WO2024046253A1 - 一种钠通道调节剂及其应用 - Google Patents

一种钠通道调节剂及其应用 Download PDF

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WO2024046253A1
WO2024046253A1 PCT/CN2023/115177 CN2023115177W WO2024046253A1 WO 2024046253 A1 WO2024046253 A1 WO 2024046253A1 CN 2023115177 W CN2023115177 W CN 2023115177W WO 2024046253 A1 WO2024046253 A1 WO 2024046253A1
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compound
lcms
reaction
mmol
reaction solution
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PCT/CN2023/115177
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English (en)
French (fr)
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段书冬
杜书奇
汪信锋
陈磊
秦继红
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上海汇伦医药股份有限公司
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Publication of WO2024046253A1 publication Critical patent/WO2024046253A1/zh

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Definitions

  • the invention relates to the field of medicine, and in particular to a sodium channel modulator, its preparation method, and its therapeutic use in disease treatment.
  • Pain is a complex, uncomfortable sensation usually caused by physical injury, illness, or adverse external stimulation.
  • the International Society for the Study of Pain defines pain as, “an unpleasant sensory and emotional experience often accompanied by actual or potential tissue damage.” As a warning signal, pain can remind the body to pay attention to potential dangers and has an indispensable protective effect on normal life activities. Pain is also a common clinical symptom. After the external stimulus that caused the pain disappears, intense or long-lasting pain will cause physiological function disorders and seriously affect the quality of life of the living body. Statistics show that approximately one in five people worldwide suffer from moderate or severe chronic pain.
  • the generation and conduction of action potentials in neurons rely on voltage-gated sodium channels (VGSCs) on the cell membrane. When the cell membrane is depolarized, the sodium ion channel is activated and the channel opens, causing the influx of sodium ions, further depolarizing the cell membrane, resulting in the generation of an action potential. Therefore, inhibiting abnormal sodium ion channel activity contributes to the treatment and relief of pain.
  • VGSCs voltage-gated sodium channels
  • Voltage-gated sodium ion channels are widely found on the cell membranes of excitable cells such as neurons and skeletal muscle cells. They are a type of transmembrane glycoprotein complex composed of one ⁇ subunit and several ⁇ subunits.
  • the ⁇ subunit is the functional carrier of the sodium ion channel and consists of 1,700 to 2,000 amino acids.
  • the ⁇ subunit mainly plays an auxiliary role and can modify the dynamics and voltage gating dependence of ion channels.
  • Sodium ion channels can be classified according to different ⁇ subunits. Currently, 9 sodium ion channel subtypes have been identified in mammals, namely Na v 1 (Na v 1.1 ⁇ Na v 1.9).
  • TTX nanomolar tetrodotoxin
  • sodium ion channels are divided into TTX-sensitive (TTX-S) and TTX-resistant (TTX-R).
  • TTX-S TTX-sensitive
  • TTX-R TTX-resistant
  • Na v 1.1, Na v 1.2, Na v 1.3 and Na v 1.7 are TTX-S types.
  • the coding genes are located on human chromosome 2q23-24, and they are abundantly expressed in neurons.
  • Na v 1.5, Na v 1.8 and Na v 1.9 are TTX-R types, and the coding genes are located on human chromosome 3p21-24.
  • Na v 1.5 mainly exists in cardiomyocytes
  • Na v 1.8 and Na v 1.9 exist in the peripheral nervous system (PNS).
  • PNS peripheral nervous system
  • Na v 1.8 is an important ion channel involved in chronic pain, atrial fibrillation, and Budd-Chiari syndrome, and is a highly selective target for the treatment of pain. It has been shown to act as a carrier of sodium current, maintain the action potential firing of neurons in the small dorsal root ganglion, and also participate in the spontaneous electrical signal firing of damaged neurons, such as driving neuropathic pain.
  • Na v 1.8 small molecule inhibitors that have been reported include PF-01247324, A-803467, PF-06305591, VX-150, HRS-4800, JMKX-000623, HBW-004 and VX-548, etc.
  • PF-01247324, A-803467, and PF-06305591 have unfavorable factors such as poor selectivity, poor pharmacokinetic data, and low bioavailability.
  • the present invention provides a compound of formula I
  • the compound further includes its stereoisomers and racemates.
  • the above-mentioned compound is further represented by formula IA or IB:
  • R a1 , R a2 , and R a3 are each independently selected from hydrogen, halogen, hydroxyl, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkoxy, -N(R c3 R c4 ) m , and the alkyl, alkoxy, cycloalkyl, and cycloalkoxy groups are optionally replaced by one or more halogen, hydroxyl, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, amino substitution.
  • any two adjacent R a1 , R a2 , and R a3 are connected to form a 5-7-membered ring, and the 5-7-membered ring can be a saturated or unsaturated carbocyclic ring or a heterocyclic ring.
  • the 5-7 membered ring may be optionally substituted by one or more halogens, hydroxyl groups, cyano groups, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, amino substitution.
  • R a1 , R a2 , and R a3 are each independently selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, Difluoromethoxy, amino.
  • any two adjacent R a1 , R a2 , and R a3 are connected to form a 5- or 6-membered carbocyclic ring or heterocyclic ring.
  • the 5- or 6-membered carbocyclic or heterocyclic ring is optionally substituted by one or more halogen, hydroxyl, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy , amino substitution.
  • R b1 , R b2 , R b3 , and R b4 are each independently selected from hydrogen, halogen, hydroxyl, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, and the alkyl, alkoxy
  • the radical is optionally substituted by one or more halogen, hydroxyl, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, amino.
  • R b1 , R b2 , R b3 , and R b4 are each independently selected from hydrogen, methyl, trifluoromethyl, ethyl, methoxy, and ethoxy.
  • R b1 and R b2 are each independently selected from hydrogen, methyl, and trifluoromethyl.
  • R b3 and R b4 are each independently selected from hydrogen, methyl, and trifluoromethyl.
  • any two of R b1 , R b2 , R b3 , and R b4 are connected to form a 3-7-membered ring;
  • the 3-7-membered ring can be a saturated or unsaturated carbocyclic ring or heterocyclic ring;
  • the 3-7 membered ring may be further optionally substituted by one or more halogens, hydroxyl groups, cyano groups, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, amino substitution.
  • R b1 and R b2 are connected to form a 3-7-membered saturated carbocyclic ring, and the 3-7-membered ring may optionally be replaced by one or more Halogen, hydroxyl, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, amino substitution.
  • R b1 and R b2 are connected to form a 3-membered saturated carbocyclic ring.
  • the 3-membered ring may be optionally substituted by one or more halogens, hydroxyl groups, cyano groups, C 1 -C 5 alkyl groups, C 1 -C 5 alkoxy, amino substitution.
  • R b3 and R b4 are connected to form a 3-7-membered saturated carbocyclic ring, and the 3-7-membered ring may be optionally surrounded by one or more halogens, hydroxyl groups, cyano groups, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, amino substitution.
  • any two of R b1 and R b2 are connected to R b3 and R b4 to form a 3-7-membered ring.
  • the 3-7-membered ring may be optionally surrounded by one or more halogens, hydroxyl groups, cyanogens, etc. group, C 1 -C 5 alkyl group, C 1 -C 5 alkoxy group, amino substitution.
  • any two of R b1 and R b2 are connected to R b3 and R b4 to form a 3-7-membered saturated carbocyclic ring.
  • the 3-7-membered saturated carbocyclic ring may be optionally replaced by one or more halogens. , hydroxyl, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, amino substitution.
  • any two of R b1 and R b2 are connected to R b3 and R b4 to form a 3-6-membered saturated carbocyclic ring.
  • the 3-6-membered saturated carbocyclic ring may be optionally replaced by one or more halogens. , hydroxyl, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, amino substitution.
  • any two connections between R b1 and R b2 and R b3 and R b4 may be R b1 and R b3 , R b1 and R b4 , R b2 and R b3 , or R b2 and R b4 .
  • ring A has a structure such as A1:
  • X 1 , X 2 , X 3 , X 4 , and It is connected to X 3 through a bond, and ring A is a five-membered ring at this time;
  • X 1 , X 2 , X 3 , X 4 , and X 5 are all selected from C atoms;
  • any of X 1 , X 2 , X 3 , X 4 , and X 5 contains one or two N atoms;
  • any of X 1 , X 2 , X 3 , X 4 , and X 5 is selected from the group consisting of bonds, C, S, and O;
  • Ring A has the following structure:
  • ring A has a structure such as A2
  • X 1 , X 2 , X 3 , and X 4 have the same definitions as Formula A1.
  • X 1 , X 2 , X 3 , and connected to form a five-membered ring; Y 1 and Y 2 may be the same or different and optionally selected from C atoms or N atoms.
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from bonds, C, N, and O;
  • Ring A has the following structure:
  • R c1 and R c2 are substituted at any substitutable position on ring A, including substitution on X 1 , X 2 , X 3 , X 4 , Y 1 , and Y 2 ; in some specific embodiments of the invention, R c1 and R c2 are substituted on carbon atoms; in some embodiments of the invention, R c1 and R c2 are substituted on heteroatoms.
  • R c3 and R c4 are each independently selected from hydrogen, hydroxyl, amino, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, 3-7 membered ring, or R c3 and R c4 are connected to form a 3-7 membered ring Ring;
  • the 3-7 membered ring can be a saturated or unsaturated carbocyclic ring or heterocyclic ring;
  • the 3-7 membered ring may be further optionally substituted by one or more halogens, hydroxyl groups, cyano groups, C 1 -C 5 alkyl groups, C 1 -C 5 alkoxy groups, and amino groups.
  • M 1 , ring A, R a1 , R a2 , R a3 , R b1 , R b2 , R b3 , R b4 , R c1 , R c2 are as defined above.
  • n and n are optionally 0, 1 or 2.
  • the present invention provides a compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof for use in the preparation of a drug for inhibiting voltage-gated sodium channels.
  • the voltage-gated sodium channel is Nav1.8.
  • a third aspect of the present invention provides a compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof for use in preparing a medicament for treating, preventing or alleviating voltage-gated sodium channel related diseases.
  • a compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof for use in preparing a medicament for treating, preventing or alleviating voltage-gated sodium channel related diseases.
  • a compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof for use in preparing a medicament for treating, preventing or alleviating voltage-gated sodium channel related diseases.
  • the pain includes: acute pain, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, and visceral pain. Therefore, the present invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating, preventing or relieving pain.
  • the fourth aspect of the present invention provides a pharmaceutical composition, which contains a compound of formula I or a pharmaceutically acceptable salt thereof, a stereoisomer and a pharmaceutically acceptable excipient.
  • Pharmaceutically acceptable excipients include fillers, disintegrants, surfactants, and solubilizers.
  • the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt according to the present invention can be administered in various known ways, such as oral, topical, rectal, parenteral, inhalation or implantation.
  • the pharmaceutical composition can be prepared in the form of tablets, capsules, bagged granules, sugar-coated pills, powders, granules, lozenges, powder injections, liquid preparations or suppositories.
  • the fifth aspect of the present invention provides the use of a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable stereoisomer thereof in preparing a drug for treating, preventing or alleviating voltage-gated sodium channel-related diseases
  • the voltage-gated sodium channel related diseases include but are not limited to: pain, multiple sclerosis, peroneal muscular atrophy (Charcot-Marie-Tooth syndrome), incontinence, pathological cough, or arrhythmia, etc.
  • the pain includes: acute pain, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, and visceral pain. Therefore, the present invention further provides a medicine containing a compound of formula I or a pharmaceutically acceptable salt thereof. Use of the composition in preparing medicines for treating, preventing or relieving pain.
  • Halogen or "halogen atom” includes fluorine, chlorine, bromine, and iodine; in the present invention, the preferred halogen is fluorine or chlorine.
  • C 1 -C 5 alkyl refers to a straight-chain or branched alkyl group containing 1-5 carbon atoms, specifically such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, Tert-butyl, n-pentyl, etc.; preferred C 1 -C 5 alkyl is C 1 -C 3 alkyl, including methyl, ethyl, propyl, isopropyl.
  • C 1 -C 5 alkoxy refers to a straight-chain or branched alkoxy group containing 1-5 carbon atoms, specifically such as methoxy, ethoxy, propoxy, isopropoxy, tert-butyl Oxygen etc.
  • Preferred C 1 -C 5 alkoxy groups are C 1 -C 3 alkoxy groups, including methoxy, ethoxy, propoxy, and isopropoxy.
  • C 3 -C 6 cycloalkyl refers to a cycloalkyl group containing 3-6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; the cycloalkyl group can also Further, the following substituents are substituted: one or more halogen, hydroxyl, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, amino.
  • C 3 -C 6 cycloalkoxy refers to a cycloalkoxy group containing 3-6 carbon atoms, including cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy; the The cycloalkoxy group can be further substituted with the following substituents: one or more halogens, hydroxyl groups, cyano groups, C 1 -C 5 alkyl groups, C 1 -C 5 alkoxy groups, and amino groups.
  • 3-7-membered ring refers to a saturated or unsaturated ring containing 3-7 carbon atoms, such as a three-membered ring, a four-membered ring, a five-membered ring, a six-membered ring, and a seven-membered ring; in the present invention, the ring
  • Plural can be two, three, four or more.
  • multiple halogen substitutions may include trifluoromethyl, difluoromethyl.
  • alkyl group, alkoxy group, cycloalkyl group, cycloalkoxy group, 5-7 membered ring, and 3-7 membered ring described in the present invention can optionally be replaced by one or more deuterium, halogen, hydroxyl, cyano, Oxo, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, amino substitution.
  • a bold or hashed straight bond (respectively ), such as in , represents the relative stereochemistry of a stereogenic center relative to other stereogenic centers to which it is connected by bold or hashed straight bonds.
  • a bold or hashed wedge bond (respectively, ), such as in middle, Represents the absolute stereochemistry of the stereogenic center, as well as the relative stereochemistry of the stereogenic center relative to other stereogenic centers to which it is connected by bold or hashed wedge bonds.
  • the prefix “rel-” refers to a single enantiomer with an unknown absolute configuration.
  • the (R)- and (S)-designators in the chemical name reflect the relative stereochemistry of the compound but not necessarily the absolute stereochemistry of the compound.
  • “Pharmaceutically acceptable salts” include, but are not limited to: acid addition salts formed by compounds of formula (I) and inorganic acids, such as hydrochlorides, hydrobromides, phosphates, sulfates, nitrates, etc.; and Acid addition salts formed between compounds of formula (I) and organic acids, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, Lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate.
  • the compounds in the present invention also include tautomers, such as tautomers of enol and keto structures, which are the same compound.
  • the present invention further prepares specific compounds by the following methods. Unless otherwise specified, the compounds, reagents, etc. used in the examples of the present invention were purchased from qualified suppliers or synthesized with reference to methods disclosed in the prior art. For the synthesis of some intermediate compounds, refer to the method described in WO2021113627A1, such as referring to the methods of the prior art to prepare intermediates 1a, 16a, etc.
  • Step 4 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-4-oxa-3 , 4-dihydrophthalazin-6-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 3)
  • Example 1 Replace 1b in Example 1 with 6-amino-3,4-dihydroquinazolin-4-one, and use a method similar to Example 1 to obtain Example 4.
  • Step 5 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-oxyylidene) -2H-benzo[d]isoxazol-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 5)
  • Example 6 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(1-oxyphenylene oxide) Base-1,2,3,4-tetrahydroisoquinoline-7- methyl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (6)
  • Example 8 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(1-oxyphenylene oxide) methyl-2,3-dihydro-1H-isoindol-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide
  • Example 1 Replace 1b in Example 1 with 5-amino-2,3-dihydro-1H-isoindol-1-one, and use a method similar to Example 1 to obtain Example 8.
  • Step 2 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1,1-dioxo-2,3-di Hydrobenzo[d]isothiazol-6-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 9)
  • Example 10 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1,3-dioxylidene-2,3 -Dihydro-1H-isoindol-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (10)
  • Example 12 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1,4-dioxylidene-2,3 -Dihydrobenzo[2,1-d][1,2]diazo Heterocyclohexan-6-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (12)
  • Example 12 Use 6-amino-1,2,3,4-tetrahydrobenzo[2,1-d][1,2]diazepine-1,4-dione to replace 1b in Example 1, Using a similar method to Example 1, Example 12 was obtained. ESI-MS m/z calc.513.1, found 514.1(M+1) + .
  • Step 3 rel-(2R,3S,4S,5R)-N-(1-amino-4-oxyylidene-3H-benzo[2,1-d][1,2]diazacycline -6-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 13)
  • Step 3 rel-4-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-trifluoromethyl Tetrahydrofuran-2-carboxamide)-N-hydroxypicolamide (Example 20)
  • Step 5 rel-4-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-trifluoromethyl Tetrahydrofuran-2-carboxamidopyridinecarboxamide (Example 21)
  • Example 22 rel-(2R,3S,4S,5R)-N-[2-(aminothiomethyl)pyridin-4-yl]-3-(3,4-difluoro-2-methoxy phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide
  • Example 1 Replace 1b in Example 1 with 4-amino-6-fluoro-1,2-dihydropyridin-2-one, and use a method similar to Example 1 to obtain Example 24.
  • ESI-MS m/z calc.464.1,found 465.1(M+1) + .
  • Step 4 rel-(2R,3S,4S,5R)-N-(3-carbamoyl-4-cyanophenyl)-3-(3,4-difluoro-2-methoxyphenyl) -4,5-Dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 25)
  • Example 25d Use 25d to replace 3b in Example 3, and use a method similar to Example 3 to obtain Example 25.
  • Example 27 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(6-oxoacetyl) Base-1H-1,2-diazacyclin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (27)
  • Example 1 Replace 1b in Example 1 with 4-aminobenzene-1,2-dicarboxamide, and use a method similar to Example 1 to obtain Example 30.
  • ESI-MS m/z calc.515.1, found 516.1(M+1) + .
  • Step 1 rel-(2R,3S,4S,5R)-4-( ⁇ [3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-( Trifluoromethyl)tetrahydrofuran-2-yl]carbonyl ⁇ amino)pyridine-2-carboxylic acid methyl ester (32a)
  • Step 2 rel-(2R,3S,4S,5R)-4-( ⁇ [3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-( Trifluoromethyl)tetrahydrofuran-2-yl]carbonyl ⁇ amino)pyridine-2-carboxylic acid (32b)
  • Step 3 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-[2-(tetrahydro Isoxazol-2-ylcarbonyl)pyridin-4-yl]-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 32)
  • Step 3 N, N-bis(2,4-dibenzyl)-4-iodopyridine-2-sulfonamide (34d)
  • Step 4 rel-(2R,3S,4S,5R)-N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfonyl)pyridin4-yl)-3-( 3,4-Difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (34e)
  • Step 5 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-sulfonylpyridine 4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 34)
  • Step 1 (3Z)-4-(3,4-difluoro-2-methoxyphenyl)-1,1,1-trifluoro-3-methylbut-3-en-2-one (59a )
  • Step 2 rel-(2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methyl-5-(trifluoromethyl)-2,3-dihydro Furan-2-carboxylic acid ethyl ester (59b)
  • Step 3 rel-(2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methyl-5-(trifluoromethyl)-2,3-dihydro Furan-2-carboxylic acid (59c)
  • Step 4 rel-(2R,3S)-4-( ⁇ [3-(3,4-difluoro-2-methoxyphenyl)-4-methyl-5-(trifluoromethyl)-2 ,3-Dihydrofuran-2-yl]carbonyl ⁇ amino)pyridine-2-carboxamide (59d)
  • Step 5 rel-(2R,3S)-4-( ⁇ [4,5-dichloro-3-(3,4-difluoro-2-methoxyphenyl)-3a-methyl-5a-( Trifluoromethyl)hexahydrocyclobuta[2,1-b]furan-2-yl]carbonyl ⁇ amino)pyridine-2-carboxamide (59e)
  • Step 6 rel-(2R,3S)-4-( ⁇ [3-(3,4-difluoro-2-methoxyphenyl)-3a-methyl-5a-(trifluoromethyl)hexahydrogen cyclobuta[2,1-b]furan-2-yl]carbonyl ⁇ amino)pyridine-2-carboxamide (59)
  • Example 79 rel-(2R,3S,4S,5)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl )-N-(1,1,3-trioxyylidene-2,3-dihydro-1 ⁇ 6-benzo[d][1,2]thiaazepine-6-yl)tetrahydrofuran-2 -Formamide(79)
  • Example 79 was obtained.
  • ESI-MS m/z calc.534.5,found 533.5(M-1) - .
  • Step 6 rel-5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoro Methyl)tetrahydrofuran-2-carboxamide)-3-fluorophthalamine (Example 80)
  • Step 3 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-sulfonylphenyl)-4 ,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 81)
  • Step 4 ((4-Bromopyridin-2-yl)sulfonyl)carbamic acid tert-butyl ester (82e)
  • Step 5 ((4-bromopyridin-2-yl)sulfonyl)(methyl-d3)carbamic acid tert-butyl ester (82f)
  • Step 6 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl) Tetrahydrofuran-2-carboxamide (82g)
  • Step 7 rel-((4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-( Trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)sulfonyl)(methyl-d3)carbamic acid tert-butyl ester (82h)
  • Step 8 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-(N- (Methyl-d3)sulfamoyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (82h)
  • Step 8 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-(N- (Methyl-d3)sulfamoyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide
  • Step 1 ((4-bromopyridin-2-yl)sulfonyl)(ethyl)carbamic acid tert-butyl ester (83a)
  • Step 2 rel-((4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-( Trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)sulfonyl)(ethyl)carbamic acid tert-butyl ester (83b)
  • Step 3 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(N-ethylaminosulfonyl)pyridine- 4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 83)
  • Step 1 4-bromo-N-(2,2,2-trifluoroethyl)pyridine-2-sulfonamide (84b)
  • Step 2 ((4-bromopyridin-2-yl)sulfonyl)(2,2,2-trifluoroethyl)carbamic acid tert-butyl ester (84c)
  • Step 3 rel-((4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-( Trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridine Tert-butyl (din-2-yl)sulfonyl)(2,2,2-trifluoroethyl)carbamate (84d)
  • Dissolve compound 84c (100mg, 0.24mmol, 1.0eq) in dioxane (5mL), add compound 82g (154mg, 0.26mmol, 1.1eq), 4,5-bisdiphenylphosphine-9,9- Dimethylxanthene (27mg, 0.048mmol, 0.2eq), cesium carbonate (155mg, 0.48mmol, 2.0eq) and palladium acetate (4mg, 0.024mml, 0.1eq). The reaction solution was reacted at 105°C under nitrogen protection for 16 hours.
  • Step 4 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-(N- (2,2,2-trifluoroethyl)sulfamoyl)pyridin-4-yl)-5-trifluoromethyltetrahydrofuran-2-carboxamide (Example 84)
  • Step 1 rel-(2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methyl-5-(trifluoromethyl)-2,3-dihydro Furan-2-carboxamide (85a)
  • Step 2 rel-(1R,3R,4R,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-(trifluoromethyl)-6- (Trimethylsilyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide (85b)
  • Step 3 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-trifluoromethyl-2-oxa Bicyclo[3.2.0]heptane-3-carboxamide (85c)
  • Step 5 rel-(1R,3R,4S,5R)-N-(3-carbamoyl-4-fluorophenyl)-4-(3,4-difluoro-2-methoxyphenyl)- 5-Methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 85)
  • Example 86 was prepared.
  • LCMS: [M+H] + 528.1.
  • Step 1 rel-(1R,3R,4S,5R)-2-(2-(3,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-4-(3,4- Difluoro-2-methoxyphenyl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (87a)
  • reaction mixture was diluted with water (10mL), extracted with ethyl acetate (10mL x 3), then washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate and concentrated to obtain compound 87a (120mg, 89% yield) It is yellow oily substance.
  • Step 2 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(2-aminosulfonylpyridine-4 -base)-1-trifluoromethyl-2- Oxabicyclo[3.2.0]heptane-3-carboxamide (Example 87)
  • Step 1 Compound ((4-bromopyridin-2-yl)sulfonyl)(methyl)carbamic acid tert-butyl ester (88a)
  • Step 2 rel-((4-((1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-(trifluoromethyl base)-2-oxabicyclo[3.2.0]heptane-3-carboxamide)pyridin-2-yl)sulfonyl)(methyl)carbamate tert-butyl ester (88b)
  • Step 3 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(2-(N-methylamino Sulfonyl)pyridin-4-yl)-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 88)
  • compound 1-(4-bromopyridin-2-yl)ethane-1-one 89a 300 mg, 1.50 mmol, 1.00 eq
  • Triflate 595 mg, 2.25 mmol, 1.50 eq
  • triethylamine 326 mg, 3.22 mmol, 2.15 eq
  • the reaction solution was stirred at 80°C for 2 hours.
  • the reaction solution was concentrated, and acetonitrile (3 mL) and selective fluorine reagent (537 mg, 1.51 mmol, 1.01 eq) were added.
  • the reaction solution was stirred at 25°C for 1 hour.
  • Step 3 4-Bromo-2-(1-((tert-butyldimethylsilyl)oxy)-2-fluoroethyl)pyridine (89d)
  • Step 4 rel-(1R,3R,4S,5R)-N-(2-(1-((tert-butyldimethylsilyl)oxy)-2-fluoroethyl)pyridin-4-yl)-4 -(3,4-Difluoro-2-methoxyphenyl)-5-methyl-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide ( 89e)
  • reaction bottle compound 89d (151mg, 0.45mmol, 1.5eq) was dissolved in anhydrous 1,4-dioxane (5mL), and cesium carbonate (196mg, 0.60mmol, 2.0eq), 85c (110mg, 0.30mmol, 1.0eq), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (35mg, 0.06mmol, 0.2eq) and palladium acetate (5mg, 0.03mmol, 0.1eq).
  • the reaction liquid was reacted at 105°C for 16 hours under a nitrogen atmosphere. LCMS monitors that the raw material reaction is complete.
  • Step 5 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-N-(2-(2-fluoro-1-hydroxyethyl) Pyridin-4-yl)-5-methyl-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 89)
  • Step 1 (S)-(4-bromopyridin-2-yl)methyl(tetrahydrofuran-3-yl)carbamic acid tert-butyl ester (90c)
  • compound 4-bromopyridinecarboxaldehyde 90a (100 mg, 0.54 mmol, 1.0 eq) was dissolved in 1,2-dichloroethane (5 mL), and (S)-tetrahydrofuran-3-amine 90b (61 mg, 0.70mmol, 1.3eq), acetic acid (32.38mg, 0.54mmol, 1.0eq) and sodium triacetoxyborohydride (171mg, 0.81mmol, 1.5eq).
  • the reaction solution was stirred at 25°C for 3 hours.
  • di-tert-butyl dicarbonate (176 mg, 0.81 mmol, 1.5 eq) was added to the reaction solution.
  • reaction solution was stirred at 25°C for 0.5 hours.
  • Step 2 rel-tert-butyl-(4-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-trifluoro Methyl-2-oxabicyclo[3.2.0]heptane-3-carboxamido)pyridin-2-yl)methyl((S)-tetrahydrofuran-3-yl)carbamate (90d)
  • Step 3 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(2-((S)-tetrahydrofuran) -3-Amino)methyl)pyridin-4-yl)-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 90)
  • Example 91 was prepared using a similar method.
  • LCMS: [M+H] + 530.2.
  • Step 2 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-(N-(thiazole-4) -(yl)aminosulfonyl)phenyl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 92)
  • Dissolve 85c (30mg, 0.08mmol, 1.0eq) in 1,4-dioxane (5mL), and add 92b (42mg, 0.12mmol, 1.5eq), 4,5-bisdiphenylphosphine-9, 9-dimethylxanthene (9.5 mg, 0.016 mmol, 0.2 eq), cesium carbonate (80 mg, 0.25 mmol, 3 eq) and palladium acetate (1.8 mg, 0.008 mmol, 0.1 eq). The mixture was stirred at 105° C.
  • Step 1 (2-(S-methylsulfonimide)pyridin-4-yl)carbamic acid benzyl ester (93b)
  • Step 3 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(2-(S-methylsulfonate) Imide)pyridin-4-yl)-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 93)
  • Dissolve compound 85d (50mg, 0.14mmol, 1.0eq) in dichloromethane (10mL), add compound 93c (28mg, 0.16mmol, 1.2eq), benzotriazole-N,N,N',N' - Tetramethylurea hexafluorophosphate (62 mg, 0.16 mmol, 1.2 eq) and N,N-diisopropylethylamine (35 mg, 0.27 mmol, 2.0 eq). The reaction solution was stirred at 25°C for 2 hours. LCMS monitored reaction completion. The reaction solution was concentrated to obtain a residue.
  • Example 93 (8.2 mg, 11.6% yield) as a white solid.
  • LCMS: [M+H] + 520.1.
  • Step 1 (2-(N,S-dimethylsulfonimide)pyridin-4-yl)carbamic acid benzyl ester (94a)
  • Step 2 (4-aminopyridin-2-yl)(methyl)(methylimino)-1-6-sulfonic acid ketone (94b)
  • Step 3 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-N-(2-(N,S-dimethylsulfonyl)pyridine -4-yl)-5-methyl-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 94)
  • Step 1 R-4-bromo-2-(2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)pyridine (95b)
  • Step 2 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-N-(2,2-dimethyl-1,3-di Oxopentane-4-yl)methoxy)pyridin-4-yl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (95d )
  • Step 3 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-N-(2-(S)-2,3-dihydroxypropane Oxypyridin-4-yl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 95)
  • Example 96 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-N-(2-(R)-2,3-dihydroxy Propoxypyridin-4-yl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (96)
  • Example 96 was prepared using a similar method.
  • LCMS: [M+H] + 533.1.
  • Example 97 was prepared in a similar manner.
  • LCMS: [M+H] + 486.1.
  • Step 4 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-N-(6-(2,2-dimethyl-1, 3-Dioxolane-4-yl)pyridin-3-yl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (98e)
  • Step 5 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-N-(6-(1,2-dihydroxyethyl)pyridine -3-yl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 98)
  • Step 1 4-(5-bromopyridin-2-yl)-3-oxopiperidine-1-carboxylic acid tert-butyl ester (100b)
  • Step 2 rel-tert-butyl 4-(4-((1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1- (Trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamido)pyridin-2-yl)-3-oxopiperazine-1-carboxylate (100c)
  • Step 3 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(2-(2-oxopiperyl) Azin-1-yl)pyridin-4-yl)-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide (100d)
  • Step 4 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(2-(4-methyl- 2-Oxopiperazin-1-yl)pyridin-4-yl)-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 100)
  • Step 3 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(2-methylsulfonyl)pyridine- 4-yl)-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 101)
  • 2-Methanesulfonylpyridin-4-amine 101c (14 mg, 0.082 mmol, 1.5 eq) was dissolved in anhydrous pyridine (5 mL), and 4-(3,4-difluoro-2-methoxyphenyl was added )-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxylic acid 85d (20mg, 0.055mmol, 1.0eq) and phosphorus oxychloride (25mg, 0.16 mmol,2.9eq). The mixture was stirred at 25°C for 5 minutes. The filtrate was concentrated under reduced pressure.
  • compound 2-bromopyridin-4-amine 102a 200 mg, 1.16 mmol, 1.0 eq was dissolved in 1,4-dioxane (3 mL) and compound dimethylphosphine oxide 2 (180 mg, 2.31mmol, 2.0eq), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (67mg, 0.12mmol, 0.1eq), tris(dibenzylideneacetone)palladium (106mg, 0.12 mmol, 0.1eq) and potassium carbonate (320mg, 2.3mmol, 2.0eq).
  • the reaction solution was subjected to microwave reaction at 130°C for 2 hours under a nitrogen atmosphere.
  • Step 2 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-N-(2-(dimethylphosphoryl)pyridine-4- methyl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (102)
  • Step 4 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1,1-dihydroxy-4H-benzo[e] [1,2,4]thiadiazin-7-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 103)
  • Step 1 5-nitro-1,3-dioxoisoindolin-2-yl acetate (104b)
  • Step 3 rel-5-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-trifluoromethyl Tetrahydrofuran-2-carboxamido)-1,3-dioxoisoindoline-2-acetate (104d)
  • Bioactivity test 1 In vitro inhibitory effect of compounds on Nav 1.8
  • Extracellular fluid components include (mM): NaCl, 137; KCl, 4; CaCl 2 , 1.8; MgCl 2 , 1; HEPES, 10; Glucose, 10; pH 7.4 (NaOH titration). All reagents were purchased from Sigma (St. Louis, MO).
  • a CHO cell line stably expressing Nav1.8 sodium channel was used for experimental testing.
  • the storage time of the extracellular fluid is 2 weeks.
  • intracellular fluid After the intracellular fluid is prepared, aliquot into 1 mL tubes and freeze in a -20°C refrigerator. Use newly thawed intracellular fluid for daily testing. All intracellular fluid is used up within three months. After three months, discard the old intracellular fluid and reconstitute it.
  • Patch clamp detection The voltage stimulation protocol for whole-cell patch clamp recording of Nav1.8 sodium current is as follows: when whole-cell sealing is formed, the cell voltage is clamped at -120mV for 30ms. The clamping voltage is depolarized to 0mV for 50ms, and then the voltage returns to -50mV (refer to the half-deactivation voltage of the IV test for the specific voltage) and maintained for 5s. Then the cell membrane potential returned to -120mV, maintained for 20ms, then depolarized to 0mV, maintained for 50ms, and finally returned to the clamping voltage -120mV, maintained for 30ms. Data collection is repeated every 20ms. Observe the effect of the drug on the sodium current peak. The test data was collected by the EPC 10 amplifier (HEKA) and stored in the PatchMaster (HEKA) software.
  • HEKA EPC 10 amplifier
  • HEKA PatchMaster
  • Electrode drawing instrument Use a microelectrode drawing instrument to draw the capillary glass tube into recording electrodes. Install the electrode filled with intracellular fluid into the electrode holder, control the microelectrode manipulator under an inverted microscope to immerse the electrode in the extracellular fluid, and record the electrode resistance (Rpip). The electrode is brought into contact with the cell surface and negative pressure is applied to form a high-resistance seal (G ⁇ ). At this time, fast capacitance compensation is performed, and then negative pressure is continued to be applied to break the cell membrane and form a whole-cell recording mode. Then slow capacitance compensation was performed and experimental parameters such as membrane capacitance (Cm) and series resistance (Rs) were recorded. No leakage compensation will be given.
  • Cm membrane capacitance
  • Rs series resistance
  • Bioactivity Test 3 The efficacy of compounds on mouse incisional pain model
  • Model establishment After isoflurane anesthesia and routine disinfection, use a blade to make a 0.5cm long longitudinal skin incision on the plantar surface of the left rear foot about 0.2cm distal to the tibiotalar joint toward the toe; separate the plantar muscles and lift them slightly. high, and then cut it longitudinally, taking care not to damage the origin and end of the muscle.
  • the incision was sutured horizontally with interrupted 5-0 nylon sutures (2 stitches).
  • Solvent The solvent used for the test compound is 5% DMSO+10% Solutol+85% Saline, and the solvent used for the positive compound TRV-130 is 10% ethanol+10% cremophor+80% water.
  • Control compound 1 is compound 7 in WO2021113627A1, which was synthesized by referring to the method in WO2021113627A1.
  • Dosing method and frequency The positive control compound TRV-130 was administered intravenously, once a day; the other groups were administered orally, once a day.
  • mice were randomly selected as the sham operation group after eliminating abnormal animals.
  • drug administration group 8 animals in each group were subjected to surgical modeling, and the remaining animals were used as backup. After surgery, the animals were divided into groups again according to their pre-administration pain threshold (PWT). If the animals' PWT value was found to be abnormal after surgery, animals were randomly selected from the spare animals to re-create the model.
  • PWT pre-administration pain threshold
  • Mechanical pain threshold measurement Measure the pre-modeling mechanical pain threshold before modeling; measure the pre-administration mechanical pain threshold 2.5 hours after modeling, take oral administration after the measurement is completed, and measure the mechanical pain threshold 2 hours after administration. The position was measured inside the surgical incision position. Each animal was measured three times, with an interval of 3-5 minutes each time, and the average value was taken.
  • the compound of the present invention has a higher pain threshold (PWT) than the control compound 1 at different doses (8 mg/kg, 25 mg/kg, 75 mg/kg) and can inhibit pain well.
  • PWT pain threshold

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Abstract

本发明提供一种钠通道调节剂及其应用，本发明的钠通道调节剂具有全新的结构，且对Nav 1.8具有优异的体外抑制作用。本发明化合物或其药学上可接受的盐能够用于治疗钠通道相关疾病，包括疼痛、多发性硬化症，腓骨肌萎缩症、失禁，病理性咳嗽，或心律失常等疾病。

Description

一种钠通道调节剂及其应用
本申请要求申请日为2022/8/28的中国专利申请202211036306.3、申请日为2022/11/03的中国专利申请202211374105.4和申请日为2023/03/31的中国专利申请202310334077.1的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及医药领域，具体涉及一种钠通道调节剂，其制备方法，以及在疾病治疗中的治疗用途。
背景技术
疼痛是一类复杂的感觉，通常由身体损伤、病患或不良的外部刺激所引起的不舒服感觉。出于临床研究的需要，国际疼痛研究协会(ISAP)将疼痛定义为，“一种不愉快的感觉和情绪体验，往往伴随有实际的或潜在的组织伤害”。疼痛作为一种警戒信号，可以提醒机体注意潜在的危险，对正常的生命活动具有不可或缺的保护作用。疼痛也是一种常见的临床症状，在引发疼痛的外界刺激消失后，强烈或持久的疼痛会造成生理功能的紊乱，严重影响生命体的生活质量。有数据显示，全世界约五分之一的人受到中度或严重慢性疼痛的困扰。
疼痛起源于周围神经系统的伤害感受器。这是一种游离的神经末梢，广泛分布于全身的皮肤、肌肉、关节和内脏组织中，可以将感受到的热的、机械的或化学的刺激转化为神经冲动(动作电位)并经由传入神经纤维传递到其位于背根神经节(dorsal root ganglia,DRG)的胞体部分，最终传递到高级神经中枢，引起痛觉。而神经元中动作电位的产生和传导又依赖于细胞膜上的电压门控钠离子通道(voltage-gated sodium channels,VGSCs)。当细胞膜去极化时，钠离子通道激活，通道打开，引起钠离子内流，使细胞膜进一步去极化，导致动作电位的产生。因此，抑制异常的钠离子通道活动有助于疼痛的治疗、缓解。
电压门控钠离子通道广泛存在于可兴奋细胞如神经元、骨骼肌细胞的细胞膜上，是一类跨膜糖蛋白复合体，由一个α亚基和数个β亚基构成。α亚基是钠离子通道的功能载体，由1700～2000个氨基酸组成。β亚基主要起辅助作用，可以对离子通道的动力学以及电压门控依赖性进行修饰。根据α亚基的不同可以对钠离子通道进行分类，目前，已经在哺乳动物中鉴定了9种钠离子通道亚型，即Nav1(Nav1.1～Nav1.9)。不同亚型表现出不同的组织分布和电生理、药理学特征。根据能否被纳摩尔河豚毒素(tetrodotoxin,TTX)有效抑制，钠离子通道被分为TTX敏感型(TTX-sensitive，TTX-S)和TTX不敏感型(TTX-resistant，TTX-R)。其中，Nav 1.1、Nav 1.2、Nav 1.3和Nav 1.7为TTX-S型，编码基因位于人类染色体2q23-24，它们在神经元中大量表达。Nav 1.5、Nav 1.8和Nav 1.9为TTX-R型，编码基因位于人类染色体3p21-24。其中，Nav1.5主要存在于心肌细胞中，Nav 1.8、Nav 1.9存在于周围神经系统(peripheral nervous system,PNS)。
Nav 1.8是参与慢性疼痛，心房纤维性颤动、布加综合征的重要离子通道，是治疗疼痛的高选择性靶点。其已被证明作为钠电流的载体，维持小背根神经节中神经元的动作电位发射，也参与了受损神经元的自发电信号发射，如驱动产生神经性疼痛等。目前已报道的Nav 1.8小分子抑制剂包括PF-01247324，A-803467，PF-06305591，VX-150，HRS-4800，JMKX-000623，HBW-004和VX-548等。PF-01247324，A-803467，PF-06305591存在选择性不好，药代数据差，生物利用度低等不利因素。
发明内容
本发明第一方面，提供一种式I化合物
或其药学上可接受的盐，当存在手性中心时，所述化合物还进一步包括其立体异构体、消旋体。
在本发明的一些实施方式中，上述化合物进一步如式I-A或I-B所示：
上述化合物中，Ra1、Ra2、Ra3各自独立选自氢、卤素、羟基、C1-C5烷基、C1-C5烷氧基、C3-C6环烷基、C3-C6环烷氧基、-N(Rc3Rc4)m，且所述烷基、烷氧基、环烷基、环烷氧基任选被一个或多个卤素、羟基、氰基、C1-C5烷基、C1-C5烷氧基、氨基取代。
在本发明的一些实施方式中，任意两个相邻的Ra1、Ra2、Ra3连接形成5-7元环，所述的5-7元环可以是饱和或不饱和的碳环或杂环；所述杂环上任选含有一个或多个N、O、S(＝O)m杂原子；所述的5-7元环可以任选被一个或多个卤素、羟基、氰基、C1-C5烷基、C1-C5烷氧基、氨基取代。
在本发明的一些具体实施方式中，Ra1、Ra2、Ra3各自独立选自氟、氯、甲基、乙基、甲氧基、乙氧基、丙氧基、三氟甲氧基、二氟甲氧基、氨基。
在一些具体实施方式中，任意两个相邻的Ra1、Ra2、Ra3连接形成5或6元碳环或杂环。
在一些具体实施方式中，所述的5元或6元杂环含有一个或两个N、O、S(＝O)m杂原子。
在一些具体实施方式中，所述的5元或6元碳环或杂环任选被一个或多个卤素、羟基、氰基、C1-C5烷基、C1-C5烷氧基、氨基取代。
上述化合物中，Rb1、Rb2、Rb3、Rb4各自独立选自氢、卤素、羟基、C1-C5烷基、C1-C5烷氧基，且所述烷基、烷氧基任选被一个或多个卤素、羟基、氰基、C1-C5烷基、C1-C5烷氧基、氨基取代。
在本发明的一个具体实施例方式中，Rb1、Rb2、Rb3、Rb4各自独立选自氢、甲基、三氟甲基、乙基、甲氧基、乙氧基。
在一些具体实施方式中，Rb1、Rb2各自独立选自氢、甲基、三氟甲基。
在一些具体实施方式中，Rb3、Rb4各自独立选自氢、甲基、三氟甲基。
在一些具体实施方式中，Rb1、Rb2、Rb3、Rb4任意两个连接形成3-7元环；所述的3-7元环可以是饱和或不饱和的碳环或杂环；所述杂环上任选含有一个或多个N、O、S(＝O)m杂原子；所述的3-7元环可以进一步任选被一个或多个卤素、羟基、氰基、C1-C5烷基、C1-C5烷氧基、氨基取代。
在一些具体实施方式中，Rb1、Rb2连接形成3-7元饱和碳环，所述的3-7元环可以任选被一个或多个 卤素、羟基、氰基、C1-C5烷基、C1-C5烷氧基、氨基取代。
在一些具体实施方式中，Rb1、Rb2连接形成3元饱和碳环，所述的3元环可以任选被一个或多个卤素、羟基、氰基、C1-C5烷基、C1-C5烷氧基、氨基取代。
在一些具体实施方式中，Rb3、Rb4连接形成3-7元环饱和碳环，所述的3-7元环可以任选被一个或多个卤素、羟基、氰基、C1-C5烷基、C1-C5烷氧基、氨基取代。
在一些具体实施方式中，Rb1、Rb2与Rb3、Rb4任意两个连接形成3-7元环，所述的3-7元环可以任选被一个或多个卤素、羟基、氰基、C1-C5烷基、C1-C5烷氧基、氨基取代。
在一些具体实施方式中，Rb1、Rb2与Rb3、Rb4任意两个连接形成3-7元饱和碳环，所述的3-7元饱和碳环可以任选被一个或多个卤素、羟基、氰基、C1-C5烷基、C1-C5烷氧基、氨基取代。
在一些具体实施方式中，Rb1、Rb2与Rb3、Rb4任意两个连接形成3-6元饱和碳环，所述的3-6元饱和碳环可以任选被一个或多个卤素、羟基、氰基、C1-C5烷基、C1-C5烷氧基、氨基取代。
在本发明中，Rb1、Rb2与Rb3、Rb4任意两个连接可以是Rb1与Rb3、Rb1与Rb4、Rb2与Rb3、Rb2与Rb4连接。
M1、M2独立地选自C、O、S(＝O)m、N-Rn，其中Rn任选自氢、C1-C5烷基；在一个具体实施方式中，Rn任选自氢、甲基或乙基。
本发明上述化合物中，环A具有如A1的结构：
任意表示单键或双键，前提是其不违背化学成键原理；
X1、X2、X3、X4、X5各自独立选自键、C、N、O、C＝O、S(＝O)m；
X1、X2、X3、X4、X5选自“键”表示直接以键的形式连接，前提是其不违背化学成键原理，例如，当X2选自键时，X1直接与X3通过键连接，此时环A为五元环；
在本发明的一些具体实施方式中，X1、X2、X3、X4、X5各自独立选自键、C、N、C＝O、S(＝O)2；
在本发明的一些具体实施方式中，X1、X2、X3、X4、X5全部选自C原子；
在本发明的一些具体实施方式中，X1、X2、X3、X4、X5中任意含有一个或两个N原子；
在本发明的一些具体实施方式中，X1、X2、X3、X4、X5中任意含有一个C＝O；
在本发明的一些具体实施方式中，X1、X2、X3、X4、X5中任意含有一个S(＝O)2；
在本发明的一些具体实施方式中，X1、X2、X3、X4、X5中任意选自键、C、S、O；
在本发明的一些具体实施方式中，环A具有以下结构：
本发明上述化合物中，环A具有如A2的结构
其中，任意表示单键或双键，前提是其不违背化学成键原理；X1、X2、X3、X4具有与式A1相同的定义。X1、X2、X3、X4选自“键”表示直接以键的形式连接，例如，当X3选自键时，X2直接与X4通过键连 接形成五元环；Y1、Y2可相同或不相同地任选自C原子或N原子。
在本发明的一些具体实施方式中，式A2中X1、X2、X3、X4各自独立选自键、C、N、C＝O；
在本发明的一些具体实施方式中，式A2中X1、X2、X3、X4各自独立选自键、C、N、O；
在本发明的一些具体实施方式中，式A2中X1、X2、X3、X4各自独立选自键、C、N、S(＝O)m；
在本发明的一些具体实施方式中，式A2中X1、X2、X3、X4各自独立选自C、N、C＝O；
在本发明的一些具体实施方式中，环A具有以下结构：
Rc1、Rc2各自独立选自氢、卤素、氰基、羟基、氨基、C1-C5烷基、C1-C5烷氧基、-S(＝O)m-Rc3Rc4、-C(＝O)-NRc3Rc4、-C(＝S)-NRc3Rc4、-N(Rc3Rc4)m、-P(＝O)m-Rc3Rc4、-C(＝N)-NRc3Rc4、-S(＝O)2NRc3Rc4、-CH2NRc3Rc4、-S(＝O)(＝NRc3)Rc4；且所述C1-C5烷基、C1-C5烷氧基可进一步被任选自一个或多个以下的取代基取代：卤素、羟基、氰基、氨基、C1-C5烷基、C1-C5烷氧基；
Rc1、Rc2在环A上的任意可取代的位置取代，包括在X1、X2、X3、X4、Y1、Y2上取代；在本发明的一些具体实施方式中，Rc1、Rc2在碳原子上取代；在本发明的一些具体实施方式中，Rc1、Rc2在杂原子上取代。
Rc3、Rc4各自独立选自氢、羟基、氨基、C1-C5烷基、C1-C5烷氧基、3-7元环，或Rc3、Rc4连接形成3-7元环；所述的3-7元环可以是饱和或不饱和的碳环或杂环；所述杂环上任选含有一个或多个N、O、S(＝O)m杂原子；所述的3-7元环可以进一步任选被一个或多个卤素、羟基、氰基、C1-C5烷基、C1-C5烷氧基、氨基取代。
当Rc1、Rc2选自取代基-S(＝O)m-Rc3Rc4时，若m＝2，则Rc3或Rc4中的任意一个不存在。
在本发明的一些具体实施方式中，上文所述式I化合物进一步如通式II所示：
其中：M1、环A、Ra1、Ra2、Ra3、Rb1、Rb2、Rb3、Rb4、Rc1、Rc2如上文所定义。
在本发明的一些具体实施方式中，Rc1、Rc2各自独立的选自氢、羟基、氨基、氟、氰基、氧代基、甲基、-C(＝O)NH2、-C(＝O)NHCH3、-C(＝O)NHC2H5、-S(O)2CH3、-S(O)2NH2、-S(O)2NHCH3、-S(O)2NHCD3、-P(O)(CH3)2、
在本发明的一些具体实施方式中，Rc1、Rc2各自独立选自氢、氟、氯、氨基、氰基、-C(＝O)NH2。
在本发明上述化合物中，m、n任意为0，1或2。
在本发明的具体实施方式中，本发明具体化合物具有如下结构：








本发明第二方面，提供一种式I化合物或其药学上可接受的盐、立体异构体，在制备用于抑制电压门控型钠通道的药物的用途。所述的电压门控型钠通道是Nav1.8。
本发明第三方面，提供一种式I化合物或其药学上可接受的盐、立体异构体，在制备治疗、预防或缓解电压门控型钠通道相关疾病的药物的用途，所述相关疾病包括但不限于：疼痛，多发性硬化症，腓骨肌萎缩症(Charcot-Marie-Tooth综合征)，失禁，病理性咳嗽，或心律失常等。
所述疼痛包括：急性疼痛、慢性疼痛，肠痛，神经性疼痛，肌肉骨骼疼痛，炎性疼痛，癌症疼痛，特发性疼痛，术后疼痛，内脏痛。因此，本发明进一步提供一种式I化合物或其药学上可接受的盐在制备治疗、预防或缓解疼痛的药物的用途。
本发明第四方面，提供一种药物组合物，所述药物组合物中含有式I化合物或其药学上可接受的盐、立体异构体和药学上可接受的辅料。药学上可接受的辅料包括填充剂、崩解剂、表面活性剂、增溶剂。
本发明所述的式(I)化合物或其药学上可接受的盐的药物组合物可以以各种已知的方式，例如口服、局部、直肠、肠胃外、吸入或植入等方式施用。所述的药物组合物可被制备成片剂、胶囊、袋装冲剂、糖衣丸、散剂、颗粒剂、含片、粉针剂、液体制剂或栓剂等制剂形式。
本发明第五方面，提供一种含有式I化合物或其药学上可接受、立体异构体的药物组合物在制备用于治疗、预防或缓解电压门控型钠通道相关疾病的药物的用途，所述电压门控型钠通道相关疾病包括但不限于：疼痛，多发性硬化症，腓骨肌萎缩症(Charcot-Marie-Tooth综合征)，失禁，病理性咳嗽，或心律失常等。
所述疼痛包括：急性疼痛、慢性疼痛，肠痛，神经性疼痛，肌肉骨骼疼痛，炎性疼痛，癌症疼痛，特发性疼痛，术后疼痛，内脏痛。因此，本发明进一步提供一种含有式I化合物或其药学上可接受的盐的药 物组合在制备治疗、预防或缓解疼痛的药物的用途。
具体实施方式
术语解释
“卤素”或“卤原子”包括氟、氯、溴、碘；在本发明中优选的卤素为氟或氯。
“C1-C5烷基”是指含有1-5个碳原子的直链或支链烷基，具体如甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基等；优选的C1-C5烷基是C1-C3烷基，包括甲基、乙基、丙基、异丙基。
“C1-C5烷氧基”是指含有1-5个碳原子的直链或支链烷氧基，具体如甲氧基、乙氧基、丙氧基、异丙氧基、叔丁氧基等。优选的C1-C5烷氧基是C1-C3烷氧基，包括甲氧基、乙氧基、丙氧基、异丙氧基。“C3-C6环烷基”是指含有3-6个碳原子的环烷基，包括环丙基、环丁基、环戊基、环己基；所述的环烷基上，还可进一步如下取代基取代：一个或多个卤素、羟基、氰基、C1-C5烷基、C1-C5烷氧基、氨基。
“C3-C6环烷氧基”是指含有3-6个碳原子的环烷氧基，包括环丙氧基、环丁氧基、环戊氧基、环己氧基；所述的环烷氧基上，还可进一步如下取代基取代：一个或多个卤素、羟基、氰基、C1-C5烷基、C1-C5烷氧基、氨基。
“3-7元环”是指含有3-7个碳原子的饱和或不饱和环，如三元环、四元环、五元环、六元环、七元环；本发明中，环上碳原子可任意被一个或多个C(＝O)、N、O、S(＝O)m取代形成3-7元杂环；所述3-7元环上可以进一步任选被一个或多个卤素、羟基、氰基、C1-C5烷基、C1-C5烷氧基、氨基取代，m为0、1、2。
“5-7元环”是指含有5-7个碳原子的饱和或不饱和环，如五元环、六元环、七元环；本发明中，环上碳原子可任意被一个或多个N、O、S(＝O)m取代形成5-7元杂环；所述5-7元环上可以进一步任选被一个或多个卤素、羟基、氰基、C1-C5烷基、C1-C5烷氧基、氨基取代，m为0、1、2。
“多个”可以为两个、三个、四个或以上。在本发明中，多个卤素取代可以如三氟甲基、二氟甲基。
本发明中所述的烷基、烷氧基、环烷基、环烷氧基、5-7元环、3-7元环可以任选被一个或多个氘、卤素、羟基、氰基、氧代基、C1-C5烷基、C1-C5烷氧基、氨基取代。
如本文所使用，在任何化学结构或式中，连接至化合物的立体异构中心的粗体或散列直键(分别为 )，诸如在中，表示立体异构中心相对于与粗体或散列直键所连接的其他立体异构中心的相对立体化学。
如本文所使用，在任何化学结构或式中，连接至化合物的立体异构中心的粗体或散列楔形键(分别为)，诸如在中， 表示立体异构中心的绝对立体化学，以及立体异构中心相对于粗体或散列楔形键所连接的其他立体异构中心的相对立体化学。
如本文所使用，当与手性化合物结合使用时，前缀“rel-”是指具有未知绝对构型的单一对映体。在带有“rel-”前缀的化合物中，化学名称中的(R)-和(S)-指示符反映化合物的相对立体化学，但未必反映化合物的绝对立体化学。
“药学上可接受的盐”包括但不限于：式(I)的化合物与无机酸形成的酸加成盐，例如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、硝酸盐等；以及式(I)的化合物与有机酸形成的酸加成盐，例如甲酸盐、乙酸盐、苹果酸盐、马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、2-羟基乙磺酸盐、苯甲酸盐。
本发明中化合物还包括互变异构体，如烯醇式与酮式结构的互变异构体，为同一化合物。
本发明进一步通过以下方法制备具体化合物。除有特别说明，本发明实施例所使用的化合物、试剂等均购自合格供应商或者参照现有技术中公开的方法合成。部分中间体化合物的合成可参考WO2021113627A1中描述的方法，如参考现有技术的方法制备中间体1a、16a等。
实施例1：
rel-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(3-氧代异吲哚啉-5-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺
向反应瓶中加入，rel-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酸(1a，100mg，0.28mmol)，加入二氯甲烷(25mL)和1滴N,N-二甲基甲酰胺，氮气保护并在冰水浴条件下，滴加入草酰氯(72mg，0.56mmol)。滴加完毕后，移除冰水浴并升温至室温，搅拌1小时；浓缩除去反应溶剂。将残留物溶于二氯甲烷(25mL)，在-10℃条件下滴加入6-氨基异吲哚啉-1-酮(1b，50mg，0.34mmol)的二氯甲烷(10mL)溶液。滴加完毕后升温至室温，搅拌1小时。向反应液中加水(25mL)淬灭，分层后，水相再用DCM萃取两遍，合并有机相并用水和饱和食盐水各洗一次，有机相用无水硫酸钠干燥后浓缩，柱层析分离得到目标产物(102mg，收率75％)。ESI-MS m/z calc.484.4,found 485.1(M+1)+。1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),8.54(s,1H),8.01(d,J＝1.8Hz,1H),7.76(dd,J＝8.2,1.9Hz,1H),7.50(d,J＝8.2Hz,1H),7.23–7.12(m,1H),5.14(d,J＝10.4Hz,1H),4.30(s,2H),4.26(dd,J＝10.4,7.6Hz,1H),3.95(d,J＝1.9Hz,3H),2.76(dt,J＝14.7,7.4Hz,1H),1.61(s,3H),0.73(d,J＝6.3Hz,3H).
实施例2：rel-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(2-氧代异吲哚啉-6-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺
以6-氨基异吲哚啉-2-酮替代实施例1中的6-氨基异吲哚啉-1-酮，用与实施例1相似的方法，得到实施例2。ESI-MS m/z calc.484.4,found 485.1(M+1)+。1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),10.32(s,1H),7.30(s,1H),7.20–7.14(m,2H),7.11–7.05(m,2H),5.08(d,J＝10.4Hz,1H),4.27–4.19(m,1H),3.95(d,J＝2.0Hz,3H),3.39(s,2H),2.78–2.70(m,1H),1.58(s,3H),0.72(d,J＝6.1Hz,3H).
实施例3：
Step 1：3-溴-6-硝基苯并呋喃-1(3H)酮(3b)
向100mL反应瓶中加入3a(3.0g)和CCl4(30mL)，搅拌下依次加入NBS(3.28g)和AIBN(275mg)，升至78℃下继续搅拌12小时，TLC跟踪反应至原料转化完全。反应液冷却至室温，用硅藻土抽滤，滤液浓缩，柱层析分离(EA/PE，0％～30％)，得黄色固体3.3g，收率77％。LCMS:m/z(254nm):257.9[M+H]+
Step 2：7-硝基酞嗪-1(2H)-酮(3c)
向反应瓶中加入3b(1.0g)和5％HCl(5mL/mmol)，于80℃下搅拌3小时，TLC跟踪反应至原料转化完全。反应液冷却至室温，加入N2H4·H2O(274mg)，于室温下继续搅拌3小时，TLC跟踪反应至原料转化完全。将反应液过滤，水洗涤，固体残余物通过柱层析分离，得白色固体237mg，收率32％。LCMS:m/z(254nm):192.0[M+H]+
Step 3：7-氨基酞嗪-1(2H)-酮(3d)
向反应瓶中加入3c(200mg)，MeOH(10mL)和THF(10mL)，搅拌均匀后，加入钯/碳(20mg)，并进行氢气置换三次，于室温下搅拌4小时，TLC跟踪反应至原料转化完全。将反应液用硅藻土抽滤，滤液浓缩，得白色固体120mg，收率71％。LCMS:m/z(254nm):162.0[M+H]+
Step 4：rel-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-4-氧杂-3，4-二氢酞嗪-6-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺(实施例3)
向25mL反应瓶中加入1a(30mg)、DMF(1mL)、HATU(49mg)和DIPEA(22mg)，搅拌5分钟，再加入3d(17mg)，于室温下搅拌12小时，LCMS监测原料基本转化完全。向反应液中加入水(10mL),乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩，硅胶板层析分离(EA/PE，50％)得到白色固体11.2mg，收率26.6％。LCMS:m/z(254nm):498.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ12.55(s,1H),10.71(s,1H),8.56(d,J＝2.0Hz,1H),8.27(s,1H),8.08(dd,J＝8.6,2.2Hz,1H),7.89(d,J＝8.6Hz,1H),7.20–7.12(m,2H),5.13(d,J＝10.3Hz,1H),4.29(dd,J＝10.1,7.8Hz,1H),3.95(d,J＝2.0Hz,3H),2.84–2.72(m,1H),1.62(s,3H),0.74(d,J＝6.1Hz,3H).
实施例4：rel-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(4-氧亚基-3H-喹唑啉-6-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺(4)
用6-氨基-3,4-二氢喹唑啉-4-酮替换实施例1中的1b，用与实施例1相似的方法，得到实施例4。ESI-MS m/z calc.484.4,found 485.1(M+1)+。1H NMR(400MHz,DMSO-d6)δ12.25–12.16(m,1H),10.60(s,1H),8.51(d,J＝2.5Hz,1H),8.11–7.94(m,2H),7.67(d,J＝8.8Hz,1H),7.28–7.15(m,2H),5.14(d,J＝10.3Hz, 1H),4.32(dd,J＝10.3,7.6Hz,1H),3.99(d,J＝2.1Hz,3H),2.81(t,J＝7.5Hz,1H),1.66(s,3H),0.78(dd,J＝7.4,2.5Hz,3H).
实施例5：
Step 1：2-羟基-5-硝基苯甲酸甲酯(5b)
向三口瓶中加入甲醇(50mL)，5a(5.0g)，缓慢滴入氯化亚砜(10mL)，65℃反应16小时，浓缩至干，加水和乙酸乙酯进行萃取，取乙酸乙酯层，浓缩得6.0g白色固体，收率111％。ESI-MS m/z calc.197.2,found 198.1(M+1)+。
Step 2：(2-羟基-5-硝基苯基)甲烷羟氨酸(5c)
向反应瓶中加入甲醇(500mL)，氢氧化钾(21g)，冰浴下加入盐酸羟胺(17.5g)，搅拌1.5h，过滤取滤液，加入5b(5g)，反应16h，LCMS检测，反应完全。浓缩除去甲醇，加盐酸调节pH至2，用水和乙酸乙酯萃取，取乙酸乙酯层，干燥浓缩得4.8g淡黄色固体，收率96％。ESI-MS m/z calc.198.0,found 198.9(M+1)+。
Step 3：5-硝基-2,3-二氢苯并[d]异恶唑-3-酮(5d)
向反应瓶中加入THF(100mL)，5c(2.76g)，氮气保护下加入三苯基磷(4.8g)，冰浴下搅拌20分钟后加入DIAD(3.7g)，反应4h，LCMS检测反应完全。浓缩除去溶剂，加入水，用氢氧化钠调节pH值至13，DCM萃取；取水层，用盐酸调节pH值至1，用DCM萃取，饱和食盐水洗涤，浓缩得1.6g白色固体，收率64％。ESI-MS m/z calc.180.0,found 181.0(M+1)+。
Step 4：5-氨基-2,3-二氢苯并[d]异恶唑-3-酮(5e)
向反应瓶中加入甲醇(50mL)和5d(800mg)，5％钯碳(200mg)，加氢条件下反应36h，LCMS检测反应完全。过滤取滤液浓缩得400mg白色固体，收率：60.6％。ESI-MS m/z calc.150.0,found 151.0(M+1)+。
Step 5：rel-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(3-氧亚基-2H-苯并[d]异恶唑-5-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺(实施例5)
用5e替换实施例1中的1b，用与实施例1相似的方法，得到实施例5。ESI-MS m/z calc.486.1,found 487.1(M+1)+。1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),10.30(s,1H),7.58(d,J＝2.0Hz,1H),7.29–7.09(m,5H),5.08(d,J＝10.4Hz,1H),4.36–4.23(m,1H),3.99(d,J＝2.1Hz,3H),2.87–2.73(m,1H),1.63(s,3H),0.80–0.73(m,3H).
实施例6：rel-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(1-氧亚基-1,2,3,4-四氢异喹啉-7- 基)-5-(三氟甲基)四氢呋喃-2-甲酰胺(6)
用7-氨基-1,2,3,4-四氢异喹啉-1-酮替换实施例1中的1b，用与实施例1相似的方法，得到实施例6。ESI-MS m/z calc.498.2,found 499.2(M+1)+。1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.11(d,J＝2.3Hz,1H),7.94(d,J＝3.3Hz,1H),7.75(dd,J＝8.2,2.4Hz,1H),7.31–7.14(m,3H),5.09(d,J＝10.4Hz,1H),4.28(dd,J＝10.4,7.6Hz,1H),3.99(d,J＝2.1Hz,3H),3.37(td,J＝6.5,2.7Hz,2H),2.87(t,J＝6.6Hz,2H),2.82–2.76(m,1H),1.64(s,3H),0.83–0.71(m,3H).
实施例8：rel-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(1-氧亚基-2,3-二氢-1H-异吲哚-5-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺
用5-氨基-2,3-二氢-1H-异吲哚-1-酮替换实施例1中的1b，用与实施例1相似的方法，得到实施例8。ESI-MS m/z calc.484.1,found 485.2(M+1)+。1H NMR(400MHz,DMSO-d6)δ10.54(s,1H),8.45(s,1H),7.98(d,J＝6.5Hz,2H),7.63(d,J＝1.1Hz,2H),7.31–7.12(m,3H),5.14(d,J＝10.3Hz,1H),4.35(s,2H),3.99(d,J＝2.1Hz,3H),2.93(s,2H),2.77(s,2H),1.64(s,3H),0.78(d,J＝7.4Hz,3H).
实施例9：
Step 1：6-氨基苯丙[d]异噻唑-3(2H)-酮-1，2-二氧(9b)
冰浴下向反应瓶中加入9a(650mg)和浓盐酸(9mL)，约30分钟内分批加入锌粉(1.1g)，于室温下继续搅拌2小时，LCMS监测原料基本转化完全。冰浴下向反应液中加入饱和碳酸氢钠溶液至弱碱性，乙酸乙酯萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，得棕褐色固体320mg(纯度约70％)，收率37.0％。LCMS:MS m/z(254nm):185.0[M+H]+.
Step 2：rel-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(1，1-二氧代-2，3-二氢苯并[d]异噻唑-6-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(实施例9)
用9b替代实施例3中的3b，用与实施例3相似的方法，得到实施例9.LCMS:Rt:2.625min；MS m/z(254nm):521.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.12(d,J＝1.5Hz,1H),7.82(t,J＝4.7Hz,1H),7.77(dd,J＝8.4,1.8Hz,1H),7.50(d,J＝8.4Hz,1H),7.16(t,J＝6.5Hz,2H),5.09(d,J＝10.3Hz,1H),4.34(d,J＝4.8Hz,2H),4.26(dd,J＝10.1,7.8Hz,1H),3.95(d,J＝2.0Hz,3H),2.78(dd,J＝14.7,7.4Hz,1H),1.61(s,3H),0.73(d,J＝6.7Hz,3H).
实施例10：rel-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(1,3-二氧亚基-2,3-二氢-1H-异吲哚-5-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(10)
用5-氨基-2H-异吲哚-1,3-二酮替代实施例1中的1b，用与实施例1相似的方法，得到实施例10。ESI-MS m/z calc.498.1,found 499.2(M+1)+。1H NMR(400MHz,DMSO-d6)δ11.24(s,1H),10.73(s,1H),8.14(d,J＝1.8Hz,1H),7.94(dd,J＝8.2,1.8Hz,1H),7.77(d,J＝8.2Hz,1H),7.27–7.11(m,2H),5.11(d,J＝10.1Hz,1H),4.32–4.16(m,1H),3.95(d,J＝2.1Hz,3H),2.85–2.71(m,1H),1.61(s,3H),0.74(d,J＝7.4Hz,3H).
实施例12：rel-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(1,4-二氧亚基-2,3-二氢苯并[2,1-d][1,2]二氮 杂环己熳-6-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(12)
用6-氨基-1,2,3,4-四氢苯并[2,1-d][1,2]二氮杂环己熳-1,4-二酮替代实施例1中的1b，用与实施例1相似的方法，得到实施例12。ESI-MS m/z calc.513.1,found 514.1(M+1)+。1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),10.76(s,0H),8.45(s,0H),8.07(s,1H),7.21(dd,J＝8.6,5.0Hz,1H),5.16(d,J＝10.2Hz,0H),4.32(dd,J＝10.3,7.6Hz,1H),3.98(dd,J＝9.9,2.1Hz,2H),2.83(q,J＝7.6Hz,0H),1.66(s,2H),0.83–0.62(m,2H).
实施例13：
Step 1：5-氨基-2-[氨基(氮亚基)甲基]苯甲酸(13b)
将化合物4-氨基邻苯二甲腈13a(500mg,3.49mmol,1.0eq)溶于甲醇：水＝3：2(5mL)中加入氢氧化钠(139mg,3.49mmol,1.0eq)。反应液在氮气保护下在100℃下反应1小时。LCMS监控原料反应完了，反应液冷却至室温，浓缩，残留物通过prep-HPLC(0.01％FA)分离纯化得到化合物5-氨基-2-氨基甲酰苯甲酸13b(733mg,82％收率)为黄色固体。LCMS:[M+H]+＝180.1
Step 2：4,7-二氨基-1,2-二氢苯并[2,1-d][1,2]二氮杂环己熳-1-酮(13c)
将化合物5-氨基-2-氨基甲酰苯甲酸13b(680mg,3.79mmol,1.0eq)溶于甲醇(10mL)中加入水合肼(7mL)。反应液在25℃下反应4小时。LCMS监控反应完毕，反应混合物浓缩，残留物用水(10mL)，乙酸乙酯(10mL x 5)萃取，然后依次用水，饱和食盐水洗，无水硫酸钠干燥后浓缩，残留物过滤，滤渣经过真空干燥得到化合物4,7-二氨基酞嗪-1-醇13c(100mg,13％收率)为黄色固体。LCMS:[M+H]+＝177.1
Step 3：rel-(2R,3S,4S,5R)-N-(1-氨基-4-氧亚基-3H-苯并[2,1-d][1,2]二氮杂环己熳-6-基)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(实施例13)
将化合物1a(50mg,0.14mmol,1.0eq)溶于N,N-二甲基甲酰胺(2mL)中加入苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(64mg,0.17mmol,1.2eq)，N,N-二异丙基乙胺(27mg,0.21mmol,1.5eq)和13c(29mg,0.17mmol,1.2eq)。反应液在25℃下反应2小时。LCMS监控反应完毕，反应混合物用水(10mL)溶解，乙酸乙酯(10mL x 3)萃取，然后依次用水，饱和食盐水洗，无水硫酸钠干燥后浓缩，残留物通过制备分离纯化(0.01％氨水)得到化合物13(21.41mg,29％收率)为白色固体。LCMS:[M+H]+＝513.1。1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.69(s,1H),8.49(d,J＝2.0Hz,1H),8.05(dd,J＝8.8,2.4Hz,1H),7.99(d,J＝8.8Hz,1H),7.21-7.16(m,2H),5.88(s,2H),5.12(d,J＝10.0Hz,1H),4.30-4.25(m,1H),3.96(d,J＝2.0Hz,3H),2.82-2.74(m,1H),1.62(s,3H),0.74(d,J＝6.4Hz,3H).19F NMR(377MHz,DMSO-d6)δ-73.36(s,3H),-138.16(d,J＝20.7Hz,1H),-154.96(d,J＝20.7Hz,1H).
实施例16：rel-2-氨基甲酰基-4-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺基)-1-甲基吡啶-1-碘化鎓
向微波管中，依次加入化合物16a(40mg,0.08mmol,1.0eq)，碘甲烷(1mL)，乙腈(2mL)。反应液在氮气保护下80℃反应16小时。LCMS监控反应完毕，反应混合物浓缩，残留物通过制备分离纯化(0.01％氨水)得到化合物16(11.06mg,27％收率)为白色固体。LCMS:[M]+＝488.1。1H NMR(400MHz,CDCl3)δ11.38(s,1H),9.92(s,1H),8.83(s,1H),8.69(s,1H),8.12(d,J＝12.8Hz,1H),7.09-7.04(m,1H),6.87-6.85(m,1H),6.06(s,1H),5.05(d,J＝11.2Hz,1H),4.31(s,3H),4.27-4.20(m,1H),3.97(d,J＝2.6Hz,3H),2.89-2.79(m,1H),0.92(s,3H),0.78(d,J＝6.4Hz,3H).
实施例20：
Step 1：4-(双(4-甲氧基苄基)氨基)-N-羟基吡啶甲酰胺(20b)
将化合物4-(双(4-甲氧基苄基)氨基)皮考啉酸20a(800mg,2.1mmol,1.0eq)溶于N,N-二甲基甲酰胺(10mL)，加入N,N'-羰基二咪唑(411.32mg,2.5mmol,1.2eq)在25℃下搅拌2小时。然后加入盐酸羟胺(882.81mg,10.6mmol,5.0eq)。反应液在25℃下搅拌反应2小时。LCMS监控反应完毕，将反应液倒入水中，加乙酸乙酯萃取，有机相加饱和食盐水洗涤，有机相干燥，浓缩。残留物通过硅胶柱分离纯化(二氯甲烷/甲醇＝10/1)得到化合物20b(500mg，60％收率)为褐色固体。LCMS:[M+H]+＝394.2
Step 2：4-氨基-N-羟基吡啶甲酰胺3(20c)
将化合物20b(500mg,1.3mmol,1.0eq)溶于三氟乙酸(3mL)。反应液在60℃下搅拌反应4小时。LCMS监控反应完毕，反应液浓缩。残留物溶于二氯甲烷中，加入盐酸乙醚溶液(2mL)浓缩得到盐酸盐形式的化合物20c(260mg,93％收率)为褐色固体。LCMS:[M+H]+＝154.2
Step 3：rel-4-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-三氟甲基四氢呋喃-2-甲酰胺)-N-羟基皮考酰胺(实施例20)
将化合物1a(50mg,0.14mmol,1.0eq)溶于N,N-二甲基甲酰胺(2mL)，依次加入苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(80.48mg,0.21mmol,1.5eq)，20c(64.8mg,0.42mmol,3.0eq)，N,N-二异丙基乙胺(91.2mg,0.7mmol,5.0eq)。反应液在25℃下搅拌反应2小时。LCMS监控反应完全，反应液倒入水中，加乙酸乙酯萃取，有机相加盐水洗涤，有机相干燥，浓缩。残留物通过制备分离纯化(0.01％甲酸)得到20(4.41mg,6％收率)为白色固体。
LCMS:[M+H]+＝490.1，1H NMR(400MHz,CH3OD)δ7.89(d,J＝6.9Hz,1H),7.26-7.16(m,2H),6.97-6.90(m,1H),6.79-6.64(m,1H),5.17(s,1H),4.33-4.27(m,1H),4.01(d,J＝2.2Hz,3H),2.84-2.77(m,1H),1.64(s,3H),0.80(d,J＝6.2Hz,3H).
实施例21：
Step 1：4-(双(4-甲氧基苄基)氨基)吡啶甲酸甲酯(21a)
在微波管中依次加入双(4-甲氧基苄基)胺(4g,1.8mmol,1.0eq)，4-溴吡啶甲酸甲酯(6.2g,2.4mmol,1.3eq)，1,1′-[1,1′-二萘]-2,2′-二基双[1,1-二苯基-(ACI)膦(580mg,0.09mmol,0.05eq)，醋酸钯(210mg,0.09mmol,0.05eq)，碳酸铯(12.06g,3.7mmol,2.0eq)，甲苯(40mL)在100℃下反应搅拌4小时。LCMS监控反应完毕，反应液过滤，滤液浓缩。残留物通过硅胶柱分离纯化(石油醚/乙酸乙酯＝1/1)得到21a(3.2g,44％收率)为黄色固体。LCMS:[M+H]+＝393.2
Step 2：4-(双(4-甲氧基苄基)氨基)皮考啉酸(21b)
将化合物4-(双(4-甲氧基苄基)氨基)吡啶甲酸甲酯21a(3.2g,8.2mmol,1.0eq)溶于甲醇/四氢呋喃/水＝3/3/1(30mL)，加入一水合氢氧化锂(1g,24.6mmol,3.0eq)在25℃下反应搅拌16小时。LCMS监控反应完毕，反应液倒入水中，加入1N稀盐酸调PH值～5，加乙酸乙酯萃取，有机相加盐水洗涤，有机相干燥，浓缩得到化合物4-(双(4-甲氧基苄基)氨基)皮考啉酸21b(2g,65％收率)为黄色固体。LCMS:[M+H]+＝379.1
Step 3：4-(双(4-甲氧基苄基)氨基)-N-甲氧基吡啶甲酰胺(21c)
将化合物4-(双(4-甲氧基苄基)氨基)皮考啉酸21b(200mg,0.53mmol,1.0eq)溶于N,N-二甲基甲酰胺(2mL)，加入N,N'-羰基二咪唑(102.8mg,0.63mmol,1.2eq)在25℃下搅拌2小时。然后加入甲氧基胺盐酸盐(221mg,10.6mmol,5.0eq)。反应液在室温下搅拌反应2小时。LCMS监控反应完毕，反应液倒入水中，加乙酸乙酯萃取，有机相加盐水洗涤，有机相干燥，浓缩。残留物通过硅胶柱分离纯化(二氯甲烷/甲醇＝20/1)得到化合物4-(双(4-甲氧基苄基)氨基)-N-甲氧基吡啶甲酰胺21c(140mg,65％收率)为褐色固体。LCMS:[M+H]+＝408.1
Step 4：4-氨基-N-甲氧基吡啶甲酰胺(21d)
将化合物4-(双(4-甲氧基苄基)氨基)-N-甲氧基吡啶甲酰胺21c(100mg,0.24mmol,1.0eq)溶于三氟乙酸(2mL)。反应液在60℃下搅拌反应4小时。LCMS监控反应完毕，反应液浓缩。残留物溶于二氯甲烷中，加入盐酸乙醚(2mL)浓缩得到盐酸盐形式的化合物4-氨基-N-甲氧基吡啶甲酰胺21d(80mg,78％收率)为褐色固体。LCMS:[M+H]+＝168.1
Step 5：rel-4-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-三氟甲基四氢呋喃-2-甲酰胺基吡啶甲酰胺(实施例21)
将化合物1a(50mg,0.14mmol,1.0eq)溶于N,N-二甲基甲酰胺(2mL)，依次加入苯并三氮唑-N,N,N',N'- 四甲基脲六氟磷酸盐(80.48mg,0.21mmol,1.5eq)，4-氨基-N-甲氧基吡啶甲酰胺21d(70.7mg,0.42mmol,3.0eq)，N,N-二异丙基乙胺(91.2mg,0.7mmol,5.0eq)。反应液在25℃下搅拌反应2小时。LCMS监控大部分原料反应完了，反应液倒入水中，加乙酸乙酯萃取，有机相加盐水洗涤，有机相干燥，浓缩。残留物通过制备分离纯化(0.01％甲酸)得到化合物21(4.5mg,6％收率)为白色固体。LCMS:[M+H]+＝504.1.1H NMR(400MHz,CH3OD)δ8.53-8.43(m,1H),8.23(s,1H),7.88(s,1H),7.10(d,J＝7.8Hz,1H),7.02-6.93(m,1H),5.06(s,1H),4.37-4.29(m,1H),3.99(d,J＝2.2Hz,3H),3.80(s,3H),2.83-2.75(m,1H),1.65(s,3H),0.81(d,J＝7.6Hz,3H).
实施例22：rel-(2R,3S,4S,5R)-N-[2-(氨基硫亚基甲基)吡啶-4-基]-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺
将化合物16a(30mg，0.06mmol，1.0eq)溶于甲苯(20mL)中，加入劳森试剂(26mg，0.06mmol，1.0eq)，升温至110℃反应24小时，反应完毕后，浓缩除去溶剂，薄层层析制备得到实施例22(15mg，48％收率)，为黄色固体。LCMS:[M+H]+＝490.5.1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),10.21(s,1H),9.93(s,1H),8.89–8.71(m,1H),8.49(d,J＝5.4Hz,1H),7.93(s,1H),7.46–7.02(m,3H),5.29(d,J＝10.7Hz,1H),4.27(d,J＝8.9Hz,1H),3.99(d,J＝2.8Hz,3H),2.75(m,1H),1.64(s,3H),0.75(s,3H).
实施例24：rel-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(6-氟-2-氧亚基-1H-吡啶-4-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(24)
用4-氨基-6-氟-1,2-二氢吡啶-2-酮替换实施例1中的1b，用与实施例1相似的方法，得到实施例24。ESI-MS m/z calc.464.1,found 465.1(M+1)+。1H NMR(400MHz,Methanol-d4)δ7.08(t,J＝7.5Hz,1H),7.01–6.93(m,1H),6.83(s,1H),6.75(d,J＝1.4Hz,1H),5.02(d,J＝10.3Hz,1H),4.30(dd,J＝10.3,8.0Hz,1H),3.99(d,J＝2.2Hz,3H),2.87–2.70(m,1H),1.63(s,3H),0.80(dd,J＝7.8,2.4Hz,3H).
实施例25：
Step 1：2-氰基-5-硝基苯甲酸甲酯(25b)
向反应瓶中加入25a(3g)、氰化亚铜(2g)和DMF(30mL)，搅拌均匀下依次加入Pd2(dba)3(527mg)和dppf(638mg)，并进行氮气置换三次，于115℃下搅拌16小时。反应液冷却至室温，加水(70mL)，乙酸乙酯萃取(40mL×3)，合并有机相，浓缩，柱层析分离(EA/PE，0％～15％)，得白色固体2g，收率84.4％。LCMS:m/z(254nm):207.0[M+H]+
Step 2：2-氰基-5-硝基苯甲酰胺(25c)
向反应液瓶中加入25a(1g)和氨甲醇溶液(7M，10mL)，于室温下搅拌16小时。将反应液抽滤，甲醇洗涤，得到淡黄色固体720mg，收率77.6％。LCMS:m/z(254nm):192.0[M+H]+
Step 3：2-氰基-5-氨基苯甲酰胺(25d)
向反应瓶中加入25c(300mg)，MeOH(10mL)和THF(10mL)，搅拌均匀后，加入钯/碳(30mg)，并进行氢气置换三次，于室温下搅拌6小时，TLC跟踪反应至原料转化完全。将反应液用硅藻土抽滤，滤液浓缩，得黄色固体179mg，收率71％。LCMS:m/z(254nm):162.0[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.00(s,2H),7.58(d,1H),6.77(d,1H),6.73(dd,1H),5.99(s,2H).
Step 4：rel-(2R,3S,4S,5R)-N-(3-氨基甲酰-4-氰基苯基)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(实施例25)
用25d替代实施例3中的3b，用与实施例3相似的方法，得到实施例25。
1H NMR(400MHz,DMSO)δ10.87(s,1H),7.26–7.20(m,1H),7.18(d,J＝8.4Hz,1H),7.08(dd,J＝17.3,9.3Hz,1H),6.85(d,J＝2.0Hz,1H),6.72(dd,J＝8.4,2.0Hz,1H),6.39(s,2H),5.22(d,J＝10.6Hz,1H),4.23(dd,J＝10.5,7.5Hz,1H),3.90(d,J＝2.0Hz,3H),2.72–2.61(m,1H),1.51(s,3H),0.71(d,J＝6.2Hz,3H).
实施例27：rel-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(6-氧亚基-1H-1,2-二氮杂环己熳-3-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺(27)
用6-氨基-3H,2H-1,2-二氮杂环己熳-3-酮替代实施例1中的1b，用与实施例1相似的方法，得到实施例27。ESI-MS m/z calc.447.1,found 448.1(M+1)+。1H NMR(400MHz,DMSO-d6)δ12.79(s,1H),10.75(s,1H),7.88(d,J＝10.1Hz,1H),7.28–7.11(m,2H),6.92(d,J＝10.1Hz,1H),5.14(d,J＝10.4Hz,1H),4.30–4.20(m,1H),3.98(t,J＝2.5Hz,3H),2.78(t,J＝7.5Hz,1H),1.62(s,3H),0.80–0.68(m,2H).
实施例29：rel-(2R,3S,4S,5R)-2-({[3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基]羰基}氨基)-1,3-硫杂氮杂环戊熳-4-甲酰胺(29)
用2-氨基-1,3-硫杂氮杂环戊熳-4-甲酰胺替换实施例3中的3b，用与实施例3相似的方法，得到实施例29。ESI-MS m/z calc.479.1,found 480.1(M+1)+。1H NMR(400MHz,DMSO-d6)δ12.63(s,1H),7.86(s,1H),7.59(s,1H),7.37(s,1H),7.26–7.15(m,2H),5.25(d,J＝10.5Hz,1H),4.30(dd,J＝10.4,7.6Hz,1H),3.98(d,J＝2.2Hz,2H),2.82(t,J＝7.5Hz,1H),1.64(s,2H),0.80–0.68(m,3).
实施例30：rel-(2R,3S,4S,5R)-4-({[3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基]羰基}氨基)苯-1,2-二甲酰胺(30)
用4-氨基苯-1,2-二甲酰胺替换实施例1中的1b，用与实施例1相似的方法，得到实施例30。ESI-MS m/z calc.515.1,found 516.1(M+1)+。1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),7.76–7.60(m,4H),7.49(d,J＝8.2Hz,1H),7.30(d,J＝20.8Hz,2H),7.22–7.09(m,2H),5.07(d,J＝10.4Hz,1H),4.24(dd,J＝10.3,7.6Hz,1H),3.95(d,J＝2.1Hz,2H),2.76(t,J＝7.5Hz,1H),1.60(s,3H),0.73(d,J＝7.4Hz,3H).
实施例30用手性SFC拆分，柱子：Daicel CHIRALPAK IH_3,3.0*150mm,3μm particle size,得到实施例30-1(RT＝1.6min)，比旋度[α]2 D 0＝35.4。实施例30-2(RT＝3.0min)，比旋度[α]2 D 0＝-35.5。
实施例31：rel-(2R,3S,4S,5R)-5-({[3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基]羰基}氨基)苯-1,3-二甲酰胺
用5-氨基苯-1,3-二甲酰胺替换实施例1中的1b，用与实施例1相似的方法，得到实施例31。ESI-MS m/z calc.515.1,found 516.1(M+1)+。1H NMR(400MHz,DMSO-d6)δ10.50(s,1H),8.23(d,J＝1.5Hz,2H),8.10(t,J＝1.6Hz,1H),7.99(d,J＝3.2Hz,2H),7.47(s,2H),7.26–7.20(m,2H),5.14(d,J＝10.5Hz,1H),4.29(dd,J＝10.5,7.6Hz,1H),3.99(d,J＝2.1Hz,3H),2.93(s,1H),1.65(s,3H),0.77(d,J＝7.4Hz,3H).
实施例32：
Step 1：rel-(2R,3S,4S,5R)-4-({[3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基]羰基}氨基)吡啶-2-甲酸甲酯(32a)
用4-氨基吡啶-2-甲酸甲酯替代实施例3中3a，用实施例3中相似的方法得到中间体32a。ESI-MS m/z calc.488.1,found 489.1(M+1)+。
Step 2：rel-(2R,3S,4S,5R)-4-({[3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基]羰基}氨基)吡啶-2-甲酸(32b)
向反应瓶中加入32a(80mg)，THF(5mL)，水(5mL)和氢氧化钠(10mg)，室温反应2小时，TLC监控反应完全。调pH至1，加入乙酸乙酯萃取，有机相干燥后浓缩，柱层析得到32b(75mg，98％)。ESI-MS m/z calc.474.1,found 473.1(M-1)+。
Step 3：rel-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-[2-(四氢异恶唑-2-基羰基)吡啶-4-基]-5-(三氟甲基)四氢呋喃-2-甲酰胺(实施例32)
向反应瓶中加入32b(30mg)，四氢异恶唑(10mg)，HATU(36mg)，二异丙基乙基胺(20mg)和DMF(1mL)，室温反应17小时，LCMS监控反应完全。加入水和乙酸乙酯萃取，有机相干燥后浓缩，薄层层析纯化后，得到实施例32(20mg，60％)。ESI-MS m/z calc.529.1,found 530.2(M+1)+。1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),8.51(d,J＝5.6Hz,1H),8.02(d,J＝27.4Hz,1H),7.76(s,1H),7.20(dd,J＝9.7,6.5Hz,2H),5.14(d,J＝10.2Hz,1H),4.29(dd,J＝10.2,7.7Hz,1H),3.98(d,J＝2.2Hz,4H),3.91(d,J＝14.6Hz,0H),2.85(d,J＝63.6Hz,2H),2.81(t,J＝7.5Hz,1H),2.32(p,J＝7.0Hz,2H),1.64(s,3H),0.77(d,J＝7.4Hz,3H).
实施例34：
Step 1：2-苄硫基-4-碘代吡啶(34b)
向反应瓶中加入苄硫醇(2.9g)和THF(50mL)搅拌均匀，冰浴下分批加入NaH(848mg)，加毕，于室温搅拌1小时。于冰浴下加入34a(5g)，加毕，于室温继续搅拌3小时，LCMS监测原料基本转化完全。向反应液中加入水(10mL),乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩，柱层析分离(EA/PE，0％～10％)得到淡红色液体6.6g，收率90.1％。LCMS:MS m/z(254nm):327.9[M+H]+.
Step 2：4-碘代吡啶-2-磺酰氯(34c)
向反应瓶中加入34b(3g)、DCM(30mL)和DIPEA(3.8g)，并于冰浴下分批加入二氯海因(6.9g)，加毕，升至室温继续搅拌4小时，LCMS检测反应基本完全。向反应液中加入水(50mL),二氯甲烷萃取(20mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩，柱层析分离(EA/PE，0％～10％)得到淡黄色固体1.4g，收率24.2％。LCMS:MS m/z(254nm):585.0[M+H]+.
Step 3：N，N-二(2，4-二苄基)-4-碘代吡啶-2-磺酰胺(34d)
向反应瓶中加入34c(800mg)、N-甲基吡咯烷酮(7mL)、乙酸铵(1.06g)、乙酰丙酮酸铜(107mg)、Ligand(115mg)和碳酸铯(1.34g)，氮气置换三次，于95℃下搅拌16小时。反应液冷却至室温，加水(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，浓缩，柱层析分离(EA/PE，50％～100％)，得黄色油状物460mg，收率70.8％。LCMS:MS m/z(254nm):475.1[M+H]+.
Step 4：rel-(2R,3S,4S,5R)-N-(2-(N，N-二(2，4-二甲氧基苄基)磺酰)吡啶4-基)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(34e)
用34d替代实施例3中的3b，用与实施例3相似的方法，得到34e.LCMS:MS m/z(254nm):810.2[M+H]+.
Step 5：rel-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(2-磺酰吡啶4-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺(实施例34)
向反应瓶中加入34e(52mg)、DCM(2mL)和三氟乙酸(146mg)，于室温下搅拌12小时，LCMS监测原料基本转化完全。将反应液浓缩，硅胶板层析分离(EA/PE，40％)得到白色固体24.5mg，收率75.2％。LC-MS：MS m/z(254nm):510.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),8.57(d,J＝5.4Hz,1H),8.26(d,J＝1.8Hz,1H),7.81(dd,J＝5.5,1.7Hz,1H),7.41(s,2H),7.23–7.11(m,2H),5.12(d,J＝10.1Hz,1H),4.36–4.15(m,1H),3.95(d,J＝1.8Hz,3H),2.93–2.66(m,1H),1.61(s,3H),0.73(d,J＝6.1Hz,3H).
实施例59：
Step 1：(3Z)-4-(3,4-二氟-2-甲氧基苯基)-1,1,1-三氟-3-甲基丁-3-烯-2-酮(59a)
向反应瓶中依次加入甲苯(25mL)，3,4-二氟-2-甲氧基苯甲醛(5.0g,29.0mmol,1.0eq)，1,1,1-三氟丁-2-酮(11g,87.2mmol,3.0eq)，哌啶乙酸盐(4.2g,29.0mmol,1.0eq)，乙酸(0.9g,14.5mmol,0.5eq)，封管室温反应两小时，升温至75℃，继续反应16小时。TLC监控反应完全。用水和乙酸乙酯萃取，取乙酸乙酯层，浓缩后柱层析分离(PE:EA＝20:1)得59a(7.5g，92％收率)为黄色液体。
Step 2：rel-(2R,3S)-3-(3,4-二氟-2-甲氧基苯基)-4-甲基-5-(三氟甲基)-2,3-二氢呋喃-2-甲酸乙酯(59b)
向反应瓶中依次加入乙腈(25mL)，化合物59a(2.5g,8.9mmol,1.0eq)，(乙氧基羰基甲基)二甲基溴化硫鎓(2.6g,11.6mmol,1.3eq)，碳酸铯(3.8g,11.6mmol,1.3eq)，室温反应16小时。TLC(PE:EA＝10:1)监控化合物59a反应完全。过滤，取滤液，浓缩后柱分离(PE:EA＝20:1)，得到2.3g黄色液体(72％收率)。
Step 3：rel-(2R,3S)-3-(3,4-二氟-2-甲氧基苯基)-4-甲基-5-(三氟甲基)-2,3-二氢呋喃-2-甲酸(59c)
向反应瓶中依次加入甲醇(25mL)，水(25mL)，化合物59b(1.0g,2.7mmol,1.0eq)，氢氧化钠(0.54g,13.6mmol,5eq)，65℃反应16小时。LCMS监控反应完全。浓缩除去甲醇，用1N盐酸调节至酸性，乙酸乙酯萃取，取乙酸乙酯层，干燥，浓缩得59c(0.8g,86％收率)为黄色液体。
Step 4：rel-(2R,3S)-4-({[3-(3,4-二氟-2-甲氧基苯基)-4-甲基-5-(三氟甲基)-2,3-二氢呋喃-2-基]羰基}氨基)吡啶-2-甲酰胺(59d)
向反应瓶中依次加入DMF(20mL)，59c(0.8g,2.3mmol,1.0eq)，HATU(1.4g,3.5mmol,1.5eq)， 三乙胺(0.7g,4.7mmol,2.0eq)，4-氨基吡啶-2-甲酰胺(0.5g,3.5mmol,1.5eq)，室温反应16小时。TLC监控反应完全。用水和乙酸乙酯萃取，取乙酸乙酯层，浓缩后柱层析分离(PE:EA＝3:1→1:2)得到59d(0.4g,40％收率)为灰色固体。MS:[M+H]+＝458。1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),8.56(d,J＝5.5Hz,1H),8.33(d,J＝2.1Hz,1H),8.11(s,1H),7.86(dd,J＝5.6,2.3Hz,1H),7.66(s,1H),7.31–7.21(m,1H),7.10(td,J＝6.9,6.5,3.1Hz,1H),5.13(d,J＝6.2Hz,1H),4.73(s,1H),3.94(d,J＝1.9Hz,3H),1.68(d,J＝2.8Hz,3H),0.88(d,J＝6.9Hz,1H)
Step 5：rel-(2R,3S)-4-({[4,5-二氯-3-(3,4-二氟-2-甲氧基苯基)-3a-甲基-5a-(三氟甲基)六氢环丁并[2,1-b]呋喃-2-基]羰基}氨基)吡啶-2-甲酰胺(59e)
向石英反应瓶中，依次加入DCE(500mL)，59d(500mg,1.1mmol,1.0eq)，1,2-二氯乙烯(2mL)，于275nm波长下光照反应3周。柱层析分离纯化回收得原料75mg，产物20mg为白色固体,收率3.4％。MS:[M+H]+＝554。1H NMR(400MHz,Methanol-d4)δ8.53(d,J＝5.5Hz,1H),8.31(d,J＝2.1Hz,1H),7.93(dd,J＝5.5,2.2Hz,1H),7.12–7.05(m,2H),5.41(d,J＝6.0Hz,1H),4.69(q,J＝7.7Hz,2H),4.61(d,J＝6.0Hz,1H),4.01(d,J＝2.4Hz,3H),0.95–0.93(m,3H).
Step 6：rel-(2R,3S)-4-({[3-(3,4-二氟-2-甲氧基苯基)-3a-甲基-5a-(三氟甲基)六氢环丁并[2,1-b]呋喃-2-基]羰基}氨基)吡啶-2-甲酰胺(59)
向反应瓶中依次加入甲苯(15mL)，59e(10mg,0.02mmol,1.0eq)，三丁基锡氢(52mg,0.2mmol,10eq)，AIBN(32mg,0.2mmol,10eq)，密封，100℃反应36小时。LCMS监控反应完全。薄层层析分离得化合物59(3.4mg，40％收率)为白色固体。MS:[M+H]+＝486。1H NMR(400MHz,Chloroform-d)δ8.94(s,1H),8.50(d,J＝5.4Hz,1H),8.26(s,1H),8.09(s,1H),6.99–6.88(m,1H),5.68(s,1H),5.03(s,1H),4.18(s,1H),3.99(d,J＝2.3Hz,2H),2.56(dd,J＝17.3,6.7Hz,1H),2.15(t,J＝13.1Hz,1H),1.92(dd,J＝14.5,6.3Hz,1H),0.90(s,2H).
实施例79：rel-(2R,3S,4S,5)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)-N-(1,1,3-三氧亚基-2,3-二氢-1λ6-苯并[d][1,2]硫杂氮杂环戊熳-6-基)四氢呋喃-2-甲酰胺(79)
用6-氨基-2,3-二氢-1λ6-苯并[d][1,2]硫杂氮杂环戊熳-1,1,3-三酮替换实施例1中的1b，用与实施例1相似的方法，得到实施例79。ESI-MS m/z calc.534.5,found 533.5(M-1)-。1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),7.97(d,J＝1.8Hz,1H),7.72(dd,J＝8.2,1.8Hz,1H),7.52(d,J＝8.2Hz,1H),7.17(dd,J＝8.5,5.2Hz,2H),5.10(d,J＝10.2Hz,1H),4.26(dd,J＝10.2,7.6Hz,1H),3.95(d,J＝2.1Hz,3H),2.77(p,J＝7.5Hz,1H),1.61(s,3H),0.76–0.60(m,3H).
实施例80：
Step 1：2-溴-3-氟-5-硝基苯甲酸(80a)
将化合物2-溴-3-氟苯甲酸(5g,22.8mmol,1.0eq)溶于浓硫酸(15mL)中，在0℃下加入发烟硝酸(1mL)。反应混合液在25℃下搅拌反应4小时，LCMS监测反应完成。将反应液缓慢倒入冰水中，用二氯甲烷(50mL x 3)萃取，收集有机相。有机相用饱和食盐水(50mL x 3)洗涤，无水硫酸钠干燥，过滤，浓缩后得到残留物。残留物使用C18柱层析(0.1％FA/乙腈＝1/4)纯化得到化合物2-溴-3-氟-5-硝基苯甲酸2(800mg,13％)为黄色固体。LCMS:[M+H]+＝263.9。
Step 2：2-溴-3-氟-5-硝基苯甲酸甲酯(80b)
将化合物2-溴-3-氟-5-硝基苯甲酸80a(800mg,3.03mmol,1.0eq)溶于甲醇(5mL)中，加入二氯亚砜(1mL)。反应混合液在80℃下搅拌反应6小时。LCMS监测反应完成。将反应液过滤，得到滤液。滤液浓缩后得到化合物2-溴-3-氟-5-硝基苯甲酸甲酯80b(800mg,95％)为黄色固体。LCMS:[M+H]+＝277.9。
Step 3：3-氟-5-硝基苯甲酸二甲酯(80c)
将化合物2-溴-3-氟-5-硝基苯甲酸甲酯80b(400mg,1.43mmol,1.0eq)溶于甲醇(10mL)中，加入Pd(dppf)Cl2(32mg,0.143mmol,0.1eq)和Et3N(437mg，4.32mmol，3.0eq)。反应液在一氧化碳(0.1MPa)存在下，在80℃下搅拌16小时。浓缩反应液得到残留物，残留物通过硅胶柱层析(石油醚/乙酸乙酯＝10/1)纯化得化合物3-氟-5-硝基苯甲酸二甲酯80c(40mg,11％)为棕色油状物。LCMS:[M+H]+＝258.1。
Step 4：3-氟-5-硝基邻苯二甲酸铵(80d)
将化合物3-氟-5-硝基苯甲酸二甲酯80c(40mg,0.155mmol,1.0eq)溶于氨甲醇(5mL)中。反应液在25℃下搅拌16小时。浓缩反应液得到残留物，残留物用二氯甲烷进行洗涤，过滤，收集固体得到化合物3-氟-5-硝基邻苯二甲酸铵80d(20mg，57％)为白色固体。LCMS:[M+H]+＝228.1。
Step 5：3-氟-5-氨基邻苯二甲酸铵(80e)
将化合物3-氟-5-硝基邻苯二甲酸铵80d(20mg,0.088mmol,1.0eq)溶于甲醇(5mL)中。反应液在氢气存在下，在25℃下搅拌1小时。将反应液过滤，收集滤液并浓缩，得到化合物3-氟-5-氨基邻苯二甲酸铵80e(13mg,75％)为黄色固体。LCMS:[M+H]+＝198.1。
Step 6：rel-5-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺)-3-氟酞胺(实施例80)
将化合物1a(28mg,0.079mmol,1.2eq)溶于DMF(3mL)中，加入化合物3-氟-5-氨基邻苯二甲酸铵(13mg,0.066mmol,1.0eq)80e，HATU(30mg,0.079mmol,1.2eq)和DIEA(10mg,0.079mmol,1.2eq)。反应液在25℃下搅拌1小时。LCMS监测反应完成。反应液通过pre-HPLC(0.1％FA)纯化得到化 合物实施例80(2.9mg,5％)为白色固体。LCMS:[M+H]+＝534.2。1H NMR(400MHz,CD3OD)δ7.72(dd,J＝2.0,2.0Hz,1H),7.63-7.61(m,1H),7.15-7.08(m,1H),7.01-6.94(m,1H),5.06(d,J＝10.4Hz,1H),4.33-4.28(m,1H),3.99(d,J＝2.4Hz,3H),2.85-2.71(m,1H),1.65(s,3H),0.83-0.80(m,3H)。
实施例81：
Step 1：2-氟-5-硝基苯磺酰胺(81b)
将化合物对氟硝基苯81a(2.0g,14.2mmol,1.0eq)溶于氯磺酸(10mL)中。反应混合液在110℃下搅拌反应24小时，将反应液冷却至室温。将反应液缓慢倒入冰浴中，等冰块全部融化后，用乙酸乙酯(50mL x 3)萃取，收集有机相。有机相用饱和食盐水(50mL x 3)洗涤，无水硫酸钠干燥，过滤，浓缩后得到残留物。残留物溶于乙酸乙酯(60mL)中，在0℃下缓慢加入氨水(60mL)。反应混合液在25℃下搅拌16小时。TLC监测反应完全后，将反应液倒入水中，用乙酸乙酯(50mL x 3)萃取，收集有机相。有机相用饱和食盐水(50mL x 3)洗涤，无水硫酸钠干燥，过滤，浓缩后得到残留物。残留物使用硅胶柱层析(石油醚/乙酸乙酯＝2/3)纯化得得到化合物2-氟-5-硝基苯磺酰胺81b(400mg,13％收率)为黄色固体。1H NMR(400MHz,DMSO)δ8.56-8.53(m,2H),8.06(s,2H),7.86-7.65(m,1H).
Step 2：5-氨基-2-氟苯磺酰胺(81c)
将化合物2-氟-5-硝基苯磺酰胺酰胺81b(200mg,0.90mmol,1.0eq)溶于甲醇(5mL)中，加入湿钯碳(193mg,1.80mmol,2.0eq)。在氢气存在的条件下，反应混合液在25℃下搅拌反应1小时。LCMS监测反应完成。将反应液过滤，得到滤液。滤液浓缩后得到化合物5-氨基-2-氟苯磺酰胺3(160mg,92％收率)为黑色固体。LCMS:[M+H]+＝191.1
Step 3：rel-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(4-氟-3-磺酰苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(实施例81)
将化合物(3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸1a(50mg,0.14mmol,1.0eq)溶于二氯甲烷(3mL)中，加入化合物5-氨基-2-氟苯磺酰胺81c(32mg,0.17mmol,1.2eq)，苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(64mg,0.17mmol,1.2eq)和N,N-二异丙基乙胺(22mg,0.17mmol,1.2eq)。反应液在25℃下搅拌1小时。浓缩反应液得到残留物，残留物通过制备分离(0.1％甲酸)纯化得化合物(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(4-氟-3-磺酰苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺HL-1127(2.3mg,3％收率)为白色固体。LCMS:[M+H]+＝527.1。1H NMR(400MHz,DMSO)δ10.61(s,1H),8.57(s,1H),8.23-8.21(m,1H),7.93-7.86(m,1H),7.72(s,1H),7.46-7.39(m,1H),7.29-7.18(m,2H),5.13(d,J＝10.4Hz,1H),4.35-4.25(m,1H),4.01(d,J＝2.4Hz,3H),2.85-2.79(m,1H),1.66(s,3H),0.79(d,J＝5.6Hz,3H).
实施例82
Step 1：2-(苄硫基)-4-溴吡啶(82b)
将化合物苯甲硫醇82a(2.0g,16.1mmol,1.0eq)溶于无水四氢呋喃(30mL)中在0℃氮气保护下加入钠氢(640mg,16.1mmol,1.0eq)。反应液在0℃下搅拌30分钟。于该温度下加入化合物4-溴-2-氟吡啶(2.8g,16.1mmol,1.0eq)的无水四氢呋喃(10mL)溶液，滴加完毕，在0℃下搅拌1.5小时。LCMS监控原料反应完了，向反应液中加入水(50mL)，乙酸乙酯(20mL x 3)萃取，然后用饱和食盐水洗，无水硫酸钠干燥后浓缩，残留物通过硅胶柱(石油醚/乙酸乙酯＝50/1)纯化得到化合物2-(苄硫基)-4-溴吡啶82b(4.3g,95％收率)为粉色油状物。LCMS:[M+H]+＝280.0
Step 2：4-溴吡啶-2-磺酰氯(82c)
将化合物2-(苄硫基)-4-溴吡啶82b(4.3g,15.3mmol,1.0eq)溶于二氯甲烷:乙酸:水＝7:1:2(80mL)中加入1,3-二氯-5,5-二甲基咪唑烷-2,4-二酮(1.1g,7.2mmol,0.7eq)。反应液在25℃氮气保护下反应16小时。TLC监控原料反应完了，向反应液中加入水(20mL)，二氯甲烷(20mL x 3)萃取，然后用饱和食盐水洗，无水硫酸钠干燥后浓缩，二氯甲烷稀释过滤，滤液旋干得到粗品化合物4-溴吡啶-2-磺酰氯5(4.5g,92％收率)为黄色油状物。
Step 3：4-溴吡啶-2-磺酰胺(82d)
将氨水(10mL)加入化合物4-溴吡啶-2-磺酰氯82c(3.0g,9.4mmol,1.0eq)中。反应液在25℃下反应1小时。LCMS监控原料反应完了，反应液浓缩，残留物通过硅胶柱(石油醚/乙酸乙酯＝1/1)纯化得到化合物4-溴吡啶-2-磺酰胺82d(1.7g,77％收率)为灰色固体。LCMS:[M+H]+＝238.9
Step 4：((4-溴吡啶-2-基)磺酰)氨基甲酸叔丁酯(82e)
将化合物4-溴吡啶-2-磺酰胺82d(500mg,2.1mmol,1.0eq)溶于二氯甲烷(10mL)中，加入三乙胺(213mg,2.1mmol,1.0eq)，4-二甲氨基吡啶(13mg,0.10mmol,0.05eq)和二碳酸二叔丁酯(483mg,2.2mmol,1.05eq)。反应液在25℃下反应1小时。LCMS监控原料反应完了，反应液浓缩，残留物通过硅胶柱(二氯甲烷/甲醇＝10/1)纯化得到化合物((4-溴吡啶-2-基)磺酰)氨基甲酸叔丁酯82e(611mg,85％收率)为黄色油状物。LCMS:[M+Na]+＝359.0
Step 5：((4-溴吡啶-2-基)磺酰基)(甲基-d3)氨基甲酸叔丁酯(82f)
将化合物((4-溴吡啶-2-基)磺酰)氨基甲酸叔丁酯82e(200mg,0.59mmol,1.0eq)溶于无水N,N-二甲基甲酰胺(5mL)中，加入碳酸钾(123mg,0.88mmol,1.5eq)和氘代碘甲烷(94mg,0.65mmol,1.1eq)。反应液在60℃下反应2小时。LCMS监控原料反应完了，向反应液中加入水(10mL)，乙酸乙酯(10mL x 3)萃取，然后依次用水，饱和食盐水洗，无水硫酸钠干燥后浓缩，残留物通过硅胶柱(石油醚/乙酸乙酯＝10/1)纯化得到82f(130mg,62％收率)为白色固体。LCMS:[M+Na]+＝376.0
Step 6：rel-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(82g)
用氯化铵替换实施例1中的1b，用与实施例1相似的方法，得到中间体82g。LCMS:[M+H]+＝354.3。
Step 7：rel-((4-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺基)吡啶-2-基)磺酰)(甲基-d3)氨基甲酸叔丁酯(82h)
将化合物82f(70mg,0.20mmol,1.0eq)溶于二氧六环(5mL)中，加入化合物82g(139mg,0.24mmol,1.2eq)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(23mg,0.04mmol,0.1eq)，碳酸铯(128mg,0.39mmol,2.0eq)和醋酸钯(3mg,0.02mml,0.1eq)。反应液在105℃氮气保护下反应16小时。LCMS监控原料反应完了，反应液浓缩，残留物通过硅胶柱(石油醚/乙酸乙酯＝5/1)纯化得到82h(65mg,52％收率)为黄色油状物。LCMS:[M+H]+＝627.2
Step 8：rel-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(2-(N-(甲基-d3)氨基磺酰基)吡啶-4-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺(82h)
Step 8：rel-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(2-(N-(甲基-d3)氨基磺酰基)吡啶-4-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺
将82h(50mg,0.08mmol,1.0eq)溶于二氯甲烷(5mL)中加入对甲苯磺酸(13.72mg,0.08mmol,1.0eq)。反应液在25℃下反应16小时。LCMS监控原料反应完了，反应混合物浓缩，残留物通过制备分离纯化(0.05％NH3)得到实施例82(10.0mg,24％收率)为类白色固体。LCMS:[M+H]+＝527.11H NMR(400MHz,CH3OD)δ8.54(d,J＝5.6Hz,1H),8.30(d,J＝2.0Hz,1H),7.86(dd,J＝5.6,2.0Hz,1H),7.14-7.09(m,1H),7.02-6.94(m,1H),5.08(d,J＝10.4Hz,1H),4.32(dd,J＝10.4,8.4Hz,1H),3.99(d,J＝2.4Hz,3H),2.80(p,J＝7.6Hz,1H),1.65(s,3H),0.83-0.79(m,3H).
实施例83：
Step 1：((4-溴吡啶-2-基)磺酰基)(乙基)氨基甲酸叔丁酯(83a)
将化合物((4-溴吡啶-2-基)磺酰)氨基甲酸叔丁酯82e(200mg,0.59mmol,1.0eq)溶于无水N,N-二甲基甲酰胺(5mL)中，加入碳酸钾(123mg,0.88mmol,1.5eq)和碘乙烷(101mg,0.65mmol,1.1eq)。反应液在60℃下反应2小时。LCMS监控原料反应完了，向反应液中加入水(10mL)，乙酸乙酯(10mL x 3)萃取，然后依次用水，饱和食盐水洗，无水硫酸钠干燥后浓缩，残留物通过硅胶柱(石油醚/乙酸乙酯＝10/1)纯化得到化合物((4-溴吡啶-2-基)磺酰基)(乙基)氨基甲酸叔丁酯83a(130mg,60％收率)为黄色油状物。LCMS:[M+Na]+＝387.0
Step 2：rel-((4-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺基)吡啶-2-基)磺酰)(乙基)氨基甲酸叔丁酯(83b)
将化合物83a(130mg,0.35mmol,1.0eq)溶于二氧六环(5mL)中，加入82g(197mg,0.39mmol,1.2eq)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(41mg,0.07mmol,0.2eq)，碳酸铯(231mg,0.71mmol,2.0eq)和醋酸钯(6mg,0.03mml,0.1eq)。反应液在105℃氮气保护下反应16小时。LCMS监控原料反应完了，反应液浓缩，残留物通过硅胶柱(石油醚/乙酸乙酯＝4/1)纯化得到83b(100mg,44％收率)为黄色油状物。LCMS:[M+H]+＝638.2
Step 3：rel-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(2-(N-乙基氨基磺酰基)吡啶-4-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(实施例83)
将化合物83b(100mg,0.16mmol,1.0eq)溶于盐酸/二氧六环(4M,30mL)中。反应液在25℃下反应2小时。LCMS监控原料反应完了，反应混合物浓缩，残留物通过制备分离纯化(0.01％FA)得到实施例83(39.5mg,47％收率)为白色固体。LCMS:[M+H]+＝538.1
1H NMR(400MHz,DMSO)δ10.88(s,1H),8.59(d,J＝5.2Hz,1H),8.27(d,J＝1.6Hz,1H),7.91-7.75(m,2H),7.18-7.15(m,2H),5.13(d,J＝10.0Hz,1H),4.28-4.23(m,1H),3.95(d,J＝2.4Hz,3H),2.97-2.86(m,2H),2.80-2.75(m,1H),1.61(s,3H),0.97(t,J＝7.2Hz,3H),0.73(d,J＝6.0Hz,3H).
实施例84：
Step 1：4-溴-N-(2,2,2-三氟乙基)吡啶-2-磺酰胺(84b)
将化合物2,2,2-三氟乙烷-1-胺(1.2g,11.7mmol,3.0eq)加入化合物4-溴吡啶-2-磺酰氯84a(1.0g,3.9mmol,1.0eq)中。反应液在25℃下反应1小时。LCMS监控原料反应完了，反应液浓缩，残留物通过硅胶柱(石油醚/乙酸乙酯＝10/1)纯化得到化合物4-溴-N-(2,2,2-三氟乙基)吡啶-2-磺酰胺84b(700mg,56％收率)为白色固体。LCMS:[M+H]+＝318.9
Step 2：((4-溴吡啶-2-基)磺酰基)(2,2,2-三氟乙基)氨基甲酸叔丁酯(84c)
将化合物4-溴-N-(2,2,2-三氟乙基)吡啶-2-磺酰胺84b(700mg,2.2mmol,1.0eq)溶于二氯甲烷(10mL)中，加入碳酸钾(604mg,4.4mmol,2.0eq)，4-二甲氨基吡啶(27mg,0.22mmol,0.1eq)和二碳酸二叔丁酯(573mg,2.6mmol,1.2eq)。反应液在25℃下反应1小时。LCMS监控原料反应完了，反应液浓缩，残留物通过硅胶柱(石油醚/乙酸乙酯＝10/1)纯化得到化合物((4-溴吡啶-2-基)磺酰基)(2,2,2-三氟乙基)氨基甲酸叔丁酯84c(700mg,76％收率)为黄色油状物。LCMS:[M+Na]+＝441.0
Step 3：rel-((4-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺基)吡 啶-2-基)磺酰基)(2,2,2-三氟乙基)氨基甲酸叔丁酯(84d)
将化合物84c(100mg,0.24mmol,1.0eq)溶于二氧六环(5mL)中，加入化合物82g(154mg,0.26mmol,1.1eq)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(27mg,0.048mmol,0.2eq)，碳酸铯(155mg,0.48mmol,2.0eq)和醋酸钯(4mg,0.024mml,0.1eq)。反应液在105℃氮气保护下反应16小时。LCMS监控原料反应完了，反应液浓缩，残留物通过硅胶柱(二氯甲烷/甲醇＝10/1)纯化得到化合物84d(80mg,48％收率)为黄色油状物。LCMS:[M+H]+＝692.1
Step 4：rel-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(2-(N-(2,2,2-三氟乙基)氨基磺酰基)吡啶-4-基)-5-三氟甲基四氢呋喃-2-甲酰胺(实施例84)
将化合物84d(80mg,0.11mmol,1.0eq)溶于盐酸/二氧六环(4M,5mL)中。反应液在25℃下反应4小时。LCMS监控原料反应完了，反应混合物浓缩，残留物通过制备分离纯化(0.1％FA)得到实施例84(15.4mg,22％收率)为白色固体。LCMS:[M+H]+＝592.1。1H NMR(400MHz,DMSO-d6)δ10.88(s,1H),8.84(t,J＝6.8Hz,1H),8.59(d,J＝5.2Hz,1H),8.29(d,J＝2.0Hz,1H),7.87-7.84(m,1H),7.20-7.14(m,2H),5.13(d,J＝10.4Hz,1H),4.28-4.23(m,1H),3.95(d,J＝2.24Hz,3H),3.84-3.75(m,2H),2.82-2.72(m,1H),1.61(s,3H),0.73(d,J＝6.0Hz,3H).
实施例85：化合物85的合成
Step 1：rel-(2R,3S)-3-(3,4-二氟-2-甲氧基苯基)-4-甲基-5-(三氟甲基)-2,3-二氢呋喃-2-甲酰胺(85a)
将化合物59b(5g,13.6mmol,1.0eq)溶于氨/甲醇(7M,15mL)中。反应液在80℃下反应16小时。LCMS监控原料反应完了，反应液浓缩，残留物通过硅胶柱(二氯甲烷/甲醇＝20/1)纯化得到化合物85a(3.8g,83％收率)为白色固体。LCMS:[M+H]+＝338.0
Step 2：rel-(1R,3R,4R,5R)-4-(3,4-二氟-2-甲氧基苯基)-5-甲基-1-(三氟甲基)-6-(三甲基硅)-2-氧杂双环[3.2.0]庚烷-3-甲酰胺(85b)
将化合物85a(2.0g,5.9mmol,1.0eq)溶于二氯乙烷(50mL)中，加入化合物三甲基(乙烯基)硅烷(11.8g,11.8mmol,20.0eq)。反应液在汞灯照射，25℃下反应16小时。将反应混合物浓缩，残留物通过制备分离纯化(0.01％FA/ACN＝1/1)得到化合物85b(600mg,23％收率)为黄色油状物。LCMS:[M+H]+＝438.2
Step 3：rel-(1R,3R,4S,5R)-4-(3,4-二氟-2-甲氧基苯基)-5-甲基-1-三氟甲基-2-氧杂双环[3.2.0]庚烷-3-甲酰胺(85c)
将化合物85b(500mg,3.0mmol,1.0eq)溶于二甲基亚砜(20mL)中，加入四丁基氟化铵三水合物(6.4g,22.8mmol,20eq)。反应液在100℃下反应16小时。将反应混合物浓缩，残留物通过制备分离纯 化(0.01％FA/ACN＝3/2)得到化合物85c(170mg,40％收率)为黄色油状物。LCMS:[M+H]+＝366.1Step 4:rel-(1R,3R,4S,5R)-4-(3,4-二氟-2-甲氧基苯基)-5-甲基-1-三氟甲基-2-氧杂双环[3.2.0]庚烷-3-羧酸(85d)
将化合物85c(170mg,0.387mmol,1.0eq)溶于乙醇/水(3mL+1mL)中，加入氢氧化钾(217m g,3.87mmol,10eq)。反应液在100℃下反应4小时。LCMS监测反应完成。向反应液中加入1M稀盐酸，调节PH至5-6，用乙酸乙酯(10mL×3)萃取，收集有机相。有机相用饱和食盐水洗，无水硫酸钠干燥后浓缩，得到化合物85d(100mg,70％收率)为黄色油状物。LCMS:[M+H]+＝367.1
Step 5:rel-(1R,3R,4S,5R)-N-(3-氨基甲酰基-4-氟苯基)-4-(3,4-二氟-2-甲氧基苯基)-5-甲基-1-三氟甲基-2-氧杂双环[3.2.0]庚烷-3-甲酰胺(实施例85)
将化合物85d(50mg,0.14mmol,1.0eq)溶于二氯甲烷(10mL)中，加入化合物5-氨基-2-氟苯甲酰胺(25mg,0.16mmol,1.2eq)，苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(62mg,0.16mmol,1.2eq)和N,N-二异丙基乙胺(21mg,0.16mmol,1.2eq)。反应液在25℃下搅拌2小时。LCMS监测反应完成。将反应液浓缩，得到残留物。残留物通过制备分离纯化(0.01％FA)得到实施例85(7.5mg,9％收率)为白色固体。LCMS:[M+H]+＝503.1。1H NMR(400MHz,CD3OD)δ7.91-7.89(m,1H),7.72-7.67(m,1H),7.11-7.06(m,1H),7.03-6.95(m,1H),6.93-6.84(m,1H),4.96(d,J＝7.6Hz,1H),4.22(d,J＝7.6Hz,1H),3.88(d,J＝2.0Hz,3H),2.42-2.34(m,1H),2.33-2.25(m,1H),2.16-2.09(m,1H),1.83-1.75(m,1H),0.81(d,J＝1.2Hz,3H).
实施例85用手性SFC拆分，柱子：Daicel CHIRALPAK IH_3,3.0*150mm,3μm particle size,得到实施例85-1(RT＝1.4min)，实施例85-2(RT＝2.0min)。
实施例86：rel-4-((1R,3R,4S,5R)-4-(3,4-二氟-2-甲氧基苯基)-5-甲基-1-(三氟甲基)-2-氧杂双环[3.2.0]庚烷-3-甲酰氨基)邻苯二甲酰胺(86)
按照实施例85中Step 5相似的方法，制备得到实施例86。LCMS:[M+H]+＝528.1。1H NMR(400MHz,MeOD)δ7.89(s,1H),7.80(d,J＝8.4Hz,1H),7.63(d,J＝8.4Hz,1H),7.05(dd,J＝25.2,18.0Hz,2H),5.10(d,J＝8.0Hz,1H),4.36(d,J＝8.0Hz,1H),4.07-3.92(m,3H),2.68(s,1H),2.46-2.17(m,2H),1.98-1.80(m,1H),1.32(s,1H),0.93(s,3H).
实施例87：
Step 1：rel-(1R,3R,4S,5R)-2-(2-(3,4-二甲氧基苄基)氨基磺酰基)吡啶-4-基)-4-(3,4-二氟-2-甲氧基苯基)-5-甲基-1-三氟甲基-2-氧杂双环[3.2.0]庚烷-3-甲酰胺(87a)
将化合物85d(60mg,0.16mmol,1.0eq)溶于无水吡啶(3mL)中加入化合物4-氨基-N,N-双(3,4-二甲氧基苄基)吡啶-2-磺酰胺34e(78mg,0.16mmol,1.0eq)和三氯氧磷(100mg,0.66mmol,4.0eq)。反应液在0℃下反应1.5小时。LCMS监控原料反应完了，反应混合物用水(10mL)稀释，乙酸乙酯(10mL x 3)萃取，然后依次用水，饱和食盐水洗，无水硫酸钠干燥后浓缩得到化合物87a(120mg,89％收率)为黄色油状物。
Step 2：rel-(1R,3R,4S,5R)-4-(3,4-二氟-2-甲氧基苯基)-5-甲基-N-(2-氨基磺酰基吡啶-4-基)-1-三氟甲基-2- 氧杂双环[3.2.0]庚烷-3-甲酰胺(实施例87)
将化合物87a(120mg,0.15mmol,1.0eq)溶于二氯甲烷(5mL)中加入三氟乙酸(5mL)。反应液在25℃下反应4小时。LCMS监控原料反应完了，反应混合物浓缩，残留物通过制备分离纯化(0.05％FA)得到实施例87(17.2mg,23％收率)为白色固体。LCMS:[M+H]+＝522.1。1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.59(d,J＝5.6Hz,1H),8.32(d,J＝2.0Hz,1H),7.90-7.88(m,1H),7.44(s,2H),7.23-7.15(m,1H),7.12-7.07(m,1H),5.16(d,J＝8.0Hz,1H),4.23(d,J＝8.0Hz,1H),3.93(d,J＝2.0Hz,3H),2.44-2.35(m,2H),2.18-2.10(m,1H),1.87-1.80(m,1H),0.82(s,3H).
实施例88：化合物88的合成
Step 1：化合物((4-溴吡啶-2-基)磺酰基)(甲基)氨基甲酸叔丁酯(88a)
将化合物((4-溴吡啶-2-基)磺酰)氨基甲酸叔丁酯82e(100mg,0.30mmol,1.0eq)溶于无水四氢呋喃(5mL)中，加入碳酸钾(82mg,0.59mmol,2.0eq)和碘甲烷(50mg,0.35mmol,1.2eq)。反应液在60℃下反应2小时。LCMS监控原料反应完了，向反应液中加入水(10mL)，乙酸乙酯(10mL x 3)萃取，然后依次用水，饱和食盐水洗，无水硫酸钠干燥后浓缩，残留物通过硅胶柱(石油醚/乙酸乙酯＝16/1)纯化得到88a(100mg,96％收率)为白色固体。LCMS:[M+Na]+＝373.0
Step 2：rel-((4-((1R,3R,4S,5R)-4-(3,4-二氟-2-甲氧基苯基)-5-甲基-1-(三氟甲基)-2-氧杂双环[3.2.0]庚烷-3-甲酰胺)吡啶-2-基)磺酰)(甲基)氨基甲酸酯叔丁酯(88b)
将化合物88a(53mg,0.15mmol,1.1eq)溶于二氧六环(5mL)中，加入化合物85c(50mg,0.14mmol,1.0eq)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(15mg,0.027mmol,0.2eq)，碳酸铯(89mg,0.27mmol,2.0eq)和醋酸钯(2mg,0.013mml,0.1eq)。反应液在105℃氮气保护下反应16小时。LCMS监控原料反应完了，反应液浓缩，残留物通过硅胶柱(二氯甲烷/甲醇＝10/1)纯化得到化合物88b(70mg,80％收率)为黄色油状物。LCMS:[M+H]+＝636.2
Step 3：rel-(1R,3R,4S,5R)-4-(3,4-二氟-2-甲氧基苯基)-5-甲基-N-(2-(N-甲基氨基磺酰基)吡啶-4-基)-1-(三氟甲基)-2-氧杂二环[3.2.0]庚烷-3-甲酰胺(实施例88)
将化合物88b(70mg,0.11mmol,1.0eq)溶于盐酸/二氧六环(4M,10mL)中。反应液在25℃下反应4小时。LCMS监控原料反应完了，反应混合物浓缩，残留物通过制备分离纯化(0.01％FA)得到实施例88(4.2mg,7.1％收率)为白色固体。LCMS:[M+H]+＝536.1。
1H NMR(400MHz,CD3OD)δ8.54(d,J＝5.6Hz,1H),8.25(d,J＝2.0Hz,1H),7.81(dd,J＝2.4,2.0Hz,1H),7.32-7.26(m,1H),7.06-6.95(m,1H),5.24(d,J＝10.4Hz,1H),3.92(d,J＝1.6Hz,3H),3.84(d,J＝10.8Hz,1H),2.63(s,3H),2.58-2.51(m,1H),2.48-2.39(m,1H),2.15-2.08(m,1H),1.49-1.48(m,1H),1.29(s,3H).
实施例89：化合物89的合成
Step 1：1-(4-溴吡啶-2-基)-2-氟乙烷-1-酮(89b)
在反应瓶中，将化合物1-(4-溴吡啶-2-基)乙烷-1-酮89a(300mg,1.50mmol,1.00eq)溶于甲苯(3mL)，加入叔丁基二甲硅基三氟甲磺酸酯(595mg,2.25mmol,1.50eq)和三乙胺(326mg,3.22mmol,2.15eq)。反应液在80℃下搅拌2小时。反应液浓缩，加入乙腈(3mL)和选择性氟试剂(537mg,1.51mmol,1.01eq)。反应液在25℃下搅拌1小时。LCMS监控原料反应完了，反应液浓缩，残留物通过硅胶柱(石油醚/乙酸乙酯＝50/1)纯化得到化合物89b(176mg,54％收率)为白色固体。LCMS:[M+H]+＝218.0。
Step 2：1-(4-溴吡啶-2-基)-2-氟乙烷-1-醇(89c)
在反应瓶中，将化合物89a(176mg,0.81mmol,1.00eq)溶于甲醇(5mL)，在0℃下加入硼氢化钠(60mg,1.60mmol,1.98eq)。反应液在25℃下搅拌16小时。LCMS监控原料反应完了，反应液浓缩，残留物通过硅胶柱(石油醚/乙酸乙酯＝3/1)纯化得到化合物89c(145mg,81％收率)为黄色油状物。LCMS:[M+H]+＝220.0。
Step 3：4-溴-2-(1-((叔丁基二甲基硅)氧)-2-氟乙基)吡啶(89d)
在反应瓶中，将化合物89c(130mg,0.59mmol,1.0eq)溶于N,N-二甲基甲酰胺(5mL)，加入咪唑(149mg,2.18mmol,3.7eq)和叔丁基二甲基氯硅烷(151mg,1.00mmol,1.7eq)。反应液在25℃下搅拌16小时。LCMS监控原料反应完了，反应液用水(15mL)稀释，乙酸乙酯(10mL x 3)萃取，然后用饱和食盐水洗，无水硫酸钠干燥后浓缩，残留物通过硅胶柱(石油醚/乙酸乙酯＝20/1)纯化得到化合物89d(173mg,87％收率)为无色油状物。LCMS:[M+H]+＝334.0。
Step 4：rel-(1R,3R,4S,5R)-N-(2-(1-((叔丁基二甲基硅)氧)-2-氟乙基)吡啶-4-基)-4-(3,4-二氟-2-甲氧基苯基)-5-甲基-1-(三氟甲基)-2-氧杂双环[3.2.0]庚烷-3-甲酰胺(89e)
在反应瓶中，将化合物89d(151mg,0.45mmol,1.5eq)溶于无水1,4-二氧六环(5mL)，加入碳酸铯(196mg,0.60mmol,2.0eq),85c(110mg,0.30mmol,1.0eq)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(35mg,0.06mmol,0.2eq)和醋酸钯(5mg,0.03mmol,0.1eq)。反应液在氮气氛围下105℃下反应16小时。LCMS监控原料反应完了，反应液用水(15mL)稀释，乙酸乙酯(10mL x 3)萃取，然后用饱和食盐水洗，无水硫酸钠干燥后浓缩，残留物通过硅胶柱(石油醚/乙酸乙酯＝2/1)纯化得到化合物89e(193mg,98％收率)为无色油状物。LCMS:[M+H]+＝619.3
Step 5：rel-(1R,3R,4S,5R)-4-(3,4-二氟-2-甲氧基苯基)-N-(2-(2-氟-1-羟基乙基)吡啶-4-基)-5-甲基-1-(三氟甲基)-2-氧杂双环[3.2.0]庚烷-3-甲酰胺(实施例89)
将化合物89e(193mg,0.31mmol,1.0eq)溶于四氢呋喃(3mL)中加入四丁基氟化铵的四氢呋喃溶液(0.4mL)。反应液在25℃下反应3小时。LCMS监控原料反应完了，反应液用水(10mL)稀释，乙酸乙酯(10mL x 3)萃取，然后用饱和食盐水洗，无水硫酸钠干燥后浓缩，残留物通过硅胶柱(石油醚/ 乙酸乙酯＝1/1)以及制备分离纯化(0.1％FA)得到化合物实施例89(68.5mg,41.3％收率)为白色固体和化合物。LCMS:[M+H]+＝505.1。1H NMR(400MHz,DMSO-d6)δ10.64(d,J＝3.6Hz,1H),8.39(d,J＝5.6Hz,1H),7.85(t,J＝2.4Hz,1H),7.61(d,J＝5.6Hz,1H),7.19(dd,J＝16.8,8.8Hz,1H),7.12-7.06(m,1H),5.95(s,1H),5.11(d,J＝8.4Hz,1H),4.80(d,J＝19.6Hz,1H),4.66(ddd,J＝47.6,9.6,2.8Hz,1H),4.50(ddd,J＝47.6,9.2,6.0Hz,1H),4.23(d,J＝8.4Hz,1H),3.93(d,J＝2.0Hz,3H),2.46-2.35(m,2H),2.21-2.13(m,1H),1.87-1.78(m,1H),0.81(s,3H).
实施例90：化合物90的合成
Step 1：(S)-(4-溴吡啶-2-基)甲基(四氢呋喃-3-基)氨基甲酸叔丁酯(90c)
在单口瓶中，将化合物4-溴吡啶甲醛90a(100mg,0.54mmol,1.0eq)溶于1,2-二氯乙烷(5mL)，加入(S)-四氢呋喃-3-胺90b(61mg,0.70mmol,1.3eq)，醋酸(32.38mg,0.54mmol,1.0eq)和三乙酰氧基硼氢化钠(171mg,0.81mmol,1.5eq)。反应液在25℃下搅拌3小时。然后向反应液中加入二碳酸二叔丁酯(176mg,0.81mmol,1.5eq)。反应液在25℃下搅拌0.5小时。LCMS监控原料反应完了，反应液浓缩，残留物通过硅胶柱(石油醚/乙酸乙酯＝4/1)纯化得到化合物90c(170mg,88％收率)为黄色油状物。
Step 2：rel-叔丁基-(4-(1R,3R,4S,5R)-4-(3,4-二氟-2-甲氧基苯基)-5-甲基-1-三氟甲基-2-氧杂双环[3.2.0]庚烷-3-甲酰胺基)吡啶-2-基)甲基((S)-四氢呋喃-3-基)氨基甲酸酯(90d)
在单口瓶中，将化合物90c(65mg,0.18mmol,1.0eq)溶于无水1,4-二氧六环(5mL)，加入碳酸铯(107mg,0.33mmol,2.0eq)，化合物85c(60mg,0.16mmol,1.0eq)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(19mg,0.03mmol,0.2eq)和醋酸钯(2.7mg,0.02mmol,0.1eq)。反应液在氮气氛围下105℃下反应16小时。LCMS监控原料反应完了，反应液用水(15mL)稀释，乙酸乙酯(10mL x 3)萃取，然后用饱和食盐水洗，无水硫酸钠干燥后浓缩，残留物通过硅胶柱(石油醚/乙酸乙酯＝20/1)纯化得到化合物90d(30mg,29％收率)为黄色油状物。
Step 3：rel-(1R,3R,4S,5R)-4-(3,4-二氟-2-甲氧基苯基)-5-甲基-N-(2-((S)-四氢呋喃-3-氨基)甲基)吡啶-4-基)-1-三氟甲基-2-氧杂双环[3.2.0]庚烷-3-甲酰胺(实施例90)
将化合物90d(30mg,0.05mmol,1.0eq)溶于二氯甲烷(2mL)中加入三氟乙酸(1mL)。反应液在25℃下反应3小时。LCMS监控原料反应完了，反应混合物浓缩，残留物通过制备分离纯化(0.1％FA)得到实施例90(1.7mg,6％收率)为白色固体。LCMS:[M+H]+＝542.2。1H NMR(400MHz,CDCl3)δ8.68(s,1H),8.46(d,J＝5.6Hz,1H),7.59(s,1H),7.52(d,J＝4.8Hz,1H),6.96(d,J＝5.6Hz,2H),6.93-6.87(m,1H),5.02(d,J＝6.4Hz,1H),4.20(s,1H),4.00(d,J＝2.4Hz,3H),3.96(s,2H),3.86-3.72(m,4H),3.55(s,1H),2.59-2.52(m,1H),2.25-2.14(m,3H),1.91-1.90(m,1H),0.90(s,3H).
实施例91：rel-(1R,3R,4S,5R)-4-(3,4-二氟-2-甲氧基苯基)-N-(2-甲氧基乙基氨基)甲基吡啶-4-基)-5-甲基-1-三氟甲基-2-氧杂双环[3.2.0]庚烷-3-甲酰胺(91)
用2-甲氧基乙烷-1-胺替换实施例90中的90b，用相似的方法制备得到实施例91。LCMS:[M+H]+＝530.2。1H NMR(400MHz,CDCl3)δ8.64(s,1H),8.47(d,J＝5.2Hz,1H),7.57-7.53(m,2H),6.97-6.86(m,2H), 5.01(d,J＝6.8Hz,1H),4.20(s,1H),4.00(s,3H),3.58(t,J＝4.8Hz,2H),3.38(s,3H),2.95(t,J＝4.8Hz,2H),2.57-2.50(m,1H),2.19-2.10(m,3H),1.94-1.89(m,2H),0.90(s,3H).
实施例92：
Step 1：5-溴-2-氟-N-(噻唑-4-基)苯磺酰胺(92b)
将4-溴-2-氟苯磺酰氯92a(200mg,1.0eq)溶于THF(5mL)中，冷却至0度，氮气保护下，滴加NaHMDS(0.9mL,1.0M,1.2eq)。1小时后，加入噻唑-4-氨基甲酸叔丁酯(161mg,1.1eq)的THF(1mL)溶液。缓慢升至室温后，加入饱和氯化铵溶液，乙酸乙酯(20mL*3)萃取，合并有机相，食盐水洗涤，硫酸钠干燥，过滤，旋干，硅胶柱层析(石油醚/乙酸乙酯＝3/1)得到5-溴-2-氟-N-(噻唑-4-基)苯磺酰胺92b(150mg,60％收率)为白色固体。LCMS：[M+H]+＝336.8,338.8。
Step 2：rel-(1R,3R,4S,5R)-4-(3,4-二氟-2-甲氧基苯基)-N-(4-氟-3-(N-(噻唑-4-基)氨基磺酰基)苯基)-5-甲基-1-三氟甲基-2-氧杂双环[3.2.0]庚烷-3-甲酰胺(实施例92)
将85c(30mg,0.08mmol,1.0eq)溶于1,4-二氧六环(5mL)，并加入92b(42mg,0.12mmol,1.5eq)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(9.5mg,0.016mmol,0.2eq)，碳酸铯(80mg,0.25mmol,3eq)和醋酸钯(1.8mg,0.008mmol,0.1eq)。将混合物在105℃搅拌16小时，滤液减压浓缩，通过制备分离纯化(0.1％FA)纯化得到化合物实施例92(2.4mg,4％收率)为白色固体。LCMS:[M+H]+＝622.1。1HNMR(400MHz,MeOD)δ8.53(s,1H),8.01-8.00(m,1H),7.74-7.72(m,1H),7.10-7.06(m,1H),6.99-6.96(m,1H),6.92-6.86(m,1H),6.67(s,1H),4.95-4.93(m,1H),4.21-4.19(m,1H),3.87(s,3H),2.41-2.22(m,2H),2.14-2.07(m,1H),1.81-1.74(m,1H),0.80(s,3H).
实施例93：化合物93的合成
Step 1：(2-(S-甲基磺酰亚胺)吡啶-4-基)氨基甲酸苄酯(93b)
称取93a(2.2g，8.0mmol，1.0eq)至于反应瓶中，加入碘苯二乙酸(8.3g，25.7mmol，3.2eq)，氨基甲酰胺(4.3g，56.2mmol，7.0eq)，二氯甲烷(150mL)和甲醇(150mL)。室温反应16小时候，LCMS检测反应完全。将反应溶液浓缩后，柱层析(石油醚：乙酸乙酯＝0～100％)纯化得到93b为黄色固体(2.3g，收率94％)。LCMS:[M+H]+＝306.4。
Step 2：(4-氨基吡啶-2-基)(亚氨基)(甲基)-1-6-磺酸酮(93c)
将化合物93b(300mg,0.98mmol,1.0eq)溶于甲醇(10mL)中，加入钯碳(314mg,2.95mmol,3.0eq)。反应液在氢气中，25℃下反应16小时。LCMS监控反应完全。将反应液过滤，收集滤液并浓缩，得到残留物。残留物通过硅胶柱(二氯甲烷/甲醇＝10/1)纯化得到化合物93c(100mg,59％收率)为白色固体。 LCMS:[M+H]+＝172.1。
Step 3：rel-(1R,3R,4S,5R)-4-(3,4-二氟-2-甲氧基苯基)-5-甲基-N-(2-(S-甲基磺酰亚胺)吡啶-4-基)-1-(三氟甲基)-2-氧杂二环[3.2.0]庚烷-3-甲酰胺(实施例93)
将化合物85d(50mg,0.14mmol,1.0eq)溶于二氯甲烷(10mL)中，加入化合物93c(28mg,0.16mmol,1.2eq)，苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(62mg,0.16mmol,1.2eq)和N,N-二异丙基乙胺(35mg,0.27mmol,2.0eq)。反应液在25℃下搅拌2小时。LCMS监测反应完成。将反应液浓缩，得到残留物。残留物通过制备分离纯化(0.01％FA)纯化得到实施例93(8.2mg,11.6％收率)为白色固体。LCMS:[M+H]+＝520.1。1H NMR(400MHz,CD3OD)δ8.06(d,J＝5.6Hz,1H),7.33(s,1H),7.01-6.96(m,2H),6.71-6.68(m,1H),4.92(d,J＝5.6Hz,1H),4.88-4.84(m,3H),4.19(s,1H),3.95-3.93(m,3H),2.45-2.18(m,2H),2.18-1.97(m,1H),1.79-1.73(m,1H),0.85(d,J＝5.2Hz,3H).
实施例94：化合物94的合成
Step 1：(2-(N,S-二甲基磺酰亚胺)吡啶-4-基)氨基甲酸苄酯(94a)
将化合物93b(300mg,0.98mmol,1.0eq)溶于乙腈(20mL)中，加入四乙基硅烷(283mg,1.96mmol,2.0eq)，甲醛(294mg,4.91mmol,5.0eq)和三氟乙酸(233mg,2.94mmol,3.0eq)。反应液在25℃下反应16小时。LCMS监控反应完全。将反应液浓缩得到残留物。残留物通过硅胶柱(二氯甲烷/甲醇＝30/1)纯化得到化合物94a(300mg,95％收率)为无色油状。LCMS:[M+H]+＝320.1。
Step 2：(4-氨基吡啶-2-基)(甲基)(甲基亚氨基)-1-6-磺酸酮(94b)
将化合物94a(300mg,0.94mmol,1.0eq)溶于甲醇(10mL)中，加入钯碳(300mg,2.82mmol,3.0eq)。反应液在氢气中25℃下反应16小时。LCMS监控反应完全。将反应液过滤，收集滤液并浓缩，得到残留物。残留物通过硅胶柱(二氯甲烷/甲醇＝10/1)纯化得到化合物94b(150mg,86％收率)为白色固体。LCMS:[M+H]+＝186.1。
Step 3：rel-(1R,3R,4S,5R)-4-(3,4-二氟-2-甲氧基苯基)-N-(2-(N,S-二甲磺酰)吡啶-4-基)-5-甲基-1-(三氟甲基)-2-氧杂双环[3.2.0]庚烷-3-羧酰胺(实施例94)
将化合物85d(50mg,0.14mmol,1.0eq)溶于无水吡啶(3mL)中，加入化合物94b(30mg,0.16mmol,1.2eq)，混合均匀后，在0℃下加入三氯氧磷(84mg,0.55mmol,4.0eq)。反应液在0℃下搅拌15min。LCMS监测反应完成。将反应液倒入水中，用乙酸乙酯萃取，收集有机相。用无水硫酸钠干燥有机相并浓缩，得到残留物。残留物通过制备分离纯化(0.01％FA)化合物实施例94(14.2mg,16％收率)为白色固体。LCMS:[M+H]+＝534.0。1H NMR(400MHz,CD3OD)δ8.62(d,J＝5.2Hz,1H),8.48(t,J＝1.6Hz,1H),7.95(dd,J＝2.0,2.0Hz,1H),7.11-7.04(m,1H),7.02-6.95(m,1H),5.11(d,J＝8.0Hz,1H),4.34(d,J＝7.6Hz,1H),3.98(t,J＝2.4Hz,3H),3.22(s,3H),2.57(s,3H),2.52-2.45(m,1H),2.39-2.31(m,1H),2.22-2.17(m,1H),1.93-1.84(m,1H),0.90(d,J＝1.2H,3H).
实施例95：化合物95的合成
Step 1：R-4-溴-2-(2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)吡啶(95b)
将4-溴-2-氟吡啶95a(1.0g,5.7mmol,1.0eq)和R-2,2-二甲基-1,3-二氧戊环-4-甲醇95b(0.9g,6.8mmol,1.2eq)溶于盐酸/1,4-二氧六环(10mL)，并加入叔丁醇钾(1.9g,17.1mmol,0.1eq)，1,1'-联萘-2,2'-双二苯膦(0.4g,0.5mmol,0.1eq)和醋酸钯(0.13g,0.5mmol,0.1eq)。反应液在105℃下搅拌16小时。LCMS监控原料反应完了，向反应液中加入1M稀盐酸(4mL)淬灭，二氯甲烷(10mL×3)萃取，然后用饱和食盐水洗，无水硫酸钠干燥后浓缩得到化合物95c(0.5g,30％收率)为白色固体。LCMS:[M+H]+＝288.0
Step 2：rel-(1R,3R,4S,5R)-4-(3,4-二氟-2-甲氧基苯基)-N-(2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)吡啶-4-基)-5-甲基-1-三氟甲基-2-氧杂双环[3.2.0]庚烷-3-甲酰胺(95d)
向85c(500mg,1.37mmol,1.0eq)溶于1,4-二氧六环溶液中，并加入(R)-4-溴-2-((2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)吡啶96b(592mg,2.0mmol,1.5eq)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(158mg,0.27mmol,0.2eq)，碳酸铯(1.3g,4.1mmol,3.0eq)和醋酸钯(31mg,0.14mmol,0.1eq)。将反应物在氮气下于105℃搅拌16小时。反应完成后，过滤混合物。滤液减压浓缩，得到残余物。残余物通过柱色谱(乙酸乙酯:石油醚＝1:3)纯化得到化合物95d(100mg,30％收率)为黄色固体。LCMS:[M+H]+＝573.2.
Step 3:rel-(1R,3R,4S,5R)-4-(3,4-二氟-2-甲氧基苯基)-N-(2-(S)-2,3-二羟基丙氧基吡啶-4-基)-5-甲基-1-三氟甲基-2-氧杂双环[3.2.0]庚烷-3-甲酰胺(实施例95)
将95d(100mg,0.17mmol,1.0eq)的混合物在25℃搅拌1小时。LCMS显示反应完成。将混合物在减压下浓缩。化合物通过制备纯化(0.1％FA)得到实施例95(23.4mg,25％收率)为白色固体。LCMS:[M+H]+＝533.2。1HNMR(400MHz,DMSO-d6)δ10.52(s,1H),8.02(d,J＝8.0Hz,1H),7.22-7.17(m,3H),7.10-7.06(m,1H),5.10(d,J＝8.0Hz,1H),4.88(d,J＝8.0Hz,1H),4.61(t,J＝8.0Hz,1H),4.25-4.21(m,2H),4.12-4.08(m,1H),3.93(d,J＝4.0Hz,3H),3.77-3.73(m,1H),3.41(t,J＝4.0Hz,2H),2.45-2.36(m,1H),2.32-2.29(m,1H),2.19-2.12(m,1H),1.86-1.79(m,1H),0.81(s,3H).
实施例96：rel-(1R,3R,4S,5R)-4-(3,4-二氟-2-甲氧基苯基)-N-(2-(R)-2,3-二羟基丙氧基吡啶-4-基)-5-甲基-1-三氟甲基-2-氧杂双环[3.2.0]庚烷-3-甲酰胺(96)
用S-2,2-二甲基-1,3-二氧戊环-4-甲醇替换实施例95中的95b，用相似的方法制备得到实施例96。LCMS:[M+H]+＝533.1。1H NMR(400MHz,DMSO-d6)δ10.55(s,1H),8.02(d,J＝5.7Hz,1H),7.24-7.15(m,3H),7.12-7.06(m,1H),5.11(d,J＝8.0Hz,1H),4.23(dd,J＝9.7,4.5Hz,2H),4.10(dd,J＝10.9,6.3Hz,1H),3.93(d,J＝2.2Hz,3H),3.77-3.59(m,5H),2.43-2.29(m,2H),2.20-2.11(m,1H),1.83(td,J＝10.7,7.0Hz,1H),0.81(s,3H).
实施例97：5-((1S,3R,4S,5S)-4-(3,4-二氟-2-甲氧基苯基)-5-甲基-1-(三氟甲基)-2-氧杂双环[3.2.0]庚烷-3-甲酰氨基)吡啶甲酰胺(97)
用5-氨基吡啶酰胺替换实施例85中的5-氨基-2-氟苯甲酰胺，用相似的方法制备得到实施例97。LCMS:[M+H]+＝486.1。1H NMR(400MHz,DMSO-d6)δ10.68(s,1H),8.87(d,J＝2.0Hz,1H),8.25(dd,J＝8.6,2.5 Hz,1H),8.01(d,J＝8.6Hz,2H),7.55(s,1H),7.22-7.07(m,2H),5.16(d,J＝8.1Hz,1H),4.25(d,J＝8.1Hz,1H),3.92(dd,J＝8.0,2.1Hz,4H),2.20-1.81(m,2H),0.82(s,4H).
实施例98：化合物98的合成
Step 1：2-溴-1-(5-溴吡啶-2-基)乙烷-1-酮(98b)
将1-(5-溴吡啶-2-基)乙酮98a(2.0g,0.01mmol,1.0eq)溶于甲醇(10mL)和乙酸(15mL)中冷却至0℃，加入30％溴化氢乙酸溶液(2.8mL)，滴加溴(1.6g,0.01mmol,1.0eq)在乙酸(5mL)中，使反应混合物达到室温，然后加热至70℃，搅拌1小时。LCMS分析表明反应完成。将混合物减压浓缩，残余物由异丙醇结晶，得到98b(1.0g,32％收率)为黄色固体。LCMS:[M+H]+＝278.9。
Step 2：1-(5-溴吡啶-2-基)乙烷-1,2-二醇(98c)
将2-溴-1-(5-溴吡啶-2-基)乙酮98b(1.0g,3.6mmol,1.0eq)和甲酸钠(1.0g,14.4mmol,4.0eq)的乙醇溶液(10mL)加热至50℃反应3小时。反应完后，将其冷却至室温，并在减压下蒸发溶剂。用水(10mL)淬灭混合物，并用二氯甲烷(50mL×3)萃取。将合并的有机相用硫酸钠干燥并过滤。滤液减压浓缩。将残留物在甲醇(10mL)中吸收并冷却至0℃。分批加入硼氢化钠(0.4g,10.8mmol,3.0eq)，并将混合物在0℃下搅拌1小时。通过加入浓盐酸将pH调节至2，并在减压下除去溶剂，用二氯甲烷(50mL)和饱和碳酸氢钠水溶液(10mL)，萃取3次。将合并的有机相用硫酸钠干燥。残留物通过硅胶柱(石油醚/乙酸乙酯＝4/1)纯化得到化合物98c(350mg,42％收率)为黄色固体。LCMS:[M+H]+＝218.0。
Step 3：5-溴-2-(2,2-二甲基-1,3-二氧戊环-4-基)吡啶(98d)
将1-(5-溴吡啶-2-基)乙烷-1,2-二醇98c(100mg,0.46mmol,1.0eq)溶于N,N-二甲基甲酰胺(5mL)中，并加入2,2-二甲氧基丙烷(48mg,0.46mmol,1.0eq)和对甲苯磺酸(7.9mg,0.05mmol,0.1eq)。将混合物在25℃下搅拌24小时。LCMS分析表明反应完成。将混合物用水(50mL)淬灭，然后用二氯甲烷(50mL×3)萃取。将合并的有机相用硫酸钠干燥并过滤。滤液减压浓缩。残余物用乙酸乙酯在石油醚中洗脱0-50％纯化得到5-溴-2-(2,2-二甲基-1,3-二氧戊环-4-基)吡啶98d(60mg,48％收率)为黄色油状物。LCMS:[M+H]+＝258.0。
Step 4：rel-(1R,3R,4S,5R)-4-(3,4-二氟-2-甲氧基苯基)-N-(6-(2,2-二甲基-1,3-二氧戊环-4-基)吡啶-3-基)-5-甲基-1-三氟甲基-2-氧杂双环[3.2.0]庚烷-3-甲酰胺(98e)
将85c(50mg,0.14mmol,1.0eq)溶于1,4-二氧六环(5mL)，并加入5-溴-2-(2,2-二甲基-1,3-二氧戊环-4-基)吡啶(53mg,0.21mmol,1.5eq)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(16mg,0.027mmol,0.2eq)，碳酸铯(134mg,0.41mmol,3.0eq)和醋酸钯(3.1mg,0.014mmol,0.1eq)。将混合物在105℃搅拌16小时。反应完成后，将混合物用水(50mL)淬灭，然后用乙酸乙酯(50mL×3)萃取。将合并的有机相用硫酸钠干燥并过滤。滤液减压浓缩。用硅胶色谱法(石油醚/乙酸乙酯＝3/1)纯化得到98e(50mg,67％收率)为黄色油状物。LCMS:[M+H]+＝543.2。
Step 5：rel-(1R,3R,4S,5R)-4-(3,4-二氟-2-甲氧基苯基)-N-(6-(1,2-二羟乙基)吡啶-3-基)-5-甲基-1-三氟甲基-2-氧杂双环[3.2.0]庚烷-3-甲酰胺(实施例98)
将98e(50mg,0.0184mmol,1.0eq)溶于盐酸/1,4-二氧六环(5mL)中，在25℃下搅拌1小时。将混合物在减压下浓缩。通过制备(0.1％NH3)得到化合物实施例98(4.2mg,9％收率)为白色固体。LCMS:[M+H]+＝503.2。1H NMR(400MHz,CD3OD)δ9.15(s,1H),8.49-8.47(m,1H),7.89-7.87(m,1H),7.12-7.07(m,1H),7.03-6.96(m,1H),5.15-5.14(m,1H),4.95-4.93(m,1H),4.34-4.31(m,1H),3.98-3.97(m,3H),3.84-3.76(m,2H),2.54-2.46(m,1H),2.40-2.33(m,1H),2.25-2.17(m,1H),1.93-1.86(m,1H),0.91(s,3H).
实施例99：化合物99的合成
用5-氨基-N,N-双(3,4-二甲氧基苄基)吡啶-2-磺酰胺替换实施例87中的34e，用相似的方法制备得到实施例99。LCMS:[M+H]+＝522.1。1H NMR(400MHz,DMSO-d6)δ10.73(s,1H),8.93(d,J＝2.4Hz,1H),8.31(dd,J＝8.4,2.4Hz,1H),7.90(d,J＝8.8Hz,1H),7.40(s,2H),7.23-7.16(m,1H),7.13-7.09(m,1H),5.17(d,J＝8.0Hz,1H),4.25(d,J＝8.0Hz,1H),3.93(d,J＝2.4Hz,3H),2.43-2.36(m,2H),2.19-2.13(m,1H),1.87-1.80(m,1H),0.83(s,3H).
实施例100：化合物100的合成
Step 1：4-(5-溴吡啶-2-基)-3-氧代哌啶-1-羧酸叔丁酯(100b)
将3-氧代-1-哌嗪羧酸叔丁酯(1.37g,6.82mmol,1.2eq)溶于DMF(15mL)中，冷却至0度，加入氢化钠(341mg,8.52mmol,1.5eq)，搅拌30分钟。加入2-氟-5-溴吡啶100a(1.0g,5.68mmol,1.0eq)后，升至60度，搅拌16小时。加入水，乙酸乙酯(50mL*3)萃取，合并有机相，食盐水洗涤，硫酸钠干燥，过滤，旋干，硅胶柱层析(石油醚/乙酸乙酯＝3/1)得到4-(5-溴吡啶-2-基)-3-氧代哌啶-1-羧酸叔丁酯100b(560mg,27.7％收率)为白色固体。LCMS：[M+H]+＝355.9,357.9。
Step 2：rel-叔丁基4-(4-((1R,3R,4S,5R)-4-(3,4-二氟-2-甲氧基苯基)-5-甲基-1-(三氟甲基)-2-氧杂双环[3.2.0]庚烷-3-甲酰胺基)吡啶-2-基)-3-氧代哌嗪-1-羧酸酯(100c)
将化合物85c(50mg,0.14mmol,1.0eq)溶于二氧六环(5mL)中加入100b(65mg,0.18mmol,1.3eq)，碳酸铯(133mg,0.41mmol,3.0eq)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(11mg,0.03mmol,0.2eq)和醋酸钯(3mg,0.01mmol,0.1eq)。反应液在氮气氛围下105℃反应16小时。LCMS监控原料反应完了，反应混合物浓缩，残留物通过硅胶柱(石油醚/乙酸乙酯＝10/1)纯化得到化合物100c(50mg,57％收率)为无色油状。
Step 3：rel-(1R,3R,4S,5R)-4-(3,4-二氟-2-甲氧基苯基)-5-甲基-N-(2-(2-氧代哌嗪-1-基)吡啶-4-基)-1-(三氟甲基)-2-氧杂二环[3.2.0]庚烷-3-甲酰胺(100d)
将化合物100c(50mg,0.078mmol,1.0eq)溶于三氟乙酸(5mL)中，反应液在25℃下反应2小时。LCMS监控原料反应完，反应混合物浓缩，得到化合物100d(40mg,95％收率)为白色固体。
Step 4：rel-(1R,3R,4S,5R)-4-(3,4-二氟-2-甲氧基苯基)-5-甲基-N-(2-(4-甲基-2-氧代哌嗪-1-基)吡啶-4-基)-1-(三氟甲基)-2-氧杂二环[3.2.0]庚烷-3-甲酰胺(实施例100)
将化合物100d(40mg,0.07mmol,1.0eq)和多聚甲醛(4mg,0.14mmol,2.0eq)溶于甲醇(5mL)中，反应液在25℃下反应30分钟，加入氰基硼氢化钠(8mg,0.14mmol,2.0eq)，反应液在40℃下反应1小时。LCMS监控原料反应完了，反应混合物浓缩，残留物通过制备分离纯化(0.1％FA)得到实施例100(6.7mg,13％收率)为白色固体。LCMS:[M+H]+＝555.2。1H NMR(400MHz,MeOD)δ8.33(d,J＝5.6Hz,1H),8.01(d,J＝1.6Hz,1H),7.64(dd,J＝5.6,2.0Hz,1H),7.16-6.90(m,2H),5.07(d,J＝8.0Hz,1H),4.33(d,J＝8.0Hz,1H),4.00-3.86(m,5H),3.28(s,2H),2.92-2.80(m,2H),2.50-2.43(m,1H),2.40(s,3H),2.35-2.17(m,2H),1.87(td,J＝10.8,6.4Hz,1H),0.90(s,3H).
实施例101：化合物101的合成
Step 1：2-(甲硫基)吡啶-4-胺(101b)
将甲硫醇钠(1.9g,27.0mmol,1.7eq)溶于到1-甲基吡咯烷酮(10mL)中，并加入2-氯吡啶-4-胺101a(2.0g,16.0mmol,1.0eq)。将容器密封并在微波炉中加热至200℃，反应15分钟。用8％的甲醇/二氯甲烷洗脱的硅胶快速色谱法纯化得到2-(甲硫基)吡啶-4-胺101b(1.5g,55％收率)为黄色固体。LCMS:[M+H]+＝141.0。
Step 2：2-(甲基磺酰基)吡啶-4-胺(101c)
将2-(甲硫基)吡啶-4-胺(100mg,0.7mmol,1.0eq)溶于四氢呋喃(5mL)中，并加入间氯过氧苯甲酸(369mg,2.1mmol,3.0eq)。将混合物在25℃下搅拌16小时。反应完成后，将混合物减压浓缩，得到混合物。混合物经柱层析(二氯甲烷/甲醇＝10/1)纯化，得到2-(甲基磺酰基)吡啶-4-胺101c(30mg,22％收率)为黄色固体。LCMS:[M+H]+＝173.0。
Step 3：rel-(1R,3R,4S,5R)-4-(3,4-二氟-2-甲氧基苯基)-5-甲基-N-(2-甲砜基)吡啶-4-基)-1-三氟甲基-2-氧杂双环[3.2.0]庚烷-3-甲酰胺(实施例101)
将2-甲磺酰基吡啶-4-胺101c(14mg,0.082mmol,1.5eq)溶于无水吡啶(5mL)中，并加入4-(3,4-二氟-2-甲氧基苯基)-5-甲基-1-三氟甲基-2-氧杂双环[3.2.0]庚烷-3-羧酸85d(20mg,0.055mmol,1.0eq)和三氯氧磷(25mg,0.16mmol,2.9eq)。将混合物在25℃下搅拌5分钟。滤液减压浓缩。通过制备(0.1％NH3)纯化得到化合物101(3.4mg,9％收率)为白色固体。LCMS:[M+H]+＝521.1。1H NMR(400MHz,CD3OD)δ8.62(s,1H),8.48(s,1H),8.01-7.99(m,1H),7.10-7.06(m,1H),7.03-6.96(m,1H),5.13-5.11(m,1H),4.34(d,J＝6.4Hz,1H),3.98(d,J＝2.0Hz,3H),3.21(s,3H),2.51-2.45(m,1H),2.38-2.31(m,1H),2.23-2.17(m,1H),2.03-2.00(m,1H),1.93-1.85(m,1H),0.91-0.88(m,3H).
实施例102：化合物102的合成
Step 1：(4-氨基吡啶-2-基)二甲基氧化膦(102b)
在微波管中，将化合物2-溴吡啶-4-胺102a(200mg,1.16mmol,1.0eq)溶于1,4-二氧六环(3mL)中加入化合物二甲基氧化膦2(180mg,2.31mmol,2.0eq)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(67mg,0.12mmol,0.1eq),三(二亚苄基丙酮)钯(106mg,0.12mmol,0.1eq)和碳酸钾(320mg,2.3mmol,2.0eq)。反应液在氮气氛围下130℃下微波反应2小时。LCMS监控原料反应完了，反应液浓缩，残留物通过硅胶柱(石油醚/乙酸乙酯＝8/1)纯化得到化合物(4-氨基吡啶-2-基)二甲基氧化膦102b(150mg,76％收率)为黄色固体。
Step 2：rel-(1R,3R,4S,5R)-4-(3,4-二氟-2-甲氧基苯基)-N-(2-(二甲基磷酰基)吡啶-4-基)-5-甲基-1-三氟甲基-2-氧杂双环[3.2.0]庚烷-3-甲酰胺(102)
将85d(50mg,0.14mmol,1.0eq)溶于无水吡啶(3mL)中加入化合物(4-氨基吡啶-2-基)二甲基氧化膦102b(23mg,0.14mmol,1.0eq)和三氯氧磷(84mg,0.55mmol,4.0eq)。反应液在0℃下反应1小时。LCMS监控原料反应完了，反应混合物用水(10mL)稀释，乙酸乙酯(10mL x 3)萃取，然后依次用水，饱和食盐水洗，无水硫酸钠干燥后浓缩，残留物通过制备分离纯化(0.05％FA)得到化合物102(15.8mg,22％收率)为白色固体。LCMS:[M+H]+＝519.1。1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),8.63(d,J＝5.6Hz,1H),8.28(dd,J＝6.8,2.0Hz,1H),7.85-7.82(m,1H),7.23-7.16(m,1H),7.13-7.07(m,1H),5.13(d,J＝8.0Hz,1H),4.23(d,J＝8.0Hz,1H),3.93(d,J＝2.0Hz,3H),2.44-2.35(m,2H),2.19-2.12(m,1H),1.87-1.80(m,1H),1.64(s,3H),1.60(s,3H),0.82(s,3H).
实施例103：化合物103的合成
Step 1：2-氨基-5-硝基苯磺酰胺(103b)
向反应瓶中加入103a(2.0g,8.45mmol,1.0eq)、碳酸铵(1.62g,16.9mmol,2.0eq)、硫酸铜(405mg,2.54mmol,0.3eq)和氨水(10mL)，于120℃下搅拌6小时，TLC监测原料基本转化完全。反应液冷却至室温，倒入水中，析出固体。混合液进行抽滤，滤饼水洗，干燥，得化合物103b(1.3g，收率71％)为氮黄色固体。LCMS:218.1[M+H]+.
Step 2：7-硝基-4H-苯并[e][1,2,4]噻二嗪1,1-二氧化物(103c)
向反应瓶中加入103b(600mg,2.76mmol,1.0eq)和原甲酸三甲酯(10mL)，于140℃下搅拌8小时，TLC监测原料基本转化完全。反应液冷却至室温，倒入水中，析出固体。混合液进行抽滤，滤饼水洗，干燥，得化合物103c(230mg，收率37％)为苍白色固体。LCMS:228.1[M+H]+.
Step 3：7-氨基-4H-苯并[e][1,2,4]噻二嗪1,1-二氧化物(103d)
向反应瓶中加入103c(200mg,0.88mmol,1.0eq)、铁粉(246mg,4.4mmol,5.0eq)、氯化铵(141mg,2.64mmol,3.0eq)、乙醇(5mL)和水(2mL)，于75℃下搅拌2小时，LCMS监测原料基本转化完全。反应液趁热用硅藻土抽滤，滤液浓缩，柱层析分离(MeOH/DCM，0～10％)得化合物103d(82mg，收率47％)为浅黄色固体。LCMS:198.2[M+H]+.
Step 4：rel-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧苯基)-N-(1,1-二羟基-4H-苯并[e][1,2,4]噻二嗪-7-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(实施例103)
向反应瓶中加入1a(144mg,0.406mmol,1.0eq)、乙腈(3mL)、NMI(167mg,2.03mmol,5.0eq)和TCFH(228mg,0.812mmol,2.0eq)，搅拌5分钟，再加入103d(80mg,0.406mmol,1.0eq)，于60℃下搅拌12小时，LCMS监测原料基本转化完全。向反应液中加入水(10mL),乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，柱层析分离(MeOH/DCM，0～10％)得到实施例103(63mg，收率29％)为白色固体。LCMS:534.4[M+H]+。1H NMR(400MHz,dmso-d6)δ12.28(s,1H),10.54(s,1H),8.22(d,J＝2.2Hz,1H),7.93(d,J＝2.3Hz,1H),7.82(dd,J＝9.0,2.3Hz,1H),7.30(d,J＝9.0Hz,1H),7.24–7.07(m,2H),5.07(d,J＝10.3Hz,1H),4.25(dd,J＝10.2,7.7Hz,1H),3.95(d,J＝1.9Hz,3H),2.85–2.70(m,1H),1.61(s,3H),0.72(d,J＝6.2Hz,3H).
实施例104：化合物104的合成
Step 1：5-硝基-1,3-二氧代异吲哚啉-2-基乙酸酯(104b)
在单口瓶中，将化合物2-羟基-5-硝基异吲哚啉-1,3-二酮104a(300mg,1.44mmol,1.0eq)溶于二氯甲烷(5mL)中加入化合物醋酸酐(221mg,2.17mmol,1.5eq)和吡啶(228mg,2.88mmol,2.0eq)。反应液在0℃下搅拌2小时。LCMS监控原料反应完了，反应液浓缩，残留物通过硅胶柱(石油醚/乙酸乙酯＝4/1)纯化得到化合物104b(300mg,83％收率)为白色固体。
Step 2：5-氨基-1,3-二氧代异吲哚啉-2-基乙酸酯(104c)
在单口瓶中，将化合物104b(300mg,1.20mmol,1.0eq)溶于N,N-二甲基甲酰胺(5mL)中，加入四羟基二硼(430mg,4.80mmol,4.0eq)和4,4'-联吡啶(19mg,0.12mmol,0.1eq)。反应液在0℃下反应20分钟。LCMS监控大部分原料反应完了，反应混合物依次加入乙酸乙酯(20mL)和水(20mL)，有机层用饱和食盐水(20mL)洗一遍，无水硫酸钠干燥，过滤，滤液浓缩，残留物通过柱层析分离纯化(石油醚/乙酸乙酯＝1/1)得到化合物104c(80mg,30％收率)为黄色油状。
Step 3：rel-5-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-三氟甲基四氢呋喃-2-甲酰胺基)-1,3-二氧代异吲哚啉-2-乙酸酯(104d)
将化合物1a(100mg,0.28mmol,1.0eq)溶于无水吡啶(3mL)中加入化合物104c(62mg,0.28mmol, 1.0eq)和三氯氧磷(173mg,1.13mmol,4.0eq)。反应液在0℃下反应1小时。LCMS监控原料反应完了，反应混合物用水(10mL)稀释，乙酸乙酯(10mL x 3)萃取，然后用饱和食盐水洗，过滤，滤液浓缩，残留物通过柱层析分离纯化(石油醚/乙酸乙酯＝4/1)得到化合物104d(100mg,64％收率)为白色固体。
Step：rel-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(2-羟基-1,3-二氧代异吲哚啉-5-基)-4,5-二甲基-5-三氟甲基四氢呋喃-2-甲酰胺(实施例104)
将化合物104d(100mg,0.18mmol,1.0eq)溶于甲醇(3mL)中加入氨甲醇溶液(0.5mL)。反应液在25℃下反应10分钟。LCMS监控原料反应完了，反应混合物浓缩，残留物通过制备分离纯化(0.1％FA)得到实施例104(28.2mg,29％收率)为白色固体。LCMS:[M-H]-＝513.1。
1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),8.14(d,J＝1.6Hz,1H),7.94(dd,J＝8.0,2.0Hz,1H),7.78(d,J＝8.0Hz,1H),7.21-7.14(m,2H),5.12(d,J＝10.0Hz,1H),4.29-4.25(m,1H),3.95(d,J＝2.0Hz,3H),2.82-2.74(m,1H),1.61(s,3H),0.74(d,J＝5.6Hz,3H).
表一：以相应的试剂为原料，按照与上述实施例所阐述的操作类似的操作，制备以下化合物。






生物活性测试1：化合物对Nav 1.8的体外抑制作用
运用手动膜片钳在稳定表达人Nav 1.8的HEK293细胞上，在Nav 1.8电流稳定后，比较给予化合物前后Nav 1.8电流的大小，得到化合物对Nav 1.8通道的影响。
将待测化合物用DMSO溶解配置成9mM的储备液，在测试当天按照所需浓度溶于细胞外液。细胞外液成分包括(mM)：NaCl，137；KCl，4；CaCl2，1.8；MgCl2，1；HEPES，10；葡萄糖，10；pH 7.4(NaOH滴定)。所有的试剂均购于Sigma(St.Louis,MO)公司。
将细胞钳制在-80mV，用持续10毫秒方波去极化到10mV，得到Nav 1.8电流，每5秒重复一次。检测方波引发的最大电流，待其稳定后，灌流测试化合物(按所需浓度溶于细胞外液)，稳定后，根据化合物灌流前后的电流计算化合物对Nav 1.8阻断的强度。采用pCLAMP 10(Molecular Devices，Union City，CA)，电流稳定指电流随时间变化在有限的范围内。
表1：抑制率测定(100nM浓度下抑制率/％：A>＝50,B<50)

采用相同的方法测定本发明其他化合物的对Nav 1.8在100nM浓度下抑制率/％，表明本发明化合物具有优异的钠通道调节活性(>＝50％)，能够用于治疗与钠通道调节相关的疾病。
生物活性测试2：测试化合物体外对Nav 1.8抑制作用IC50
采用稳定表达Nav1.8钠通道的CHO细胞系，进行实验检测，基因信息：Sodium channel，voltage-gated，type 8，alpha(SCN10A)，cDNA strictly similar to GenBank accession number：NM_006514。
膜片钳检测前，细胞用0.25％-Trypsin-EDTA分离，将6.5×103细胞铺到盖玻片上，在24孔板中培养(最终体积：500μL)，18个小时后，进行试验检测。
电生理记录所用液体：细胞外液：K-007-1，140mM NaCl，3.5mM KCl，1mM MgCl2·6H2O，2mM CaCl2·2H2O，10mM D-Glucose，10mM HEPES，1.25mM NaH2PO4·2H2O，NaOH调节pH＝7.4。细胞内液：Nav-001-2，50mM CsCl，10mM NaCl，10mM HEPES，60mM CsF，20mM EGTA，CsOH调节pH＝7.2。细胞外液保存时间为2周，细胞内液配好后分装为每管1mL，冻存于-20℃冰箱，每天试验使用新融化的细胞内液。所有细胞内液在三个月内用完。超过三个月，丢弃旧细胞内液，并重新配制。
膜片钳检测：全细胞膜片钳记录Nav1.8钠电流的电压刺激方案如下：当形成全细胞封接后细胞电压钳制于-120mV维持30ms。钳制电压除极至0mV维持50ms，然后电压恢复至-50mV(具体电压参考IV测试的半失活电压)，维持5s。接着细胞膜电位恢复至-120mV，维持20ms，然后再除极至0mV，维持50ms，最后恢复至钳制电压-120mV，维持30ms。每隔20ms重复采集数据。观察药物对钠电流峰值的作用。试验数据由EPC 10放大器(HEKA)进行采集并储存于PatchMaster(HEKA)软件中。
用微电极拉制仪将毛细玻璃管拉制成记录电极。将充灌细胞内液的电极装入电极夹持器，在倒置显微镜下操控微电极操纵器使电极浸入细胞外液并记录电极电阻(Rpip)。将电极接触到细胞表面，给予负压抽吸形成高阻封接(GΩ)。此时执行快电容补偿，再继续给予负压，吸破细胞膜，形成全细胞记录模式。然后进行慢电容补偿并记录膜电容(Cm)及串联电阻(Rs)等实验参数。不给予漏电补偿。
当全细胞记录的Nav1.8电流稳定后开始给药，每个药物浓度作用至5min(或者电流至稳定)后检测下一个浓度，每一个测试化合物检测多个浓度。将铺有细胞的盖玻片置于倒置显微镜下的记录浴槽中，空白对照外液以及待测化合物工作液利用重力灌流的方法从低浓度到高浓度依次流经记录浴槽从而作用于细胞，在记录中利用蠕动泵进行液体交换。每一个细胞在不含化合物的外液中检测到的电流作为自己的对照组。每个浓度至少使用三个细胞独立重复检测三次。所有电生理试验在室温下进行。
数据分析：首先将每一个药物浓度作用后的电流和空白对照电流归一化然后计算每一个药物浓度对应的抑制率并对每一个浓度抑制率计算平均数(Mean)，标准差(SD)和标准误(SE)。
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
用以上方程计算每种化合物的IC50值，并对剂量依赖效应进行非线性拟合，其中IC50为半抑制浓度。IC50的计算以及曲线拟合利用GraphPad Prism软件完成。
采用相同的方法测试本发明其他化合物对Nav 1.8抑制作用，表明本发明化合物对Nav 1.8具有良好的抑制作用。
生物活性测试3：化合物对小鼠切口痛模型的药效
模型建立：通过异氟烷麻醉，常规消毒，在左后脚掌足底面胫距关节远侧约0.2cm处，用刀片将0.5cm长的纵向皮肤切口伸向足趾；分离足底肌，稍微抬高，然后纵向切开，注意不能破坏肌肉起止部。切口用5-0尼龙线间断水平缝合(2针缝合)。
溶媒：受试化合物使用的溶媒为5％DMSO+10％Solutol+85％Saline，阳性化合物TRV-130使用的溶媒为10％ethanol+10％cremophor+80％water。
对照化合物1为WO2021113627A1中的化合物7，参照WO2021113627A1中的方法合成。
给药方式和频次：阳性对照化合物TRV-130静脉注射给药，每日一次；其余组口服给药，每日一次。
实验分组：造模前根据PWT基础值，剔除异常动物后随机挑选8只作为假手术组，给药组每组8只动物进行手术造模，剩余动物作为备用。手术后根据动物给药前痛阈值(PWT)再次分组，如若手术后发现动物PWT值异常，则从备用动物中随机选择动物重新造模。
机械痛阈值测量：建模前测量造模前机械痛阈值；在建模后2.5h测量给药前机械痛阈值，测量完成后口服给药，并在给药后2h进行机械痛阈测量，测量位置在手术切口位置内测，每只动物测量3次，每次间隔3-5分钟，取其平均值。
数据分析：相关数据在Office Excel 2013和GraphPad Prism6.0中进行整理，数据以Mean±SEM(标准误)表示。利用One-way ANOVA进行分析，分析方法选用Tukey进行组间比较差异显著性检验方法；两组间进行比较时，用T-test进行两组间双尾检测，当p<0.05时，两组之间具有显著性差异。当组内检测数据有少数差异较大时，可使用GraphPad Prism9.0进行identify outliters数据分析，剔除差异性数值(Q＝5％)；数据统计时，对于剔除药效实验的动物，该动物的所有相关数据都将不列入统计分析。
实验表明本发明化合物在不同剂量下(8mg/kg、25mg/kg、75mg/kg)相对于对照化合物1均具有更高的疼痛阈值(PWT)，能够很好的抑制疼痛。

Claims (11)

  1. 式I化合物
    或其药学上可接受的盐、立体异构体，其中，
    Ra1、Ra2、Ra3各自独立选自氢、卤素、羟基、C1-C5烷基、C1-C5烷氧基、C3-C6环烷基、C3-C6环烷氧基、-N(Rc3Rc4)m，或任意两个相邻的Ra1、Ra2、Ra3连接形成5-7元环，所述的5-7元环可以是饱和或不饱和的碳环或杂环；所述杂环上任选含有一个或多个N、O、S(＝O)m杂原子；
    Rb1、Rb2、Rb3、Rb4各自独立选自氢、卤素、羟基、C1-C5烷基、C1-C5烷氧基；或Rb1、Rb2、Rb3、Rb4任意两个连接形成3-7元环；
    M1、M2独立地选自C、O、S(＝O)m、N-Rn，其中Rn任选自氢、C1-C5烷基；
    环A为A1或A2：
    任意表示单键或双键
    X1、X2、X3、X4、X5各自独立选自键、C、N、O、C＝O、S(＝O)m；
    Y1、Y2可相同或不相同地任选自C原子或N原子；
    Rc1、Rc2各自独立选自氢、卤素、氰基、羟基、氨基、C1-C5烷基、C1-C5烷氧基、-S(＝O)m-Rc3Rc4、-C(＝O)-NRc3Rc4、-C(＝S)-NRc3Rc4、-N(Rc3Rc4)m、-P(＝O)m-Rc3Rc4、-C(＝N)-NRc3Rc4、-S(＝O)2NRc3Rc4、-C1-C5烷基NRc3Rc4、-S(＝O)(＝NRc3)Rc4；
    Rc3、Rc4各自独立选自氢、羟基、氨基、C1-C5烷基、C1-C5烷氧基、3-7元环，或Rc3、Rc4连接形成3-7元环；
    m、n任意为0，1或2；
    所述的烷基、烷氧基、环烷基、环烷氧基、5-7元环、3-7元环可以任选被一个或多个氘、卤素、羟基、氰基、氧代基、C1-C5烷基、C1-C5烷氧基、氨基取代。
  2. 根据权利要求1所述的式I化合物，Ra1、Ra2、Ra3各自独立选自氟、氯、甲基、乙基、甲氧基、乙氧基、丙氧基、三氟甲氧基、二氟甲氧基、氨基。
  3. 根据权利要求1所述的式I化合物，任意两个相邻的Ra1、Ra2、Ra3连接形成5或6元碳环或杂环。
  4. 根据权利要求1所述的式I化合物，Rb1、Rb2Rb3、Rb4各自独立选自氢、甲基、三氟甲基、乙基、甲氧基、乙氧基。
  5. 根据权利要求1所述的式I化合物，Rb1、Rb2、Rb3、Rb4任意两个连接形成3元环、4元环、5元环。
  6. 根据权利要求1所述的式I化合物，环A具有以下结构：
  7. 根据权利要求1所述的式I化合物，所述式I具有如式I-A或式I-B所示结构：
  8. 根据权利要求1或7所述的式I化合物，其具有如下结构：








  9. 一种药物组合物，所述组合物含有式I化合物或其药学上可接受的盐、立体异构体和药学上可接受的辅料。
  10. 根据权利要求9所述的药物组合物或权利要求1所述的式I化合物或其药学上可接受的盐、立体异构体在制备治疗、预防或缓解电压门控型钠通道相关疾病的药物的用途。
  11. 根据权利要求10所述的用途，所述疾病为疼痛、多发性硬化症、腓骨肌萎缩症、失禁、病理性咳嗽，或心律失常。
PCT/CN2023/115177 2022-08-28 2023-08-28 一种钠通道调节剂及其应用 WO2024046253A1 (zh)

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