TW202448433A - Heterocyclic compounds as α5-GABAA receptor modulators and use thereof - Google Patents

Abstract

The present disclosure provides heterocyclic compounds shown in formula I, and tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof; this compound has regulatory function on α 5-GABAA receptors.

Description

Heterocyclic compounds as α5-GABAA receptor modulators and their uses

The present invention claims: The priority of the prior application with patent application number 202310662536.9, filed with the National Intellectual Property Administration of China on June 5, 2023, entitled “Heterocyclic compounds as α5-GABAA receptor modulators and their uses”; The priority of the prior application with patent application number 202410658952.6, filed with the National Intellectual Property Administration of China on May 24, 2024, entitled “Heterocyclic compounds as α5-GABA _A receptor modulators and their uses”; The full text of the prior application is incorporated into the present invention by reference.

The present invention belongs to the field of medicine. Specifically, the present invention relates to heterocyclic compounds of α5-GABA _A receptor modulators and uses thereof.

GABA _A receptors are associated with a variety of diseases and are possible therapeutic targets, which has also promoted the study of the physiological and pharmacological effects of different subunits of GABA _A receptors. For example, studies using genetically modified mice have shown that the most widely distributed α5 subunit γ-aminobutyric acid A receptor (α5-GABA _A receptor) is the main target of benzodiazepines (BDZ) drugs to produce sedative and amnesic effects, while α2-GABA _A receptors and α3-GABA _A receptors are related to the anticonvulsant and anti-anxiety effects of drugs. α5-GABA _A receptor is an inhibitory receptor in the central nervous system of mammals. It is mainly distributed in the hippocampus of the brain. It produces an inhibitory effect on hippocampal neurons by regulating the outward current of chloride ions. Its expression level in the cerebral cortex is very low and almost not expressed in other brain regions. The hippocampus is the main site for cognitive functions such as learning and memory, indicating that α5-GABA _A receptor may be related to cognitive functions such as learning and memory. In addition to BDZ drugs, there are many other drugs such as propofol, etomidate, barbiturates and neurosteroids that can enhance the neural function of GABA by stimulating the allosteric regulatory sites of GABA _A receptors, thereby producing corresponding pharmacological effects, and clinically play an anesthetic, anti-anxiety, sedative or anti-epileptic role. However, they often bind non-specifically to various subunits of GABA _A receptors, leading to many adverse reactions such as drug tolerance, sedation, anxiety or convulsions. Therefore, researchers have always been committed to studying and discovering drugs that have selective and specific effects on a certain GABA _A receptor subunit.

Numerous studies have shown that changes in the excitability of α5-GABA _A receptors can affect cognitive functions such as learning and memory, leading to the occurrence of some diseases such as postoperative cognitive dysfunction, pain, depression, schizophrenia and Down syndrome. Its allosteric modulators can treat or improve these diseases.

Considering the specific distribution and functional research of α5-GABA _A receptors in the brain hippocampus, many pharmaceutical companies including Roche are engaged in the research of α5-GABA _A receptor ligands. A large number of compounds have been synthesized, especially the inverse agonists containing α5-GABA _A receptors in the brain hippocampus. Among them, α5IA and MRK-016 have shown good effects in treating cognitive diseases in animal disease models and human trials, especially Alzheimer's disease. It is generally believed that the inverse agonists of α5-GABA _A receptors can be used to treat cognitive diseases, especially Alzheimer's disease. US Patent Publication No. US20110224278A1 discloses that an inverse agonist containing α5-GABA _A receptor can be used to treat multi-infarct dementia and stroke-related diseases.

The object of the present invention is to provide a new class of compounds having α5-GABA _A receptor modulatory activity, in particular, having α5-GABA _A receptor inhibitory activity. To this end, the present invention also provides the use of these compounds and their pharmaceutically acceptable salts in the preparation and manufacture of pharmaceutical compositions or drugs for treating, preventing, or improving diseases associated with α5-GABA _A receptors, such as Alzheimer's disease, multi-infarct dementia, pain and stroke, or in the preparation of pain relief drugs. The present invention also provides methods for preparing compounds of formula I, as well as intermediates that can be used in such methods.

In the first aspect of the present invention, there is provided a compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug: ; wherein, X ₁ is N or C; X ₂ is N, O, S or CR ₅ ; the dashed line represents a single bond or a double bond; m is selected from 0, 1, 2, 3, 4 or 5; Ring A does not exist or is selected from a benzene ring, a 5-6 membered heteroaryl ring; wherein, when Ring A does not exist, m is 1, and R ₁ is connected to X ₁ ; R ₁ is selected from hydrogen, a halogen, a hydroxyl, an amine, a nitrile, a C _1-6 alkyl, a C _{1-6 alkoxy, a C 1-6 alkylamino} , a C _3-7 cycloalkyl or a 3-6 membered heterocycloalkyl; the C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C wherein the _{C 1-6} alkyl, C _{1-6 alkoxy, C 3-7} cycloalkyl, 3-7 membered heterocycloalkyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents selected from the following groups: deuterium, halogen, hydroxyl, amine, nitrile, C _1-6 alkyl, C 1-6 alkoxy, C _3-7 cycloalkyl; R ₂ is selected from hydrogen, halogen, hydroxyl, amine, nitrile, C _{1-6 alkyl, C 1-6 alkoxy} , C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl or 5-6 membered heteroaryl; the C 1-6 alkyl, C _1-6 alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents selected from the following groups: deuterium, halogen, hydroxyl, amine, nitrile, C _1-6 alkyl, C _1-6 alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl or 5-6 membered heteroaryl R3 and _R4 are each _{independently} selected from _hydrogen , _halogen , hydroxyl, amine, nitrile, pendoxy _{, -C0-6alkyl} -C(=O _{) Ra - C0-6alkyl} , -C0-6alkyl-C(= _{O)ORa-C0-6alkyl, -C0-6alkyl - C ( =} O) _NRa R _b -C _0-6 alkyl, -C _0-6 alkyl-NR _a R _b -C _0-6 alkyl, -C _0-6 alkyl-NR _a C(═O)R _b -C _0-6 alkyl, -C _0-6 alkyl-NR _a SO ₂ R _b -C _0-6 alkyl, -C _0-6 alkyl-SO ₂ R _a -C _0-6 alkyl, -C _0-6 alkyl-SO ₂ NR _a R _b -C _0-6 alkyl, C 1-6 alkyl, C _3-7 cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered heteroaryl; the C _1-6 alkyl, C _3-7 cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered heteroaryl _3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered heteroaryl are optionally substituted by 1-4 substituents selected from the following groups: deuterium, halogen, pendoxy, hydroxyl, amine, nitrile, C _1-6 alkyl, C _3-7 cycloalkyl; M is absent or selected from O; R ₅ is selected from hydrogen, deuterium, halogen, hydroxyl, nitrile, C _1-6 alkyl, C _1-6 alkoxy or C _3-7 cycloalkyl; the C _1-6 alkyl, C _1-6 alkoxy or C _3-7 cycloalkyl are optionally substituted by 1-4 substituents selected from the following groups: halogen, hydroxyl, amine, nitrile, C _1-6 alkyl, C _3-7 cycloalkyl; R ₆ is selected from deuterium, halogen, C wherein the C _1-6 alkyl, C _1-6 alkoxy or C _3-7 cycloalkyl is optionally substituted by 1-4 substituents selected from the following groups: halogen, hydroxyl, amine, nitrile, C _1-6 alkyl, C _3-7 cycloalkyl; R _a and R _b are _each independently selected from hydrogen, deuterium, halogen, hydroxyl, amine, -C _0-6 alkyl-S(=O) ₂ -C _0-6 alkyl, _{-C 0-6} alkyl-P(=O) ₂ -C _0-6 alkyl, C _1-6 alkyl or 3-6 membered heterocycloalkyl, wherein the C _1-6 alkyl is optionally substituted by 1-3 substituents selected from the following groups: halogen, _hydroxyl , -OC _1-6 alkyl, -NH ₂ , -NHC _1-6 alkyl, -OC(＝O)C _1-6 alkyl or -N(C _1-6 alkyl)C _1-6 alkyl; and the 3-6 membered heterocycloalkyl is a monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S atoms.

In a preferred embodiment of the present invention, _R3 and _R4 are each independently selected from hydrogen, halogen, hydroxyl, amine, nitrile, pendoxy, _-C0-6 alkyl-C(=O) _Ra , _-C0-6 alkyl-C(=O) _ORa , _{-C0-6 alkyl} -C(=O) _NRaRb , -C0-6 _alkyl - _NRaRb , _-C0-6 alkyl-NRaC( ₌ O) _Rb , -C0-6 alkyl _{- NRaSO2Rb} , -C0-6 alkyl- _{SO2Ra , -C0-6} alkyl _{- SO2NRaRb} , _{C1-6 alkyl ,} C3-7 cycloalkyl, _3-6 membered heterocycloalkyl, _6-10 membered heteroaryl; the _{C1-6 alkyl} , _C3-7 cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered heteroaryl The _3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, and 6-10 membered heteroaryl are optionally substituted with 1-4 substituents selected from the following groups: deuterium, halogen, pendoxy, hydroxyl, amine, nitrile, C _1-6 alkyl, and C _3-7 cycloalkyl.

In a preferred embodiment of the present invention, the Selected from , , , ; Preferably, the Selected from , , .

In a preferred embodiment of the present invention, the compound is selected from the following structures: , , wherein ring A, ring B, ring D, R ₁ , R ₂ , R ₃ , R ₄ , L, M, p, m and n are as defined in the first aspect of the present invention.

In a preferred embodiment of the present invention, the ring A does not exist or is selected from a benzene ring or a 6-membered heteroaromatic ring; the 6-membered heteroaromatic ring contains 1, 2, or 3 heteroatoms; m is 0, 1, 2, 3, 4, or 5; _R1 is selected from hydrogen, halogen, hydroxyl, amino, nitrile, _C1-6 alkyl, _C1-6 halogenated alkyl, _C3-7 cycloalkyl, _C3-7 halogenated cycloalkyl, _C1-6 alkoxy, and _C1-6 halogenated alkoxy; the heteroatoms are selected from N, O, and S; when there are multiple heteroatoms, the heteroatoms are the same or different.

In a preferred embodiment of the present invention, the ring A is absent or selected from benzene ring, pyridine, pyrimidine, oxazine, pyrazine or triazine.

In a preferred embodiment of the present invention, the ring A is absent or selected from a benzene ring or pyridine.

In a preferred embodiment of the present invention, the ring A is selected from , ; * terminal is connected to X ₁ .

In a preferred embodiment of the present invention, Selected from , ,For example , .

In a preferred embodiment of the present invention, when ring A does not exist, m is 1, and R ₁ is connected to X ₁ .

In a preferred embodiment of the present invention, the compound is selected from the following structures: , , , , , wherein ring B, ring D, R ₁ , R ₂ , R ₃ , R ₄ , L, M, m, n and p are as defined in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , , wherein ring B, ring D, R ₁ , R ₂ , R ₃ , R ₄ , L, M, n and p are as defined in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: , , , , , , , , ; wherein ring A, ring B, ring D, R ₁ , R ₂ , R ₃ , R ₄ , M, m, n and p are defined as described in the first aspect of the present invention.

In a preferred embodiment of the present invention, the compound is selected from the following structures: ; wherein, ring B, R ₁ , R ₂ , R ₃ , m and n are defined as described in the first aspect of the present invention; when M is absent, ring D, R ₄ and p are absent at the same time; when M is selected from O, ring D, R ₄ and p are defined as described in the first aspect of the present invention. In a preferred embodiment of the present invention, the ring B is selected from a 5-14 membered heteroaromatic ring containing 1, 2, 3, 4 or 5 heteroatoms; preferably, the heteroatoms are selected from N, O, S; when there are multiple heteroatoms, the heteroatoms are the same or different; Preferably, Ring B is selected from acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, quinazolinyl, pyrazolyl, indolyl, isoindolyl, benzotriazolyl, furanyl, thienyl, pyridoquinolinyl, pyridopiperidinyl, pyridopyrrolidyl, benzothienyl, benzofuranyl, benzodioxane, benzodioxane, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, benzoxazolyl, tetrahydronaphthyridine, imidazolyl, pyrazinyl , oxazine, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinolinyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, triazinyl, tetrazinyl, tetrazolyl, xanthanol, phenazinyl, phenothiazinyl, phenoxazinyl, azobenzoic acid, oxazinyl, thiobenzoic acid, hexahydropyrazinopyridinooxazine, 6,7,8,9-tetrahydropyridino[2',3':4,5]imidazo[1,2-a]pyrazine, etc.; More preferably, ring B is selected from pyridine, pyrimidine, oxazine, tetrahydronaphthyridine, pyridopiperidine, or .

In a preferred embodiment of the present invention, the ring B is selected from pyridine, pyrimidine, oxazine, tetrahydronaphthyridine, pyridopiperidine, or .

In a preferred embodiment of the present invention, the ring B is selected from , , ; * end is connected to L.

In a preferred embodiment of the present invention, Selected from , , , , , ; * end is connected to L.

In a preferred embodiment of the present invention, L is selected from _-CH2- O-, -CH( _R6 )-O- or -C(=O) _-NRaRb- ; _R6 is selected from _C1-3 alkyl or _{C3-5 cycloalkyl} ; the _C1-3 alkyl or _C3-5 cycloalkyl is optionally substituted with 1-4 substituents selected from the following groups: halogen, hydroxyl, amine, nitrile, _C1-6 alkyl, _C3-7 cycloalkyl; preferably, L is selected from -CH2 _- O-, -CH( _CH3 )-O- or -C(=O) _-NH2- .

In a preferred embodiment of the present invention, L is selected from -CH ₂ -O-, -CH(CH ₃ )-O- or -C(=O)-NH ₂ -.

In a preferred embodiment of the present invention, L is selected from _-CH2- O-, -CH( _R6 )-O- or -C(=O) _-NRa- ; _R6 is selected from _C1-3 alkyl or _C3-5 cycloalkyl; the _C1-3 alkyl or _C3-5 cycloalkyl is optionally substituted with 1-4 substituents selected from the following groups: halogen, hydroxyl, amino, nitrile, _C1-6 alkyl, _C3-7 cycloalkyl.

In a preferred embodiment of the present invention, L is selected from -CH ₂ -O-, -CH(CH ₃ )-O- or -C(=O)-NH-.

In a preferred embodiment of the present invention, L is selected from (like , ）、 ; *End and connection.

In a preferred embodiment of the present invention, the ring D does not exist or is selected from 4-6 membered heterocycloalkyl and 3-6 membered cycloalkyl containing 1-3 heteroatoms; Preferably, the heteroatoms are selected from N, O, and S; when there are multiple heteroatoms, the heteroatoms are the same or different.

In a preferred embodiment of the present invention, the ring D is absent or is selected from cyclopropyl, cyclobutyl, cyclopentyl, azetidine, pyrrolidine, piperidine, and piperazine.

In a preferred embodiment of the present invention, the ring D is selected from , , , , .

In a preferred embodiment of the present invention, Selected from , , , , , .

In a preferred embodiment of the present invention, R ₁ is selected from hydrogen, halogen, hydroxyl, amine, nitrile, C _1-6 alkyl, C _3-7 cycloalkyl, C _1-6 alkoxy; the C _1-6 alkyl, C _3-7 cycloalkyl, C _1-6 alkoxy is optionally substituted with 1-4 substituents selected from the following groups: deuterium, halogen, hydroxyl, amine, nitrile, C _1-6 alkyl, C _3-7 cycloalkyl; m is selected from 0, 1, 2, 3, 4 or 5; preferably, R ₁ is selected from F, methyl, cyclopropyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl.

In a preferred embodiment of the present invention, R ₁ is selected from halogen, C _1-6 alkyl, C _3-7 cycloalkyl, C _1-6 alkoxy, and halogenated alkyl.

In a preferred embodiment of the present invention, R ₁ is selected from F, methyl, cyclopropyl, methoxy, trifluoromethyl, difluoromethyl, and monofluoromethyl.

In a preferred embodiment of the present invention, _R2 is selected from halogen, _C1-6 alkyl, _C3-7 cycloalkyl, _C1-6 alkoxy; the _C1-6 alkyl, _C3-7 cycloalkyl, _C1-6 alkoxy is optionally substituted with 1-4 substituents selected from the following groups: deuterium, halogen, hydroxyl, amino, nitrile, _C1-6 alkyl, _C3-7 cycloalkyl; preferably, _R2 is selected from methyl.

In a preferred embodiment of the present invention, the _R3 is selected from hydrogen, halogen, hydroxyl, amine, nitrile, pendoxy, _-C0-6 alkyl-C(=O) _Ra - _C0-6 alkyl, _-C0-6 alkyl- _C (=O) _ORa - _C0-6 alkyl, _-C0-6 alkyl-C(=O) _NRaRb - _C0-6 alkyl, _C1-6 alkyl, _{C3-7 cycloalkyl, 3-6 membered heterocycloalkyl; the C1-6 alkyl} , _C3-7 cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with 1-4 substituents selected from the following groups: deuterium, halogen, pendoxy, hydroxyl, amine, nitrile, _C1-6 alkyl, _C3-7 cycloalkyl; n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; preferably, R ₃ is selected from hydrogen, halogen, oxo, -C(=O)R _a , -C(=O)NR _a R _b , -C _0-3 alkyl, C _1-3 alkyl, cyclopropyl, cyclobutyl, azocyclobutyl, oxocyclobutyl, pyrrolidine, piperidine, piperazine, piperidone, piperazinone.

In a preferred embodiment of the present invention, _R3 is selected from hydrogen, halogen, hydroxyl, amino, nitrile, pendooxy, _-C0-6 alkyl-C(=O) _Ra , -C0-6 alkyl-C(=O) _ORa , _-C0-6 alkyl- _C (=O) _NRaRb , _C1-6 alkyl, _C3-7 cycloalkyl, 3-6 membered heterocycloalkyl; the _C1-6 alkyl, _C3-7 cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with 1-4 substituents selected from the following groups: _deuterium , halogen, pendooxy, hydroxyl, amino, nitrile, _C1-6 alkyl, _C3-7 cycloalkyl.

In a preferred embodiment of the present invention, R ₃ is selected from hydrogen, halogen, oxo, -C(=O)R _a , -C(=O)NR _a R _b , C _1-3 alkyl, cyclopropyl, cyclobutyl, azocyclobutyl, oxocyclobutyl, pyrrolidine, piperidine, piperazine, piperidone, piperazinone.

In a preferred embodiment of the present invention, R ₃ is selected from hydrogen, oxo, -C(=O)-CH ₃ , -C(=O)NH ₂ -C _0-3 alkyl, methyl, piperazinone; and n is selected from 0 or 1.

In a preferred embodiment of the present invention, R ₃ is selected from hydrogen, oxo, -C(=O)-CH ₃ , -C(=O)NH ₂ , -C(=O)NH-C _1-3 alkyl, methyl, piperazinone; and n is selected from 0 or 1.

In a preferred embodiment of the present invention, R ₃ is selected from hydrogen, oxo, -C(=O)-CH ₃ , -C(=O)NH ₂ , -C(=O)NH-C _1-3 alkyl, methyl, piperazinone, and methyl-substituted piperazinone.

In a preferred embodiment of the present invention, R ₃ is selected from hydrogen, pendoxy, -C(=O)-CH ₃ , -C(=O)NH ₂ , ,methyl, , .

In a preferred embodiment of the present invention, n is selected from 0 or 1.

In a preferred embodiment of the present invention, _R4 is selected from hydrogen, halogen, hydroxyl, amine, nitrile, pendoxy, _-C0-6 alkyl-C(=O) _Ra - _C0-6 alkyl _{, -C0-6} alkyl-C(=O) _ORa - _C0-6 alkyl, -C0-6 alkyl-C(=O) _NRaRb - _C0-6 alkyl, _{C1-6 alkyl, C3-7 cycloalkyl, 3-6 membered heterocycloalkyl; the C1-6 alkyl , C3-7} cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with 1-4 substituents selected _from the following groups: deuterium, halogen, hydroxyl, amine, nitrile, _C1-6 alkyl, _C3-7 cycloalkyl; p is 0, 1, 2, 3, 4, 5, 6 or 7; preferably, R ₄ is selected from hydrogen, oxo, -C(=O)-CH ₃ , -C(=O)NH ₂ -C _0-3 alkyl, methyl; p is selected from 0, 1 or 2.

In a preferred embodiment of the present invention, the _R4 is selected from hydrogen, halogen, hydroxyl, amine, nitrile, pendoxy, _-C0-6 alkyl-C(=O) _Ra , -C0-6 alkyl-C(=O) _ORa , _-C0-6 alkyl- _C (=O) _NRaRb , _C1-6 alkyl, _C3-7 cycloalkyl, 3-6 membered heterocycloalkyl; the _{C1-6 alkyl} , _C3-7 cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with 1-4 substituents selected from the following groups: deuterium, halogen, hydroxyl, amine, nitrile, _C1-6 alkyl, _C3-7 cycloalkyl;

In a preferred embodiment of the present invention, R ₄ is selected from hydrogen, oxo, -C(=O)-CH ₃ , -C(=O)NH ₂ , -C(=O)NH-C _1-3 alkyl, methyl; p is selected from 0, 1 or 2.

In a preferred embodiment of the present invention, R ₄ is selected from hydrogen, oxo, -C(=O)-CH ₃ , -C(=O)NH ₂ , and methyl.

In a preferred embodiment of the present invention, p is selected from 0, 1 or 2.

In a preferred embodiment of the present invention, the compound comprises: I-1 I-2 I-3 I-4 I-5 I-6 I-7 I-8 I-9 I-10 I-11 I-12 I-13 I-14 .

The second aspect of the present invention is a pharmaceutical composition comprising the compound of formula I as described in the first aspect, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug; and a pharmaceutically acceptable carrier.

The third aspect of the present invention is the use of the compound of formula I as described in the first aspect, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the use of the pharmaceutical composition as described in the second aspect, the uses comprising: regulating α5-GABA _A receptor; and/or, preventing and/or treating diseases related to α5-GABA _A receptor; and/or, preparing drugs, pharmaceutical compositions or preparations for regulating α5-GABA _A receptor, and/or preventing and/or treating diseases related to α5-GABA _A receptor.

Provided is a compound of formula I as described in the first aspect, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the drug composition as described in the second aspect, which is expected to be used for pain, Alzheimer's disease, multi-infarct dementia or stroke.

Pain that should be mentioned is neuropathic pain, inflammatory pain or cancer pain.

The pain that should be mentioned is selected from the group consisting of headache, facial pain, neck pain, shoulder pain, back pain, chest pain, abdominal pain, low back pain, leg pain, musculoskeletal pain, vascular pain, gout, arthritis pain, visceral pain, pain caused by infectious diseases, polyostotic pain, sickle cell anemia, autoimmune diseases, pain associated with multiple sclerosis or inflammation, chronic pain caused by injury or surgery, nociceptive pain, painful diabetes, trigeminal neuralgia, lumbar or cervical radiculopathy, glossopharyngeal neuralgia, autonomic reflex pain, reflex sympathetic malnutrition, nerve root avulsion, cancer, chemical damage, toxins, nutritional deficiencies, viral or bacterial infections, and pain associated with degenerative osteoarthritis.

Infectious diseases that should be mentioned are selected from AIDS or post-herpetic neuralgia.

Additional aspects and advantages of the present invention will be given in part in the following description, and in part will be obvious from the following description, or will be understood by practice of the present invention.

Beneficial Effects

After extensive and intensive research, the inventors unexpectedly developed a compound or a pharmaceutically acceptable salt thereof, as well as a preparation method and use thereof.

The present invention provides a compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug. The compound of formula I has a significant regulatory effect on α5-GABA _A receptor, can treat diseases or conditions mediated by α5-GABA _A receptor, exhibits excellent pharmacokinetic properties, and has high safety and drugability.

The present invention provides a method and intermediate for preparing the compound shown in I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug. The method is simple to operate, has high yield and high purity, and can be used for industrial production of medicines.

Definitions and Explanations

Unless otherwise stated, the definitions of groups and terms described in the specification and patent application, including their definitions as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, etc., can be arbitrarily combined and coupled with each other. The group definitions and compound structures after such combination and coupling should fall within the scope described in the specification.

Unless otherwise defined, all technical terms used herein have the same meaning as those commonly understood by persons of ordinary skill in the art to which the subject matter of the present invention belongs. Unless otherwise stated, all patents, patent applications, and publications cited throughout this article are incorporated herein by reference. If there are multiple definitions of a term in this article, the definition in this chapter shall prevail.

It should be understood that the above brief description and the detailed description below are exemplary and are only used for explanation, and do not limit the subject matter of the present invention. In the present invention, unless otherwise specifically stated, the use of the singular also includes the plural. It must be noted that unless otherwise clearly stated in the text, the singular form used in this specification and the scope of the patent application includes the plural form of the referenced thing. It should also be noted that unless otherwise stated, the use of "or" and "or" means "and/or". In addition, the use of the term "including" and other forms, such as "including", "containing" and "containing" are not restrictive.

Definitions of standard chemical terms can be found in the reference literature, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4THED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods within the skill of the art to which the present invention belongs, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy and pharmacological methods, are employed. Unless specific definitions are provided, the terms employed herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and drugs and medicinal chemistry are known in the art to which the present invention belongs. Standard techniques may be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and treatment of patients. For example, the manufacturer's instructions for use of the kit can be used, or the reaction and purification can be carried out in a manner known in the art or as described herein. The above techniques and methods can generally be carried out according to conventional methods known in the art, based on the descriptions in the various general and more specific literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one of ordinary skill in the art to which the present invention belongs to provide stable structural parts and compounds.

When substituents are described by a conventional chemical formula written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, CH ₂ O is equivalent to OCH ₂ . As used herein, or Indicates the attachment site of the group. As used herein, "R ₁ ", "R1" and "R ¹ " have the same meaning and can be interchanged with each other. For other symbols such as R ₂ , similar definitions have the same meaning.

The section headings used herein are for the purpose of organizing the article only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this invention, including but not limited to patents, patent applications, articles, books, manuals and theses, are incorporated herein by reference in their entirety.

In addition to the foregoing, when used in the specification and patent application of the present invention, unless otherwise specifically indicated, the following terms have the following meanings.

When the numerical range described in the specification and patent application is understood as an "integer", it should be understood as recording the two end points of the range and every integer within the range. For example, "integers from 0 to 14" should be understood as recording every integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14.

In the present invention, when specifying the number of substituents, the term "one or more" refers to one substitution to the maximum possible number of substitutions, i.e., replacing one hydrogen to all hydrogens being replaced by substituents. When specifying the number of substituents, the term "1-4" refers to 1, 2, 3 or 4 substitutions, i.e., 1, 2, 3 or 4 hydrogens being replaced by substituents.

In the present invention, "saturated, partially saturated or unsaturated" includes a substituent saturated with hydrogen, a substituent completely unsaturated with hydrogen and a substituent partially saturated with hydrogen.

In the present invention, the term "halogen" refers to fluorine, chlorine, bromine, or iodine, either alone or as part of another substituent.

As used herein, the term "hydroxyl" when used alone or as part of another substituent refers to -OH.

In the present invention, the term "nitrile" when used alone or as part of other substituents refers to -CN.

In the present invention, the term "amino" when used alone or as part of other substituents refers to -NH ₂ .

In the present invention, the term "alkyl" when used alone or as part of other substituents means a straight or branched alkyl group consisting only of carbon atoms and hydrogen atoms, having, for example, 1 to 6 carbon atoms and connected to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl and hexyl. Alkyl groups may be unsubstituted or substituted with one or more suitable substituents. Alkyl groups may also be isotopomeric isomers of natural abundance alkyl groups enriched in isotopes of carbon and/or hydrogen (i.e., deuterium or tritium).

In the present invention, the term "C _α-β alkyl" when used alone or as part of other substituents refers to an alkyl group containing a minimum of α and a maximum of β carbon atoms in a branched or linear relationship or any combination of the three, where α and β represent integers, and can also be represented in the form of "C _α- C _β alkyl". The alkyl groups described in this section may also contain one or two double or triple bonds. The designation of C ₀ alkyl represents a direct bond. Examples of _{C 1-6} alkyl groups include, but are not limited to, the following: , , , .

In the present invention, "benzo group" alone or in combination refers to a divalent group C ₄ H ₄ =, one of which is -CH=CH-CH=CH-, which forms a benzene ring when attached to another ring at the adjacent position, such as tetrahydronaphthalene, indole, and the like.

In the present invention, the term "C _{α-β haloalkyl} " when alone or as part of another substituent refers to an alkyl group as described above, wherein any number (at least one) of the hydrogen atoms attached to the alkyl chain are replaced by fluorine, chlorine, bromine or iodine.

In the present invention, the term "alkoxy" when used alone or as part of another substituent refers to the group -OR ^Q , wherein R ^Q is an "alkyl" as defined above.

In the present invention, the term "oxo" when used alone or as part of other substituents refers to the replacement of two hydrogen atoms on a methylene group by oxygen atoms, that is, the methylene group is replaced by a carbonyl group, which represents =0.

In the present invention, the term "thio" when used alone or as part of other substituents refers to the replacement of two hydrogen atoms on a methylene group with sulfur, representing =S.

In the present invention, the term "cycloalkyl" or "carbocyclic group" refers to a cyclic alkyl group when it is used alone or as part of other substituents. The term "mn-membered cycloalkyl", "C _m -C _n cycloalkyl" or "C _{m n} cycloalkyl" should be understood to mean a saturated, unsaturated or partially saturated carbocyclic ring having m to n atoms. For example, "3-15 membered cycloalkyl" or "C ₃ -C ₁₅ cycloalkyl" refers to a cyclic alkyl group containing 3 to 15; 3 to 9; 3 to 7; 3 to 6 or 3 to 5 carbon atoms, which may contain 1 to 4 rings. "5-8 membered cycloalkyl" contains 5-8 carbon atoms. It includes monocyclic, bicyclic, tricyclic, spirocyclic or bridged rings. Examples of unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl, or bicyclic hydrocarbon groups such as decahydronaphthalene. Cycloalkyl groups may be substituted with one or more substituents. In some embodiments, the cycloalkyl group may be a cycloalkyl group fused with an aryl or heteroaryl group. The term "C ₃ -C ₆ cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic systems. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

In the present invention, the term "heterocycloalkyl" or "heterocyclic group" when used alone or as part of other substituents refers to a cycloalkyl group in which one or more (in some embodiments, 1 to 3) carbon atoms are replaced by heteroatoms, such as but not limited to N, O, S and P. "Heterocycloalkyl" or "heterocyclic group" can be saturated or unsaturated, but not aromatic. "Heterocycloalkyl" or "heterocyclic group" can also contain 1, 2 or 3 rings, including bridged rings and spirocyclic structures. The term "3-8 membered heterocyclic group" or "3-8 membered heterocyclic alkyl" should be understood to mean a monocyclic, bicyclic or tricyclic ring having 3 to 8 atoms, wherein the heteroatom is preferably selected from N, O and S. It should be understood that when the total number of S atoms and O atoms in the heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other, such as 3-6 membered heterocyclic alkyl or 3-7 membered heterocyclic alkyl. Examples of heterocyclic alkyl include, but are not limited to, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl.

In the present invention, the term "C _α-β cycloalkenyl" when used alone or as part of other substituents refers to a monocyclic group having α to β atoms, having a double bond, but not aromatic. Examples of cycloalkenyl groups are cyclopropene, cyclobutene, cyclohexene, cyclobutadiene, cyclopentadiene, cycloheptatriene, cyclooctatetraene, etc.

In the present invention, the term "heteroalkene ring" when used alone or as part of other substituents refers to a monocyclic group having a heteroatom (the monocyclic group has a double bond but is not aromatic), preferably a monocyclic ring containing 1, 2 or 3 ring heteroatoms independently selected from N, O and S. Examples of heterocycloalkenyl groups include dihydrofuranyl, dihydrothienyl, dihydropyrrolyl, dioxacyclopentenyl, dihydroimidazolyl, dihydropyrazolyl, dihydrothiazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrothiadiazolyl, dihydrotriazolyl, dihydrotetrazolyl, tetrahydropyridinyl, 3,4-dihydro-2H-pyran, pyranyl, thiopyranyl, dihydropyridinyl, dihydropyrazinyl, dihydropyrimidinyl, oxazinyl, dihydrotetrazolyl, etc. The term "heterocycloalkenyl" may be used interchangeably with the term "heterocycloalkenyl".

In the present invention, the term "aryl" or "aromatic ring" refers to a monovalent aromatic carbocyclic ring system containing 6-14, preferably 6-10 carbon atoms and having at least one aromatic ring or multiple condensed rings in which at least one ring is an aromatic ring when used alone or as part of other substituents. Examples of aryl include, but are not limited to, phenyl, naphthyl, biphenyl or indanyl.

In the present invention, the term "5-14 membered heteroaryl ring" or "5-14 membered heteroaryl" when alone or as part of other substituents means a stable monocyclic, bicyclic or tricyclic ring having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, wherein at least one ring is aromatic and at least one ring contains 1-5 heteroatoms independently selected from N, O and S. It should be understood that when the total number of S atoms and O atoms in the heteroaryl exceeds 1, these heteroatoms are not adjacent to each other. The 5-14 membered heteroaryl can be connected to the rest of the molecule via a heteroatom or a carbon atom. 5-14 membered heteroaryl groups within the scope of this definition include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, quinazolinyl, pyrazolyl, indolyl, isoindolyl, 1H,3H-1-oxoisoindolyl, benzotriazolyl, furanyl, thienyl, pyridoquinolinyl, pyridopiperidinyl, pyridopyrrolidyl, benzothienyl, benzofuranyl, benzodioxane, benzodioxane, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, benzotriazolyl, oxazolyl, imidazolyl, pyrazinyl, oxazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinolinyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,4,5-tetrazinyl, tetrazolyl, xanthyl, phenazinyl, phenothiazinyl, phenoxazinyl, azozelinyl, oxazinyl and thiozelinyl, etc. The term "5-10 membered heteroaromatic ring" or "5-10 membered heteroaryl group" should be understood as a monocyclic, bicyclic or tricyclic ring having 5 to 10 atoms, wherein at least one ring is aromatic and contains at least 1 to 5 heteroatoms independently selected from N, O and S. Examples of 5-10 membered heteroaromatic rings include, but are not limited to, furanyl, pyridyl, oxazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridoquinolinyl, pyridopiperidinyl, pyridopyrrolidinyl and the like.

In the present invention, the term "monocyclic" when used alone or as part of other substituents means a group having only one ring which may be saturated, unsaturated or partially saturated and may be a carbocyclic ring (all ring atoms are carbon atoms) or a heterocyclic ring (in addition to carbon atoms, the ring atoms include, for example, 1, 2 or 3 heteroatoms, such as N, O or S).

In the present invention, the term "bicyclic" when used alone or as part of other substituents means a group having two connected rings. The bicyclic ring can be a carbocyclic ring (all ring atoms are carbon atoms) or a heterocyclic ring (in addition to carbon atoms, the ring atoms include, for example, 1, 2 or 3 heteroatoms, such as N, O or S). Both rings can be aliphatic (such as decalin and norbornane), or can be aromatic (such as naphthalene), or a combination of aliphatic and aromatic (such as tetrahydronaphthalene). Bicyclic rings include (a) spirocyclic compounds, in which the two rings share only one single atom (the spiro atom, which is usually a quaternary carbon). Examples of spirocyclic compounds include, but are not limited to: , also includes spirocycloalkyl groups in which monospirocycloalkyl groups and heterocycloalkyl groups share a spiro atom, non-limiting examples include: (b) fused bicyclic compounds, in which two rings share two adjacent atoms. In other words, the rings share a covalent bond, i.e., the bridge atoms are directly connected (e.g., α-thujene and decalin). Examples of fused bicyclic compounds include, but are not limited to: ; and (c) bridged bicyclic compounds in which two rings share three or more atoms and the two bridgehead atoms are separated by a bridge comprising at least one atom. For example, norbornane, also known as bicyclo[2.2.1]heptane, can be considered a pair of cyclopentane rings, each ring sharing three of their five carbon atoms. Examples of bridged bicyclic rings include, but are not limited to: .

In the present invention, when alone or as part of other substituents, the NR ^a R ^a group can be In the form of, or may include two ^Ra groups together to form a ring, the ring optionally contains N, O or S atoms, and may also include the following groups, for example: , , .

In the present invention, the group N(C _α-β alkyl)C _α-β alkyl (wherein α and β are as defined above) when alone or as part of other substituents includes substituents in which two C _α-β alkyl groups are taken together to form a ring (optionally containing N, O or S atoms), and includes groups such as: , , , , .

In the present invention, the term "inert solvent" includes but is not limited to: toluene, benzene, water, methanol, ethanol, isopropyl alcohol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a combination thereof.

Compounds provided herein include intermediates that can be used to prepare compounds provided herein, which contain reactive functional groups (such as but not limited to carboxyl, hydroxyl and amine moieties), and protected derivatives thereof. "Protected derivatives" are those compounds in which one or more reactive sites are blocked by one or more protecting groups (also referred to as protecting groups). Suitable carboxyl moiety protecting groups include benzyl, tert-butyl, etc., as well as isotopes, etc. Suitable amine and amide protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable hydroxyl protecting groups include benzyl, etc. Other suitable protecting groups are well known to those with ordinary knowledge in the art to which the present invention belongs.

In the present invention, the phrase "optionally substituted by..." or "optionally substituted by..." means that the specified group is unsubstituted or substituted by one or more substituents independently selected from possible substituents. For example, "aryl is optionally substituted by 1-4 substituents independently selected from the following groups: halogen, nitrile, hydroxyl, C _1-6 alkyl" means that aryl is unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from the following groups: halogen, nitrile, hydroxyl, C _1-6 alkyl, and the description includes both substituted aryl and unsubstituted aryl.

In the present invention, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.

In the present invention, the term "pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic acid or an organic acid that can retain the biological effectiveness of the free base without other side effects. "Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects. In addition to pharmaceutically acceptable salts, other salts are also contemplated in the present invention. They can serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or can be used for the identification, characterization or purification of the compounds of the present invention.

In the present invention, the term "amine salt" refers to the product obtained by neutralizing an alkyl primary amine, secondary amine or tertiary amine with an acid. The acid includes the inorganic acid or organic acid described in the present invention.

In the present invention, the term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, mirror isomers, non-mirror isomers and conformational isomers.

Depending on the choice of starting materials and methods, the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, for example as pure optical isomers, or as a mixture of isomers, such as as a racemic and amorphous isomer mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the rotation of plane polarized light caused by the compound, where (–) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory.

When the bonds to the chiral carbon in the formula of the present invention are drawn as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the mirror-pure compounds and mixtures thereof produced therefrom are included within the scope of the general formula. The schematic representation of racemates or mirror-pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. The absolute configuration of a stereocenter is represented by a wedge-shaped bond and a dashed bond.

In the present invention, the term "tautomer" refers to functional group isomers produced by the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. There may be two or more interconvertible species of tautomeric compounds. Prototropic tautomers come from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form is dominant; while in phenols, the enol form is dominant. The present invention includes all tautomeric forms of the compounds.

In the present invention, "pharmaceutical composition" refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals (such as humans). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote drug administration in an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

In the present invention, "pharmaceutically acceptable carriers" 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 relevant government regulatory authorities as acceptable for human or livestock use.

In the present invention, the term "solvate" means that the compound of the present invention or its salt includes a stoichiometric or non-stoichiometric solvent bound by intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

In the present invention, the term "prodrug" refers to a compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvent decomposition. The prodrug of the present invention is prepared by modifying the functional group in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. Prodrugs include compounds formed by connecting a hydroxyl or amine group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group and a free amine group, respectively.

The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compound may be labeled with a radioactive isotope, such as deuterium ( ^2H ), tritium ( ^3H ), iodine-125 ( ^125I ) or C-14 ( ^14C ). All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.

In the present invention, the term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, but are not limited to, adhesives, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients can enhance the handling characteristics of drug formulations, i.e., make the formulation more suitable for direct compression by increasing fluidity and/or adhesion.

As used herein, the term "treat" and other similar synonyms include the following: (i) preventing a disease or condition from occurring in a mammal, particularly when such mammal is susceptible to the disease or condition but has not yet been diagnosed with the disease or condition; (ii) inhibiting the disease or condition, i.e., arresting its development; (iii) relieving the disease or condition, i.e., causing the disease or condition to regress; or (iv) alleviating the symptoms caused by the disease or condition.

The reaction temperature of each step can be appropriately selected according to the solvent, starting material, reagent, etc., and the reaction time can also be appropriately selected according to the reaction temperature, solvent, starting material, reagent, etc. After the reaction of each step is completed, the target compound can be separated and purified from the reaction system by common methods, such as filtration, extraction, recrystallization, washing, silica gel column chromatography, etc. Under the condition that it does not affect the next reaction, the target compound can also directly enter the next reaction without separation and purification.

The following will further explain the technical solution of the present invention in combination with specific embodiments. It should be understood that the following embodiments are only for illustrative purposes to illustrate and explain the present invention, and should not be interpreted as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope of protection intended by the present invention.

Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

The present invention has the following definitions:

Symbols or units: _IC50 : half-maximal inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved. M: mol/L, for example, n-butyl lithium (14.56 mL, 29.1 mmol, 2.5 M in n-hexane) means a n-butyl lithium solution with a molar concentration of 2.5 mol/L in n-hexane. N: equivalent concentration, for example, 2 N hydrochloric acid means a 2 mol/L hydrochloric acid solution. RT: retention time

Reagents: PE: Petroleum ether EA: Ethyl acetate, also called EtOAc DMF: N,N-dimethylformamide DIPEA: N,N-diisopropylethylamine RuPhos-Pd-G3: Palladium (II) methanesulfonate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) or (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium (II) methanesulfonate

Test method: LCMS: Liquid chromatography-mass spectrometry TLC: Thin layer chromatography

Example 1 : Preparation of target compound I-1

4-(6-(1-(1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)ethoxy)oxazin-3-yl)piperazin-2-one

The synthetic route of the target compound I-1 is as follows:

Step 1: Synthesis of 1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazole-5-carboxylic acid

Dissolve 1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazole-5-carboxylic acid ethyl ester (3.0 g, 10.67 mmol) in anhydrous tetrahydrofuran (20 mL) and methanol (5 mL), then weigh lithium hydroxide monohydrate (1.34 g, 32.0 mmol) and dissolve it in water (10 mL) and add it to the above solution. After the addition, the reaction solution was reacted at room temperature for 16 hours. TLC (PE:EA(V/V)=3:1) showed that the reaction was complete. The reaction solution was extracted with ethyl acetate (20 mL×3), the organic phases were combined and washed with water (15 mL×2), the aqueous phases were combined and the pH was adjusted to 3 with 2 N hydrochloric acid, then extracted with ethyl acetate (30 mL×3), the organic phases were combined and washed with saturated brine (20 mL), the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and vortexed to obtain 1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazole-5-carboxylic acid (2.80 g, crude product), which was directly used in the next step.

Step 2: Synthesis of 1-(4-(difluoromethyl)phenyl)-N-methoxy-N,4-dimethyl-1H-1,2,3-triazole-5-carboxamide

Under ice bath conditions, 1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazole-5-carboxylic acid (2.80 g, 11.06 mmol) was dissolved in anhydrous acetonitrile (30 mL), and then N,O-dimethylhydroxylamine hydrochloride (1.29 g, 13.27 mmol) and N,N-diisopropylethylamine (7.15 g, 55.29 mmol) were weighed, and then 1-propylphosphoric anhydride (11.95 g, 50% in EtOAc, 16.59 mmol) was slowly added dropwise under the same conditions. After the addition, the reaction solution was reacted at room temperature for 16 hours. TLC (PE:EA=1:1) showed that the reaction was complete. Water (20 mL) was added to the reaction solution, and the reaction solution was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and vortexed. The crude product was separated by normal phase silica gel column chromatography (PE/EtOAc (V/V) = 1:0-1:1) to obtain 1-(4-(difluoromethyl)phenyl)-N-methoxy-N,4-dimethyl-1H-1,2,3-triazole-5-carboxamide (2.70 g, yield: 82.41%).

Step 3: Synthesis of 1-(1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)ethan-1-one

Under nitrogen protection, 1-(4-(difluoromethyl)phenyl)-N-methoxy-N,4-dimethyl-1H-1,2,3-triazole-5-carboxamide (1.40 g, 4.73 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) in an ice bath. Then, a tetrahydrofuran solution of methylmagnesium bromide (1.13 g, 1 M, 9.45 mmol) was added. After the addition, the temperature was raised to room temperature and reacted at room temperature for 4 hours. TLC (PE:EA(V/V)=3:1) showed that the reaction was complete. A saturated aqueous solution of ammonium chloride (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and spun down. The crude product was separated by normal phase silica gel column chromatography (PE/EtOAc (V/V) = 1:0-1:1) to obtain 1-(1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)ethan-1-one (1.10 g, yield: 92.66%).

Step 4: Synthesis of 1-(1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)ethan-1-ol

Under ice bath conditions, weigh 1-(1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)ethan-1-one (1.10 g, 4.38 mmol) and dissolve it in methanol (10 mL), then add sodium borohydride (331.28 mg, 8.76 mmol) in batches. After the addition, the reaction solution was reacted at room temperature for 2 hours. TLC (PE:EA(V/V)=3:1) showed that the reaction was complete. Saturated ammonium chloride solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and spun down. The crude product was separated by normal phase silica gel column chromatography (PE/EtOAc (V/V) = 1:0-1:1) to obtain 1-(1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)ethan-1-ol (1.0 g, yield: 90.19%).

Step 5: Synthesis of 3-chloro-6-(1-(1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)ethoxy)oxazine

Under the protection of nitrogen in an ice bath, 1-(1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)ethan-1-ol (1.00 g, 4.38 mmol) was weighed and dissolved in tetrahydrofuran (10 mL), and then sodium hydroxide (236.90 mg, 60%, 5.92 mmol) was added in batches. After the addition, the reaction solution was reacted in an ice bath for 30 minutes, and then 3,6-dichlorooxazine (882.36 mg, 5.92 mmol) was added and reacted at room temperature for 10 hours. TLC (PE:EA(V/V)=1:1) showed that the reaction was complete. Saturated ammonium chloride solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and vortexed. The crude product was separated by normal phase silica gel column chromatography (PE/EtOAc (V/V) = 1:0-1:1) to obtain 3-chloro-6-(1-(1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)ethoxy)oxazine (1.33 g, yield: 92.09%).

Step 6: Synthesis of 4-(6-(1-(1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)ethoxy)piperazin-3-yl)piperazin-2-one

Under argon protection, 3-chloro-6-(1-(1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)ethoxy)oxazine (1.33 g, 3.64 mmol) and 2-piperazinone (364.06 mg, 3.64 mmol) were dissolved in dioxane (15 mL), and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (169.68 mg, 0.364 mmol), cesium carbonate (1.18 g, 3.64 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (304.12 g, 40 mmol) were added in sequence. After the addition of 1% paraformaldehyde (2-[4 ... The residue was purified by reverse phase HPLC column chromatography (column: SunFileTM Prep C18 OBDTM 5μm 30mm×150mm); solvent: A = acetonitrile, B = water; gradient: 1% - 25%, 8 minutes) to obtain 4-(6-(1-(1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)ethoxy)oxazin-3-yl)piperazin-2-one (600.0 mg, yield: 38.42%).

¹ H NMR (400 MHz, DMSO _- d ₆ ): δ 8.14 - 8.10 (m, 1H), 7.82 (dd, 4H, J ₁ =8.0 Hz, J ₂ =20.0 Hz), 7.38 (d, 1H, J = 12.0 Hz), 7.18-7.04 (m, 2H), 6.15-6.10 (m, 1H), 3.95 (s, 2H), 3.66-3.63 (m, 2H), 3.28-3.25 (m, 2H), 2.36 (s, 3H), 1.60 (d, 3H, J =8.0 Hz).

LC-MS, M/Z (ESI): 430.1[M+H] ⁺

Example 2 : Preparation of target compound I-7

1-(3-((6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)oxazin-3-yl)oxy)azepan-1-yl)ethan-1-one

The synthetic route of the target compound I-7 is as follows:

Step 1: Synthesis of (1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methanol

To a solution of ethyl 1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazole-5-carboxylate (2.60 g, 9.24 mmol) in tetrahydrofuran (30 mL) was added 2.5 M lithium aluminum tetrahydrogen solution (5.2 mL) at 0°C, and the reaction solution was stirred at 0°C for 0.5 hours. After the reaction was completed, water (0.5 mL), 15% sodium hydroxide solution (0.5 mL) and water (1.5 mL) were added dropwise under a nitrogen atmosphere. The quenched mixture was dried over anhydrous sodium sulfate, filtered and concentrated to obtain (1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methanol (2.06 g, 8.61 mmol).

LC-MS, M/Z (ESI):240.0 [M+H] ⁺

Step 2: Synthesis of 3-chloro-6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)oxazine

To a solution of (1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methanol (250 mg, 1.05 mmol) and 3,6-dichlorooxazine (156 mg, 1.05 mmol) in tetrahydrofuran (3 mL) was slowly added sodium hydride (84.0 mg, 2.10 mmol, 60%) at 0°C under nitrogen protection, and the reaction solution was stirred at 25°C for 2 hours. After the reaction was completed, the reaction solution was quenched with a saturated aqueous solution of ammonium chloride (20 mL), extracted three times with ethyl acetate (20 mL), and the organic phase was dried over anhydrous sodium sulfate and then filtered and concentrated to obtain 3-chloro-6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)oxazine (350 mg, crude product).

LC-MS, M/Z (ESI): 351.9 [M+H] ⁺

Step 3: Synthesis of 1-(3-((6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)oxazin-3-yl)oxy)azinecyclobutane-1-yl)ethan-1-one

Under nitrogen protection at 0 ° C, sodium hydride (119 mg, 2.98 mmol, 60%) was added to a solution of 1-(3-hydroxyazacyclobutane-1-yl)ethan-1-one (115 mg, 995 μmol) in tetrahydrofuran (4 mL) and N-methylpyrrolidone (2 mL), and then 3-chloro-6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)oxazine (350 mg, 995 μmol) was added to the reaction mixture. The reaction solution was stirred at 80 ° C for 1 hour under nitrogen atmosphere. After the reaction was completed, the reaction solution was quenched with water (20 mL), extracted three times with ethyl acetate (20 mL), and the organic phase was dried over anhydrous sodium sulfate and filtered and concentrated to obtain a crude product. The crude product was purified by high performance liquid chromatography (column chromatography column: Phenomenex luna C18 150*25mm* 10μm; mobile phase: solvent A=water+0.1% formic acid, B=acetonitrile; gradient: 25%-55%, 10 min) to obtain 1-(3-((6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)oxazin-3-yl)oxy)azin-1-yl)ethan-1-one (80.0 mg, 182 μmol).

LC-MS, M/Z (ESI):431.1 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.71-7.66 (m, 4H), 7.06 (d, J = 9.2, 1H), 7.00 (d, J = 9.2, 1H), 6.73 (t, J = 56 Hz , 1H), 5.44 - 5.49 (m, 3H), 4.49-4.47 (m, 1H), 4.44-4.42 (m, 1H), 4.19-4.11 (m, 2H), 2.51 (s, 3H), 1.92 (s, 3H).

Example 3 : Preparation of target compound I-9

1-(4-(Difluoromethyl)phenyl)-4-methyl-N-(6-(4-methyl-3-oxopiperazin-1-yl)oxazin-3-yl)-1H-1,2,3-triazole-5-carboxamide

The synthetic route of the target compound I-9 is as follows:

Step 1: Synthesis of 4-(6-aminopiperazine-3-yl)-1-methylpiperazine-2-one

At 25°C, 6-chlorooxazin-3-amine (200 mg, 1.54 mmol) and 1-methylpiperazin-2-one (212 mg, 1.85 mmol) were mixed together and then stirred at 150°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then methyl tert-butyl ether (5 mL) was added and stirred for 0.5 hours, and 4-(6-aminooxazin-3-yl)-1-methylpiperazin-2-one (200 mg, crude product) was obtained by filtration.

LC-MS, M/Z (ESI):208.0 [M+H] ⁺

Step 2: Synthesis of 1-(4-(difluoromethyl)phenyl)-4-methyl-N-(6-(4-methyl-3-oxopiperazin-1-yl)oxazin-3-yl)-1H-1,2,3-triazole-5-carboxamide

To a solution of 1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazole-5-carboxylic acid (170 mg, 672 μmol) in dichloromethane (3.00 mL) was added a drop of N,N-dimethylformamide and oxalyl chloride (128 mg, 1.01 mmol) at room temperature, and the reaction solution was stirred at 25°C for 0.5 hours. After the reaction is completed, the crude product is directly concentrated, and the crude product is dispersed with dichloromethane (2 mL). The dispersion is then slowly added dropwise to a dichloromethane (3 mL) solution of 4-(6-aminopiperazine-3-yl)-1-methylpiperazine-2-one (146 mg, 705 μmol) and N,N-diisopropylethylamine (260 mg, 2.01 mmol), and the reaction solution is continuously stirred at 25°C for 0.5 hours. After the reaction is completed, the crude product is directly concentrated. The crude product was purified by HPLC column chromatography (column: Phenomenex luna C18 150*25mm* 10μm; mobile phase: solvent A = water + 0.1% formic acid, B = acetonitrile; gradient: 25%-45%, 10 min) to obtain 1-(4-(difluoromethyl)phenyl)-4-methyl-N-(6-(4-methyl-3-oxopiperazin-1-yl)oxazin-3-yl)-1H-1,2,3-triazole-5-carboxamide (81.7 mg, 177 μmol).

LC-MS, M/Z (ESI):443.2 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.3 (s, 1H), 8.31 (d, J = 8 Hz, 1H), 7.67-7.62 (m, 4H), 6.94(d, J = 9.6 Hz, H) , 6.72 (t, J = 56.4 Hz, 1H), 4.03 (s, 2H), 3.77 (t, J = 5.6 Hz, 2H), 3.43 (t, J = 5.6 Hz, 1H), 3.03 (s, 3H), 2.57 (s, 3).

Example 4 : Preparation of target compound I-14

2-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

The synthetic route of the target compound I-14 is as follows:

Step 1: Synthesis of tert-butyl 2-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

At 25°C, (1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methanol (300 mg, 1.25 mmol) and tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (371 mg, 1.37 mmol) were dissolved in tetrahydrofuran (6 mL), and potassium tert-butoxide (281 mg, 2.51 mmol) was added in batches, and the reaction system was stirred at 60°C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and diluted with water (10 mL). The mixed solution was extracted three times with ethyl acetate (30 mL), and the combined organic phase was washed with saturated sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate, and then filtered and concentrated to obtain tert-butyl 2-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (520 mg, crude product).

LC-MS, M/Z (ESI): 472.2 [M+H] ⁺

Step 2: Synthesis of 2-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine

At 25°C, tert-butyl 2-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (500 mg, 1.06 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, and the reaction solution was stirred at 25°C for 0.5 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated and purified by reverse phase high performance liquid chromatography (column chromatography column: Phenomenex luna C18 150*25mm*10μm; mobile phase: solvent A=water+0.1% formic acid, B=acetonitrile; gradient: 12%-42%, 9 min) to obtain 2-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine (250 mg, 63.5% yield).

LC-MS, M/Z (ESI): 372.2 [M+H] ⁺

Step 3: Synthesis of 2-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-formamide

2-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine (200 mg, 538 μmol) was dissolved in dichloromethane (4 mL) at 25°C, and triethylamine (218 mg, 2.15 mmol) and trimethylsilyl isocyanate (186 mg, 1.63 mmol) were added, and the reaction solution was stirred at 25°C for 1 hour. After the reaction was completed, the reaction solution was poured into water (10 mL) for dilution, and then dichloromethane (5 mL) was added for extraction three times. The organic phases were combined, washed with saturated sodium chloride solution (10 mL) and dried over anhydrous sodium sulfate, and then filtered to obtain a crude product. The crude product was separated and purified by reverse phase high performance liquid chromatography (column: Phenomenex luna C18 150*25mm* 10μm; mobile phase: solvent A = water + 0.1% formic acid, B = acetonitrile; gradient: 30%-60%, 9 min) to obtain 2-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-formamide (151 mg, 67.0% yield).

LC-MS, M/Z (ESI): 415.1 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.75 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 1H), 6.72 (t , J = 56.4 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 5.36 (s, 2H), 4.68 (br s, 2H), 4.52 (s, 2H), 3.69 (t, J = 6 Hz, 2H), 2.88 (t, J = 5.6 Hz, 2H), 2.51 (s, 3H).

Example 5 : The following compounds were prepared by referring to the preparation methods of the above compounds. No. Structural name LC-MS, M/Z (ESI) I-2 8-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-3,4,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-2(1H)-one 443.2 I-3 8-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-2,3,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-4(1H)-one 443.2 I-4 4-((6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)oxazin-3-yl)oxy)piperidin-2-one 431.2 I-5 3-((6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)oxazin-3-yl)oxy)pyrrolidin-2-one 417.1 I-6 3-((6-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)oxazin-3-yl)oxy)cyclobutane-1-carboxamide 431.2 I-8 1-(4-(Difluoromethyl)phenyl)-4-methyl-N-(6-(3-oxopiperazin-1-yl)oxazin-3-yl)-1H-1,2,3-triazole-5-carboxamide 429.2 I-10 3-(4-(Difluoromethyl)phenyl)-5-methyl-N-(6-(3-oxopiperazin-1-yl)oxazin-3-yl)isoxazole-4-carboxamide 429.1 I-11 4-(6-((3-(4-(difluoromethyl)phenyl)-5-methylisoxazol-4-yl)methoxy)oxazin-3-yl)piperazin-2-one 416.2 I-12 1-(2-((1-(5-(difluoromethyl)pyridin-2-yl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one 415.2 I-13 2-((1-(4-(difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-N-methyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide 429.2

Test Example 1 : Inverse agonist activity of compounds on α5-GABAA receptor

This experiment uses the HEK-293 cell line that transiently expresses the GABAA (α5β3γ2) receptor. The final concentration of the test compound was prepared on the same day and then dissolved in the extracellular solution. The extracellular solution is: 140 mM NaCl, 5 mM CsCl, 2 mM CaCl ₂ •2H ₂ O, 1 mM MgCl ₂ •6H ₂ O, 5 mM HEPES, 10 mM D-Glucose, and NaOH adjusts pH=7.4. The intracellular solution is: 130 mM CsCl, 0.1 mM CaCl ₂ •2H ₂ O, 2 mM MgCl ₂ •6H ₂ O, 1.1 mM EGTA, 5 mM Na2-ATP, 10 mM HEPES, and CsOH adjusts pH=7.2. Test compounds were dissolved in dimethyl sulfoxide (DMSO) and redissolved in the extracellular fluid on the day of the assay to a final concentration of 100 nM.

First, use a microelectrode puller to pull a capillary glass tube into a recording electrode, then install the electrode filled with intracellular fluid into the microelectrode holder, and manipulate the microelectrode manipulator under an inverted microscope to immerse the electrode in the extracellular fluid and record the electrode resistance (Rpip). Then slowly contact the electrode to the cell surface, apply negative pressure suction to form a GΩ high-resistance seal. At this time, fast capacitance compensation is performed, and negative pressure suction is continued to break the cell membrane to form a whole-cell recording mode. Finally, slow capacitance compensation is performed and experimental parameters such as series resistance (Rs) are recorded. No leakage compensation is given. After whole-cell seal was formed, the cell membrane voltage was clamped at -70 mV and GABA receptor currents were recorded in the gap-free mode.

When detecting the reverse excitatory effect of the test substance, the peak current after the EC50 concentration of GABA, the mixture of EC50 concentration of GABA and the test concentration of the test substance, and the saturated concentration of GABA are given to the cell surface in sequence. After each switching of the working solution, the cells are eluted with extracellular fluid, and the next working solution is switched after the current stabilizes. The experimental data are collected by the patch clamp amplifier (HEKA, EPC 10) and stored in the data acquisition software (HEKA, Patch Master). At least 2 cells are used for each concentration to repeat the test twice independently. All electrophysiological experiments are carried out at room temperature. During the test, the peak current stimulated by GABA before drug administration (I _GABA ), the peak current after the test concentration of the test substance (I _Cmpd ), the peak current after the test concentration of the test substance and the mixed solution of GABA (I _GABA+Cmpd ) and the peak current stimulated by saturated concentration of GABA (I _{GABA saturated} ) were measured. During the analysis, the antagonistic effect of the test substance, i.e. (1-(I _Cmpd /I _GABA )*100%), and the reverse agonistic effect, i.e. (1-(I _GABA+Cmpd )/(I _GABA )*100%) were calculated.

Table 1. Data of the reverse agonist activity of compounds (100 nM) on α5-GABAA receptor Compound Reverse excitation rate I-1 45%

The experimental results show that the compound of the present invention has strong reverse agonist activity of α5-GABAA receptor.

The above is an exemplary description of the implementation of the technical solution of the present invention. It should be understood that the protection scope of the present invention is not limited to the above implementation. Any modification, equivalent replacement, improvement, etc. made by a person with ordinary knowledge in the technical field to which the present invention belongs within the spirit and principles of the present invention shall be included in the protection scope of the patent application of the present invention.

without

Claims (16)

A compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug: ; wherein X ₁ is N or C; X ₂ is N, O, S or CR ₅ ; the dashed line represents a single bond or a double bond; m is selected from 0, 1, 2, 3, 4 or 5; Ring A does not exist or is selected from a benzene ring, a 5-6 membered heteroaryl ring; wherein, when Ring A does not exist, m is 1, and R ₁ is connected to X ₁ ; R ₁ is selected from hydrogen, a halogen, a hydroxyl, an amine, a nitrile, a C _1-6 alkyl, a C _{1-6 alkoxy, a C 1-6 alkylamino} , a C _3-7 cycloalkyl or a 3-6 membered heterocycloalkyl; the C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C wherein the _{C 1-6} alkyl, C _{1-6 alkoxy, C 3-7} cycloalkyl, 3-7 membered heterocycloalkyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents selected from the following groups: deuterium, halogen, hydroxyl, amine, nitrile, C _1-6 alkyl, C 1-6 alkoxy, C _3-7 cycloalkyl; R ₂ is selected from hydrogen, halogen, hydroxyl, amine, nitrile, C _{1-6 alkyl, C 1-6 alkoxy} , C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl or 5-6 membered heteroaryl; the C 1-6 alkyl, C _1-6 alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents selected from the following groups: deuterium, halogen, hydroxyl, amine, nitrile, C _1-6 alkyl, C _1-6 alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl or 5-6 membered heteroaryl R3 and _R4 are each _{independently} selected from _hydrogen , _halogen , hydroxyl, amine, nitrile, pendoxy _{, -C0-6alkyl} -C(=O _{) Ra - C0-6alkyl} , -C0-6alkyl-C(= _{O)ORa-C0-6alkyl, -C0-6alkyl - C ( =} O) _NRa R _b -C _0-6 alkyl, -C _0-6 alkyl-NR _a R _b -C _0-6 alkyl, -C _0-6 alkyl-NR _a C(═O)R _b -C _0-6 alkyl, -C _0-6 alkyl-NR _a SO ₂ R _b -C _0-6 alkyl, -C _0-6 alkyl-SO ₂ R _a -C _0-6 alkyl, -C _0-6 alkyl-SO ₂ NR _a R _b -C _0-6 alkyl, C 1-6 alkyl, C _3-7 cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered heteroaryl; the C _1-6 alkyl, C _3-7 cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered heteroaryl _3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered heteroaryl are optionally substituted by 1-4 substituents selected from the following groups: deuterium, halogen, pendoxy, hydroxyl, amine, nitrile, C _1-6 alkyl, C _3-7 cycloalkyl; M is absent or selected from O; R ₅ is selected from hydrogen, deuterium, halogen, hydroxyl, nitrile, C _1-6 alkyl, C _1-6 alkoxy or C _3-7 cycloalkyl; the C _1-6 alkyl, C _1-6 alkoxy or C _3-7 cycloalkyl are optionally substituted by 1-4 substituents selected from the following groups: halogen, hydroxyl, amine, nitrile, C _1-6 alkyl, C _3-7 cycloalkyl; R ₆ is selected from deuterium, halogen, C wherein the C _1-6 alkyl, C _1-6 alkoxy or C _3-7 cycloalkyl is optionally substituted by 1-4 substituents selected from the following groups: halogen, hydroxyl, amine, nitrile, C _1-6 alkyl, C _3-7 cycloalkyl; R _a and R _b are _each independently selected from hydrogen, deuterium, halogen, hydroxyl, amine, -C _0-6 alkyl-S(=O) ₂ -C _0-6 alkyl, _{-C 0-6} alkyl-P(=O) ₂ -C _0-6 alkyl, C _1-6 alkyl or 3-6 membered heterocycloalkyl, wherein the C _1-6 alkyl is optionally substituted by 1-3 substituents selected from the following groups: halogen, _hydroxyl , -OC _1-6 alkyl, -NH ₂ , -NHC _1-6 alkyl, -OC(＝O)C _1-6 alkyl or -N(C _1-6 alkyl)C _1-6 alkyl; and the 3-6 membered heterocycloalkyl is a monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S atoms. The compound of formula I as described in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein the Selected from , , , ; Preferably, the Selected from , , . The compound of formula I as described in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein the ring A does not exist or is selected from a benzene ring or a 6-membered heteroaromatic ring; the 6-membered heteroaromatic ring contains 1, 2 or 3 heteroatoms; m is 0, 1, 2, 3, 4 or 5; _R1 is selected from hydrogen, halogen, hydroxyl, amino, nitrile, _C1-6 alkyl, _C1-6 halogenated alkyl, _C3-7 cycloalkyl, _C3-7 halogenated cycloalkyl, _C1-6 alkoxy, _C1-6 halogenated alkoxy; preferably, the heteroatoms are selected from N, O and S; when there are multiple heteroatoms, the heteroatoms are the same or different; Preferably, Ring A is absent or selected from benzene ring, pyridine, pyrimidine, oxazine, pyrazine or triazine; Preferably, Ring A is selected from , ; * terminal connected to X ₁ ; preferably, Selected from , ,For example , ; When ring A does not exist, m is 1, and R ₁ is connected to X ₁ ; More preferably, ring A does not exist or is selected from a benzene ring or pyridine. The compound of formula I as described in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein the compound is selected from the following structures: , , , , , ; wherein Ring B, Ring D, R ₁ , R ₂ , R ₃ , R ₄ , L, M, m, n and p have the definitions as described in claim 1. The compound of formula I as described in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein the compound is selected from the following structures: , , , , , , , , ; wherein Ring A, Ring B, Ring D, R1, R2, R3, R4, M, m, n and p have the definitions as described in claim 1. The compound of formula I as described in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein the compound is selected from the following structures: ; wherein ring B, R ₁ , R ₂ , R ₃ , m and n have the definitions as described in claim 1; when M is absent, ring D, R ₄ and p are absent at the same time; when M is selected from O, ring D, R ₄ and p have the definitions as described in claim 1. The compound of formula I as described in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein the ring B is selected from a 5-14 membered heteroaromatic ring containing 1, 2, 3, 4 or 5 heteroatoms; preferably, the heteroatom is selected from N, O, S; when there are multiple heteroatoms, the heteroatoms are the same or different; Preferably, Ring B is selected from acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, quinazolinyl, pyrazolyl, indolyl, isoindolyl, 1H,3H-1-oxoisoindolyl, benzotriazolyl, furanyl, thienyl, pyridoquinolinyl, pyridopiperidinyl, pyridopyrrolidyl, benzothienyl, benzofuranyl, benzodioxane, benzodioxane, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, benzoxazolyl, tetrahydronaphthyridine , imidazolyl, pyrazinyl, oxazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinolinyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, triazinyl, tetrazinyl, tetrazolyl, xanthanol, phenazinyl, phenothiazinyl, phenoxazinyl, azoquinoline, oxazinyl, thioquinoline, hexahydropyrazinopyridinooxazine, 6,7,8,9-tetrahydropyrido[2',3':4,5]imidazo[1,2-a]pyrazine, etc.; More preferably, ring B is selected from pyridine, pyrimidine, oxazine, tetrahydronaphthyridine, pyridopiperidine, or Preferably, the ring B is selected from , , ; * end connected to L; preferably, Selected from , , , , , ; * end is connected to L. The compound represented by formula I as described in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein L is selected from -CH ₂ -O-, -CH(R ₆ )-O- or -C(=O)-NR _a -; R ₆ is selected from C _1-3 alkyl or C _3-5 cycloalkyl; the C _1-3 alkyl or C _3-5 cycloalkyl is optionally substituted with 1-4 substituents selected from the following groups: halogen, hydroxyl, amine, nitrile, C _1-6 alkyl, C _3-7 cycloalkyl; preferably, L is selected from -CH ₂ -O-, -CH(R ₆ )-O- or -C(=O)-NR _a -; R ₆ is selected from C _1-3 alkyl or C _3-5 cycloalkyl; The _{C 1-3} alkyl or C _3-5 cycloalkyl is optionally substituted by 1-4 substituents selected from the following groups: halogen, hydroxyl, amine, nitrile, C _1-6 alkyl, C _3-7 cycloalkyl; preferably, the L is selected from -CH ₂ -O-, -CH(CH ₃ )-O- or -C(=O)-NH-; preferably, the L is selected from (like , ）、 ; *End and connection. The compound of formula I as described in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein the ring D is absent or selected from 4-6 membered heterocycloalkyl and 3-6 membered cycloalkyl containing 1-3 heteroatoms; preferably, the heteroatom is selected from N, O, S; when there are multiple heteroatoms, the heteroatoms are the same or different; preferably, the ring D is absent or selected from cyclopropyl, cyclobutyl, cyclopentyl, azacyclobutane, pyrrolidine, piperidine, piperazine; preferably, the ring D is selected from , , , , ; preferably, Selected from , , , , , . The compound of formula I as described in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein the R ₁ is selected from hydrogen, halogen, hydroxyl, amine, nitrile, C _1-6 alkyl, C 3-7 cycloalkyl, C _1-6 alkoxy; the C _1-6 alkyl, C _3-7 cycloalkyl, C _1-6 alkoxy is optionally substituted with 1-4 substituents selected from the following groups: deuterium, halogen, hydroxyl, amine, nitrile, C _1-6 alkyl, C _3-7 cycloalkyl; m is selected from 0, 1, 2, 3, 4 or 5; preferably, the R ₁ is selected from halogen, C _1-6 alkyl, C _3-7 cycloalkyl, C _1-6 alkoxy, halogenated alkyl _; Preferably, R ₁ is selected from F, methyl, cyclopropyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl. The compound of formula I as described in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein _R2 is selected from halogen, _C1-6 alkyl, _C3-7 cycloalkyl, _C1-6 alkoxy; the _C1-6 alkyl, _C3-7 cycloalkyl, _C1-6 alkoxy is optionally substituted with 1-4 substituents selected from the following groups: deuterium, halogen, hydroxyl, amino, nitrile, _C1-6 alkyl, _C3-7 cycloalkyl; preferably, _R2 is selected from methyl. The compound of formula I as described in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein _R3 is selected from hydrogen, halogen, hydroxyl, amine, nitrile, pendoxy, _-C0-6 alkyl-C(=O) _Ra - _C0-6 alkyl, _-C0-6 alkyl-C(=O) _ORa - _C0-6 alkyl, _-C0-6 alkyl-C(=O) _{NRaRb - C0-6} alkyl, _C1-6 alkyl, _C3-7 cycloalkyl, 3-6 membered heterocycloalkyl; the _C1-6 alkyl, C _3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl is optionally substituted by 1-4 substituents selected from the following groups: deuterium, halogen, oxo, hydroxyl, amine, nitrile, C _1-6 alkyl, C _3-7 cycloalkyl; n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; preferably, R ₃ is selected from hydrogen, halogen, oxo, -C(=O)R _a , -C(=O)NR _a R _b , C _1-3 alkyl, cyclopropyl, cyclobutyl, azocyclobutyl, oxocyclobutyl, pyrrolidine, piperidine, piperazine, piperidone, piperazinone; more preferably, R ₃ is selected from hydrogen, oxo, -C(=O)-CH ₃ , -C(=O)NH ₂ , -C(=O)NH-C _1-3 alkyl, methyl, piperazinone, methyl substituted piperazinone; Preferably, R ₃ is selected from hydrogen, pendoxy, -C(=O)-CH ₃ , -C(=O)NH ₂ , ,methyl, , ; n is selected from 0 or 1. The compound of formula I as described in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein _R4 is selected from hydrogen, halogen, hydroxyl, amine, nitrile, pendoxy, _-C0-6 alkyl-C(=O) _Ra - _C0-6 alkyl, _-C0-6 alkyl-C(=O) _ORa - _C0-6 alkyl, _-C0-6 alkyl-C(=O) _{NRaRb - C0-6} alkyl, _C1-6 alkyl, _C3-7 cycloalkyl, 3-6 membered heterocycloalkyl; the _C1-6 alkyl, C The _3-7 membered cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted by 1-4 substituents selected from the following groups: deuterium, halogen, hydroxyl, amine, nitrile, C _1-6 alkyl, C _3-7 cycloalkyl; p is 0, 1, 2, 3, 4, 5, 6 or 7; preferably, R ₄ is selected from hydrogen, oxo, -C(=O)-CH ₃ , -C(=O)NH ₂ , -C(=O)NH-C _1-3 alkyl, methyl; p is selected from 0, 1 or 2. The compound of formula I as described in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein the compound comprises: I-1 I-2 I-3 I-4 I-5 I-6 I-7 I-8 I-9 I-10 I-11 I-12 I-13 I-14 . A pharmaceutical composition, wherein the pharmaceutical composition comprises: a compound of formula I as described in any one of claims 1 to 14, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug; and a pharmaceutically acceptable carrier. A use of a compound of formula I as described in any one of claims 1 to 14, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the use of a pharmaceutical composition as described in claim 15, the use comprising: regulating α5-GABA _A receptor; and/or, preventing and/or treating diseases associated with α5-GABA _A receptor; and/or, preparing a drug, a pharmaceutical composition or a formulation for regulating α5-GABA _A receptor, and/or preventing and/or treating diseases associated with α5-GABA _A receptor; preferably, the diseases associated with α5-GABA _A receptor include pain, Alzheimer's disease, multi-infarct dementia or stroke; preferably, the pain is neuropathic pain, inflammatory pain or cancer pain; Preferably, the pain is selected from headache, facial pain, neck pain, shoulder pain, back pain, chest pain, abdominal pain, low back pain, lower limb pain, muscle and bone pain, vascular pain, gout, arthritis pain, visceral pain, pain caused by infectious diseases, polyostotic pain, sickle cell anemia, autoimmune diseases, pain associated with multiple sclerosis or inflammation, chronic pain caused by injury or surgery, nociceptive pain, painful diabetes, trigeminal neuralgia, lumbar or cervical root pain, glossopharyngeal neuralgia, autonomic reflex pain, reflex sympathetic malnutrition, nerve root avulsion, cancer, chemical damage, toxins, nutritional deficiencies, viral or bacterial infections, and pain associated with degenerative osteoarthritis; Preferably, the infectious disease is selected from AIDS or post-herpetic neuralgia.