WO2022194261A1 - 嘧啶并环类化合物及其用于制备治疗疼痛、脊髓损伤药物中的用途 - Google Patents

嘧啶并环类化合物及其用于制备治疗疼痛、脊髓损伤药物中的用途 Download PDF

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WO2022194261A1
WO2022194261A1 PCT/CN2022/081573 CN2022081573W WO2022194261A1 WO 2022194261 A1 WO2022194261 A1 WO 2022194261A1 CN 2022081573 W CN2022081573 W CN 2022081573W WO 2022194261 A1 WO2022194261 A1 WO 2022194261A1
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cycloalkyl
ring
compound
formula
alkyl
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PCT/CN2022/081573
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English (en)
French (fr)
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李进
杨民民
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南京药石科技股份有限公司
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Priority to CN202280007273.1A priority Critical patent/CN116490498A/zh
Publication of WO2022194261A1 publication Critical patent/WO2022194261A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
    • C07D255/04—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the application belongs to the field of chemical medicine, and in particular relates to a pyrimidocyclic compound and its use in preparing a medicine for treating pain and spinal cord injury.
  • Pain is a common form of physical distress and distress, and one of the most common reasons patients report to their doctors. It can be differentiated by form (nociceptive or neuropathic), duration (chronic or acute) and degree (mild, moderate or severe).
  • nociceptive pain is acute and caused by an injury, such as a burn, sprain, burn, fracture, or inflammation (inflammatory pain, including osteoarthritis and rheumatoid arthritis).
  • the International Association for the Study of Pain defines neuropathic pain as a chronic pain caused by a disorder or dysfunction of the nervous system.
  • neuropathic pain is caused by diabetic neuropathy, HIV infection, and postherpetic neuralgia.
  • neuropathic pain Other disorders associated with neuropathic pain include complex regional pain syndromes, trigeminal neuralgia, low back pain, sciatica, phantom limb pain, impingement pain, fibromyalgia, and other disorders that cause chronic pain (see Jensen, European Journal of Pain ,year 2002).
  • the K + -Cl - cotransporter KCC2 is responsible for maintaining low Cl - concentrations in central nervous system (CNS) neurons, which is required for postsynaptic inhibition via GABAA and glycine receptors. While no CNS disease has been associated with KCC2 mutations, loss of this transporter activity has emerged as a key mechanism in several neurological and psychiatric disorders, including epilepsy, motor spasms, stress, anxiety, schizophrenia, and morphine-induced hyperalgesia and chronic pain. Studies have shown that enhancing KCC2 activity may be a favorable therapeutic strategy to restore inhibition and normal function in pathological conditions involving impaired Cl - transport (Gagnon, Martin. et al. Nature Medicine (2013), 19(11), 1524-1528 ).
  • KCC2 agonists mimicked in inhibitory interneurons between and around staggered spinal cord injuries by selectively expressing KCC2, restoring the ability to step in spinal cord-injured mice.
  • these treatments transform injury-induced spinal circuit dysfunction into a functional state that facilitates the transmission of brain-derived instructions to the lumbar spinal cord. Therefore, KCC2 agonists hold promise as a therapeutic approach to promote functional recovery after spinal cord injury (Bo Chen, Yi Li. et al. Cell (2018), 174(3), 521-535).
  • the present application discloses a pyrimidocyclic compound, which can be used as a potential KCC2 agonist, and its use in the preparation of a medicament for treating pain and spinal cord injury.
  • the application provides a compound of formula (I), a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:
  • ring A is a cycloalkyl, heterocyclyl, aryl or heteroaryl containing 0-4 heteroatoms and 5-14 ring atoms;
  • Ring B is a cycloalkyl, heterocyclyl, aryl or heteroaryl containing 0-2 heteroatoms, 5-7 ring atoms;
  • X is C or N
  • R 1 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, amino, hydroxy, hydroxyalkyl, alkoxy, alkylacyl or sulfonyl;
  • R 2 is each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, amino, hydroxy, hydroxyalkyl, alkoxy, alkylacyl or sulfonyl;
  • n, n' are selected from 0, 1, 2 or 3;
  • Formula (I) is Formula (Ia):
  • ring A is a heterocyclic group or a heteroaryl group containing 1-4 heteroatoms and 5-14 ring atoms;
  • Ring B is a cycloalkyl, heterocyclyl, aryl or heteroaryl containing 0-2 heteroatoms, 5-7 ring atoms;
  • X is C or N
  • R 1 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, amino, hydroxy, hydroxyalkyl, alkoxy, alkylacyl or sulfonyl;
  • R 2 is each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, amino, hydroxy, hydroxyalkyl, alkoxy, alkylacyl or sulfonyl;
  • n are selected from 0, 1, 2 or 3;
  • Formula (I) is Formula (Ib):
  • ring A is a heterocyclic group or a heteroaryl group containing 1-3 heteroatoms and 5-7 ring atoms;
  • Ring B is a cycloalkyl or heterocyclic group containing 0-2 heteroatoms and 5-7 ring atoms;
  • R 1 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, amino, hydroxy, hydroxyalkyl, alkoxy, alkylacyl or sulfonyl;
  • R 2 is each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, amino, hydroxy, hydroxyalkyl, alkoxy, alkylacyl or sulfonyl; and
  • n are selected from 0, 1, 2 or 3.
  • Formula (I) is Formula (Ic) or (Id):
  • ring B is a cycloalkyl or heterocyclic group containing 0-2 heteroatoms and 5-7 ring atoms;
  • R 1 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, amino, hydroxy, hydroxyalkyl, alkoxy, alkylacyl or sulfonyl;
  • R 2 is each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, amino, hydroxy, hydroxyalkyl, alkoxy, alkylacyl or sulfonyl; and
  • n are selected from 0, 1, 2 or 3.
  • the compound of formula (I) is selected from:
  • its structure is:
  • its structure is:
  • its structure is:
  • H at any position in the foregoing compounds may be deuterium.
  • the present application also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned compound, or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, hydrate or isomer thereof body; and a pharmaceutically acceptable carrier or excipient.
  • the present application also provides the use of the aforementioned compounds, or pharmaceutically acceptable salts, esters, prodrugs, complexes, solvates, hydrates or isomers thereof, for the preparation of KCC2 agonist drugs.
  • the present application also provides the use of the aforementioned compounds, or pharmaceutically acceptable salts, esters, prodrugs, complexes, solvates, hydrates or isomers thereof, for preparing a medicament for treating spinal cord injury.
  • the present application also provides the use of the aforementioned compounds, or pharmaceutically acceptable salts, esters, prodrugs, complexes, solvates, hydrates or isomers thereof, for the preparation of analgesic drugs.
  • isomer includes enantiomeric, diastereomeric, and geometric (or conformational) isomeric forms of a given structure.
  • this application includes the R and S configurations, Z and E double bond isomers, Z and E conformational isomers, single stereochemical isomers as well as enantiomers, diastereomers for each asymmetric center Isomers and geometric (or conformational) isomer mixtures.
  • Suitable acid addition salts are formed from acids, which form non-toxic salts such as hydrochloride/chloride.
  • Suitable base salts are formed from bases, which form non-toxic salts such as calcium and sodium salts. Hemi-salts of acids and bases, such as hemi-sulfate and hemi-calcium salts, can also be formed.
  • terapéuticaally effective amount refers to an amount of a compound of the present application that (i) treats a particular disease, condition or disorder; (ii) alleviates, alleviates or eliminates one or more symptoms of a particular disease, condition or disorder or (iii) preventing or delaying the onset of one or more symptoms of the specified disease, condition or disorder described herein.
  • pharmaceutically acceptable carrier or excipient refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms atom of the alkyl group.
  • Non-limiting examples of lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl , 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl base, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2 ,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3 - Dimethylbutyl, etc.
  • alkenyl refers to aliphatic hydrocarbons having at least one carbon-carbon double bond, including straight and branched chains having at least one carbon-carbon double bond.
  • an alkenyl group has 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, or 2 to 4 carbon atoms.
  • C 2-6 alkenyl includes straight or branched chain unsaturated groups of 2 to 6 carbon atoms (having at least one carbon-carbon double bond), including but not limited to vinyl, 1-propenyl , 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.
  • alkynyl refers to aliphatic hydrocarbons having at least one carbon-carbon triple bond, including straight and branched chains having at least one carbon-carbon triple bond.
  • the alkynyl group has 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 3 to 6 carbon atoms.
  • C 2-6 alkynyl includes straight or branched chain unsaturated groups (having at least one carbon-carbon triple bond) of 2 to 6 carbon atoms.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms carbon atoms (eg 3, 4, 5 or 6 carbon atoms), most preferably 5 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • spirocycloalkyl refers to a 5- to 20-membered monocyclic polycyclic group sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but each ring does not have complete Conjugated pi electron system.
  • a spiro atom which may contain one or more double bonds, but each ring does not have complete Conjugated pi electron system.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • the spirocycloalkyl groups are divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl, More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl.
  • fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple double bonds, but each ring does not have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl.
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly connected carbon atoms, which may contain one or more double bonds, but not each ring. Has a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) heteroatoms excluding ring moieties of -O-O-, -O-S- or -S-S-, the remaining ring atoms being carbon.
  • It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; and most preferably contains 5 to 6 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazolyl Hydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, and pyrrolidinyl.
  • Polycyclic heterocyclyls include spiro heterocyclyls, fused heterocyclyls and bridged heterocyclyls.
  • spiroheterocyclyl refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O )m (where m is an integer from 0 to 2) heteroatoms and the remaining ring atoms are carbon. It may contain one or more double bonds, but each ring does not have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiroheterocyclyl groups are divided into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiro-heterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl, More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group.
  • fused heterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more of the rings may contain one or more double bonds, but each ring does not have a fully conjugated pi-electron system, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), The remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the number of constituent rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • bridged heterocyclyl refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but each ring does not have A fully conjugated pi-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O)m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon.
  • m is an integer from 0 to 2
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the number of constituent rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • the heterocyclic group includes the above-mentioned heterocyclic group (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the same as the parent structure
  • the rings linked together are heterocyclyl, non-limiting examples of which include:
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered, such as benzene base and naphthyl.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10-membered, containing 1 to 3 heteroatoms; more preferably 5- or 6-membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridine oxazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and pyridazinyl and the like.
  • the heteroaryl group includes a heteroaryl group as described above fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include :
  • hydroxyalkyl refers to an alkyl group substituted with hydroxy, wherein alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • deuterated alkoxy refers to an alkoxy group substituted with one or more deuterium atoms, wherein alkoxy is as defined above.
  • cycloalkylalkyl refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.
  • cycloalkyloxy refers to -O-cycloalkyl, wherein cycloalkyl is as defined above.
  • heterocyclylalkyl refers to an alkyl group substituted with one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.
  • arylalkyl refers to an alkyl group substituted with one or more aryl groups, wherein aryl and alkyl are as defined above.
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • Figure 1 is the effect of the compound of Example 5 on hindpaw mechanical allodynia in the SNI nerve injury model.
  • Figure 2 is the effect of the compound of Example 4 on hindpaw mechanical allodynia in the SNI nerve injury model.
  • Figure 3 is the effect of the compound of Example 2 on hindpaw mechanical allodynia in the SNI nerve injury model.
  • Step 2 Preparation of 4-(bromomethyl)-3,5-dichloropyridine.
  • (3,5-Dichloropyridin-4-yl)methanol 5.0g, 28.08mmol, 1.0eq.
  • Triphenylphosphine 11.05g, 42.13mmol, 1.5eq.
  • Carbon tetrabromide 13.96g, 42.13mmol , 1.5eq.
  • DCM 200mL
  • MS (m/z) 242 [M+H] + .
  • Step 1 Preparation of 1-amino-1H-pyrrole-2-carboxylic acid ethyl ester.
  • NaH 50%, 3.73g, 93.41mmol, 1.3eq.
  • DMF 100mL
  • ethyl 1H-pyrrole-2-carboxylate 10.0g, 71.86mmol, 1.0eq
  • the title compound (10 g
  • Step 2 Preparation of 1-(3-benzoylthioureido)-1H-pyrrole-2-carboxylic acid ethyl ester.
  • MS (m/z) 318 [M+H] + .
  • Step 3 Preparation of 2-thio-2,3-dihydropyrrolo[2,1-f][1,2,4]triazin-4(1H)-one.
  • Step 1 Preparation of 2-thio-1,2,3,5,6,7-hexahydro-4H-cyclopenta[d]pyrimidin-4-one.
  • Ethyl 2-oxocyclopentane-1-carboxylate (5.0g, 32.42mmol, 1.0eq.), Thiourea (3.70g, 48.63mmol, 1.5eq.), DBU (7.40g, 48.63mmol, 1.5eq.) .) was added to acetonitrile (50mL), reacted at 95°C for 12 hours, dropped to 0°C after the reaction was finished, stirred for 30 minutes, the precipitated solid was filtered, put into 50mL water, adjusted pH to 1 with 2N hydrochloric acid, filtered, and dried used directly in the next step.
  • MS (m/z) 242 [M+H] + .
  • Step 2 Preparation of 2-(3,5-dichloropyridin-4-ylmethylsulfanyl)-3,5,6,7-tetrahydrocyclopentapyrimidin-4-one.
  • 2-thio-1,2,3,5,6,7-hexahydro-4H-cyclopenta[d]pyrimidin-4-one (6.31g, 35.72mmol, 1.0eq.)
  • 4-(bromomethyl )-3,5-dichloropyridine (8.6g, 37.50mmol, 1.05eq.)
  • triethylamine (5.42g, 53.53mmol, 1.5eq.) were added to ethanol (100mL) and reacted at 25°C for 12 hours.
  • Step 1 Preparation of 2-chloro-5,7-dihydrofuran[3,4-d]pyrimidin-4-ol.
  • 2,4-Dichloro-5,7-dihydrofuro[3,4-d]pyrimidine 2.0g, 10.47mmol, 1.0eq.
  • 3N sodium hydroxide solution 17.47mmol, 1.0eq.
  • EA 20 mL
  • water 20 mL
  • MS (m/z) 174 [M+H] + .
  • Step 2 Preparation of 2-mercapto 5,7-dihydrofuran[3,4-d]pyrimidin-4-ol.
  • Step 3 Preparation of 2-(((3,5-dichloropyridin-4-yl)methyl)sulfanyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-ol.
  • 4-(bromomethyl)-3,5-dichloropyridine 0.361g, 1.501mmol, 1.2eq.
  • triethylamine 0.379g, 3.75mmol, 3.0eq.
  • Step 1 Preparation of 4-oxo-2-thio-1,2,3,4,5,7-hexahydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester .
  • Step 2 2-(((3,5-dichloropyridin-4-yl)methyl)sulfanyl)-4-oxo-3,4,5,7-tetrahydro-6H-pyrrolo[3, Preparation of 4-d]pyrimidine-6-carboxylate tert-butyl ester.
  • Step 3 2-(((3,5-dichloropyridin-4-yl)methyl)sulfanyl)-3,5,6,7-tetrahydro-4H-pyrrolo[3,4-d]pyrimidine - Preparation of 4-keto hydrochloride.
  • Step 1 2-(((3,5-dichloropyridin-4-yl)methyl)sulfanyl)-3,7-bis(methylsulfonyl)-3,5,6,7,8,9 - Preparation of hexahydro-4H-pyrimidin[4,5-d]aza-4-one.
  • the water bath was cooled to 0-5° C., and a solution of chloro(methyl)dimethylene- ⁇ 6 -sulfoxide in dichloromethane (3.21 g, 27.99 mmol, 4.0 eq.) was added dropwise, and the reaction was completed for 4 hours.
  • the reaction solution was quenched by adding water (20 mL), the solution was separated, and the organic phase was evaporated to dryness to obtain the crude product, which was directly put into the next reaction.
  • Step 2 2-(((3,5-dichloropyridin-4-yl)methyl)sulfanyl)-7-(methylsulfonyl)-3,5,6,7,8,9-hexahydro Preparation of -4H-pyrimidinyl[4,5-d]aza-4-ones.
  • Step 1 2-thio-1,2,3,5,6,7,8,9-octahydro-4H-pyrimidine[4,5-d]azepan-4-one (990.0mg , 5.02mmol, 1eq.) was added to MeOH (15mL), (226.04mg, 7.53mmol, 1.5eq.) aqueous formaldehyde solution was added at room temperature, and after the addition was stirred for 1 to 2 hours, sodium triacetoxyborohydride STAB ( 2.13g, 10.04mmol, 2.0eq.) and reacted for 2 hours.
  • reaction solution was quenched by adding water (10 mL), the pH was adjusted to alkaline with sodium carbonate solid, the insoluble solid was filtered, the filtrate was evaporated to dryness, ethanol was added to dissolve the product, the inorganic salt was removed by filtration, and the filtrate was directly put into the next reaction.
  • Step 2 2-(((3,5-dichloropyridin-4-yl)methyl)sulfanyl)-7-methyl-3,5,6,7,8,9-hexahydro-4H-pyrimidine
  • MS (m/z) 372.28 [M+H] + .
  • 1 H NMR (400MHz, DMSO-d6) ⁇ 8.66(s, 2H), 4.68(s, 2H), 2.84 ⁇ 2.87(t, 2H), 2.67 ⁇ 2.70(t, 2H), 2.53 ⁇ 2.55(t, 2H), 2.43-2.46 (t, 2H), 2.30 (s, 3H).
  • the adult male C57BL/6J mice used in the experiment were purchased from Shanghai Lingchang Biotechnology Co., Ltd. (8-week-old mice, weighing about 21-23 g).
  • the experimental animals were kept in a barrier environment of SPF grade (temperature of 21.0 ⁇ 2° C., humidity of 40-70%, 12/12 hours light and dark alternation, 3-5 animals/cage). Before the experiment, they were acclimated to the rearing environment for 5-7 days, and were allowed to eat and drink freely.
  • the relevant operating procedures involved in the execution of animal experiments follow the guidelines of the International Committee for the Care and Use of Laboratory Animals.
  • the tested compound and vehicle control group consisted of 10 animals. Intraperitoneal administration was used at a dose of 100 mg/kg.
  • the vehicle used was 10% DMSO in 20% HPCD. All compounds to be tested were formulated into 5 mg/mL stock solutions and stored at 4°C until use.
  • C57BL/6J mice were given intramuscular injection of Shutai ( 20 mg/kg), shave the left hind leg and buttock hair after complete anesthesia.
  • the skin was repeatedly disinfected with alcohol and iodophor, the skin of the hind leg of the mouse was incised using a scalpel, and the subcutaneous tissue and muscle were bluntly separated downward with a hemostat to expose the sciatic nerve branch.
  • the peroneal and tibial nerves were ligated with 6-0 silk thread, and about 1 mm of the peroneal and tibial branches were cut from the ligation along the foot end.
  • the wounds were repeatedly cleaned with normal saline and cotton swabs, and the muscles and skin were sutured surgically, and then the experimental mice were placed in an incubator and awake.
  • mice The classification and integration were performed by averaging the changes in the paw withdrawal threshold of mice at each time point. According to the experimental design, the data were grouped by GraphPad Prism 8 software for graphing and statistical analysis. Experimental data are expressed as mean ⁇ standard deviation (Mean ⁇ SEM). Repeated-measures two-way ANOVA followed by Bonfinero multiple comparison test method, when P ⁇ 0.05, the corresponding experimental results were considered to have significant statistical differences.

Abstract

一种如式(I)所示的化合物、其立体异构体、互变异构体或其药学上可接受的盐，以及其用于制备治疗疼痛、脊髓损伤药物中的用途。

Description

嘧啶并环类化合物及其用于制备治疗疼痛、脊髓损伤药物中的用途 技术领域
本申请属于化学医药领域，具体涉及一种嘧啶并环类化合物及其用于制备治疗疼痛、脊髓损伤药物中的用途。
背景技术
疼痛是身体痛苦和痛苦的一种常见形式，也是患者向医生报告的最常见原因之一。它可以形式(伤害性或神经性)、持续时间(慢性或急性)和程度(轻度、中度或重度)区分。通常，伤害性疼痛是急性的，由损伤引起，如烧伤、扭伤、烧伤、骨折或炎症(炎症性疼痛，包括骨关节炎和类风湿性关节炎)。另一方面，国际疼痛研究协会将神经病理性疼痛定义为一种由神经系统病变或功能障碍引起的慢性疼痛。通常，神经性疼痛是由糖尿病神经病变、HIV感染和带状疱疹后神经痛引起的。与神经病理性疼痛相关的其他疾病包括复杂的局部疼痛综合征、三叉神经痛、腰痛、坐骨神经痛、幻肢痛、冲击痛、纤维肌痛和其他导致慢性疼痛的疾病(见Jensen，European Journal of Pain，2002年)。
K +-Cl -协同转运蛋白KCC2负责维持中枢神经系统(CNS)神经元的低Cl -浓度，这是通过GABAA和甘氨酸受体进行突触后抑制所必需的。虽然没有中枢神经系统疾病与KCC2突变相关，但这种转运体活性的丧失已成为一些神经和精神疾病的关键机制，包括癫痫、运动性痉挛、压力、焦虑、精神分裂症、吗啡引起的痛觉过敏和慢性疼痛。研究表明，增强KCC2活性可能是在涉及受损Cl -转运的病理条件下恢复抑制和正常功能的有利治疗策略(Gagnon,Martin.et al.Nature Medicine(2013),19(11),1524-1528)。
现有研究还表明，KCC2激动剂通过选择性表达KCC2在交错脊髓损伤之间和周围的抑制性中间神经元中进行模拟，使得脊髓损伤的小鼠恢复了步进能力。从机制上讲，这些治疗方法将损伤引起的脊髓回路功能障碍转变为功能状态，促进脑源性指令向腰脊髓的传递。因此，KCC2激动剂有希望成为促进脊髓损伤后功能恢复的治疗方法(Bo Chen,Yi Li.et al.Cell(2018),174(3),521-535)。
发明内容
本申请公开了一种嘧啶并环类化合物，其可作为潜在的KCC2激动剂，以及用于制备治疗疼痛、脊髓损伤药物中的用途。
一方面，本申请提供了式(I)化合物、其立体异构体、互变异构体或其药学上可接受的盐：
Figure PCTCN2022081573-appb-000001
其中，环A为含有0-4个杂原子、5-14个环原子的环烷基、杂环基、芳基或杂芳基；
环B为含有0-2个杂原子、5-7个环原子的环烷基、杂环基、芳基或杂芳基；
X为C或N；
R 1各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基；
R 2各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基；
m、n、n’选自0、1、2或3；以及
Figure PCTCN2022081573-appb-000002
代表单键或双键。
在某些实施方案中，式(I)是式(Ia)：
Figure PCTCN2022081573-appb-000003
其中，环A为含有1-4个杂原子、5-14个环原子的杂环基或杂芳基；
环B为含有0-2个杂原子、5-7个环原子的环烷基、杂环基、芳基或杂芳基；
X为C或N；
R 1各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、 卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基；
R 2各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基；
m、n选自0、1、2或3；以及
Figure PCTCN2022081573-appb-000004
代表单键或双键。
在某些实施方案中，式(I)是式(Ib)：
Figure PCTCN2022081573-appb-000005
其中，环A为含有1-3个杂原子、5-7个环原子的杂环基或杂芳基；
环B为含有0-2个杂原子、5-7个环原子的环烷基或杂环基；
R 1各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基；
R 2各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基；以及
m、n选自0、1、2或3。
在某些实施方案中，式(I)是式(Ic)或(Id)：
Figure PCTCN2022081573-appb-000006
其中，环B为含有0-2个杂原子、5-7个环原子的环烷基或杂环基；
R 1各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基；
R 2各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基；以及
m、n选自0、1、2或3。
在某些实施方案中，式(I)所示的化合物，其选自：
Figure PCTCN2022081573-appb-000007
在某些实施方案中，其结构为：
Figure PCTCN2022081573-appb-000008
在某些实施方案中，其结构为：
Figure PCTCN2022081573-appb-000009
在某些实施方案中，其结构为：
Figure PCTCN2022081573-appb-000010
前述化合物中任一位置的H可以为氘。
另一方面，本申请还提供一种药物组合物，其包含治疗有效量的前述的化合物，或其药学上可接受的盐、酯、前药、络合物、溶剂化物、水合物或异构体；以及药学上可接受的载体或赋形剂。
另一方面，本申请还提供前述化合物，或其药学上可接受的盐、酯、前药、络合物、溶剂化物、水合物或异构体用于制备KCC2激动剂药物中的用途。
另一方面，本申请还提供前述化合物，或其药学上可接受的盐、酯、前药、络合物、溶剂化物、水合物或异构体用于制备治疗脊髓损伤药物中的用途。
另一方面，本申请还提供前述化合物，或其药学上可接受的盐、酯、前药、络合物、溶剂化物、水合物或异构体用于制备镇痛药物中的用途。
术语：
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“异构体”包括给定结构的对映异构形式、非对映异构形式和几何(或构象)异构形式。例如，本申请包括每个不对称中心的R和S构型、Z和E双键异构体、Z和E构象异构体、单一立体化学异构体及对映异构体、非对映异构体和几何(或构象)异构体混合物。
术语“药学上可接受的盐”指，诸如其酸加成盐和/或碱盐。合适的酸加成盐由酸形成，其形成无毒盐，例如盐酸盐/氯化物。合适的碱盐由碱形成，其形成无毒盐，例如钙盐和钠盐。还可形成酸和碱的半盐，例如半硫酸盐和半钙盐。
术语“治疗有效量”是指本申请化合物的以下量，其(i)治疗具体的疾病、病症或障碍；(ii)减轻、缓解或消除具体的疾病、病症或障碍的一种或多种症状；或(iii)预防或延迟本申请所述具体的疾病、病症或障碍的一种或多种症状的发作。
术语“药学上可接受的载体或赋形剂”是指不破坏用其配制的化合物的药理活性的无毒载体、辅料或媒介物。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。含有1至6个碳原子的低级烷基的非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。
术语“烯基”指具有至少一个碳-碳双键的脂族烃，包括具有至少一个碳-碳双键的直链和支链。在一些实施方案中，烯基基团具有2至20个碳原子、2至10个碳原子、2至6个碳原子、3至6个碳原子或2至4个碳原子。例如，术语“C 2-6烯基”包括2至6个碳原子的直链或支链不饱和基团(具有至少一个碳-碳双键)，包括但不限于乙烯基、1-丙烯基、2-丙烯基(烯丙基)、异丙烯基、2-甲基-1-丙烯基、1-丁烯基、2-丁烯基等。
术语“炔基”指具有至少一个碳-碳三键的脂族烃，包括具有至少一个碳-碳三键的直链和支链。在一些实施方案中，炔基基团具有2至20个碳原子、2至10个碳原子、2至6个碳原子、或3至6个碳原子。例如，“C 2-6炔基”包括2至6个碳原子的直链或支链不饱和基团(具有至少一个碳-碳三键)。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基如上所定义。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子(例如3、4、5或6个碳原子)，最优选包含5至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多 环基团，其可以含有一个或多个双键，但每个环均不具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基，更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但每个环均不具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但每个环均不具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至8个环原子，其中1～3个是杂原子；最优选包含5至6个环原子，其中1～2或1～3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等，优选四氢吡喃基、哌啶基、吡咯烷基。多环杂环基包括螺杂环基、稠杂环基和桥杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但每个环均不具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基，更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但每个环均不具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但每个环均不具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。
所述杂环基包括如上所述的杂环基(包括单环、螺杂环、稠杂环和桥杂环)稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2022081573-appb-000011
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基和哒嗪基等。
所述杂芳基包括如上所述的杂芳基稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2022081573-appb-000012
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。
术语“氘代烷氧基”指烷氧基被一个或多个氘原子取代，其中烷氧基如上所定义。
术语“环烷基烷基”指烷基被一个或多个环烷基取代，其中环烷基和烷基如上所定义。
术语“环烷基氧基”指-O-环烷基，其中环烷基如上所定义。
术语“杂环基烷基”指烷基被一个或多个杂环基取代，其中杂环基和烷基如上所定义。
术语“芳基烷基”指烷基被一个或多个芳基取代，其中芳基和烷基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“羧基”指-C(O)OH。
附图说明
图1是实施例5化合物对SNI神经损伤模型的后爪机械性触诱发痛的效应。
图2是实施例4化合物对SNI神经损伤模型的后爪机械性触诱发痛的效应。
图3是实施例2化合物对SNI神经损伤模型的后爪机械性触诱发痛的效应。
具体实施方式
中间体制备
中间体1.1的制备：4-(溴甲基)-3,5-二氯吡啶
Figure PCTCN2022081573-appb-000013
步骤一：(3,5-二氯吡啶-4-基)甲醇的制备。3,5-二氯吡啶-4-甲醛(20.0g，113.63mmol，1.0eq.)硼氢化钠(6.44g,170.45mmol，1.5eq.)加入到MeOH(200mL)中，25℃反应12小时，反应结束后旋干，用EA(200mL)和水(200mL)萃取，有机相用饱和氯化钠洗一次，有机相用硫酸镁干燥，过滤，制砂，EA:PE＝1:8柱层析得到标题化合物(15.1g，收率75.5％)。MS(m/z)＝179[M+H] +。
步骤二：4-(溴甲基)-3,5-二氯吡啶的制备。(3,5-二氯吡啶-4-基)甲醇(5.0g，28.08mmol，1.0eq.)三苯基膦(11.05g，42.13mmol，1.5eq.)四溴化碳(13.96g，42.13mmol，1.5eq.)加入到DCM(200mL)中，20℃反应12小时，反应结束后旋干，制砂，EA:PE＝1:20柱层析得到标题化合物(5.6g，收率83.58％)。MS(m/z)＝242[M+H] +。
实施例1：2-(((3,5-二氯吡啶-4-基)甲基)硫)吡咯并[2,1-f][1,2,4]三嗪-4(3H)-酮
Figure PCTCN2022081573-appb-000014
步骤一：1-氨基-1H-吡咯-2-羧酸乙酯的制备。0℃下，NaH(60％，3.73g，93.41mmol，1.3eq.)加入到DMF(100mL)中，氮气保护下加入1H-吡咯-2-羧酸乙酯(10.0g，71.86mmol，1.0eq.)和O-(2,4-二硝基-苯基)-羟胺(21.45g，107.79mmol，1.5eq.)，25℃反应12小时，反应结束后旋干，将体系泼入水(200mL)中，用EA:甲叔醚＝1:1(100mL)萃取两次，有机相用饱和氯化钠洗一次，有机相用硫酸镁干燥，过滤，制砂，EA:PE＝1:8柱层析得到标题化合物(10g，收率85.4％)。MS(m/z)＝155[M+H] +。
步骤二：1-(3-苯甲酰基硫脲基)-1H-吡咯-2-羧酸乙酯的制备。1-氨基-1H-吡咯-2-羧酸乙酯(10.0g，64.86mmol，1.0eq.)加入到THF(100mL)中，然后加入苯甲酰异硫氰酸酯的THF(100mL)溶液(10.58g，64.86mmol，1.0eq.)， 25℃反应12小时，反应结束后旋干，用PE:甲叔醚＝9:1打浆，过滤，滤饼烘干，直接用于下一步。MS(m/z)＝318[M+H] +。
步骤三：2-硫代-2,3-二氢吡咯并[2,1-f][1,2,4]三嗪-4(1H)-酮的制备。1-(3-苯甲酰基硫脲基)-1H-吡咯-2-羧酸乙酯(18.86g，59.47mmol，1.0eq.)加入到2N的氢氧化钠溶液(118mL，4.0eq.)中，加热至85℃，反应1.5小时，降至室温后，加入乙醇(35mL)，降温至0℃，加入乙酸(14.46g，240.85mmol，4.05eq.)，25℃反应12小时，反应结束后析出的固体过滤烘干，直接用于下一步。MS(m/z)＝168[M+H] +。
步骤四：2-(((3,5-二氯吡啶-4-基)甲基)硫)吡咯并[2,1-f][1,2,4]三嗪-4(3H)-酮的制备。2-硫代-2,3-二氢吡咯并[2,1-f][1,2,4]三嗪-4(1H)-酮(660.9mg，3.95mmol，1.0eq.)，4-(溴甲基)-3,5-二氯吡啶(1.0g，4.15mmol，1.05eq.)和三乙胺(599.5mg，5.92mmol，1.5eq.)加入到乙醇(10mL)中，25℃反应12小时，反应结束后析出的固体过滤，溶于THF中，制砂，THF:PE＝1:1柱层析，得到标题化合物(1.4g，收率100％)。MS(m/z)＝328[M+H] +。 1H NMR(400MHz,DMSO)δ12.21(s,1H),8.66(s,2H),7.55-7.56(m,1H),6.87-6.88(m,1H),6.51-6.52(m,1H),4.63(s,2H)。
实施例2：2-(3,5-二氯吡啶-4-基甲基硫烷基)-3,5,6,7-四氢环戊嘧啶-4-酮
Figure PCTCN2022081573-appb-000015
步骤一：2-硫代-1,2,3,5,6,7-六氢-4H-环戊[d]嘧啶-4-酮的制备。2-氧代环戊烷-1-羧酸乙酯(5.0g，32.42mmol，1.0eq.)，硫脲(3.70g，48.63mmol，1.5eq.)，DBU(7.40g，48.63mmol，1.5eq.)加入到乙腈(50mL)中，95℃反应12小时，反应结束后降至0℃，搅拌30分钟，析出的固体过滤，放入50mL水中，用2N盐酸调pH至1，过滤，烘干直接用于下一步。MS(m/z)＝242[M+H] +。
步骤二：2-(3,5-二氯吡啶-4-基甲基硫烷基)-3,5,6,7-四氢环戊嘧啶-4-酮的制备。2-硫代-1,2,3,5,6,7-六氢-4H-环戊[d]嘧啶-4-酮(6.31g，35.72mmol，1.0eq.)，4-(溴甲基)-3,5-二氯吡啶(8.6g，37.50mmol，1.05eq.)和三乙胺(5.42g，53.53mmol，1.5eq.)加入到乙醇(100mL)中，25℃反应12小时，反应结束后析出的固体 过滤，固体用乙醇50mL打浆两次，烘干，得到标题化合物(7.6g，收率64.95％)。MS(m/z)＝329[M+H] +。 1H NMR(400MHz,DMSO)δ12.69(s,1H),8.66(s,2H),4.67(s,2H),2.77-2.80(m,2H),2.59-2.61(d,2H),1.94-2.01(m,2H)。
实施例3：2-((3,5-二氯吡啶-4-基)甲基)硫代)-5,7-二氢呋喃[3,4-d]嘧啶-4(3H)-酮
Figure PCTCN2022081573-appb-000016
步骤一：2-氯-5,7-二氢呋喃[3,4-d]嘧啶-4-醇的制备。2,4-二氯-5,7-二氢呋喃[3,4-d]嘧啶(2.0g,10.47mmol，1.0eq.)，3N的氢氧化钠溶液(17mL，52.35mmol，5.0eq.)加入到THF(20mL)中，50℃反应12小时，用3N盐酸调pH至6，加入EA(20mL)和水(20mL)萃取，有机相干燥，旋干，用EA(5mL)打浆，过滤，烘干，直接用于下一步。MS(m/z)＝174[M+H] +。
步骤二：2-巯基5,7-二氢呋喃[3,4-d]嘧啶-4-醇的制备。2-氯-5,7-二氢呋喃[3,4-d]嘧啶-4-醇(0.5g，2.89mmol，1.0eq.)，硫氢化钠(0.19mg，3.47mmol，1.2eq.)加入到DMAc(5mL)中，100℃反应12小时，反应结束后，将体系泼入水中，析出的固体，过滤，烘干，直接用于下一步。MS(m/z)＝171[M+H] +。
步骤三：2-(((3,5-二氯吡啶-4-基)甲基)硫基)-5,7-二氢呋喃[3,4-d]嘧啶-4-醇的制备。2-巯基5,7-二氢呋喃[3,4-d]嘧啶-4-醇(0.213g，1.25mmol，1.0eq.)，4-(溴甲基)-3,5-二氯吡啶(0.361g，1.501mmol，1.2eq.)和三乙胺(0.379g，3.75mmol，3.0eq.)加入到乙醇(10mL)中，25℃反应12小时，反应结束后析出的固体过滤，固体用乙醇(10mL)打浆两次，烘干，得到标题化合物(396mg，收率95％)。MS(m/z)＝331[M+H] +。 1H NMR(400MHz,DMSO)δ13.05(s,1H),8.67(s,2H),4.84-4.86(t,4H),4.68(s,2H)。
实施例4：2-((嘧啶-5-基甲基)硫基)-3,5,6,7-四氢-4H-环戊[d]嘧啶-4-酮
Figure PCTCN2022081573-appb-000017
2-硫代-1,2,3,5,6,7-六氢-4H-环戊[d]嘧啶-4-酮(0.194g，1.15mmol，1.0eq.)，5-氯甲基嘧啶(0.2g，1.211mmol，1.05eq.)和DIPEA(0.372g，2.88mmol，2.5eq.)加入到乙醇(10mL)中，80℃反应48小时，反应结束后旋干，固体用甲醇(5mL)打浆两次，烘干，得到标题化合物(120mg，收率40％)。MS(m/z)＝261[M+H] +。 1H NMR(400MHz,DMSO)δ12.61(s,1H),9.05(s,1H),8.86(s，2H)4.37(s,2H),2.74-2.77(m,2H)，2.56-2.59(m，2H)，1.93-1.97(m，2H)。
实施例5：2-(((3,5-二氯吡啶-4-基)甲基)硫基)-3,5,6,7-四氢-4H-吡咯并[3,4-d]嘧啶-4-酮盐酸盐
Figure PCTCN2022081573-appb-000018
步骤一：4-氧代-2-硫代-1,2,3,4,5,7-六氢-6H-吡咯并[3,4-d]嘧啶-6-羧酸叔丁酯的制备。1-(叔丁基)3-乙基2-氧吡咯烷-1,3-二羧酸酯(20.00g，77.74mmol，1eq.)和硫脲(8.88g，116.60mmol，1.5eq.)在室温下加入到乙腈(300mL)中，加入DBU(17.75g，116.60mmol，1.5eq.)后加热到80℃反应16小时。反应液蒸干乙腈，加水溶解后用2N盐酸调pH＝4～5，析出大量白色固体，过滤，滤饼水洗至中性，烘干得到标题化合物(17.20g，收率82.16％)。
步骤二：2-(((3,5-二氯吡啶-4-基)甲基)硫基)-4-氧代-3,4,5,7-四氢-6H-吡咯并[3,4-d]嘧啶-6-羧酸叔丁酯的制备。将4-氧代-2-硫代-1,2,3,4,5,7-六氢-6H-吡咯并[3,4-d]嘧啶-6-羧酸叔丁酯(9.50g，35.27mmol，1eq.)溶于EtOH(100mL)中，室温下加入4-(溴甲基)-3,5-二氯吡啶(12.75g，52.91mmol，1.5eq.)和TEA (5.35g，52.91mmol，1.5eq.)，加完在室温下反应12小时。反应液中析出的固体直接过滤，滤饼用乙醇(20mL)洗涤，烘干得到标题化合物(11.35g，收率74.9％)。
步骤三：2-(((3,5-二氯吡啶-4-基)甲基)硫基)-3,5,6,7-四氢-4H-吡咯并[3,4-d]嘧啶-4-酮盐酸盐的制备。将2-(((3,5-二氯吡啶-4-基)甲基)硫基)-4-氧代-3,4,5,7-四氢-6H-吡咯并[3,4-d]嘧啶-6-羧酸叔丁酯(11.35g，26.44mmol，1eq.)溶于1,4-二氧六环(100mL)中，室温下加入HCl的二氧六环溶液(9.64g，264.37mmol，10eq.)，加完在室温下反应8小时。反应液中析出的固体直接过滤，滤饼用二氧六环(50mL)洗涤，EA(50mL)洗涤，烘干滤饼得到标题化合物(7.90g，收率90.7％)。MS(m/z)＝367[M+H] +。 1H NMR(400MHz,DMSO-d6)δ＝10.29(brs,2H),8.67(d,2H),4.68(s,2H),4.34(m,2H),4.26(m,2H)。
实施例6：2-(((3,5-二氯吡啶-4-基)甲基)硫基)-6-甲基-3,5,6,7-四氢-4H-吡咯并[3,4-d]嘧啶-4-酮
Figure PCTCN2022081573-appb-000019
2-(((3,5-二氯吡啶-4-基)甲基)硫基)-3,5,6,7-四氢-4H-吡咯并[3,4-d]嘧啶-4-酮盐酸盐(100mg，0.303mmol，1.0eq.)，多聚甲醛(40mg，0.455mmol，1.5eq.)，硼氢化钠(17mg，0.455mmol，1.5eq.)加入到甲醇(5mL)中，70℃反应14小时。反应结束后，旋干加入水(10mL)打浆过滤，滤饼用甲醇(5mL)打浆过滤，固体烘干，得到标题化合物(20mg，收率19.23％)。MS(m/z)＝344[M+H] +。 1H NMR(400MHz,DMSO)δ12.59(s，1H)，8.67(s,2H),4.68(s,2H),4.35(s,2H),4.17(s,2H)，3.23-3.28(m，3H)。
实施例7：2-(((3,5-二氯吡啶-4-基)甲基)硫基)-3,5,6,7,8,9-六氢-4H-嘧啶[4,5-d]氮杂环庚烷-4-酮盐酸盐
Figure PCTCN2022081573-appb-000020
参考实施例5的制备方法，得到标题化合物。MS(m/z)＝393[M+H] +。 1H NMR(400MHz,DMSO-d6)δ＝9.64(brs,2H),8.66(s,2H),4.68(s,2H),3.23(t,2H),3.14(m,4H),2.94(t,2H)。
实施例8：2-((嘧啶-5-基甲基)硫代)-3,5,6,7,8,9-六氢-4H-嘧啶基[4,5-d]氮杂-4-酮盐酸盐
Figure PCTCN2022081573-appb-000021
参考实施例5的制备方法，得到标题化合物。MS(m/z)＝326[M+H] +。 1H NMR(400MHz,DMSO-d6)δ＝9.64(brs,2H),9.08(s,1H),8.92(s,2H),4.37(s,2H),3.19(t,2H),3.11(m,4H),2.90(t,2H)。
实施例9：2-(((3,5-二氯吡啶-4-基)甲基)硫基)-5,6,7,8-四氢喹唑啉-4(3H)-酮
Figure PCTCN2022081573-appb-000022
参考实施例2的制备方法，得到标题化合物。MS(m/z)＝343[M+H]+。 1H NMR (400MHz,DMSO)δ12.64(s,1H),8.65(s,2H),4.67(s,2H),2.55(s,2H),2.30(s,2H),1.64-1.71(m,4H)。
实施例10：2-(((四氢-2H-吡喃-4-基)甲基)硫基)-3,5,6,7-四氢-4H-环戊[d]嘧啶-4-酮
Figure PCTCN2022081573-appb-000023
参考实施例4的制备方法，得到标题化合物。MS(m/z)＝267[M+H]+。 1H NMR(400MHz,DMSO)δ12.53(s,1H),3.81-3.85(m,2H),3.22-3.28(m，2H)3.08-3.10(d,2H),2.70-2.74(m,2H)，2.55-2.59(m，2H)，1.90-1.98(m，2H)，1.82-1.83(m，1H)，1.63-1.66(d，2H)，1.19-1.29(m，2H)。
实施例11：2-(((3,5-二氯吡啶-4-基)甲基)硫基)-7-(甲基磺酰基)-3,5,6,7,8,9-六氢-4H-嘧啶基[4,5-d]氮杂-4-酮
Figure PCTCN2022081573-appb-000024
步骤一：2-(((3,5-二氯吡啶-4-基)甲基)硫基)-3,7-双(甲基磺酰基)-3,5,6,7,8,9-六氢-4H-嘧啶[4,5-d]氮杂-4-酮的制备。将2-(((3,5-二氯吡啶-4-基)甲基)硫基)-3,5,6,7,8,9-六氢-4H-嘧啶[4,5-d]氮杂环庚烷-4-酮盐酸盐(2.50g，7.00mmol，1eq.)加入DCM(50mL)中，室温下加入TEA(4.25g，41.99mmol，6.0eq.)，原料溶解后用冰水浴冷却到0～5℃，滴加氯(甲基)二亚甲基-λ 6-亚砜的二氯甲烷溶液(3.21g，27.99mmol，4.0eq.)，加完反应4小时。反应液加水(20mL)淬灭，分液，有机相蒸干得到粗品直接投入下一步反应。
步骤二：2-(((3,5-二氯吡啶-4-基)甲基)硫基)-7-(甲基磺酰基)-3,5,6,7,8,9-六氢-4H-嘧啶基[4,5-d]氮杂-4-酮的制备。将2-(((3,5-二氯吡啶-4-基)甲基)硫基)-3,7-双 (甲基磺酰基)-3,5,6,7,8,9-六氢-4H-嘧啶[4,5-d]氮杂-4-酮(3.59g，6.99mmol，1eq.)加入MeOH(35mL)中，室温下加K 2CO 3(1.93g，13.98mmol，2.0eq)，加完反应12小时。粗品经100～200目硅胶柱分离纯化(洗脱剂:DCM:MeOH＝30:1～10:1)得到标题化合物(650.0mg，收率：21.35％)。MS(m/z)＝436.35[M+H] +。 1H NMR(400MHz,DMSO-d6)δ＝8.60(s,2H),4.47(s,2H),3.27(t,2H),3.17(t,2H),2.84(s,3H),2.72(t,2H),2.66(t,2H) .。
实施例12：2-(((3,5-二氯吡啶-4-基)甲基)硫基)-7-甲基-3,5,6,7,8,9-六氢-4H-嘧啶基[4,5-d]氮杂-4-酮
Figure PCTCN2022081573-appb-000025
步骤一：将2-硫代-1,2,3,5,6,7,8,9-八氢-4H-嘧啶[4,5-d]氮杂环庚烷-4-酮(990.0mg，5.02mmol，1eq.)加入MeOH(15mL)中，室温下加入(226.04mg，7.53mmol，1.5eq.)甲醛水溶液，加完搅拌1～2小时后，加入三乙酰氧基硼氢化钠STAB(2.13g，10.04mmol，2.0eq.)并反应2小时。反应液加水(10mL)淬灭，用碳酸钠固体调pH至碱性，过滤不溶固体，滤液蒸干后加乙醇溶解产品，过滤除去无机盐，滤液直接投入下一步反应。
步骤二：2-(((3,5-二氯吡啶-4-基)甲基)硫基)-7-甲基-3,5,6,7,8,9-六氢-4H-嘧啶基[4,5-d]氮杂-4-酮的制备。参考实施例2得到标题化合物。MS(m/z)＝372.28[M+H] +。 1H NMR(400MHz,DMSO-d6)δ＝8.66(s,2H),4.68(s,2H),2.84～2.87(t,2H),2.67～2.70(t,2H),2.53～2.55(t,2H),2.43～2.46(t,2H),2.30(s,3H)。
实验例1 小鼠坐骨神经分支选择性神经损伤模型检测待试化合物的镇痛作用
实验所使用的成年雄性C57BL/6J小鼠，购于上海灵畅生物科技有限公司(8周龄鼠，体重约为21-23g)。实验动物饲养在SPF级(温度为21.0±2℃，湿度为40-70％，12/12小时明暗交替，3-5只/笼)的屏障环境。实验前适应饲养环境5-7天，允许自由进食与饮水。在动物实验执行过程中所涉及的相关操作流程遵循国际实验动物关爱与使用委员会的指导方针执行。所测化合物以及溶媒对照 每组动物数量为10只。采用腹腔给药，给药剂量为100mg/kg。所采用溶媒为含10％DMSO的20％HPCD溶液。所有待测化合物配制成5mg/mL母液，存储于4℃待用。
阳性对照CLP290结构：
Figure PCTCN2022081573-appb-000026
给予C57BL/6J小鼠肌肉注射舒泰(
Figure PCTCN2022081573-appb-000027
20mg/kg)，待其完全麻醉后剃除左侧后腿及臀部毛发。用酒精和碘伏反复消毒皮肤，使用手术刀在切开小鼠后腿部皮肤，并用止血钳向下钝性分离皮下组织和肌肉，暴露坐骨神经分支。在保证保持腓肠神经完整性的前提下用6-0丝线结扎腓神经和胫神经，并从结扎处沿脚端剪除约1mm腓神经和胫神经分支。完毕后用生理盐水和棉签反复清洗创口，并手术缝合肌肉和皮肤，然后将实验小鼠放置于恒温箱内并待其苏醒。
实验所进行的冯弗雷纤毛机械痛敏测试所有行为学测试均遵循双盲准则。参考文献报道的50％缩爪阈值测试与计算方法(Chaplan et al.,1994)，采用手动冯弗雷纤毛(von Frey filaments,North Coast Medical Inc.,USA)测量SNI造模小鼠给药前后不同时间点的缩爪阈值变化，用以评价待测化合物对机械痛敏的潜在镇痛作用。测试前先将C57BL/6J小鼠放置在金属铁丝网格支架上的单个透明有机玻璃容器65*85*60mm)中直至其停止明显的探索活动并处于趴伏不动的安静状态(约90-100分钟)。从0.008g力度冯弗雷纤毛开始施加不同强度的触觉刺激。透过金属网格空隙接触小鼠鼠后爪足底跖面，然后给予足够的力度促使其明显弯曲并持续2-3秒。每一相同力度刺激的冯弗雷纤毛重复测试3次，间隔大于5秒。如果10次刺激中出现缩爪阳性反应(迅速撤足、舔舐后爪、爪子退缩或者逃避刺激)低于6次，则换用力度较大的纤毛，相反其缩爪阳性反应≥6次，则换用力度较小的纤毛，如此重复测量直到其反应模式可用以计算出50％缩爪阈值。
通过各时间点的小鼠缩爪阈值变化取平均值进行归类整合。根据实验设计分组对数据采用GraphPad Prism 8软件进行作图及统计分析。实验数据表达为平均值±标准差(Mean±SEM)。采用重复测量双因素方差分析后邦费尼罗多重比较检验方法，当P<0.05时，对应的实验结果被视为具有显著统计差异。
采用手动冯弗雷纤毛(von Frey)测试小鼠后足的缩爪阈值(PWT)来评估机械性触诱发痛，其相应的测试时间点为待测化合物给药前、给药后0.5小时、1小时和2小时。图1、图2和图3显示，与溶媒对照组相比较，实施例2、实施例4以及实施例5的化合物在给药后0.5小时、1小时和2小时对机械性缩爪阈值有显著的逆转效应。在给药后0.5小时、1小时优于阳性化合物CLP290。

Claims (12)

  1. 一种如下式(I)所示的化合物、其立体异构体、互变异构体或其药学上可接受的盐：
    Figure PCTCN2022081573-appb-100001
    其中，环A为含有0-4个杂原子、5-14个环原子的环烷基、杂环基、芳基或杂芳基；
    环B为含有0-2个杂原子、5-7个环原子的环烷基、杂环基、芳基或杂芳基；
    X为C或N；
    R 1各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基；
    R 2各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基；
    m、n、n’选自0、1、2或3；以及
    Figure PCTCN2022081573-appb-100002
    代表单键或双键。
  2. 根据权利要求1所述的化合物，其中式(I)是式(Ia)：
    Figure PCTCN2022081573-appb-100003
    其中，环A为含有1-4个杂原子、5-14个环原子的杂环基或杂芳基；
    环B为含有0-2个杂原子、5-7个环原子的环烷基、杂环基、芳基或杂芳基；
    X为C或N；
    R 1各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基；
    R 2各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、 卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基；
    m、n选自0、1、2或3；以及
    Figure PCTCN2022081573-appb-100004
    代表单键或双键。
  3. 根据权利要求1所述的化合物，其中式(I)是式(Ib)：
    Figure PCTCN2022081573-appb-100005
    其中，环A为含有1-3个杂原子、5-7个环原子的杂环基或杂芳基；
    环B为含有0-2个杂原子、5-7个环原子的环烷基或杂环基；
    R 1各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基；
    R 2各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基；以及
    m、n选自0、1、2或3。
  4. 根据权利要求1所述的化合物，其中式(I)是式(Ic)或(Id)：
    Figure PCTCN2022081573-appb-100006
    其中，环B为含有0-2个杂原子、5-7个环原子的环烷基或杂环基；
    R 1各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、 卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基；
    R 2各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基或磺酰基；以及
    m、n选自0、1、2或3。
  5. 根据权利要求1所述的式(I)所示的化合物，其选自：
    Figure PCTCN2022081573-appb-100007
  6. 根据权利要求1所述的式(I)所示的化合物，其结构为：
    Figure PCTCN2022081573-appb-100008
  7. 根据权利要求1所述的式(I)所示的化合物，其结构为：
    Figure PCTCN2022081573-appb-100009
  8. 根据权利要求1所述的式(I)所示的化合物，其结构为：
    Figure PCTCN2022081573-appb-100010
  9. 一种药物组合物，其包含治疗有效量的权利要求1所述的化合物，或其药学上可接受的盐、酯、前药、络合物、溶剂化物、水合物或异构体；以及药学上可接受的载体或赋形剂。
  10. 权利要求1所述的化合物，或其药学上可接受的盐、酯、前药、络合物、溶剂化物、水合物或异构体用于制备KCC2激动剂药物中的用途。
  11. 权利要求1所述的化合物，或其药学上可接受的盐、酯、前药、络合物、溶剂化物、水合物或异构体用于制备治疗脊髓损伤药物中的用途。
  12. 权利要求1所述的化合物，或其药学上可接受的盐、酯、前药、络合物、溶剂化物、水合物或异构体用于制备镇痛药物中的用途。
PCT/CN2022/081573 2021-03-19 2022-03-18 嘧啶并环类化合物及其用于制备治疗疼痛、脊髓损伤药物中的用途 WO2022194261A1 (zh)

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