Fused ring compound, pharmaceutical composition comprising same, and use thereof

Abstract

The present invention provides the following compound (I) or a pharmaceutically acceptable salt and ester thereof, and a pharmaceutical composition comprising the compound of the present invention. The present invention further provides a use of the compound of the present invention as a potassium ion channel modulator, a use of the compound in the preparation of a drug for diseases related to potassium ion channels, and a corresponding pharmaceutical composition.

Description

Fused-ring compounds, pharmaceutical compositions comprising them, and their uses Technical Field

[0001] This invention belongs to the fields of chemistry and biomedicine, specifically relating to a novel fused-ring compound with a novel skeleton, its preparation method, and its uses. Background Technology

[0002] Kv7 potassium channels are a class of voltage-dependent potassium ion channels characterized by low-threshold activation, slow activation, and non-inactivation. There are five family members of Kv7 potassium channels (Kv7.1-Kv7.5, or KCNQ1-KCNQ5). All Kv7 potassium channel members have a similar structure, consisting of four subunits forming a functional channel, with each subunit containing six transmembrane segments (S1-S6). S1-S4 are the voltage-sensing regions, playing a crucial role in sensing changes in membrane potential and controlling conformational changes; S5-S6 are the main components of the channel pore region, the primary combination and action area of ​​potassium channel openers. Kv7.1 potassium channels are a non-neuronal pathway distributed in peripheral tissues and expressed in the heart to mediate myocardial Iks; mutations in Kv7.1 can lead to Long QT syndrome. Kv7.2-Kv7.5 potassium channels are fundamental to neuronal M-currents, widely distributed throughout the nervous system, and possess various physiological activities. Voltage-gated potassium channel KCNQ2 is primarily expressed in the nervous system. It assembles with voltage-gated potassium channel KCNQ3 to form a heterotetramer, jointly mediating M-currents (IKMs). IKMs are slow-activating, slow-deactivating, and non-inactivating currents that play a crucial role in maintaining resting membrane potential and reducing intrinsically linked discharges and repetitive action potentials triggered by excitatory stimuli. In 1998, KCNQ2 gene mutations were first discovered in families with benign familial neonatal seizures, revealing the association between KCNQ2 channels and epilepsy. Numerous clinical studies have found that KCNQ2 gene mutations are associated with epilepsy, benign familial neonatal seizures or neonatal epileptic encephalopathy, and peripheral nerve hyperexcitability (PNH, myotonia, or neuromyotonia). The expression of KCNQ2 channels in neurons at various levels of the pain sensory pathway and in brain regions involved in pain suggests the potential of KCNQ2 channels as an analgesic target. Functional experiments have demonstrated that KCNQ2 expression is downregulated in models of neuropathic pain, osteoarthritis pain, and bone cancer pain, and activation of the KCNQ2 channel can alleviate neuropathic pain and fibromyalgia. GOF (gain-of-function) mutations in the KCNQ2 channel are associated with intellectual disability, encephalopathy, autism spectrum disorders, and other neurological diseases, highlighting the therapeutic potential of KCNQ2 inhibitors. Studies have shown that pharmacologically blocking the KCNQ2 channel can enhance cognitive and memory abilities (Hippocampus 21, 22-32 (2011), Brain Research Bulletin 137, 132-139 (2018)). However, to our knowledge, no non-blocking KCNQ2 channel inhibitors have been validated in a biological setting. Furthermore, the regulation of KCNQ2 channel activity is also associated with neurological diseases such as Parkinson's disease, ischemia, schizophrenia, smooth muscle disorders, and depression.Given the crucial role of IKM in controlling neuronal excitability in the central and peripheral nervous systems, the KCNQ2 channel is considered an important pharmacological target for the development of new drugs for neurological and metabolic diseases. Developing KCNQ2 channel modulators has potential applications in the treatment of pain, epilepsy, or neurological disorders. KCNQ4 potassium channels are highly expressed in the outer hair cells of the cochlea and the auditory nucleus of the brainstem; mutations in these channels may lead to hereditary deafness. KCNQ5 potassium channels are highly expressed in skeletal muscle and the brain; mutations in these channels may lead to retinopathy, among other conditions.

[0003] Retigabin, a potassium channel agonist, was approved for marketing in 2011 as a novel antiepileptic drug for adjunctive treatment of partial-onset epilepsy. However, its poor target selectivity can cause a range of side effects, such as retinal pigment deposition, skin discoloration, and urinary retention. A series of compounds with different skeletons, including BMS-204352, ICA-069673, NH29, ZnPy, and ML213, have been reported to activate KCNQ2 channels. Some of these compounds have shown anticonvulsant effects in mouse seizure models, but extensive preclinical data are still lacking. Considering that most of these new molecules have not yet begun clinical trials, or that molecules like ICA-069673, which have entered Phase II clinical trials, have failed to proceed to the next stage of clinical research due to tolerability and pharmacokinetics issues, it is currently impossible to predict whether they will successfully enter the market.

[0004] XEN1101, a promising compound that activates the KCNQ2 channel, is another antiepileptic drug candidate in clinical trials, primarily developed to address the seizure control needs of epilepsy patients. Epilepsy is a common neurological disorder, and some patients experience resistance or intolerance to existing first-line drugs. The development of XEN1101 aims to fill this treatment gap. Preliminary studies suggest that this compound may reduce the frequency and intensity of seizures by regulating specific potassium ion channels on neuronal cell membranes, thereby stabilizing abnormally excited neuronal activity. It has already demonstrated some antiepileptic activity in early clinical trials, providing a potential new treatment direction for some patients with refractory epilepsy. XEN1101 is unique in that it has a long terminal elimination half-life, allowing for once-daily oral administration. Clinical trial results show that it significantly reduces the frequency of seizures. However, similar to other KCNQ potassium channel openers, it has a wide range of neurotoxic side effects, with extensive behavioral side effects observed clinically. Summary of the Invention

[0005] Currently, besides retigabin and XEN1101, although many small molecule agonists of potassium ion channels have been discovered, no other products have been successfully marketed. Through computer-aided drug design combined with rational design and modification methods, we discovered a new class of small molecule modulators with promising drug-like skeletal potassium channels and completed related in vitro and in vivo activity studies. To address the aforementioned problems in existing technologies, the inventors, through dedicated research and in-depth exploration, developed a compound with potassium channel modulator functions and conducted thorough testing of its pharmacological activity.

[0006] Specifically, the present invention provides fused-ring compounds of formula (I) or their pharmaceutically acceptable salts or esters.

[0007] L 1 Selected from NH, C1-6 alkylene groups, saturated or partially unsaturated C3-10 cyclic hydrocarbon groups, -O-, -NR b A divalent group consisting of one or more of -, -S-, and R; b Each is independently selected from H, C1-C8 alkyl, saturated or partially unsaturated C3-6 cyclic hydrocarbon groups; L 2 Selected from single-bond, C1-3 alkylene groups; L 3 Selected from single bonds and C1-3 alkylene groups; L3 is selected from single bonds and -(C=O)-; L 4 Selected from single-bond, C1-3 alkylene groups; L 5 Selected from single-bonded, C1-3 alkylene groups;

[0008] R 1 Selected from H, C1-C9 alkyl, C1-C6 haloalkyl, C3-6 cycloalkyl, C1-C3 alkyl-substituted C3-6 cycloalkyl, C3-6 cycloalkyl-substituted C1-C3 alkyl, and C3-6 halocycloalkyl;

[0009] R 2 Selected from C1-C6 alkyl, C2-C6 alkynyl, C3-6 cyclic hydrocarbon, C6-10 heteroaryl, cyano-substituted C1-C3 alkyl, -C(O)NH2, -C(O)CH3, methanesulfonyl;

[0010] R 3 Selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and C3-6 cycloalkyl;

[0011] R 4 Selected from C1-C6 alkyl or H;

[0012] R 5 Selected from H or C1-C3 alkyl groups.

[0013] In an optional embodiment of the present invention, L1 is selected from single bonds and methylene; L2 is selected from single bonds and methylene; L3 is selected from -(C=O)-; R 1 Selected from C1-C9 alkyl groups; R 2 Selected from C2-C6 alkynyl groups; R 3 Selected from difluoromethoxy; R 4 Selected from H;R 5 Selected from H.

[0014] In an optional embodiment of the present invention, R 2 Selected from the following groups:

[0015] R 3 Selected from the following groups:

[0016] R 1 Selected from the following groups:

[0017] * Represents a connection point.

[0018] In preliminary pharmacological experiments, the compounds of the present invention have demonstrated their use as potassium ion channel modulators. In summary, the present invention also provides the above-mentioned compounds and their various derivatives (pharmaceutically acceptable inorganic or organic salts, hydrates or solvates), as well as pharmaceutical compositions containing the compounds of the present invention as the main active ingredient, for use in the preparation of medicaments for alleviating and treating diseases related to potassium ion channels.

[0019] In the preferred embodiment of the present invention, the potassium ion channel preferably refers to the type 2 voltage-gated potassium ion channel KCNQ2, which is sometimes simply referred to as the KCNQ2 channel.

[0020] In embodiments of the present invention, the modifier is preferably an activator (or agonist) or an inhibitor.

[0021] Generally speaking, diseases related to potassium ion channels refer to diseases or conditions of the central nervous system, including episodic disorders, anxiety disorders, neuropathic pain and migraines, neurodegenerative diseases, stroke, cocaine abuse, nicotine withdrawal symptoms, alcohol withdrawal symptoms, tinnitus and Alzheimer's disease, depression, sleep disorders in the aging process, and neurodevelopmental disorders. The paroxysmal diseases mentioned are selected from acute paroxysmal diseases, seizures, status epilepticus, epilepsy such as epilepsy syndromes and epileptic seizures, neonatal spasms, neonatal epileptic seizures, benign familial neonatal epilepsy (KCNQ2-BFNE), epileptic encephalopathy (KCNQ2-NEE), benign familial neonatal seizure type 1 (BFNC), benign familial neonatal epileptic seizure 1 (BFNS1), neonatal epileptic seizures associated with hypoxic-ischemic injury, epileptic spasms, epileptic encephalopathy, early epileptic encephalopathy in infancy 7 (EIEE7), early epileptic encephalopathy in infancy with psychomotor developmental delay, generalized tonic-clonic seizures, globus pallidus morphology abnormalities, apnea, cerebral edema, dystonia, facial erythema, hypotonia, febrile seizures, agenesis of the corpus callosum, high-grade arrhythmia, focal clonic seizures, generalized tonic-clonic seizures, myofascitis, spastic quadriplegia, and myofascitis.

[0022] The anxiety disorder is selected from anxiety and diseases and conditions associated with the following: panic attacks, agoraphobia, panic disorder with agoraphobia, panic disorder without agoraphobia, agoraphobia without a history of panic disorder, specific phobia, social phobia and other specific phobias, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder caused by general physical symptoms, substance-induced anxiety disorder, separation anxiety disorder, adjustment disorder, performance anxiety, hypochondriasis disorder, anxiety disorder caused by general physical symptoms and substance-induced anxiety disorder and anxiety disorder unless otherwise specified.

[0023] The neuropathic pain and migraine mentioned are selected from abnormal pain, hyperalgesic pain, phantom pain, neuropathic pain associated with diabetic neuropathy, neuropathic pain associated with trigeminal neuralgia, neuropathic pain associated with sciatica, and neuropathic pain associated with migraine; or,

[0024] The neurodegenerative diseases mentioned are selected from Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, Creutzfeld-Jakob's disease, Parkinson's disease, encephalopathy caused by AIDS or induced by rubella virus, herpes virus, spirochetes or unknown pathogens, trauma-induced neurodegenerative diseases, neuronal hyperexcitability such as in drug withdrawal or poisoning symptoms, and neurodegenerative diseases of the peripheral nervous system such as polyneuropathy and polyneuritis.

[0025] The depression mentioned is selected from bipolar depression, postpartum depression, severe depression, psychogenic depression, atypical depression, psychogenic depression, treatment-resistant depression, depression associated with Huntington's disease, depression associated with multiple sclerosis, or depression associated with anxiety disorder.

[0026] The neurodevelopmental disorders mentioned are selected from developmental delay, intellectual disability, non-syndromic intellectual disability, and autism spectrum disorder (ASD).

[0027] The specific examples and preferred examples of each group in the compounds of the present invention, as well as the specific examples of the compounds of the present invention, are the same as the specific examples and preferred examples of each group in the compounds used in the above-mentioned pharmaceutical applications, and the preferred examples of the compounds, and will not be repeated here.

[0028] These compounds have a novel skeleton type compared to retigabine and XEN1101, and in vivo and in vitro experimental results show that the compounds of this invention have better effects than retigabine. Detailed Implementation

[0029] The following describes the other elements of the invention in more detail.

[0030] definition

[0031] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0032] In this invention, the terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other elements or method steps not listed.

[0033] As used herein, the term "alkylene" means a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.

[0034] As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example, 1 to 6 carbon atoms. For example, as used herein, the term "C1-6 alkyl" refers to a linear or branched group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl) of 1 to 6 carbon atoms, optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as halogens (in which case the group is referred to as "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term “C1-4 alkyl” refers to a linear or branched aliphatic hydrocarbon chain with 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0035] As used herein, the term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing a double bond and having 2–6 carbon atoms ("C"). 2-6 The alkenyl group is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the present invention contain an alkenyl group, the compounds may exist in pure E (iso-side) form, pure Z (iso-side) form, or any mixture thereof.

[0036] As used herein, the term "alkynyl" refers to a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.

[0037] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused, or bridged systems (e.g., bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, or bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.)) which is optionally substituted with one or more (e.g., one to three) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-6 "Cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) with 3 to 6 cyclic carbon atoms, which is optionally substituted with one or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0038] As used herein, the terms “cycloalkylene group,” “cycloalkylene group,” and “hydrocarbon ring” refer to a saturated (i.e., “cycloalkylene group” and “cycloalkylene group”) or unsaturated (i.e., having one or more double and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon ring having, for example, 3 to 10 (suitably 3 to 8, more preferably 3 to 6) cyclic carbon atoms, including but not limited to (cycloalkylene group) propyl(ring), (cycloalkylene group) butyl(ring), (cycloalkylene group) pentyl(ring), (cycloalkylene group) hexyl(ring), (cycloalkylene group) heptyl(ring), (cycloalkylene group) octyl(ring), (cycloalkylene group) nonyl(ring), (cycloalkylene group) hexenyl(ring), etc.

[0039] As used herein, the terms “heterocyclic group,” “sub-heterocyclic group,” and “heterocycle” refer to a cyclic group having, for example, 3 to 10 (suitably 3 to 8, more preferably 3 to 6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O, and S, and the remaining ring atoms are C-based saturated (i.e., heterocyclic alkyl) or partially unsaturated (i.e., having one or more double and / or triple bonds within the ring). For example, “3-10 membered (sub)heterocyclic group” is a saturated or partially unsaturated (sub)heterocyclic group having 2 to 9 (e.g., 2, 3, 4, 5, 6, 7, 8, or 9) ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from N, O, and S. Examples of heterocyclic groups and heterocyclic groups include, but are not limited to: (heterocyclic)epoxyalkyl, (heterocyclic)aziridinyl, (heterocyclic)azetidinyl, (heterocyclic)oxetanyl, (heterocyclic)tetrahydrofuranyl, (heterocyclic)dioxolinyl, (heterocyclic)pyrrolylyl, (heterocyclic)pyrrolidone, (heterocyclic)imidazylyl, (heterocyclic)pyrrolinyl, (heterocyclic)tetrahydropyranyl, (heterocyclic)piperidinyl, (heterocyclic)morpholinyl, (heterocyclic)dithianyl, (heterocyclic)thiomorpholinyl, (heterocyclic)piperazinyl, or (heterocyclic)trithianyl. The groups also encompass bicyclic systems, including spirocyclic, fused, or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azabicyclo[2.2.2]octane, etc.). The heterocyclic and heterocyclic groups may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

[0040] As used herein, the terms “(aryl)aryl” and “aromatic ring” refer to all-carbon monocyclic or fused-ring polycyclic aromatic groups having a conjugated π-electron system. For example, as used herein, the term “C…” 6-10 (Asyl) aryl" and "C 6-10"Aromatic ring" refers to an aromatic group containing 6 to 10 carbon atoms, such as ()phenylene (benzene ring) or ()naphthyl (naphthalene ring). The ()aryl and aromatic rings are optionally substituented with one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C). 1-6 Alkyl groups, etc., are substituted.

[0041] As used herein, the terms “(sub)heteroaryl” and “heteroary ring” refer to monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms, and containing at least one heteroatom that may be the same or different (the heteroatom being, for example, oxygen, nitrogen, or sulfur), and additionally, in each case, may be benzofused. Specifically, "(hybrid)aryl" or "heteroary ring" is selected from (hybrid)thienyl, (hybrid)furanyl, (hybrid)pyrroleyl, (hybrid)oxazolyl, (hybrid)thiazolyl, (hybrid)imidazolyl, (hybrid)pyrazolyl, (hybrid)isooxazolyl, (hybrid)isothiazolyl, (hybrid)oxadiazolyl, (hybrid)triazolyl, (hybrid)thiadiazolyl, etc., and their benzo[derivatives]; or (hybrid)pyridinyl, (hybrid)pyridinyl, (hybrid)pyrazinyl, (hybrid)triazinyl, etc., and their benzo[derivatives].

[0042] As used herein, the term "aralkyl" preferably refers to an aryl or heteroaryl-substituted alkyl group, wherein the aryl, heteroaryl, and alkyl groups are as defined herein. Typically, the aryl group may have 6-14 carbon atoms, the heteroaryl group may have 5-14 ring atoms, and the alkyl group may have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0043] A more specific explanation of the terminology is as follows:

[0044] "alkyl" refers to a saturated aliphatic hydrocarbon group comprising 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms of a saturated straight-chain or branched monovalent hydrocarbon group, wherein the alkyl group may be independently and optionally substituted by one or more substituents described in this invention. Further examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be optionally substituted or unsubstituted.

[0045] "Alkenyl" refers to a monovalent hydrocarbon group with 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, in which at least one C or C group is sp. 2 The double bond, wherein the alkenyl group may be independently and optionally substituted by one or more substituents described in this invention, specific examples of which include, but are not limited to, vinyl, allyl, and olefinic groups. The alkenyl group may be optionally substituted or unsubstituted.

[0046] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring comprises 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. The cycloalkyl group may be optionally substituted or unsubstituted.

[0047] The cycloalkyl ring can be fused to an aryl, heteroaryl, or heterocyclic ring, wherein the ring connected to the parent structure is a cycloalkyl ring, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.

[0048] The terms “heterocyclic group,” “heterocyclic,” or “heterocyclic” are used interchangeably in this application. They all refer to a non-aromatic heterocyclic group comprising 3-12 saturated or partially unsaturated monocyclic, bicyclic, or tricyclic rings, wherein at least one ring atom is a heteroatom, such as oxygen, nitrogen, or sulfur. Preferably, it has a 5- to 7-membered monocyclic or a 7- to 10-membered bicyclic or tricyclic ring, which may contain 1, 2, or 3 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of “heterocyclic group” include, but are not limited to, morpholino, oxobutyryl, thiomorpholino, tetrahydropyrano, 1,1-dioxo-thiomorpholino, piperidinyl, 2-oxo-piperidinyl, pyrrolyl, 2-oxo-pyrrolyl, piperazine-2-one, 8-oxa-3-aza-bicyclic [3.2.1]octyl, and piperazine. The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group. The heterocyclic group may be optionally substituted or unsubstituted.

[0049] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be connected together in a fused manner. The term "aryl" includes aromatic groups such as phenyl, naphthyl, and tetrahydronaphthyl. Preferably, aryl groups are C6-C. 10 Aryl, more preferably phenyl and naphthyl, most preferably phenyl. The aryl group may be substituted or unsubstituted. The "aryl" group may be fused with a heteroaryl, heterocyclic, or cycloalkyl group, wherein the aryl ring is attached to the parent structure. Non-limiting embodiments include, but are not limited to:

[0050] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 9- to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of "heteroaryl" include, but are not limited to, furanyl, pyridinyl, 2-oxo-1,2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiopheneyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo[a]dioxacyclopentenyl, benzimidazolyl, indoleyl, isoyindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazoleyl, benzisothiazolyl, benzo[a]oxazolyl, and benzisothiazolyl. Heteroaryl groups may be optionally substituted or unsubstituted. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. Non-limiting embodiments include, but are not limited to:

[0051] "Alkoxy" refers to an (alkyl-O-) group. Alkyl groups are defined in the relevant section of this document. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0052] "Halogenated alkyl" refers to an alkyl group having one or more halogen substituents, wherein the alkyl group has the meaning as described in this invention. Examples of halogenated alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1-dichloroethyl, 1,2-dichloropropyl, etc.

[0053] "Hydroxy" refers to the -OH group.

[0054] "Halogen" refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.

[0055] "Amino" refers to -NH2.

[0056] “Cyano” refers to -CN.

[0057] "Nitro" refers to -NO2.

[0058] "Benzyl" refers to -CH2-phenyl.

[0059] "Carboxyl group" refers to -C(O)OH.

[0060] "Acetyl" refers to -C(O)CH3 or Ac.

[0061] "Carboxylic acid ester group" refers to -C(O)O (alkyl) or (cycloalkyl), where alkyl and cycloalkyl are defined as described above.

[0062] As used herein, the term “halogenated” or “halogenated” is defined as including F, Cl, Br, or I.

[0063] As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and at least one nitrogen atom in a ring, and optionally also comprising one or more (e.g., one, two, three, or four) ring members selected from N, O, C=O, S, S=O, and S(=O)2, which are connected to the remainder of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any of the remaining ring atoms, wherein the nitrogen-containing heterocycle is optionally benzofused, and preferably connected to the remainder of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any of the carbon atoms in the fused benzene ring.

[0064] The term "substitution" refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0065] If a substituent is described as “optionally substituted,” then the substituent may be (1) unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and / or together with independently selected optional substituents. If the nitrogen of the substituent is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may each be substituted with independently selected optional substituents.

[0066] If a substituent is described as being “independently selected” from a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0067] As used herein, the term “one or more” means one or more under reasonable conditions, such as two, three, four, five or ten.

[0068] Unless otherwise specified, as used herein, the connection point of a substituent may be located at any suitable position of the substituent.

[0069] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0070] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of the present invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature.

[0071] Unless otherwise specified, "substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0072] Unless otherwise specified, the terms "substitution" or "substituted" in this specification refer to the substitution of a group by one or more groups selected from the following: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic acid ester, =O, -C(O)R b -OC(O)Rb -NR b R b -C(O)NR b R b -NR b C(O)R b -S(O)NR b R b or -S(O)2NR b R b , where R b The definition is as stated in general formula (I).

[0073] As used in this article, the “effective amount” of a compound refers to an amount sufficient to activate or inhibit potassium ion channels.

[0074] As used herein, a "therapeuticly effective dose" of a compound refers to an amount sufficient to improve or reduce symptoms in some way, or to stop or reverse disease progression. This dose can be used as a single dose or taken in a regimen to be effective.

[0075] As used here, “treatment” means any way of improving or otherwise altering a patient’s condition, disorder, or the symptoms or pathology of a disease.

[0076] As stated herein, “to improve the symptoms of a particular disease by using a particular compound or pharmaceutical composition” means any reduction, whether permanent or temporary, lasting or transient, that is attributable to or related to the use of the composition.

[0077] The definition and conventional use of stereochemistry in this invention are generally referenced in the following literature:

[0078] SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The compounds of this invention may contain asymmetric or chiral centers, and therefore exist as different stereoisomers. All stereoisomers of the compounds of this invention, including, but not limited to, diastereomers, enantiomers, transisomers, and mixtures thereof, such as racemic mixtures, constitute a part of this invention. Diastereomers can be separated into individual diastereomers based on their physicochemical differences by methods such as chromatography, crystallization, distillation, or sublimation. Enantiomers can be separated to convert a mixture of chiral isomers into a mixture of diastereomers by reacting with a suitable optically active compound (e.g., a chiral auxiliary agent, such as a chiral alcohol or Mosher's acyl chloride), separating the diastereomers and converting individual diastereomers into their corresponding pure enantiomers. The intermediates and compounds of this invention can also exist in different tautomeric forms, and all such forms are included within the scope of this invention. Many organic compounds exist in optically active forms, meaning they are capable of rotating the plane of polarized light. In describing optically active compounds, the prefixes D, L, or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l, or (+), (-) are used to name the symbol for the plane polarization rotation of the compound; (-) or l indicates that the compound is levorotatory, and the prefix (+) or d indicates that the compound is dextrorotatory. These stereoisomers have the same order of atomic or atomic groups connected to each other, but their stereostructures are different. Specific stereoisomers can be enantiomers, and mixtures of isomers are generally called enantiomer mixtures. A 50:50 enantiomer mixture is called a racemic mixture or racemate, which may result in a lack of stereoselectivity or stereodirection in chemical reactions. The terms "racemic mixture" and "racemate" refer to a mixture of two equimolar enantiomers that lack optical activity.

[0079] "Tautomer" or "tautomer form" refers to isomers of structures with different energies that can interconvert through a low energy barrier. For example, proton tautomers (i.e., proton-transfer tautomers) include interconversions via proton transfer, such as isomerizations of keto-enol and imine-enamine forms. Valence (composition) tautomers include interconversions involving the recombination of bonding electrons. Unless otherwise indicated, the structural formulas described in this invention include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers): for example, R, S configurations containing an asymmetric center, (Z), € isomers of double bonds, and (Z), € conformational isomers. Therefore, individual stereochemical isomers of the compounds of this invention, or mixtures of their enantiomers, diastereomers, or geometric isomers, are within the scope of this invention.

[0080] "Pharmaceutically acceptable salts" refers to salts of the compounds of this invention that are safe and effective when used in humans or animals. Salts of the compounds can be obtained by adding the corresponding addition salts in a pure solution or a suitable inert dissolution with sufficient amounts of base or acid. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, etc., and pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts, including hydrochloric acid, hydrobromic acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, acetic acid, maleic acid, malonic acid, succinic acid, benzoic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, and methanesulfonic acid, etc. (See Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)).

[0081] This invention covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0082] It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, chelates, complexes, inclusion compounds, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites or residues. Therefore, when referring to "compounds of the present invention" herein, it is also intended to cover the various derivative forms of the compounds described above.

[0083] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts, including but not limited to salts containing hydrogen bonds or coordination bonds.

[0084] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include acetates, adipates, aspartates, benzoates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, borates, camphor sulfonates, citrates, cyclohexanesulfonates, ethanedisulfonates, ethanesulfonates, formates, fumarates, glucohepanoates, glucuronates, hexafluorophosphates, hymenates, hydrochlorides / chlorides, hydrobromates / bromines, hydroiodates / iodides, hydroxyethyl sulfonates, lactates, malates, maleates, malonates, methanesulfonates, methyl sulfates, naphthylcarbamates, 2-naphthalenesulfonates, nicotinates, nitrates, orotates, oxalates, palmitates, dihydroxynaphthyl salts, phosphates / hydrogen phosphates / dihydrogen phosphates, pyroglutamates, glycosides, stearates, succinates, tannins, tartrates, toluenesulfonates, trifluoroacetates, and xinofoate.

[0085] Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts.

[0086] For a review of suitable salts, see Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts for the compounds of the present invention are known to those skilled in the art.

[0087] As used herein, the term "ester" means an ester derived from the various general formula compounds of this application, including physiologically hydrolyzable esters (the compounds of the present invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of the present invention may themselves also be esters.

[0088] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0089] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in TW Greene & P. ​​GMWuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0090] The term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0091] Preferred compounds of the present invention

[0092] The general formula and preferred scope of the compounds of the present invention have been described. More preferably, specific examples of the compounds of the present invention may be selected from any of the following structures, but are not limited to the following compounds:

[0093] Table 1 List of example compounds:

[0094] Typical compounds of the present invention include, but are not limited to, the compounds listed in the table above.

[0095] Example

[0096] The method of the present invention will be described below through specific embodiments to make the technical solution of the present invention easier to understand and master, but the present invention is not limited thereto.

[0097] The following examples 1 The 1H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad peak, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, its unit is Hz.

[0098] The mass spectrometry results were obtained using an LC / MS instrument, with ESI as the ionization method.

[0099] High-performance liquid chromatograph (HPLC) models: Agilent 1260, Thermo Fisher U3000; Column model: Waters xbrige C18 (4.6*150mm, 3.5μm); Mobile phase: A: ACN, B: Water (0.1% H3PO4); Flow rate: 1.0 mL / min; Gradient: 5% A for 1 min, increase to 20% A within 4 min, increase to 80% A within 8 min, 80% A for 2 min, back to 5% A within 0.1 min; Wavelength: 220 nm; Column oven: 35℃.

[0100] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used in TLC are 0.2mm-0.3mm in diameter, and the plates used for TLC separation and purification are 0.4mm-0.5mm in diameter.

[0101] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0102] In the following examples, unless otherwise specified, all temperatures are in Celsius; unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods; commercially available materials and reagents are used directly without further purification; unless otherwise specified, commercially available manufacturers include, but are not limited to, Sinopharm Group, Bailingwei Technology Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Shanghai Bid Pharmaceutical Technology Co., Ltd., and Shanghai Mairui Chemical Technology Co., Ltd.

[0103] CD3OD: deuterated methanol; CDCl3: deuterated chloroform; DMSO-d6: deuterated dimethyl sulfoxide; Pd2(dba)3: tris(dibenzylacetone)dipalladium; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride; XantPhos: 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene; XPhos: 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl; HATU: 2-(7-benzotriazole oxide)-N,N,N', N'-Tetramethylurea hexafluorophosphate; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DMAP: 4-dimethylaminopyridine; PE: petroleum ether; EA: ethyl acetate; DCM: dichloromethane; MeOH: methanol; DMF: N,N-dimethylformamide; DIPEA: N,N-diisopropylethylamine; DPPA: diphenyl azidophosphate; BOC: tert-butyloxycarbonyl; TLC: thin-layer chromatography; HPLC: high-performance liquid chromatography; purity: purity; R fIn thin-layer chromatography, the ratio of the distance from the origin to the center of the spot to the distance from the origin to the solvent front is used.

[0104] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0105] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0106] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃-30℃.

[0107] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system used for column chromatography to purify the compounds, or the developing solvent system for TLC included: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane: ethyl acetate. The volume ratio of the solvent varied depending on the polarity of the compound and could also be adjusted by adding a small amount of acidic or basic reagents, such as acetic acid or triethylamine.

[0108] Medicinal Chemistry Experimental Section

[0109] Example 1

[0110] N-(7-Cyclopropyl-5-methyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-3-fluoro-3-methylbutyramide

[0111] The first step is to synthesize compound 1b.

[0112] 1.5 g (6.44 mmol) of 3-bromo-2-fluoro-5-methylbenzoic acid 1a was suspended in 20 mL of anhydrous dichloromethane under nitrogen protection and cooled to 0 °C. Oxaloyl chloride (1.1 g, 8.67 mmol) and DMF (0.3 mL) were added dropwise. After the addition was complete, the reaction mixture was allowed to react at room temperature for 1 hour. The reaction mixture was concentrated, and the crude product was dissolved in 10 mL of anhydrous tetrahydrofuran. The mixture was cooled to 0 °C, and 10 mL of 25%-28% ammonia solution was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for 16 hours. TLC (dichloromethane:methanol = 20:1, new point R) f =0.4) indicates that the starting material was completely converted. The reaction solution was concentrated, the precipitate was filtered, washed with water (10 mL), the filter cake was collected and dried to give a white solid title compound 1b (1.45 g, yield 97%).

[0113] The second step involves the synthesis of compound 1c.

[0114] Under nitrogen protection, compound 1b (1.39 g, 5.99 mmol) was dissolved in acetonitrile (20 mL), and phosphorus oxychloride (3.67 g, 23.94 mmol) was slowly added dropwise at room temperature. After the addition was complete, the temperature was raised to 80 °C and the reaction was carried out for 2 hours. TLC (PE:EA = 3:1, new point R) f =0.8) indicates complete conversion of the starting material. The reaction solution was cooled to room temperature, concentrated, and the crude product was dissolved in ethyl acetate (20 mL). It was washed with a saturated sodium carbonate aqueous solution (30 mL), separated into layers, and the organic phase was separated. The aqueous phase was then extracted with ethyl acetate (15 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid, title compound 1c (1.25 g, 98% yield).

[0115] The third step involves the synthesis of compound 1d.

[0116] Compound 1c (1.25 g, 5.84 mmol) was dissolved in ethanol (25 mL), and hydrazine hydrate (80%, 1.4 g, 22.37 mmol) was added dropwise. After the addition was complete, the mixture was heated under reflux for 16 hours. TLC (PE:EA = 3:1, new point R) f =0.05) indicates the formation of a new point with increased polarity, indicating incomplete conversion of the starting material; therefore, the reaction was stopped. The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA = 5:1-1:1) to give a yellow solid title compound 1d (516 mg, yield 39%).

[0117] LC-MS: m / z=226.0 / 228.0[M+H] +

[0118] Step 4: Synthesis of compound 1e

[0119] Compound 1d (100 mg, 0.44 mmol) and DMAP (11 mg, 0.090 mmol) were added sequentially to tetrahydrofuran (4 mL). After the addition was complete, di-tert-butyl dicarbonate (483 mg, 2.21 mmol) was added dropwise at room temperature. After the addition was complete, the reaction was continued at room temperature for 16 hours. TLC (PE:EA = 5:1, new spot R) f =0.5) indicates that the starting material was completely converted. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (PE:EA = 30:1-15:1) to give the foamed title compound 1e (194 mg, yield 83%).

[0120] Step 5: Synthesis of compound 1f

[0121] Compound 1e (194 mg, 0.37 mmol), cyclopropylboronic acid (190 mg, 2.21 mmol), palladium acetate (8.3 mg, 0.037 mmol), tricyclohexylphosphine (10.5 mg, 0.037 mmol), and potassium phosphate (273 mg, 1.29 mmol) were added sequentially to toluene (2 mL) and water (0.5 mL), and the mixture was heated to 100 °C for 16 hours under nitrogen protection. TLC (PE:EA = 5:1, R f =0.5, product and starting material have the same polarity) and LCMS showed that the starting material was completely converted. The reaction solution was cooled to room temperature, diluted with water (5 mL), extracted with ethyl acetate (8 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA = 10:1) to give a yellow liquid title compound 1f (105 mg, yield 58%).

[0122] LC-MS: m / z = 488.3 [M+H] +

[0123] Step 6: Synthesize 1g of compound

[0124] Compound 1f (105 mg, 0.22 mmol) was dissolved in dioxane (1 mL), and a hydrogen chloride / dioxane solution (4 M, 1 mL, 4.0 mmol) was added dropwise at room temperature. After the addition was complete, the reaction was continued at room temperature for 4 hours. TLC (PE:EA = 3:1, new spot R) f =0.01) indicates complete conversion of the starting material. The reaction solution was concentrated, and the crude product was separated into layers using ethyl acetate (8 mL) and saturated sodium bicarbonate aqueous solution (15 mL). The organic phase was separated, and the aqueous phase was extracted again with ethyl acetate (8 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 1 g of the title compound as a brown liquid. The crude product was used directly in the next step.

[0125] LC-MS: m / z = 188.2 [M+H] +

[0126] Step 7: Synthesis of compound 1 hour

[0127] 1 g (500 mg, 2.67 mmol) of the compound was dissolved in 1,4-dioxane (15 mL), and phthalic anhydride (514 mg, 3.47 mmol) was added at room temperature. The mixture was heated to 120 °C and stirred for 2 hours. TLC (PE:EA = 2:1, RL) was performed. f =0.3) indicates that the reaction of the starting material is complete. The reaction solution is cooled to room temperature, concentrated, and the crude product is purified by silica gel column chromatography (PE:EA = 5:1-1:3) to give a brown solid title compound 1h (660mg, yield 78%).

[0128] LC-MS: m / z = 318.2 [M+H] +

[0129] Step 8: Synthesis of compound 1i

[0130] The compound 1h (660 mg, 2.08 mmol) was dissolved in tetrahydrofuran (10 mL), and 4-dimethylaminopyridine (51 mg, 0.41 mmol) and di-tert-butyl dicarbonate (681 mg, 3.12 mmol) were added at room temperature. The mixture was stirred at room temperature for 2 hours. TLC (PE:EA = 5:1, R f =0.7) indicates that the reaction of the starting material is complete. Water (10 mL) is added to quench the reaction, and ethyl acetate is extracted (10 mL x 3). The organic phases are combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the crude product is purified by silica gel column chromatography (PE:EA = 10:1-3:1) to give a brown solid title compound 1i (745 mg, yield 86%).

[0131] LC-MS: m / z = 418.2 [M+H] +

[0132] Step 9: Synthesis of compound 1j

[0133] Compound 1i (745 mg, 1.78 mmol) was dissolved in ethanol (10 mL), and hydrazine hydrate (334 mg, 5.34 mmol, 80%) was added at room temperature. The mixture was stirred at room temperature for 4 hours, and the solution was analyzed by TLC (PE:EA = 2:1, R0). f =0.2) indicates that the reaction of the starting material is complete. After filtration, the sample was washed with ethyl acetate (20 mL), the filtrate was concentrated, and the crude product was purified by silica gel column chromatography (PE:EA = 5:1-1:3) to obtain a brown solid title compound 1j (220 mg, yield 43%) and compound 1g (150 mg, yield 45%).

[0134] LC-MS: m / z = 232.1 [M-55] +

[0135] Step 10: Synthesis of compound 1k

[0136] Compound 1j (220 mg, 0.77 mmol) was dissolved in ethyl acetate (2 mL), followed by the addition of β-hydroxyisovaleric acid (182 mg, 1.54 mmol), 1-propylphosphonic anhydride (1.47 g, 2.31 mmol, 50% wt), and pyridine (365 mg, 4.61 mmol). The mixture was heated to 70 °C and stirred for 3 hours. TLC (PE:EA = 2:1, R0) was performed. f=0.2) indicates that the reaction of the starting material is complete. The reaction solution is cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phases are combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the crude product is purified by silica gel column chromatography (PE:EA = 5:1-2:1) to give a white solid title compound 1k (150 mg, yield 50%).

[0137] LC-MS: m / z = 388.2 [M+H] +

[0138] Step 11: Synthesis of compound 1m

[0139] Compound 1k (140 mg, 0.36 mmol) was dissolved in dichloromethane (3 mL), cooled to -70 °C, and bis(2-methoxyethyl)aminosulfur trifluoride (236 mg, 1.07 mmol) was added dropwise. The mixture was stirred at this temperature for 1 hour. TLC (PE:EA = 5:1, R0) was performed. f =0.3) indicates that the reaction of the raw materials is complete. Quenching is performed by adding saturated sodium bicarbonate aqueous solution (10 mL), followed by extraction with dichloromethane (10 mL x 3). The organic phases are combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the crude product is purified by silica gel column chromatography (PE:EA = 20:1-5:1) to give a white solid title compound 1m (103 mg, yield 73%).

[0140] LC-MS: m / z = 390.2 [M+H] +

[0141] Step 12: Synthesis of compound 1n

[0142] 1 mg (103 mg, 0.26 mmol) of compound was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 hours. TLC (PE:EA = 1:1, RL) was performed. f =0.3) indicates that the reaction of the raw materials is complete. Quenching is performed by adding saturated sodium bicarbonate aqueous solution (20 mL), followed by extraction with dichloromethane (10 mL x 3). The organic phases are combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the crude product is purified by silica gel column chromatography (PE:EA = 10:1-1:1) to give a white solid title compound 1n (64 mg, yield 85%).

[0143] LC-MS: m / z = 290.2 [M+H] +

[0144] Step 13: Synthesis of Compound 1

[0145] Compound 1n (64 mg, 0.22 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 3-bromopropyne (32 mg, 0.27 mmol) and potassium carbonate (61 mg, 0.44 mmol) were added at room temperature. The mixture was stirred at room temperature for 3 hours. TLC (PE:EA = 5:1, Rm) was performed. f =0.2) indicates a small amount of raw material remaining, so the reaction is stopped. Water (10 mL) is added to quench the reaction, and the mixture is extracted with ethyl acetate (10 mL x 3). The organic phases are combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the crude product is purified by silica gel column chromatography (PE:EA = 20:1-10:1) to give a white solid title compound 1 (16 mg, yield 22%).

[0146] LC-MS: m / z = 328.2 [M+H] + (97.40% purity, 220nm)

[0147] 1 H NMR (400MHz, DMSO-d6) δ10.36(s,1H),7.27(s,1H),6.97(s,1H),5.45(d,J=2.0Hz,2H),3.38(t,J=2.0Hz,1H),2.76 (d,J=16.4Hz,2H),2.45-2.37(m,1H),2.32(s,3H),1.52(s,3H),1.47(s,3H),1.07-1.01(m,2H),0.85-0.79(m,2H).

[0148] Example 2

[0149] N-(7-(difluoromethoxy)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-3-fluoro-3-methylbutyramide 2

[0150] The first step is to synthesize compound 2b.

[0151] 3-Bromo-2-fluorophenol 2a (1.3 g, 6.81 mmol) was dissolved in N,N-dimethylformamide (20 mL), and sodium difluorochloroacetate (2.0 g, 13.12 mmol) and cesium carbonate (4.4 g, 13.50 mmol) were added at room temperature. After the addition was complete, the reaction solution was heated to 80 °C and reacted for 2 hours. TLC (PE / EA = 10 / 1, R f =0.6) The reaction of the starting materials was checked to ensure complete reaction. The reaction solution was cooled to room temperature, diluted with water (160 mL), extracted with ethyl acetate (50 mL x 2), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give a pale yellow oily title compound 2b (1.58 g, yield 96%).

[0152] 1 H NMR (400MHz, CDCl3) δ7.46-7.39(m,1H),7.21(t,J=7.6Hz,1H),7.03(td,J=8.4,1.2Hz,1H),6.56(t,J=72.8,1H).

[0153] The second step involves the synthesis of compound 2c.

[0154] Compound 2b (1.58 g, 6.55 mmol) was dissolved in N,N-dimethylformamide (20 mL), and zinc cyanide (1.15 g, 9.83 mmol) and tetrakis(triphenylphosphine)palladium (600 mg, 0.52 mmol) were added at room temperature. After the addition was complete, the reaction solution was heated to 130 °C for 2 hours under nitrogen protection. TLC (PE / EA = 10 / 1, RL) was performed. f =0.4) The reaction mixture was tested to ensure complete reaction of the starting materials. The reaction solution was cooled to room temperature, diluted with water (120 mL), extracted with ethyl acetate (50 mL x 2), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (EA / PE = 1 / 10) to give a pale yellow oily title compound 2c (901 mg, yield 73%).

[0155] The third step involves the synthesis of compound 2d.

[0156] Compound 2c (901 mg, 4.81 mmol) was dissolved in ethanol (10 mL), and hydrazine hydrate (80%, 1.9 g, 30.36 mmol) was added at room temperature. After the addition was complete, the reaction mixture was heated to 80 °C and stirred for 5 hours. TLC (DCM / MeOH = 30 / 1, RL) was performed. f =0.8) The reaction mixture was tested to ensure the reaction was complete. The reaction solution was cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with water (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was added to petroleum ether (10 mL) and stirred for 30 minutes. The mixture was filtered, washed with petroleum ether (1 mL), the filter cake was collected, and dried to give the pale yellow oily title compound 2d (736 mg, yield 77%).

[0157] LC-MS: m / z = 200.1 [M+H] +

[0158] Step 4: Synthesis of compound 2e

[0159] Compound 2d (200 mg, 1.00 mmol) was dissolved in tetrahydrofuran (5 mL), and Boc anhydride (219 mg, 1.00 mmol) and 4-dimethylaminopyridine (10 mg) were added. After the addition was complete, the reaction mixture was allowed to react at room temperature for 2 hours. TLC (petroleum ether:ethyl acetate = 5:1, R0) was performed. f =0.6) to determine if the reaction was complete. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give a white solid title compound 2e (100 mg, yield 33%).

[0160] LC-MS: m / z = 298.1 [MH] -

[0161] Step 5: Synthesis of compound 2f

[0162] Compound 2e (100 mg, 0.33 mmol) was dissolved in acetonitrile (5 mL), and 3-hydroxy-3-methylbutyric acid (59 mg, 0.50 mmol), pyridine (79 mg, 1.00 mmol), and 1-propylphosphonic anhydride (424 mg, 0.67 mmol, 50%) were added sequentially. After the addition was complete, the reaction solution was heated to 70 °C and reacted for 3 hours. TLC (petroleum ether:ethyl acetate = 2:1, R) was performed. f =0.3) The reaction was checked to ensure it was complete. The reaction solution was cooled to room temperature, water (10 mL) was added, ethyl acetate was extracted (20 mL), saturated brine was washed (10 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC (petroleum ether: ethyl acetate = 1:1) to give brown oil title compound 2f (58 mg, yield 58%).

[0163] LC-MS: m / z = 300.2 [M+H] +

[0164] Step 6: Synthesize 2g of compound

[0165] Compound 2f (58 mg, 0.19 mmol) was dissolved in dichloromethane (10 mL). The reaction solution was cooled to -65 °C, and bis(2-methoxyethyl)aminosulfur trifluoride (86 mg, 0.39 mmol) was added. After the addition was complete, the reaction solution was reacted at -65 °C for 1 hour. TLC (dichloromethane:methanol = 25:1, R0) was performed. f =0.4) to determine if the reaction was complete. The reaction solution was concentrated, and the crude product was purified by Prep-TLC (dichloromethane:methanol = 30:1) to give 2 g (43 mg, yield 74%) of the title compound as a white solid.

[0166] LC-MS: m / z = 302.1 [M+H] +

[0167] Step 7: Synthesize compound 2

[0168] 2 g (20 mg, 0.066 mmol) of the compound was dissolved in 2 mL of N,N-dimethylformamide, followed by the addition of potassium carbonate (18 mg, 0.13 mmol) and bromopropyne (8 mg, 0.067 mmol). After the addition was complete, the reaction mixture was reacted at 25 °C for 5 hours. TLC (petroleum ether:ethyl acetate = 4:1, R0) was performed. f =0.5) to detect complete reaction. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (15 mL), washed with saturated salt (10 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC (petroleum ether:ethyl acetate = 4:1) to give a white powdery solid title compound 2 (14 mg, yield 62%).

[0169] LC-MS: m / z = 340.1 [M+H] + (99.28% purity, 220nm)

[0170] 1 H NMR (400MHz, DMSO-d6) δ10.61(s,1H),7.60(d,J=8.0Hz,1H),7.40(t,J=73.6Hz,1H),7.21(d,J=7.2Hz,1H),7.13 (t,J=8.0Hz,1H),5.25(d,J=2.4Hz,2H),3.36(t,J=2.4Hz,1H),2.78(d,J=16.8Hz,2H),1.52(s,3H),1.47(s,3H).

[0171] Example 3

[0172] N-(7-(difluoromethoxy)-1-propyl-1H-indazol-3-yl)-3-fluoro-3-methylbutyramide

[0173] The first step is to synthesize compound 3.

[0174] 2 g (23 mg, 0.076 mmol) of the compound was dissolved in 2 mL of N,N-dimethylformamide, cooled to 0 °C, and sodium hydride (6 mg, 0.15 mmol, 60%) was added. The mixture was stirred for ten minutes, and then bromopropane (10 mg, 0.081 mmol) was added. After the addition was complete, the reaction mixture was heated to 50 °C and reacted for 3 hours. TLC (dichloromethane:methanol = 20:1, R0) was performed. f=0.5) to detect complete reaction. The reaction solution was cooled to room temperature, diluted with water (15 mL), extracted with ethyl acetate (15 mL × 3), washed with saturated salt (10 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-HPLC to give a white powdery solid title compound 3 (2.63 mg, yield 10%).

[0175] LC-MS: m / z = 344.2 [M+H] + (98.27% purity, 220nm)

[0176] 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),7.56(d,J=8.0Hz,1H),7.42(t,J=73.2Hz,1H),7.15(d,J=7.6Hz,1H),7.06(t,J=8.0 Hz,1H),4.40(t,J=6.8Hz,2H),2.77(d,J=16.8Hz,2H),1.87-1.73(m,2H),1.52(s,3H),1.47(s,3H),0.84(t,J=7.2Hz,3H).

[0177] Example 4

[0178] N-(7-(difluoromethoxy)-5-methyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-3-fluoro-3-methylbutyramide 4

[0179] The first step is to synthesize compound 4a.

[0180] Compound 1c (300 mg, 1.40 mmol), pinacol diboronate (463 mg, 1.82 mmol), potassium acetate (276 mg, 2.84 mmol), and Pd(dppf)Cl2 dichloromethane complex (58 mg, 0.070 mmol) were sequentially added to dioxane (8 mL), and the mixture was heated to 90 °C for 2 hours under nitrogen protection. TLC (PE:EA = 20:1, new point R) f =0.1) indicates complete conversion of the starting material. The reaction solution was cooled to room temperature, filtered, washed with ethyl acetate (15 mL), the filtrate was concentrated, the crude product was diluted with water (15 mL), extracted with ethyl acetate (10 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude title compound 4a, which was used directly in the next step.

[0181] The second step involves the synthesis of compound 4b.

[0182] Compound 4a (crude product) was dissolved in tetrahydrofuran (5 mL), cooled to 0 °C, and sodium bicarbonate (471 mg, 5.61 mmol) and hydrogen peroxide (30%, 2 mL) were added sequentially. After the addition was complete, the mixture was allowed to react at room temperature for 1.5 hours. The reaction solution was diluted with water (15 mL), extracted with ethyl acetate (10 mL * 3), and the combined organic phases were washed with saturated sodium thiosulfate solution (15 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA = 10:1-5:1) to give a white solid title compound 4b (139 mg, two-step yield 66%).

[0183] 1 H NMR (400MHz, DMSO-d6) δ10.59(s,1H),7.13-7.05(m,2H),2.24(s,3H).

[0184] The third step involves the synthesis of compound 4c.

[0185] Compound 4b (139 mg, 0.92 mmol), cesium carbonate (600 mg, 1.84 mmol), and sodium difluorochloroacetate (281 mg, 1.84 mmol) were added sequentially to DMF (3 mL). After the additions were complete, the mixture was heated to 80 °C and reacted for 2 hours. TLC (PE:EA = 5:1, new point R) f =0.4) indicates that the starting material was completely converted. The reaction solution was cooled to room temperature, poured into water (30 mL), extracted with ethyl acetate (7 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a yellow oily title compound 4c (134 mg, yield 72%).

[0186] 1 H NMR (400MHz, DMSO-d6) δ7.66(d,J=5.2Hz,1H),7.62(d,J=7.6Hz,1H),7.30(t,J=72.4Hz,1H),2.35(s,3H).

[0187] Step 4: Synthesis of compound 4d

[0188] Compound 4c (134 mg, 0.67 mmol) and hydrazine hydrate (80%, 417 mg, 6.67 mmol) were added sequentially to n-butanol (2 mL). After the addition was complete, the mixture was heated to 110 °C and reacted for 3 hours. TLC (PE:EA = 3:1, new point R) f =0.05) indicates that the starting material was completely converted. The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA = 10:1-1:1) to give a yellow solid title compound 4d (114 mg, yield 80%).

[0189] LC-MS: m / z = 214.1 [M+H] +

[0190] 1 H NMR (400MHz, DMSO-d6) δ11.62(s,1H),7.33(s,1H),7.26(t,J=74.4Hz,1H),6.88(s,1H),5.32(s,2H),2.35(s,3H).

[0191] Step 5: Synthesis of compound 4e

[0192] Compound 4d (280 mg, 1.31 mmol) was dissolved in tetrahydrofuran (5 mL), and 4-dimethylaminopyridine (16 mg, 0.13 mmol) and di-tert-butyl dicarbonate (286 mg, 1.31 mmol) were added at room temperature. The mixture was stirred at room temperature for 16 hours, and the solution was analyzed by TLC (PE:EA = 5:1, R0). f =0.3) indicates that the reaction of the raw materials is complete. Water (10 mL) is added to quench the reaction, and ethyl acetate is extracted (10 mL x 3). The organic phases are combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the crude product is purified by silica gel column chromatography (PE:EA = 20:1-5:1) to give a brownish solid title compound 4e (165 mg, yield 40%).

[0193] LC-MS: m / z = 214.1[M+1-Boc] +

[0194] 1 H NMR (400MHz, DMSO-d6) δ7.43(t,J=74.8Hz,1H),7.36(s,2H),7.32-7.31(m,1H),6.77(s,1H),2.23(d,J=0.8Hz,3H),1.62(s,9H).

[0195] Step 6: Synthesis of compound 4f

[0196] Compound 4e (165 mg, 0.53 mmol) was dissolved in 3 mL of water, and β-hydroxyisovaleric acid (125 mg, 1.06 mmol), 1-propylphosphonic anhydride (1.01 g, 1.59 mmol, 50% wt), and pyridine (252 mg, 3.18 mmol) were added sequentially. The mixture was heated to 70 °C and stirred for 3 hours. TLC (PE:EA = 1:1, R f=0.1) indicates that the reaction of the starting material is complete. The reaction solution is cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phases are combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the crude product is purified by silica gel column chromatography (PE:EA = 5:1-1:1) to give brown solid title compound 4f (100 mg, yield 60%).

[0197] LC-MS: m / z = 314.1 [M+H] +

[0198] Step 7: Synthesize 4g of compound

[0199] Compound 4f (80 mg, 0.26 mmol) was dissolved in dichloromethane (3 mL), cooled to -70 °C, and bis(2-methoxyethyl)aminosulfur trifluoride (288 mg, 1.30 mmol) was added dropwise. The mixture was stirred at this temperature for 1 hour. LC-MS showed a small amount of starting material remaining, at which point the reaction was stopped. The reaction was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with dichloromethane (10 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA = 5:1-2:1) to give 4 g (50 mg, yield 61%) of the title compound as a white solid.

[0200] LC-MS: m / z = 316.1 [M+H] +

[0201] Step 8: Synthesis of compound 4

[0202] 4 g (50 mg, 0.16 mmol) of the compound was dissolved in N,N-dimethylformamide (1 mL), and 23 mg (0.19 mmol) of 3-bromopropyne and 44 mg (0.32 mmol) were added at room temperature. The mixture was stirred at room temperature for 3 hours. TLC (PE:EA = 5:1, R0) was performed. f =0.2) showed a small amount of raw material remaining, which was quenched with water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA = 20:1-10:1) to give a white solid title compound 4 (21 mg, yield 37%).

[0203] LC-MS: m / z = 354.2 [M+H] + (95.16% purity, 220nm)

[0204] 1H NMR (400MHz, DMSO-d6) δ10.52(s,1H),7.38(t,J=73.2Hz,1H),7.35(s,1H),7.07(s,1H),5.21(d,J =2.0Hz,2H),3.34(t,J=2.4Hz,1H),2.77(d,J=16.4Hz,2H),2.39(s,3H),1.52(s,3H),1.47(s,3H).

[0205] Example 5

[0206] N-(7-Cyclopropyl-1-(Prop-2-yn-1-yl)-1H-indazol-3-yl)-3,3-dimethylbutyramide 5

[0207] The first step is to synthesize compound 5b.

[0208] 7-Bromo-1H-indazole-3-amine 5a (2.00 g, 9.43 mmol) was dissolved in toluene (20 mL) and water (6 mL), followed by the addition of cyclopropylboronic acid (5.67 g, 66.01 mmol), tricyclohexylphosphine (0.53 g, 1.89 mmol), potassium phosphate (6.01 g, 28.29 mmol), and palladium acetate (0.42 g, 1.89 mmol). The mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. TLC (PE:EA = 1:1, R0) was performed. f =0.1) indicates that the reactants have reacted completely. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, quenched with water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA = 2:1-2:3) to give a white solid title compound 5b (0.69 g, yield 42%).

[0209] LC-MS: m / z = 174.2 [M+H] +

[0210] The second step involves the synthesis of compound 5c.

[0211] Compound 5b (200 mg, 1.15 mmol) was dissolved in pyridine (3 mL), cooled to 0 °C, and 3,3-dimethylbutyryl chloride (124 mg, 0.92 mmol) was added. After the addition was complete, the reaction solution was brought to room temperature and reacted for 1 hour. TLC (petroleum ether:ethyl acetate = 3:1, R0) was performed. f =0.4) to detect complete reaction. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give brown solid title compound 5c (100 mg, yield 32%).

[0212] Step 3: Synthesis of Compound 5

[0213] Compound 5c (100 mg, 0.37 mmol) was dissolved in N,N-dimethylformamide (2 mL), followed by the addition of potassium carbonate (153 mg, 1.10 mmol) and bromopropyne (44 mg, 0.37 mmol). After the addition was complete, the reaction mixture was allowed to react at 25 °C for 5 hours. TLC analysis confirmed the reaction was complete (petroleum ether:ethyl acetate = 4:1, R0). f =0.5). The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (15 mL), washed with saturated salt (10 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-HPLC to give a white powdery solid title compound 5 (40 mg, yield 35%).

[0214] LC-MS: m / z = 310.2 [M+H] + (99.58% purity, 210nm)

[0215] 1 H NMR (400MHz, DMSO-d6) δ10.26(s,1H),7.54(d,J=8.0Hz,1H),7.13(d,J=6.8Hz,1H),7.01(t,J=7.6Hz ,1H),5.49(d,J=2.4Hz,2H),3.39(t,J=2.4Hz,1H),2.47-2.41(m,1H),2.26(s,2H),1.07(s,9H),1.04 -1.02(m,2H),0.85-0.81(m,2H).

[0216] Example 6

[0217] N-(7-(difluoromethoxy)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-3,3-dimethylbutyramide 6

[0218] The first step is to synthesize compound 6a.

[0219] 7-(difluoromethoxy)-1H-indazole-3-amine 2d (100 mg, 0.50 mmol) was dissolved in pyridine (1 mL). The reaction solution was cooled to 0 °C, and 3,3-dimethylbutyryl chloride (67 mg, 0.50 mmol) was added. After the addition was complete, the mixture was allowed to rise to room temperature and reacted for 3 hours. TLC (petroleum ether:ethyl acetate = 3:1, new spot R) was performed. f=0.5) indicates that a small amount of raw material remains, so the reaction is stopped. The reaction solution is poured into dilute hydrochloric acid (1N, 10mL), extracted with ethyl acetate (5mL×2), the organic phases are combined, washed with saturated brine (5mL), dried over anhydrous sodium sulfate, concentrated, and the crude product is purified by Pre-TLC (petroleum ether:ethyl acetate = 3:2) to give a white powder, title compound 6a (145mg, yield 97%).

[0220] LC-MS: m / z = 298.2 [M+H] +

[0221] Step 2: Synthesis of compound 6

[0222] Compound 6a (80 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (1.5 mL), potassium carbonate (75 mg, 0.53 mmol) was added, the mixture was cooled to 0 °C, and bromopropyne (38 mg, 0.32 mmol) was added. After the addition was complete, the reaction mixture was heated to 25 °C and reacted for 16 hours. TLC (petroleum ether:ethyl acetate = 3:1, new point R) was used. f =0.5) indicates that the reaction mixture has reacted completely. The reaction mixture was extracted with water (15 mL) and ethyl acetate (3 mL × 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Pre-HPLC to give a white powder, title compound 6 (22 mg, yield 24%).

[0223] LC-MS: m / z = 336.1 [M+1] + (99.47% purity, 220nm)

[0224] 1 H NMR (400MHz, DMSO-d6) δ10.42(s,1H),7.60(d,J=7.6Hz,1H),7.40(t,J=73.2Hz,1H),7.21(d,J=7.2H z,1H),7.12(t,J=8.0Hz,1H),5.24(d,J=2.4Hz,2H),3.36(t,J=2.4Hz,1H),2.28(s,2H),1.07(s,9H).

[0225] Example 7

[0226] N-(7-(difluoromethoxy)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-2-(1-methylcyclopropyl)acetamide 7

[0227] The first step is to synthesize compound 7a.

[0228] Compound 2e (99 mg, 0.33 mmol) was dissolved in ethyl acetate (3 mL), followed by the sequential addition of 2-(1-methylcyclopropyl)acetic acid (25 mg, 0.22 mmol), 1-propylphosphoric anhydride (630 mg, 0.99 mmol, 50% wt), and pyridine (252 mg, 3.18 mmol). After the addition was complete, the mixture was heated to 70 °C and stirred for 3 hours. TLC (PE:EA = 3:1, R0) was performed. f =0.2) indicates that the starting material has reacted completely. The reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA = 20:1-3:1) to give a white solid title compound 7a (50 mg, yield 51%).

[0229] LC-MS: m / z = 296.1 [M+H] +

[0230] Step 2: Synthesis of compound 7

[0231] Compound 7a (50 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 3-bromopropyne (24 mg, 0.20 mmol) and potassium carbonate (47 mg, 0.34 mmol) were added at room temperature. The mixture was stirred at room temperature for 3 hours. TLC (PE:EA = 5:1, R0) was performed. f =0.2) indicates that the reaction of the raw materials is complete. Water (10 mL) is added to quench the reaction, and ethyl acetate is extracted (10 mL x 3). The organic phases are combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the crude product is purified by silica gel column chromatography (PE:EA = 20:1-5:1) to give a white solid title compound 7 (22 mg, yield 39%).

[0232] LC-MS: m / z = 334.1 [M+H] + (97.95% purity, 210nm)

[0233] 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),7.63(d,J=8.0Hz,1H),7.40(t,J=73.2Hz,1H),7.24-7.20(m,1H),7.13(t,J=8 .0Hz,1H),5.25(d,J=2.4Hz,2H),3.41-3.37(m,1H),2.32(s,2H),1.16(s,3H),0.57-0.51(m,2H),0.36-0.30(m,2H).

[0234] Example 8

[0235] N-(7-Cyclopropyl-1-(Prop-2-yn-1-yl)-1H-indazol-3-yl)-2-(1-Methylcyclopropyl)acetamide

[0236] The first step is to synthesize compound 8a.

[0237] 7-Cyclopropyl-1H-indazole-3-amine 5b (1.34 g, 7.74 mmol) and phthalic anhydride (1.49 g, 10.06 mmol) were added sequentially to dioxane (30 mL), and the mixture was heated to 120 °C and reacted for 5 hours. TLC (PE:EA = 5:1, new spot R) was performed. f =0.05) indicates that the starting material was completely converted. The reaction solution was cooled to room temperature, concentrated, and the crude product was slurried with ethyl acetate (15 mL) to give a white solid, title compound 8a (1.77 g, 75% yield).

[0238] The second step involves the synthesis of compound 8b.

[0239] Compound 8a (1.77 g, 5.84 mmol) and DMAP (142 mg, 1.17 mmol) were dissolved in tetrahydrofuran (20 mL), and Boc anhydride (1.95 g, 8.94 mmol) was added. After the addition was complete, the reaction was allowed to proceed at room temperature for 24 hours. TLC (PE:EA = 3:1, new spot R) f =0.5) indicates that a small amount of raw material remains. Stop the reaction. Concentrate the reaction solution, and the crude product is subjected to silica gel column chromatography (3%-15% EA in PE) to give a white, foamy title compound 8b (1.31 g, yield 56%).

[0240] The third step involves the synthesis of compound 8c.

[0241] Compound 8b (1.31 g, 3.25 mmol) was dissolved in ethanol (10 mL), and hydrazine hydrate (609 mg, 9.71 mmol, 80%) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 hour. TLC (PE:EA = 3:1, new spot R) was recorded. f =0.2) indicates complete conversion of the starting material. The precipitate was filtered, washed with ethanol (15 mL), concentrated, and the crude product was subjected to silica gel column chromatography (25% EA in PE) to give a white solid title compound 8c (702 mg, yield 79%).

[0242] Step 4: Synthesis of compound 8d

[0243] Compound 8c (90 mg, 0.33 mmol) was dissolved in ethyl acetate (1 mL), followed by the addition of 2-(1-methylcyclopropyl)acetic acid (25 mg, 0.22 mmol), 1-propylphosphoric anhydride (630 mg, 0.99 mmol, 50% wt), and pyridine (157 mg, 1.98 mmol). The mixture was heated to 70 °C and stirred for 3 hours. TLC (PE:EA = 5:1, R0) was performed. f =0.2) indicates that the starting material has reacted completely. The reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA = 20:1-5:1) to give a white solid title compound 8d (78 mg, yield 64%).

[0244] LC-MS: m / z = 370.2 [M+H] +

[0245] Step 5: Synthesis of compound 8e

[0246] Compound 8d (78 mg, 0.21 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. TLC (PE:EA = 1:1, RL) was then performed. f =0.4) indicates that the reaction of the raw materials is complete. Quenching is performed by adding saturated sodium bicarbonate aqueous solution (20 mL), followed by extraction with dichloromethane (10 mL x 3). The organic phases are combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the crude product is purified by silica gel column chromatography (PE:EA = 3:1-1:1) to give a white solid title compound 8e (55 mg, yield 97%).

[0247] LC-MS: m / z = 270.2 [M+H] +

[0248] Step 6: Synthesize compound 8

[0249] Compound 8e (55 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 3-bromopropyne (29 mg, 0.24 mmol) and potassium carbonate (55 mg, 0.40 mmol) were added at room temperature. The mixture was stirred at room temperature for 16 hours. TLC (PE:EA = 5:1, R0) was performed. f=0.2) indicates a small amount of raw material remaining, so the reaction is stopped. Water (10 mL) is added to quench the reaction, followed by extraction with ethyl acetate (10 mL x 3). The organic phases are combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the crude product is purified by silica gel column chromatography (PE:EA = 20:1-10:1) to give a white solid title compound 8 (11 mg, yield 18%).

[0250] LC-MS: m / z = 308.2 [M+H] + (99.19% purity, 210nm)

[0251] 1 H NMR (400MHz, DMSO-d6) δ10.23(s,1H),7.56(d,J=8.0Hz,1H),7.14(d,J=7.2Hz,1H),7.02(t,J=7.6Hz,1H),5.49(d,J=2.0Hz,2H),3.41- 3.39(m,1H),2.48-2.40(m,1H),2.30(s,2H),1.16(s,3H),1.09-1.02(m,2H),0.87-0.80(m,2H),0.58-0.51(m,2H),0.36-0.30(m,2H).

[0252] Example 9

[0253] N-(7-(difluoromethoxy)-5-methyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-3,3-dimethylbutyramide 9

[0254] The first step is to synthesize compound 9a.

[0255] Compound 4d (68 mg, 0.32 mmol) was dissolved in pyridine (1 mL), cooled to 0 °C, and 3,3-dimethylbutyryl chloride (43 mg, 0.32 mmol) was added dropwise. The mixture was then brought to room temperature and stirred for 2 hours. TLC (PE:EA = 2:1, R f =0.4) indicates that the reaction of the starting material is complete. After concentration, the crude product is purified by silica gel column chromatography (PE:EA = 10:1-3:1) to give a white solid title compound 9a (73 mg, yield 73%).

[0256] LC-MS: m / z = 312.2 [M+H] +

[0257] Step 2: Synthesis of compound 9

[0258] Compound 9a (73 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 3-bromopropyne (33 mg, 0.28 mmol) and potassium carbonate (64 mg, 0.46 mmol) were added at room temperature. The mixture was stirred at room temperature for 16 hours. TLC (PE:EA = 5:1, R f =0.3) indicates that the reaction of the starting material is complete. Water (10 mL) is added to quench the reaction, and ethyl acetate is extracted (10 mL x 3). The organic phases are combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the crude product is purified by silica gel column chromatography (PE:EA = 10:1-5:1) to give a white solid title compound 9 (28 mg, yield 35%).

[0259] LC-MS: m / z = 350.2 [M+H] + (99.54% purity, 220nm)

[0260] 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),7.38(t,J=73.2H,1H),7.35(s,1H),7.06(s,1 H),5.20(d,J=2.4Hz,2H),3.35-3.34(m,1H),2.39(s,3H),2.27(s,2H),1.06(s,9H).

[0261] Example 10

[0262] N-(7-Cyclopropyl-5-methyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-3,3-dimethylbutyramide 10

[0263] The first step is to synthesize compound 10a.

[0264] 1 g (50 mg, 0.27 mmol) of the compound was dissolved in pyridine (1 mL). The reaction solution was cooled to 0 °C, and 3,3-dimethylbutyryl chloride (36 mg, 0.27 mmol) was added. After the addition was complete, the reaction was carried out at 25 °C for 3 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 3:1, R0). f =0.4) indicates that the reactants have reacted completely. The reaction solution was diluted with dilute hydrochloric acid (1N, 5mL), and a solid precipitated out. The mixture was filtered, the filter cake was collected, and dried to give a white solid, title compound 10a (56mg, yield 73%).

[0265] LC-MS: m / z = 286.2 [M+H] +

[0266] Step 2: Synthesis of compound 10

[0267] Compound 10a (56 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (1 mL), potassium carbonate (55 mg, 0.40 mmol) was added, the mixture was cooled to 0 °C, and bromopropyne (28 mg, 0.24 mmol) was added. After the addition was complete, the reaction mixture was heated to 25 °C and reacted for 16 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 2:1, R0). f =0.4) indicates that a small amount of raw material remains, so the reaction is stopped. The reaction solution is diluted with water (7 mL), extracted with ethyl acetate (3 mL × 2), the organic phases are combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product is purified by Pre-TLC (petroleum ether:ethyl acetate = 4:1) to give a white powder, title compound 10 (19 mg, yield 30%).

[0268] LC-MS: m / z = 324.2 [M+1] + (99.59% purity, 220nm)

[0269] 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),7.28(s,1H),6.96(s,1H),5.44(d,J=2.0Hz,2H),3.37(t,J=2.4H z,1H),2.45-2.36(m,1H),2.32(s,3H),2.25(s,2H),1.06(s,9H),1.05-1.01(m,2H),0.85-0.79(m,2H).

[0270] Example 11

[0271] N-(7-(difluoromethoxy)-1-isopropyl-1H-indazol-3-yl)-3,3-dimethylbutyramide 11

[0272] The first step is to synthesize compound 11.

[0273] Compound 6a (50 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 2-bromopropane (32 mg, 0.26 mmol) and cesium carbonate (110 mg, 0.34 mmol) were added at room temperature. The mixture was heated to 60 °C and stirred for 2 hours. TLC (PE:EA = 5:1, R0) was performed. f=0.4,0.2) indicates that the starting material has reacted completely. The reaction solution was cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA = 20:1-5:1) to give a white solid title compound 11 (18 mg, yield 31%) and byproduct 11-P (9 mg, yield 16%).

[0274] Compound 11:

[0275] LC-MS: m / z = 340.2 [M+H] + (98.86% purity, 210nm)

[0276] 1 H NMR (400MHz, DMSO-d6) δ10.36(s,1H),7.54(d,J=8.0Hz,1H),7.41(t,J=73.6Hz,1H),7.16(d,J=7.6 Hz,1H),7.06(t,J=8.0Hz,1H),5.25-5.15(m,1H),2.27(s,2H),1.46(d,J=6.8Hz,6H),1.07(s,9H).

[0277] Compound 11-P:

[0278] LC-MS: m / z = 340.2 [M+H] + (98.61% purity, 210nm)

[0279] 1 H NMR(400MHz,DMSO-d6)δ10.13(s,1H),7.55(t,J=74.8H,1H),7.29-7.24(m,1H),7.0 1-6.94(m,2H),4.79-4.70(m,1H),2.34(s,2H),1.49(d,J=6.8Hz,6H),1.10(s,9H).

[0280] Example 12

[0281] N-(1-Cyclopropyl-7-(Difluoromethoxy)-1H-Indazol-3-yl)-3,3-Dimethylbutyramide 12

[0282] The first step is to synthesize compound 12.

[0283] Compound 6a (50 mg, 0.17 mmol) was dissolved in 1,4-dioxane (1 mL), followed by the sequential addition of cyclopropylboronic acid (14 mg, 0.16 mmol), copper acetate (34 mg, 0.17 mmol), 4-dimethylaminopyridine (61 mg, 0.50 mmol), and pyridine (16 mg, 0.20 mmol). After the addition was complete, the reaction mixture was heated to 100 °C and reacted for 10 hours. TLC monitoring was performed (petroleum ether:ethyl acetate = 4:1, new spot R). f =0.5) indicates that the reactants have reacted completely. The reaction solution was cooled to room temperature, filtered through a diatomaceous earth filter, and the filter cake was washed with methanol (3 mL). The filtrate was concentrated, and the crude product was purified by Pre-TLC (petroleum ether: ethyl acetate = 5:1) to give a white solid title compound 12 (2 mg, yield 3.6%).

[0284] LC-MS: m / z = 338.2 [M+1] + (99.48% purity, 210nm)

[0285] 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),7.55(d,J=7.6Hz,1H),7.37(t,J=73.6Hz,1H),7.18(d,J=5.6Hz,1H) ,7.07(t,J=8.0Hz,1H),3.90-3.84(m,1H),2.25(s,2H),1.27-1.21(m,2H),1.20-1.13(m,2H),1.06(s,9H).

[0286] Example 13

[0287] N-(1-(tert-butyl)-7-(difluoromethoxy)-1H-indazol-3-yl)-3,3-dimethylbutyramide 13

[0288] The first step is to synthesize compound 13.

[0289] Compound 6a (100 mg, 0.35 mmol) was dissolved in N-methylpyrrolidone (3 mL), followed by the addition of sodium hydroxide (43 mg, 1.06 mmol) and tert-butyl bromide (3 mL). After the addition was complete, the reaction mixture was heated to 90 °C and reacted for 16 hours. TLC analysis showed that a large amount of raw material remained (petroleum ether: ethyl acetate = 5:1, R...). f=0.6), stop the reaction. Cool the reaction solution to room temperature, dilute with water (10 mL), extract with ethyl acetate (15 mL), wash with saturated salt (10 mL), dry with anhydrous sodium sulfate, concentrate, and purify the crude product by Prep-TLC (petroleum ether:ethyl acetate = 5:1) to give a white powdery solid title compound 13 (6 mg, yield 5%).

[0290] LC-MS: m / z = 354.2 [M+H] + (96.73% purity, 210nm)

[0291] 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),7.55(t,J=73.2Hz,1H),7.47-7.42(m,1H),7.14-7.09(m,2H),2.26(s,2H),1.71(s,9H),1.07(s,9H).

[0292] Example 14

[0293] N-(1-Cyclobutyl-7-(difluoromethoxy)-1H-indazol-3-yl)-3,3-dimethylbutyramide 14

[0294] The first step is to synthesize compound 14.

[0295] Compound 6a (70 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of cesium carbonate (161 mg, 0.50 mmol) and cyclobutyl bromide (37 mg, 0.27 mmol). After the addition was complete, the reaction mixture was heated to 90 °C and reacted for 2 hours. The reaction was confirmed to be complete by TLC (petroleum ether:ethyl acetate = 5:1, R0). f =0.6). The reaction solution was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (15 mL), washed with saturated salt (10 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-HPLC to give a white powdery solid title compound 14 (30 mg, yield 34%).

[0296] LC-MS: m / z = 352.2 [M+H] + (99.94% purity, 220nm)

[0297] 1H NMR (400MHz, DMSO-d6) δ10.39(s,1H),7.55(d,J=8.0Hz,1H),7.39(t,J=73.6Hz,1H),7.16(d,J=7.6Hz,1H),7.06(t, J=8.0Hz,1H),5.48-5.37(m,1H),2.69-2.54(m,2H),2.46-2.35(m,2H),2.28(s,2H),1.88-1.75(m,2H),1.07(s,9H).

[0298] Example 15

[0299] N-(7-(difluoromethoxy)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-3,3-difluorocyclobutane-1-carboxamide 15

[0300] The first step is to synthesize compound 15b.

[0301] 200 mg (1.47 mmol) of 3,3-difluorocyclobutane-1-carboxylic acid 15a was dissolved in 5 mL of dichloromethane, purged twice with nitrogen, and cooled to 0 °C. Oxaloyl chloride (746 mg, 5.88 mmol) and dry N,N-dimethylformamide (0.1 mL) were added. After the addition was complete, the reaction mixture was brought to room temperature and reacted for 3 hours. The reaction mixture was concentrated to obtain a colorless, transparent, oily title compound 15b (225 mg, crude product), which was directly added to the next step of the reaction.

[0302] The second step involves the synthesis of compound 15c.

[0303] Compound 2d (200 mg, 1.00 mmol) was dissolved in pyridine (5 mL). The reaction solution was cooled to 0 °C, and a dry tetrahydrofuran solution (4 mL) of compound 15b (225 mg, crude product) was slowly added dropwise. After the addition was complete, the reaction solution was slowly raised to room temperature and reacted for 1 hour. The reaction was confirmed to be complete by TLC (petroleum ether: ethyl acetate = 3:1, R0). f =0.5). The reaction solution was acidified to pH=6 with dilute hydrochloric acid (1N), extracted with ethyl acetate (15mL), washed with saturated brine (10mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was pulped (petroleum ether:ethyl acetate = 5:1, 6mL) to give a white solid title compound 15c (184mg, yield 58%).

[0304] LC-MS: m / z = 318.1 [M+H] +

[0305] Step 3: Synthesis of compound 15

[0306] Compound 15c (50 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (2 mL), followed by the addition of potassium carbonate (44 mg, 0.32 mmol) and bromopropyne (19 mg, 0.16 mmol). After the addition was complete, the reaction mixture was incubated at 25 °C for 4 hours. TLC analysis confirmed the reaction was complete (petroleum ether:ethyl acetate = 5:1, R0). f =0.5). The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (15 mL), washed with saturated salt (10 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC (petroleum ether:ethyl acetate = 5:1) to give a white solid title compound 15 (15 mg, yield 27%).

[0307] LC-MS: m / z = 356.1 [M+H] + (97.53% purity, 210nm)

[0308] 1 H NMR (400MHz, DMSO-d6) δ10.77(s,1H),7.67(d,J=8.4Hz,1H),7.40(t,J=73.2Hz,1H),7.22-7.19 (m,1H),7.13(t,J=7.6Hz,1H),5.25(s,2H),3.37(s,1H),3.27-3.18(m,1H),2.92-2.77(m,4H).

[0309] Example 16

[0310] 2-(3,3-Difluorocyclobutyl)-N-(7-(difluoromethoxy)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)acetamide 16

[0311] The first step is to synthesize compound 16b.

[0312] 2-(3,3-difluorocyclobutyl)acetic acid 16a (50 mg, 0.33 mmol) was dissolved in dichloromethane (1.5 mL), cooled to 0 °C, and oxaloyl chloride (0.08 mL, 0.95 mmol) and DMF (2 drops) were added. After the addition was complete, the mixture was heated to room temperature and reacted for 2 hours. The mixture was then concentrated to obtain a colorless oily substance 16b (53 mg, 95% yield).

[0313] The second step involves the synthesis of compound 16c.

[0314] Compound 2d (60 mg, 0.30 mmol) was dissolved in pyridine (1 mL), cooled to 0 °C, and compound 16b (51 mg, 0.30 mmol) was added. After the addition was complete, the mixture was allowed to rise to room temperature and reacted for 1 hour. TLC (PE:EA = 1:1, RL) was performed.f =0.3) The reaction was detected as complete. Water (30 mL) was added to quench the reaction, and the mixture was concentrated. The aqueous phase was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 10:1-5:1-2:1) to give a yellow solid title compound 16c (30 mg, yield 30%).

[0315] Step 3: Synthesis of compound 16

[0316] Compound 16c (30 mg, 0.09 mmol) was dissolved in DMF (1 mL), cooled to 0 °C, and potassium carbonate (25 mg, 0.18 mmol) and 3-bromopropyne (11 mg, 0.09 mmol) were added. After the addition was complete, the mixture was allowed to react at room temperature for 16 hours. TLC (PE:EA = 2:1, R f =0.4) The reaction was detected as complete, water (30 mL) was added to quench, ethyl acetate (10 mL × 3) was used for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC (PE:EA = 3:1) to give a white solid title compound 16 (20 mg, yield 60%).

[0317] LC-MS: m / z = 370.1 [M+H] + (98.07% purity, 220nm)

[0318] 1 H NMR (400MHz, DMSO-d6) δ10.58(s,1H),7.62(d,J=8.0Hz,1H),7.40(t,J=73.2Hz,1H),7.24-7.18(m,1H),7.11(t,J=8.0Hz,1H ),5.24(d,J=2.4Hz,2H),3.36(t,J=2.4Hz,1H),2.82-2.69(m,2H),2.68-2.62(m,2H),2.59-2.52(m,1H),2.46-2.32(m,2H).

[0319] Example 17

[0320] N-(7-(difluoromethoxy)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-2-propylpentanamide 17

[0321] The first step is to synthesize compound 17b.

[0322] Valproic acid 17a (72 mg, 0.50 mmol) was dissolved in dichloromethane (1 mL). Under nitrogen protection, the mixture was cooled to 0 °C, and oxaloyl chloride (82 mg, 0.65 mmol) and N,N-dimethylformamide (36 mg, 0.50 mmol) were slowly added dropwise. After the addition was complete, the reaction solution was heated to 25 °C and reacted for 1 hour. The reaction solution was concentrated to give brown oily title compound 17b (81 mg, crude product was used directly in the next step of the reaction).

[0323] The second step involves the synthesis of compound 17c.

[0324] 7-(difluoromethoxy)-1H-indazole-3-amine 2d (100 mg, 0.50 mmol) was dissolved in pyridine (1 mL). The reaction solution was cooled to 0 °C, and compound 17b (crude product) was added. After the addition was complete, the reaction solution was heated to 25 °C and reacted for 1 hour. TLC monitoring was performed (petroleum ether:ethyl acetate = 3:1, R0). f =0.4) indicates that the starting material has reacted completely. The reaction solution was concentrated, and the crude product was purified by Pre-TLC (petroleum ether: ethyl acetate = 5:1) to give a white solid title compound 17c (52 mg, two-step yield 32%).

[0325] LC-MS: m / z = 326.2 [M+H] +

[0326] Step 3: Synthesis of compound 17

[0327] Compound 17c (52 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (1 mL), and potassium carbonate (44 mg, 0.32 mmol) was added. The mixture was cooled to 0 °C, and bromopropyne (19 mg, 0.16 mmol) was added. After the addition was complete, the reaction mixture was heated to 25 °C and reacted for 16 hours. TLC monitoring was performed (petroleum ether:ethyl acetate = 5:1, new spot R). f =0.5) indicates that the reaction of the starting materials is complete. The reaction solution was diluted with water (8 mL), extracted with ethyl acetate (3 mL × 3), the organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Pre-HPLC to give a white powder, title compound 17 (14 mg, yield 24%).

[0328] LC-MS: m / z = 364.2 [M+1] + (97.22% purity, 210nm)

[0329] 1H NMR (400MHz, DMSO-d6) δ10.52(s,1H),7.56(d,J=8.0Hz,1H),7.40(t,J=73.2Hz,1H),7.21(d,J=6.0Hz,1H),7.12(t,J=8.0Hz, 1H),5.25(d,J=2.0Hz,2H),3.38-3.36(m,1H),2.59-2.52(m,1H),1.66-1.53(m,2H),1.44-1.27(m,6H),0.91(t,J=7.2Hz,6H).

[0330] Example 18

[0331] N-(7-(difluoromethoxy)-1-(pyridin-4-ylmethyl)-1H-indazol-3-yl)-3,3-dimethylbutyramide 18

[0332] The first step is to synthesize compound 18.

[0333] Compound 6a (30 mg, 0.10 mmol) and potassium carbonate (35 mg, 0.25 mmol) were added sequentially to DMF (0.5 mL), and the mixture was stirred for 10 minutes. Then, 4-(bromomethyl)pyridine hydrobromide (31 mg, 0.12 mmol) was added. After the addition was complete, the mixture was allowed to react at room temperature for 16 hours. TLC (PE:EA = 3:1, new spot R) f =0.05) indicates that the starting material was completely converted. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (5 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by prep-TLC (PE:EA = 1:1) to give a pale yellow solid title compound 18 (25.8 mg, yield 66%).

[0334] LC-MS: m / z = 389.2 [M+H] + (99.81% purity, 220nm)

[0335] 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.49(dd,J=4.8,1.6Hz,2H),7.63(d,J=7.6Hz,1H),7.33(t,J=73.2Hz, 1H),7.17(t,J=7.2Hz,1H),7.11(t,J=8.0Hz,1H),7.06-7.02(m,2H),5.69(s,2H),2.27(s,2H),1.06(s,9H).

[0336] Example 19

[0337] 7-(difluoromethoxy)-1-(prop-2-yn-1-yl)-1H-indazole-3-amine 19

[0338] The first step is to synthesize compound 19a.

[0339] Compound 2d (150 mg, 0.75 mmol) and phthalic anhydride (134 mg, 0.91 mmol) were added sequentially to dioxane (6 mL), and the mixture was heated to 120 °C and reacted for 5 hours. After cooling to room temperature, the solvent was removed by concentration, and the crude product was slurried with ethyl acetate (8 mL) to give a pale yellow solid, title compound 19a (174 mg, 70% yield).

[0340] The second step involves the synthesis of compound 19b.

[0341] Compound 19a (174 mg, 0.53 mmol) was dissolved in DMF (2 mL), followed by the addition of potassium carbonate (110 mg, 0.80 mmol) and 3-bromopropyne (69 μL, 0.80 mmol). The reaction was allowed to proceed at room temperature for 16 hours. TLC (PE:EA = 3:1, new spot R) f =0.25) indicates that the starting material was completely converted. The reaction solution was poured into water (20 mL), extracted with ethyl acetate (7 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a yellow oily compound title compound 19b (226 mg, crude product), which was used directly in the next step.

[0342] Step 3: Synthesis of compound 19

[0343] Compound 19b (226 mg, crude) was dissolved in ethanol (3 mL), and hydrazine hydrate (99 mg, 1.58 mmol, 80%) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 hour. TLC (PE:EA = 3:1, new point R) f =0.1) indicates complete conversion of the starting material. The reaction solution was concentrated, and the crude product was purified by prep-HPLC to give a white solid, title compound 19 (23 mg, two-step yield 18%).

[0344] LC-MS: m / z = 238.1 [M+H] + (92.33% purity, 220nm)

[0345] 1H NMR (400MHz, DMSO-d6) δ7.61(d,J=8.0Hz,1H),7.34(t,J=73.6Hz,1H),7.13(d,J=7.6Hz ,1H),7.01(t,J=8.0Hz,1H),6.08(br,2H),4.97(d,J=2.4Hz,2H),3.18(t,J=2.0Hz,1H).

[0346] Example 20

[0347] N-(1-(cyanomethyl)-7-(difluoromethoxy)-1H-indazol-3-yl)-3,3-dimethylbutyramide 20

[0348] The first step is to synthesize compound 20.

[0349] Compound 6a (100 mg, 0.34 mmol) was dissolved in N,N-dimethylformamide (1 mL), followed by the addition of potassium carbonate (93 mg, 0.67 mmol) and bromoacetonitrile (48 mg, 0.40 mmol). After the addition was complete, the reaction was carried out at room temperature for 16 hours. TLC (PE:EA = 2:1, R0) was performed. f =0.4) The reaction was detected as complete, water (20 mL) was added to quench the reaction, ethyl acetate (10 mL × 3) was used for extraction, the organic phases were combined and concentrated, and the crude product was purified by Prep-TLC (PE:EA = 5:1) to give a white solid title compound 20 (36 mg, yield 32%).

[0350] LC-MS: m / z = 337.1 [M+H] + (94.75% purity, 220nm)

[0351] 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),7.68-7.63(m,1H),7.60-7.27(m,2H),7.23-7.17(m,1H),5.64(s,2H),2.29(s,2H),1.07(s,9H).

[0352] Example 21

[0353] N-(1-(2-amino-2-oxoethyl)-7-(difluoromethoxy)-1H-indazol-3-yl)-3,3-dimethylbutyramide 21

[0354] The first step is to synthesize compound 21.

[0355] Compound 6a (100 mg, 0.34 mmol) was dissolved in N,N-dimethylformamide (1 mL), cooled to 0 °C, and potassium carbonate (93 mg, 0.67 mmol) and 2-bromoacetamide (56 mg, 0.41 mmol) were added. After the addition was complete, the mixture was brought to room temperature and reacted for 16 hours. TLC (PE:EA = 2:1, R0) was performed. f =0.1) The reaction was detected as complete, water (30 mL) was added to quench the reaction, ethyl acetate (10 mL × 3) was used for extraction, the organic phases were combined and concentrated, and the crude product was slurried with ethyl acetate (5 mL) to give a white solid title compound 21 (22 mg, yield 18%).

[0356] LC-MS: m / z = 355.1 [M+H] + (97.26% purity, 210nm)

[0357] 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),7.68-7.49(m,2H),7.42-7.25(m,2H),7.06-6.91(m,2H),4.98(s,2H),2.31(s,2H),1.07(s,9H).

[0358] Example 22

[0359] N-(1-(cyanomethyl)-7-(difluoromethoxy)-1H-indazol-3-yl)-2-propylpentanamide 22

[0360] The first step is to synthesize compound 22.

[0361] Compound 17c (100 mg, 0.31 mmol) was dissolved in N,N-dimethylformamide (1 mL), cooled to 0 °C, and potassium carbonate (85 mg, 0.61 mmol) and bromoacetonitrile (44 mg, 0.37 mmol) were added. After the addition was complete, the mixture was brought to room temperature and reacted for 16 hours. TLC (PE:EA = 2:1, R f =0.5) The reaction was detected as complete, water (30 mL) was added to quench, ethyl acetate (10 mL × 3) was used for extraction, the organic phases were combined, concentrated, and the crude product was purified by Prep-TLC (PE:EA = 5:1) to give white solid title compound 22 (40 mg, yield 35%).

[0362] LC-MS: m / z = 365.1 [M+H] + (98.99% purity, 220nm)

[0363] 1H NMR(400MHz,DMSO-d6)δ10.62(s,1H),7.66-7.56(m,1H),7.45-7.14(m,3H),5.65(s, 2H),2.63-2.54(m,1H),1.68-1.52(m,2H),1.47-1.24(m,6H),0.91(t,J=7.2Hz,6H).

[0364] Example 23

[0365] N-(7-(difluoromethoxy)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)pentanamide 23

[0366] The first step is to synthesize compound 23a.

[0367] 7-(difluoromethoxy)-1H-indazole-3-amine 2d (100 mg, 0.50 mmol) was dissolved in pyridine (1 mL). The reaction solution was cooled to 0 °C, and valeryl chloride (60 mg, 0.50 mmol) was added. After the addition was complete, the reaction solution was heated to 25 °C and reacted for 1 hour. TLC monitoring was performed (petroleum ether:ethyl acetate = 3:1, R0). f =0.4) indicates that the reactants reacted completely. The reaction solution was concentrated and purified by Prep-TLC (petroleum ether:ethyl acetate = 2:1) to give a yellow solid title compound 23a (62 mg, yield 43%).

[0368] LC-MS: m / z = 284.1 [M+H] +

[0369] Step 2: Synthesis of compound 23

[0370] Compound 23a (62 mg, 0.22 mmol) was dissolved in N,N-dimethylformamide (1 mL), potassium carbonate (60 mg, 0.44 mmol) was added, the mixture was cooled to 0 °C, and bromopropyne (28 mg, 0.24 mmol) was added. After the addition was complete, the reaction mixture was heated to 25 °C and reacted for 2 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1, R0). f =0.5) indicates that the starting material has reacted completely. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC (PE:EA = 5:1) to give a white solid title compound 23 (29 mg, yield 41%).

[0371] LC-MS: m / z = 322.1 [M+H] + (99.22% purity, 210nm)

[0372] 1 H NMR (400MHz, DMSO-d6) δ10.48(s,1H),7.62(d,J=8.0Hz,1H),7.57-7.18(m,1H),7.20(d,J=6.0Hz,1H),7.11(t,J=8.0Hz,1H),5 .24(d,J=2.8Hz,2H),3.36(t,J=2.4Hz,1H),2.40(t,J=7.6Hz,2H),1.67-1.55(m,2H),1.41-1.31(m,2H),0.92(t,J=7.2Hz,3H).

[0373] Example 24

[0374] The following compounds were synthesized using the same synthetic methods as compounds 1-23:

[0375] The compounds of this invention synthesized in the above pharmaceutical chemistry experiments were used for the following pharmacological experiments.

[0376] Pharmacological Experiment Section

[0377] Test Example 1: Activity Test of KCNQ2

[0378] 1. Plasmid preparation

[0379] The gene for the human voltage-gated potassium channel KCNQ2 (NP_004509.2) was cloned into the pIRES2-EGFP expression vector and heterologously expressed in CHO-K1 cells.

[0380] 2. Cell culture and transfection

[0381] CHO-K1 cells (purchased from the Cell Bank of the Chinese Academy of Sciences) were cultured in DMEM / F12 medium with 10% fetal bovine serum added, and incubated in a CO2 incubator (5% CO2, 37℃). Cells were passaged using 25% trypsin. When the cell density reached 80%–100%, plasmid transfection was performed according to the Lipofectamine 300 manual: 125 μL of OPTI-MEM and 5 μL of P3000 were added to tube A; 125 μL of OPTI-MEM, 2.5 μg of plasmid, and 5 μL of P3000 were added to tube B. The tubes A and B were mixed, incubated for 15 min, and then added to 6-well plates. 24 h after transfection, the cells were digested with trypsin, centrifuged, resuspended in extracellular fluid, and added to culture dishes. Cells with green fluorescent markers were selected for electrophysiological testing.

[0382] 3. Whole-cell patch-clamp experiment

[0383] Whole-cell electrophysiological recordings were performed at room temperature (23–25°C) using a HEKA EPC10 patch-clamp amplifier with a 1kHz filter and a 10kHz sampling frequency. Patch-clamp electrodes were prepared using a P-97 horizontal electrode puller via a multi-step procedure, with a resistance of 3–5 MΩ. The extracellular solution used for cell recording consisted of 145 mM NaCl, 5 mM KCl, 1 mM CaCl2, 3 mM MgCl2, and 10 mM HEPES (pH 7.4, adjusted with NaOH), while the intracellular solution consisted of 150 mM KCl, 3 mM MgCl2, 5 mM EGTA, and 10 mM HEPES (pH 7.3, adjusted with KOH). After sealing and membrane rupture, the voltage was clamped at -80 mV. Then, using Step recording mode, a series of depolarization voltages from -90 mV to +60 mV (incrementing in 10 mV increments, with a sweep every 2 seconds) were applied to extract the outward current. A superpolarization voltage of -120 mV was then applied to extract and record the tail current. Next, Ramp recording mode was activated. Extracellular fluid was first recorded at -10 mV. Once the channel current stabilized, the compound (the compound in this embodiment, used as a potassium ion channel modulator) was administered. The drug administration time was at least 3 minutes. Finally, after the drug effect stabilized, the cells were washed back with extracellular fluid. The rapid drug delivery system was an RSC-200, with a rate of approximately 0.2 mL / min.

[0384] 4. Data analysis and statistics

[0385] Data analysis and graphing were performed using software such as Clampfit 10.4 and GraphPad Prism 8.0.2. Specific statistical methods are as follows:

[0386] (1) Statistical analysis of drug effects. The effect of the drug was determined by recording the steady outward current before and after drug administration at -10mV. The average steady current before drug administration was denoted as I. control The average steady-state current after drug administration is denoted as I. The drug's effect on the channel is expressed as I / I. control .

[0387] (2) Fitting the dose-response curve of the drug. Using the formula E = E max / (1+(EC 50 / C) P Fitting is performed, where EC 50 It is the drug concentration that produces half of the maximum response, where P is the Hill coefficient and C is the drug concentration.

[0388] (3) Conductivity-Voltage Curve (GV curve) statistics. The tail current generated by instantaneous hyperpolarization to -120mV from a depolarization voltage (-90mV to +60mV, increasing in 10mV increments) was recorded to statistically analyze the channel's inherent voltage sensitivity or the effect of the test drug on the channel's voltage sensitivity. The calculated maximum conductance GV was used as the basis for the statistical analysis. max Normalization was performed as a standard to statistically analyze G / G at each voltage. max Using the Boltzmann equation: G = G min +(G max -G min ) / (1+exp(VV 1 / 2 Fitting is performed using ) / S), G max For maximum conductivity, G min For minimum conductance, V 1 / 2 S is the slope factor, representing the voltage at which the maximum conductance is achieved (50%).

[0389] The data were statistically analyzed using the Student's paired t test. All experimental data are expressed as mean ± standard error (mean ± SEM). A p-value < 0.05 was considered statistically significant between the two groups.

[0390] The experimental results are shown in Table 2. A value greater than 1 for I / I0±SEM(+50mV) indicates activation, while a value less than 1 indicates inhibition.

[0391] Table 2 shows the effect of the compounds in this invention at different concentrations on the current of the voltage-gated potassium ion channel KCNQ2.

[0392] In conclusion, compounds 5 and 6 of this patent exhibit better activation of the KCNQ2 channel than retigabine, suggesting that these compounds may have a good therapeutic effect on diseases such as epilepsy, depression, analgesia, and ALS. Compounds 17, 22, 27, 29, 30, and 31 have excellent KCNQ2 inhibitory activity, thereby enhancing cognitive and memory abilities.

[0393] Activity test of test example 2KCNQ2 / 3

[0394] 1. Plasmid preparation

[0395] The genes of human voltage-gated potassium channels KCNQ2 (NP_004509.2) and KCNQ3 were cloned into the pIRES2-EGFP expression vector and heterologously expressed in CHO-K1 cells. Other test methods were the same as in test example 1.

[0396] The test results are shown in Table 3.

[0397] Table 3. Effects of the compounds in this invention at different concentrations on the current of the voltage-gated potassium ion channel KCNQ2 / 3.

[0398] In conclusion, the compounds in this patent activate KCNQ2 / 3 channels, suggesting that these compounds may have a good therapeutic effect on diseases such as epilepsy, depression, analgesia, and ALS.

[0399] Test Example 3: In vivo epilepsy experiment

[0400] MES Experiment:

[0401] Experimental process

[0402] 1. Grouping: After the animal adaptation period, the mice were fasted for 4 hours but allowed free access to water, and then randomly grouped according to their body weight.

[0403] 2. Administration: The drugs were administered according to the groups (N=8), and each group was given the corresponding test drug, retigabine or solvent orally.

[0404] 3. Modeling: The physiological pharmacological electronic stimulator was set to: Configuration 8, Type: Continuous wave output, Wave number 75, Stimulation voltage 160V. 0.5h after drug administration, the animal's ear was moistened with physiological saline, and the mouse was stimulated once with an ear clip electrode. The behavioral performance of the experimental animals was observed and recorded.

[0405] 4. End of experiment: The animals were euthanized by inhaling CO2.

[0406] Evaluation indicators

[0407] The animal exhibits generalized rigidity, displaying a straight-line state with forelimbs flexed and hind limbs extended. If the animal exhibits generalized rigidity, it indicates that the compound has no anti-epileptic protective effect.

[0408] Data statistics

[0409] Experimental data are expressed as rates, and the data were processed. The experimental results are shown in Table 4.

[0410] Table 4. In vivo epilepsy experiments of the compounds of the present invention.

[0411] In conclusion, it is evident that the compounds of the present invention have a lower effective dose and a stronger protective rate than retigabine, i.e., a stronger antiepileptic effect.

[0412] In this experiment, some compounds of the present invention were tested to increase the potassium current of voltage-gated potassium ion channels KCNQ2 and KCNQ2 / 3, while making the channels more sensitive to low voltages, i.e., enabling the voltage-gated potassium ion channels to open at lower voltages. Other compounds, while not significantly affecting the current, similar to retigabine, could shift the voltage activation curve to the left (ΔV1 / 2 becomes negative), influencing channel opening and closing dynamics. It is expected that these compounds can modulate the activity of neural networks; therefore, the compounds of the present invention could be effectively used to treat diseases that regulate neuronal activity, such as epilepsy, pain, depression, and amyotrophic lateral sclerosis (ALS).

[0413] However, the various activities of the compounds of this invention may also involve other mechanisms. Whether the speculation on the mechanism in this invention is correct or not does not affect the specific activity effect of the compounds of this invention. The therapeutic uses for treating or alleviating related diseases are not limited to the above embodiments, that is, it does not mean that this invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of the raw materials of the product of this invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of this invention.

[0414] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0415] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. A fused-ring compound of formula (I) or a pharmaceutically acceptable salt, ester, tautomer, or stereoisomer thereof: L1 is selected from single bonds and C1-3 alkylene groups; L2 is selected from single-bonded, C1-3 alkylene groups; L3 is selected from single bonds, -(C=O)-; R 1 Selected from H, C1-C9 alkyl, C1-C6 haloalkyl, C3-6 cycloalkyl, C1-C3 alkyl-substituted C3-6 cycloalkyl, C3-6 cycloalkyl-substituted C1-C3 alkyl, and C3-6 halocycloalkyl; R 2 Selected from C1-C6 alkyl, C2-C6 alkynyl, C3-6 cyclic hydrocarbon, C6-10 heteroaryl, cyano-substituted C1-C3 alkyl, -C(O)NH2, -C(O)CH3, methanesulfonyl; R 3 Selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and C3-6 cycloalkyl; R 4 Selected from C1-C6 alkyl or H; R 5 Selected from H or C1-C3 alkyl groups.

2. The fused-ring compound of claim 1 or its pharmaceutically acceptable salt, ester, tautomer, or stereoisomer, wherein, L1 is selected from single bonds and methylene groups; L2 is selected from single bonds and methylene groups; L3 is selected from -(C=O)-; R 1 Selected from C1-C9 alkyl groups; R 2 Selected from C2-C6 ynyl groups; R 3 Selected from difluoromethoxy; R 4 Selected from H; R 5 Selected from H.

3. The fused-ring compound of claim 1 or 2, or its pharmaceutically acceptable salt, ester, tautomer, or stereoisomer, wherein, R 2 Selected from the following groups: R 3 Selected from the following groups: R 1 Selected from the following groups: * represents a connection point.

4. The fused-ring compound of claim 1 or 2, or its pharmaceutically acceptable salt, ester, tautomer, or stereoisomer, wherein, The compound is selected from the following specific compounds:

5. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a fused-ring compound as described in any one of claims 1-4 or a pharmaceutically acceptable salt, ester, tautomer or stereoisomer thereof; preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or excipient.

6. Use of the fused-ring compound of any one of claims 1-4 or its pharmaceutically acceptable salt, ester, tautomer or stereoisomer thereof, or the pharmaceutical composition of claim 5 as a potassium channel modulator.

7. The use according to claim 6, specifically in the preparation of a medicament for treating or alleviating diseases related to potassium ion channels. Preferably, diseases related to potassium ion channels are selected from central nervous system diseases or conditions. More preferably, central nervous system diseases or conditions are selected from paroxysmal disorders, anxiety disorders, neuropathic pain and migraines, neurodegenerative diseases, stroke, cocaine abuse, nicotine withdrawal symptoms, alcohol withdrawal symptoms, tinnitus and Alzheimer's disease, depression, sleep disorders in the aging process, and neurodevelopmental disorders. Further preferably, the paroxysmal diseases are selected from acute paroxysmal diseases, seizures, status epilepticus, epilepsy such as epilepsy syndromes and epileptic seizures, neonatal spasms, neonatal epileptic seizures, benign familial neonatal epilepsy KCNQ2-BFNE, epileptic encephalopathy KCNQ2-NEE, benign familial neonatal seizure type 1 BFNC, benign familial neonatal epileptic seizure 1BFNS1, neonatal epileptic seizures associated with hypoxic-ischemic injury, epileptic spasms, epileptic encephalopathy, early epileptic encephalopathy in infants 7EIEE7, early epileptic encephalopathy in infants with psychomotor developmental delay, generalized tonic-clonic seizures, globus pallidus morphology abnormalities, apnea, cerebral edema, dystonia, facial erythema, hypotonia, febrile seizures, agenesis of the corpus callosum, high-grade arrhythmia, focal clonic seizures, generalized tonic-clonic seizures, myofibrosis, spastic tetracycline Hemiparesis and fibromyalgia; the anxiety disorder is selected from anxiety and diseases and conditions associated with the following: panic attacks, agoraphobia, panic disorder with agoraphobia, panic disorder without agoraphobia, agoraphobia without a history of panic disorder, specific phobia, social phobia and other specific phobias, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder caused by general physical symptoms, substance-induced anxiety disorder, separation anxiety disorder, adaptation disorder, performance anxiety, hypochondriasis, anxiety disorder caused by general physical symptoms and substance-induced anxiety disorder and anxiety disorder unless otherwise specified; the neuropathic pain and migraine are selected from abnormal pain, hyperalgesic pain, phantom pain, neuropathic pain associated with diabetic neuropathy, neuropathic pain associated with trigeminal neuralgia and neuropathic pain associated with sciatica and neuropathic pain associated with migraine; More preferably, the neurodegenerative diseases are selected from Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, Creutzfeld-Jakob's disease, Parkinson's disease, encephalopathy caused by AIDS or induced by rubella virus, herpes virus, spirochetes or unknown pathogens, trauma-induced neurodegenerative diseases, neuronal hyperexcitability states such as in drug withdrawal or poisoning symptoms, and neurodegenerative diseases of the peripheral nervous system such as polyneuropathy and polyneuritis; More preferably, the depression is selected from bipolar depression, postpartum depression, severe depression, psychogenic depression, atypical depression, psychogenic depression, treatment-resistant depression, depression associated with Huntington's disease, depression associated with multiple sclerosis, or depression associated with anxiety disorder. More preferably, the neurodevelopmental disorder is selected from developmental delay, intellectual disability, non-syndromic intellectual disability, and autism spectrum disorder (ASD).

8. A method for treating or preventing epilepsy, depression, ALS, cognitive impairment, comprising administering to a human or animal a therapeutically effective amount of any of the fused-ring compounds of claims 1-4 or a pharmaceutically acceptable salt, ester, tautomer or stereoisomer thereof, or the pharmaceutical composition of claim 5.

9. A method of analgesia comprising administering to a human or animal a therapeutically effective amount of any of the fused-ring compound of claims 1-4 or a pharmaceutically acceptable salt, ester, tautomer or stereoisomer thereof, or the pharmaceutical composition of claim 5.

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