate aggregated cells. The cell suspension was transferred to a sterile centrifuge tube and centrifuged at 1000 rpm for 5 min to collect the cells. After propagation or maintenance culture, the cells were seeded into 6 cm cell culture dishes, and the amount of cells seeded in each cell culture dish was 2.5*10 ⁵ cells (final volume: 5 mL).

4) Cell density must be below 80% to maintain cell electrophysiological activity.

5) Patch-clamp assay, before the experiment, cells were detached with 0.25% -trypsin -EDTA and placed in a 24-well plate of pre-populated coverslips at a density of 8* ¹⁰³ cells per well (final volume: 500 μL), tetracycline was added, and experimental detection was performed the next day.

3.2. Electrophysiological solution 1) Extracellular solution: 140mM NaCl, 3.5mM KCl, 2mM _CaCl2 , 10mM HEPES, _{1.25mM NaH2PO4} , 1mM _MgCl2 , 10mM glucose , pH=7.4 (NaOH).

2) Intracellular solution: 50mM CsCl, 10mM NaCl, 10mM HEPES, 20mM EGTA, 60mM CsF, pH=7.2 (CsOH).

4. Test method 4.1. The measuring instruments are shown in Table 3.

4.2. Patch-clamp measurements The voltage stimulation scheme for whole-cell patch-clamp recording of Nav channel currents is as follows. First, the membrane potential of the cell was clamped to -130 mV, and then the voltage was stepped to -40 mV or -20 mV with a step interval of 10 mV for 8 s. The clamping voltage was maintained at −120 mV and data collection was repeated every 20 seconds. The peak amplitude of the inward current was measured and its half-inactivation voltage was determined.

Cell clamp potential was set at -120 mV. Pause and semi-inactivation inhibition of sodium current was measured by double pulse mode. Double-pulse mode was achieved with two 50 ms sustained 0 mV depolarizing test pulses (TP1 and TP2). The conditional voltage between the two depolarizing pulses was set around the half-inactivating voltage (duration 8 s). Before applying the second depolarizing pulse, the cell membrane potential was clamped to −120 mv and lasted 20 ms to allow unlabeled compound and channels in an inactive state to recover. Data collection was repeated at 20 s intervals and the current peak values at the two test pulses were measured.

Experimental data were collected with an EPC-10 amplifier (HEKA) and stored in PatchMaster (HEKA) software (software version: v2x73.2).

A capillary glass tube (BF150-86-10, Sutter Instruments) was stretched with a microelectrode making machine (P97, Sutter Instruments) to serve as a recording electrode. Using an inverted microscope (IX71), a microelectrode manipulator (MP285) was operated to bring the recording electrode into contact with the cells, and negative pressure suction was applied to form a GΩ seal. After forming a GΩ seal, rapid capacitance compensation was performed, and then negative pressure was continuously applied to disrupt the cell membrane by suction to form a whole-cell recording pattern. Compensation for slow capacitance was then performed, membrane capacitance and series resistance were recorded, and no leakage compensation was provided.

After the Nav channel current recorded in all cells stabilizes, drug administration begins, and each drug concentration is allowed to act for 5 min (or the current stabilizes), then the next concentration is detected, and multiple The concentration of was detected. The cover glass covered with cells was placed in a recording bath in an inverted microscope, and the test compound and an external solution containing no compound were sequentially flowed through the recording cell from low to high concentrations using gravity perfusion to act on the cells. During the recording process, liquid exchange was performed using a vacuum pump. The current detected by each cell in external solution without compound served as its own control group. Multiple cells were detected repeatedly and independently. All electrophysiological experiments were performed at room temperature.

4.3. Data Analysis The above equation was used for non-linear fitting for dose-dependent effects, where c represented the drug concentration, IC ₅₀ was the half-inhibitory concentration, and h represented the Hill coefficient. Curve fitting and IC ₅₀ calculations were completed using IGOR software (Software version: 6.0.1.0).

In this example, NaV 1 . Table 4 shows the results of measuring the half-half blocking activity (IC ₅₀ ) of some compounds of the present invention against NaV1.8, and Table 5 shows the blocking rates of some compounds at 100 nM against NaV1.8.

As can be seen from the measurement results, the compounds of the present disclosure have a significant blocking effect on NaV1.8 channel activity.

2. Pharmacokinetic experimental results of the compound of the present invention In this experimental example, in vivo pharmacokinetic evaluation was conducted in rats by single intravenous injection or forced oral administration.

Experimental methods and conditions: Male Sprague Dawley rats, all animals fasted overnight, were injected with the test compound at 1 mg/Kg (intravenous injection, vehicle 5% DMSO/10% Solutol/85% Saline) and 10 mg/Kg (forced), respectively. Oral administration) was administered once, and submandibular vein blood was collected at 5, 15, 30 min, 1, 2, 4, 6, 8, and 24 hours after drug administration. Approximately 0.20 mL of each sample was collected, and the blood was collected with heparin sodium. After anticoagulation and collection, place on ice and centrifuge the plasma within 1 hour for measurement. The drug concentration in plasma is measured using liquid chromatography/tandem mass spectrometry (LC/MS/MS), and the measured concentration is used to calculate pharmacokinetic parameters. The results are shown in Tables 6 and 7.

As can be seen from the measurement results, the compounds of the present disclosure have good pharmacokinetic absorption in rats and have pharmacokinetic advantages.

All documents mentioned in the present invention are herein incorporated by reference as if each document were individually incorporated by reference. Furthermore, those skilled in the art will be able to make various changes and modifications to the present invention after reading the above teachings of the present invention, and all of these equivalent forms will be described in the accompanying text. It should be fully understood that the invention falls within the scope of protection determined by the claims.

Claims (20)

A compound represented by formula (I), an optical isomer thereof , or a pharmaceutically acceptable salt thereof.
(In the formula,
T ₁ is selected from N or C (R ₇ ),
T ₂ is selected from N or C (R ₈ ),
T ₃ is selected from N or C (R ₉ ),
T ₄ is selected from N or C (R ₁₀ ),
R ₁ , R ₂ , R ₈ , and R ₉ each independently represent H, halogen, OH, NH ₂ , CN, SF ₅ , C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 alkylamino group, vinyl- C _1-6 alkyl-, C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C _3-6 cycloalkyl-C _1-6 alkyl-, 3-6 membered heterocycloalkyl -C _1-6 alkyl-, 3- to 6-membered heterocycloalkyl-C _1-6 alkyl-O-, phenyl-C _1-3 alkyl-, C _3-6 cycloalkyl-C _1-3 alkyl-O-, 3- to 6-membered heterocycloalkyl-C _1-3 alkyl-O-, phenyl-C _1-3 alkyl-O-, phenyl-C _1-3 alkyl-NH-, 5- to 6-membered heteroaryl-C _1-3 alkyl-, 5- to 6-membered heteroaryl-C _1-3 alkyl-O-, and 5- to 6-membered heteroaryl-C _1-3 alkyl-NH-, and the C _1-6 alkyl group, C _1-6 Alkoxy group, C _1-6 alkylamino group, vinyl-C _1-6 alkyl-, C _3-6 cycloalkyl group, 3- to 6-membered heterocycloalkyl group, C _3-6 cycloalkyl-C _1-6 alkyl- , 3-6 membered heterocycloalkyl-C _1-6 alkyl-, 3-6 membered heterocycloalkyl-C _1-6 alkyl-O-, phenyl-C _1-3 alkyl-, C _3-6 cycloalkyl-C _1-3 alkyl-O-, 3-6 membered heterocycloalkyl-C _1-3 alkyl-O-, phenyl-C _1-3 alkyl-O-, phenyl-C _1-3 alkyl-NH-, 5-6 Member heteroaryl-C _1-3 alkyl-, 5- to 6-membered heteroaryl-C _1-3 alkyl-O-, or 5- to 6-membered heteroaryl-C _1-3 alkyl-NH- is optionally 1, 2 or substituted by 3 R,
And if T ₃ is selected from N, R ₁ is not selected from H,
R ₃ , R ₄ , R ₅ , R ₆ and R ₁₀ each independently represent H, halogen, OH, NH ₂ , SF ₅ , CN, C _1-6 alkyl group, C _1-6 alkylamino group, C _{1 -6} alkoxy group, C _3-6 cycloalkyl group, -O-C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C _3-6 cycloalkyl-C _1-6 alkyl-, and 3-6 member heterocycloalkyl -C _1-6 alkyl-, the above-mentioned C _1-6 alkyl group, C _1-6 alkylamino group, C _1-6 alkoxy group, C _3-6 cycloalkyl group, -O-C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C _3-6 cycloalkyl-C _1-6 alkyl- or 3-6 membered heterocycloalkyl-C _1-6 alkyl- is optionally 1, 2 or substituted by 3 R,
R ₇ is selected from H, F, Cl, Br, I, a C _1-6 alkyl group, a C _1-6 alkoxy group, and a C _1-6 alkylamino group, and the above C _1-6 alkyl group, C _1-6 an alkoxy group or a C _1-6 alkylamino group optionally substituted with 1, 2 or 3 R;
L ₁ is C (=O), NH and
selected from
L ₂ is selected from O, S, NH and CH ₂ , said CH ₂ is optionally substituted with 1 or 2 R, NH is optionally substituted with R,
R ₁₁ and R ₁₂ are each independently selected from H, halogen, OH, NH ₂ and a C _1-6 alkyl group, and the C _1-6 alkyl group is optionally substituted with 1, 2 or 3 R. , or R ₁₁ and R ₁₂ are joined together to form a 3- to 6-membered ring,
each R ₁₃ is independently selected from H, halogen and a C _1-6 alkyl group, said C _1-6 alkyl group being optionally substituted with 1, 2 or 3 R;
n is selected from 1, 2 or 3,
R each independently represents H, D, halogen, OH, NH ₂ , CN,
selected _from a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkylthio group, and _a C _1-6 alkylamino group _{; 6} alkylthio group or C _1-6 alkylamino group optionally substituted with 1, 2 or 3 R',
R' is selected from F, Cl, Br, I, OH, _NH2 and _CH3 ,
The above 3- to 6-membered heterocycloalkyl group or 5- to 6-membered heteroaryl group is -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S( 1, 2 or 3 heteroatoms or heteroatoms independently selected from =O)-, -S(=O) ₂ - and N. ) R is H, D, F, Cl, Br, I, OH, _NH2 ,
Me, CF ₃ , CHF ₂ , CH ₂ F,
The compound according to claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from: R ₁ , R ₂ , R ₈ , and R ₉ each independently represent H, halogen, OH, NH ₂ , CN, SF ₅ , C _1-3 alkyl group, C _1-3 alkoxy group, C _1-3 alkylamino group, vinyl-C _1-3 alkyl-, C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C _3-6 cycloalkyl-C _1-3 alkyl-, 3-6 membered heterocycloalkyl- C _1-3 alkyl-, 3- to 6-membered heterocycloalkyl-C _1-3 alkyl-O-, phenyl-C _1-3 alkyl-, phenyl-C _1-3 alkyl-O-, phenyl-C _1-3 Alkyl-NH-, pyridyl-C _1-3 alkyl-, pyrimidinyl-C _1-3 alkyl-, thienyl-C _1-3 alkyl-, thiazolyl -C _1-3 alkyl-, pyrazolyl -C _{1- 3} alkyl-, imidazolyl -C _1-3 alkyl-, pyridyl-C _1-3 alkyl-O-, pyrimidinyl-C _1-3 alkyl-O-, thienyl-C _1-3 alkyl-O-, thiazoli Ru-C _1-3 alkyl-O-, pyrazolyl -C _1-3 alkyl-O-, imidazolyl -C _1-3 alkyl-O-, pyridyl-C _1-3 alkyl-NH-, pyrimidinyl- C _1-3 alkyl-NH-, thienyl-C _1-3 alkyl-NH-, thiazolyl -C _1-3 alkyl-NH-, pyrazolyl -C _1-3 alkyl-NH- and imidazolyl- selected from C _1-3 alkyl-NH-, the above-mentioned C _1-3 alkyl group, C _1-3 alkoxy group, C _1-3 alkylamino group, vinyl-C _1-3 alkyl-, C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C _3-6 cycloalkyl-C _1-3 alkyl-, 3-6 membered heterocycloalkyl-C _1-3 alkyl-, 3-6 membered heterocycloalkyl-C _{1 -3alkyl} -O-, phenyl-C _1-3alkyl- , phenyl-C _1-3alkyl -O-, phenyl-C _1-3alkyl -NH-, pyridyl-C _1-3alkyl- , pyrimidinyl-C _1-3 alkyl-, thienyl-C _1-3 alkyl-, thiazolyl -C _1-3 alkyl-, pyrazolyl -C _1-3 alkyl-, imidazolyl -C _1-3 alkyl-, pyridyl- C _1-3 alkyl-O-, pyrimidinyl-C _1-3 alkyl-O-, thienyl-C _1-3 alkyl-O-, thiazolyl -C _1-3 alkyl-O-, pyrazolyl -C _{1 -3} alkyl-O-, imidazolyl -C _1-3 alkyl-O-, pyridyl-C _1-3 alkyl-NH-, pyrimidinyl-C _1-3 alkyl-NH-, thienyl-C _1-3 alkyl- NH-, thiazolyl -C _1-3 alkyl-NH-, pyrazolyl -C _1-3 alkyl-NH- or imidazolyl -C _1-3 alkyl-NH- is optionally 1, 2 or 3 3. The compound according to claim 1 or 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, which is substituted with R. R ₁ , R ₂ , R ₈ , and R ₉ each independently represent H, F, Cl, Br, I, OH, NH ₂ , CN, SF ₅ , Me, CF ₃ , CHF ₂ , CF ₃ CF ₂ , CH _{2F , OCF3 , HOCH2CH2O , CH3NHCH2CH2O ,} ( _CH3 ) _{2NCH2CH2O ,}
The compound according to claim 3, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from. structural unit
The compound according to claim 1 or 4, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from. R ₃ , R ₄ , R ₅ , R ₆ and R ₁₀ each independently represent H, halogen, OH, NH ₂ , SF ₅ , CN, C _1-3 alkyl group, C _1-3 alkylamino group, C _{1 -3} alkoxy group, C _3-6 cycloalkyl group, -O-C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C _3-6 cycloalkyl-C _1-3 alkyl-, and 3-6 member heterocycloalkyl -C _1-3 alkyl-, the above-mentioned C _1-3 alkyl group, C _1-3 alkylamino group, C _1-3 alkoxy group, C _3-6 cycloalkyl group, -O-C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C _3-6 cycloalkyl-C _1-3 alkyl- or 3-6 membered heterocycloalkyl-C _1-3 alkyl- is optionally 1 or 2 or the compound according to claim 1 or 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, which is substituted by three R's. R ₃ , R ₄ , R ₅ , R ₆ and R ₁₀ each independently represent H, F, Cl, Br, I, OH, NH ₂ , SF ₅ , Me, CF ₃ , CHF ₂ , CH ₂ F, CN , CH( _F2 ) _CH3 , _CD3 , _OCD3 ,
7. The compound according to claim 6, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. structural unit
The compound according to claim 1 or 7, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from. structural unit
The compound according to claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from: R ₁₁ and R ₁₂ each independently represent H, F, Cl, Br, I, OH, NH ₂ , Me, CHF ₂ , CF ₃ ,
The compound according to claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from: The compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₁₁ and R ₁₂ are bonded together to form a cyclopropyl group, an oxetanyl group, an azetidinyl group, and a cyclopentanonyl group. . _L1 is C(=O), _CH2 , NH, CH( _CH3 ), CHF, _CF2 , _CHCHF2 , _CHCF3 ,
The compound according to claim 10 or 11, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from. The compound according to any one of claims 1 to 12, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from.
(In the formula,
T ₁ is as defined in claim 1 or 9;
R ₁ , R ₂ , T ₂ , T ₃ are as defined in claim 1, 3, 4 or 5;
R ₃ , R ₄ , R ₅ , R ₆ , T ₄ are as defined in claim 1, 6, 7 or 8;
L ₁ is as defined in claim 1, 10, 11 or 12;
L ₂ is as defined in claim 1;
R _13a and R _13b are each independently selected from H, halogen and C _1-6 alkyl group, said C _1-6 alkyl group is optionally substituted with 1, 2 or 3 R,
R is as defined in claim 1 or 2. ) A compound selected from the following formula, an optical isomer thereof , or a pharmaceutically acceptable salt thereof.





A pharmaceutical composition comprising the compound according to any one of claims 1 to 14, an optical isomer thereof , or a pharmaceutically acceptable salt thereof. 16. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient. A compound according to any one of claims 1 to 14, an optical isomer thereof or a pharmaceutically acceptable salt thereof, or claim 15, in the manufacture of a medicament for inhibiting voltage-gated sodium channels in an individual. Use of the pharmaceutical composition according to item 16. The voltage-gated sodium channels are Nav 1 . 18. The use according to claim 17, wherein the method is 8. A compound according to any one of claims 1 to 14, an optical isomer thereof or its Use of a pharmaceutically acceptable salt or a pharmaceutical composition according to claim 15 or 16. The pain includes chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, post-operative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth pain. 20. The use according to claim 19, selected from disease, incontinence and arrhythmia.