WO2020135454A1 - Class of steroid compounds and use thereof - Google Patents

Class of steroid compounds and use thereof Download PDF

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Publication number
WO2020135454A1
WO2020135454A1 PCT/CN2019/128092 CN2019128092W WO2020135454A1 WO 2020135454 A1 WO2020135454 A1 WO 2020135454A1 CN 2019128092 W CN2019128092 W CN 2019128092W WO 2020135454 A1 WO2020135454 A1 WO 2020135454A1
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alkyl
compound
alkenyl
alkynyl
aryl
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PCT/CN2019/128092
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French (fr)
Chinese (zh)
Inventor
吴振
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张家口华健致远生物科技有限公司
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Priority to CN201980085667.7A priority Critical patent/CN113272315B/en
Publication of WO2020135454A1 publication Critical patent/WO2020135454A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton

Definitions

  • the present invention relates to novel compounds of formula (I) and (II) or pharmaceutically acceptable salts, tautomers or hydrolysable precursors in vivo, their compositions and methods of their use, and these novel compounds and Its use in medicine.
  • GABA Gamma-aminobutyric acid
  • GABA receptors can be divided into three pharmacological subtypes-GABA A , GABA B and GABA C.
  • GABA A receptor is the most important one of the three types of receptors. Its dysfunction is closely related to neurological and mental disorders such as depression, insomnia, epilepsy, anxiety, and schizophrenia.
  • the GABA A receptor is a pentagonal heterogeneous polypeptide oligomer composed of 5 different subunits, and a GABA-gated Cl - channel with a diameter of 0.5 nm is formed in the central part.
  • the presence of six ⁇ , three ⁇ , three ⁇ , one ⁇ , one ⁇ , one ⁇ , one ⁇ , and three ⁇ subunits in GABA A receptor and their distribution in different regions and cells in the brain produces The composition of multiple GABA A receptor subtypes with different subunits and different pharmacological properties.
  • the natural GABA A receptor in the mammalian brain is mainly composed of ⁇ , ⁇ and ⁇ subunits, and 2 ⁇ 1 , 2 ⁇ 2 and 1 ⁇ 2 subunits are the most common combined forms.
  • the binding sites of the GABA A receptor include GABA sites, benzodiazepine sites, barbiturate sites, steroid sites, tetrodotoxin sites and metal ion sites.
  • the GABA A receptor When the GABA A receptor binds to GABA, the GABA A receptor opens the chloride ion channel, increases the permeability of the cell membrane to chloride ions, and chloride ion influx, so that the neurons become hyperpolarized and the neuron excitability decreases accordingly.
  • GABA A receptor modulators have a variety of pharmacological activities, including anti-anxiety, sedation, anti-convulsant, anti-depression, and treatment of epilepsy.
  • Depression also known as depressive disorder, is the main type of mood disorder.
  • the main clinical feature is a significant and persistent mood depression.
  • traditional drugs have a slow onset of action, and it takes a relatively long time to gradually eliminate the symptoms; they cannot cover all the symptoms or characteristics of depression, and the effect is not prominent, such as postpartum depression, there are currently no drugs on the market; and, some drugs will Adverse reactions occur, and many patients even experience sexual dysfunction, which affects the quality of life in the future.
  • the present invention provides a compound of formula (I), its stereoisomer, tautomer or pharmaceutically acceptable salt,
  • R 1 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or -C 3-6 carbocyclyl, wherein alkyl, alkenyl, alkynyl or carbon Cyclic groups can be optionally substituted; including fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, deuterium atoms;
  • Ring A is a nitrogen-containing heteroaromatic heterocyclic ring which may be optionally substituted.
  • R 1 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or -C 3-6 carbocyclyl, wherein alkyl, alkenyl, alkynyl or carbon
  • the cyclic group may be substituted with a substituent selected from halogen, -C 1-6 alkoxy, -C 1-6 alkyl; including fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, deuterium atoms;
  • X is a nitrogen atom or a carbon atom
  • R 5 and R 6 are independently selected from hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, heteroalkyl, aryl , Aralkyl, heteroaryl or heterocyclic group, wherein, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, aralkyl, heteroaryl or heterocyclic group may be optionally substituted ;
  • R 5 and R 6 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring which may be substituted with at least one R 7 ;
  • Each R 7 is independently selected from -H, halogen, -C 1-6 alkyl or oxo;
  • n is selected from 0, 1 or 2;
  • n is selected from 1, 2 or 3.
  • R 1 is selected from -C 1-6 alkyl, -CF 3, -CHF 2, -CH 2 F, -CH 2 OCH 3 or -CH 2 OCH 2 CH 3 .
  • R 5 and R 6 are independently selected from hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, heteroalkyl, aryl , Aralkyl, heteroaryl or 3 to 8 membered heterocyclic group, wherein, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, aralkyl, heteroaryl or heterocyclic group May be substituted by a substituent selected from -C 1-6 alkyl, halogen, -OH, oxo, -C 1-6 alkoxy;
  • R 5 and R 6 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring which may be substituted with at least one R 7 ;
  • Each R 7 is independently selected from -H, halogen, -C 1-6 alkyl or oxo;
  • n is selected from 0, 1 or 2;
  • n is selected from 1, 2 or 3.
  • the present invention provides a compound of formula (III), its stereoisomer, tautomer or pharmaceutically acceptable salt,
  • R 1 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or -C 3-6 carbocyclyl, wherein alkyl, alkenyl, alkynyl or carbon
  • the cyclic group can be optionally substituted, including fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, deuterium atoms;
  • Ring B is a nitrogen-containing heterocyclic ring which may be optionally substituted.
  • the present invention provides a method for preparing the compound of formula (I), its stereoisomer, tautomer or pharmaceutically acceptable salt, which includes the following steps:
  • Step 1 In a suitable solvent and at a suitable temperature, compound SM and paraformaldehyde are coupled to form compound M1;
  • Step 2 In the presence of a suitable solvent and a suitable base, at a suitable temperature, compound M1 is reacted with compound M2 to obtain a compound of formula (I).
  • the present invention provides a compound of formula (IV), its stereoisomer, tautomer or pharmaceutically acceptable salt,
  • R 1 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or -C 3-6 carbocyclyl, wherein alkyl, alkenyl, alkynyl or carbon Cyclic groups can be optionally substituted; including fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, deuterium atoms;
  • R a , R b are selected from hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, heteroalkyl, aryl, aryl Alkyl, heteroaryl or 3- to 8-membered heterocyclic group, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, aralkyl, heteroaryl or heterocyclic group may be It is substituted with a substituent selected from -C 1-6 alkyl, halogen, -OH, oxo, and -C 1-6 alkoxy.
  • the present invention includes the following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
  • the present invention provides a pharmaceutical composition and its use in the preparation of a medicament for preventing and/or treating diseases related to GABA function.
  • the present invention provides a method for treating and/or preventing diseases related to GABA function, which comprises administering to a patient a therapeutically effective amount of a compound of the present invention and a pharmaceutical composition comprising the compound of the present invention, wherein the disease related to GABA function For various nervous system diseases.
  • the present invention provides a method for treating and/or preventing various neurological diseases, which comprises administering to a patient a therapeutically effective amount of a compound of the present invention and a pharmaceutical composition comprising the compound of the present invention, wherein the neurological disease is selected from depression , Sleep disorders, schizophrenia, autism, personality disorders, emotional disorders, anxiety, epilepsy.
  • halogen refers herein to -F, -Cl, -Br and -I.
  • fluorine refers herein to -F.
  • chlorine refers herein to -Cl.
  • bromine refers herein to -Br.
  • cyano refers herein to -CN.
  • amino herein refers to -NH 2.
  • hydroxyl refers herein to -OH.
  • nitro refers to -NO 2.
  • aryl refers to a 6 to 10 membered all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) groups, a polycyclic (ie, with There are rings of adjacent pairs of carbon atoms.
  • the aryl group can be covalently linked to the defined chemical structure on any carbon atom that results in a stable structure.
  • aryl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, acyl, amide Group, ester group, amine group, sulfonyl group, sulfinyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, alkenyl group, alkynyl group and cycloalkoxy group.
  • substituents fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, acyl, amide Group, ester group, amine group, sulfonyl group, sulfinyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, alkenyl group, alkyny
  • heteroaryl refers to an aromatic group composed of 5 to 10 atoms and containing at least one heteroatom selected from N, O, or S.
  • the term may have a single ring (non-limiting examples include furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, oxazole, thiazole, etc.) or multiple condensed rings (non-limiting examples include benzothiophene, benzofuran , Indole, isoindole, etc.), where the fused ring may or may not be an aromatic group containing a heteroatom, assuming that the point of attachment is through an atom of an aromatic heteroaryl group.
  • heteroaryl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, amino, alkyl, alkoxy, acyl, acyloxy Group, amido group, ester group, amine group, sulfonyl group, sulfinyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, alkenyl group, alkynyl group and cycloalkoxy group.
  • cycloalkyl refers herein to cyclic alkyl groups having 3 to 10 carbon atoms and having monocyclic or polycyclic rings (including fused rings, bridged rings, and spiro ring systems).
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • cycloalkyl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, oxo, alkoxy , Acyl, acyloxy, amido, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, aryl or heteroaryl .
  • heterocyclic group refers to a substituted or unsubstituted saturated or unsaturated aromatic ring containing at least 1 to 5 heteroatoms selected from N, O or S, non-aromatic ring, aromatic ring, non-aromatic ring may be
  • the 3 to 10 membered monocyclic ring, the 4 to 20 membered spiro ring, the bicyclic or bridged ring, and the N, S optionally substituted in the heterocyclic ring can be oxidized to various oxidation states.
  • a 3 to 12-membered heterocyclic ring is preferred.
  • Non-limiting examples include oxepanyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, aziridine, azetidine Group, azacyclopentyl, azacyclohexyl, azacyclopropenyl, 1,3-dioxacyclopentyl, 1,4-dioxacyclopentyl, 1,3-dioxacyclopentyl, 1 ,3-Dioxocyclohexyl, 1,3-dithiocyclohexyl, azepanyl, morpholinyl, piperazinyl, pyridyl, furyl, thienyl, pyrrolyl, pyranyl, N- Alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl,
  • heterocycloalkyl refers herein to a non-aromatic cycloalkyl group containing at least one heteroatom selected from O, N, and S, and optionally containing one or more double or triple bonds.
  • the heterocycloalkyl group as a whole may have 3 to 10 ring atoms.
  • the heterocycloalkyl group can be covalently linked to the defined chemical structure on any heteroatom or carbon atom that results in a stable structure.
  • Non-limiting examples of heterocycloalkyl include: pyrrolinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyranyl, and the like.
  • heterocycloalkyl group can be oxidized (eg morpholine N-oxide, thiomorpholine S-oxide, thiomorpholine S, S-dioxide).
  • Heterocycloalkyl can also contain one or more oxo groups, such as phthalimido, piperidone, oxazolidinyl, 2,4(1H,3H)-dioxo-pyrimidinyl , Pyridine-2(1H)-keto, etc.
  • heterocycloalkyl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, oxygen Substituted, acyl, acyloxy, amido, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, aryl or heteroaryl base.
  • alkenyl refers herein to an alkenyl group having 2 to 8 carbon atoms and having at least one site of alkenyl unsaturation.
  • alkenyl groups include vinyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl and the like.
  • alkenyl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, oxo, Acyl, acyloxy, amido, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, cycloalkoxy, aryl or Heteroaryl.
  • substituents fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, oxo, Acyl, acyloxy, amido, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl,
  • alkyl refers herein to a saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, and the term includes straight-chain and branched-chain hydrocarbon groups.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, and the like.
  • alkyl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, acyl, acyl Oxygen, oxo, amido, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, heterocycloalkyloxy, Aryloxy, heteroaryloxy, aryl or heteroaryl.
  • the above-mentioned alkyl group also includes an alkyl group substituted with one or more deuterium atoms.
  • heteroalkyl refers herein to an alkyl group that includes at least one heteroatom.
  • alkoxy refers herein to an alkyl group attached to the rest of the molecule through an oxygen atom (-O-alkyl), where the alkyl group is as defined herein.
  • alkoxy groups include methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, n- Pentoxy etc.
  • ⁇ refers herein to -NR 8 -C(O)-alkyl, -NR 8 -C(O)-cycloalkyl, -NR 8 -C(O)-cycloalkenyl, -NR 8 -C(O)-aryl, -NR 8 -C(O)-heteroaryl and -NR 8 -C(O)-heterocycloalkyl, where R 8 is hydrogen, cycloalkyl, cycloalkenyl , Aryl, heteroaryl, heterocycloalkyl and alkyl. Wherein said hydrogen, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl and alkyl groups are as defined herein.
  • acyl refers herein to HC(O)-, R 9 R 10 NC(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, cycloalkenyl-C( O)-, heterocycloalkyl-C(O)-, aryl-C(O)- and heteroaryl-C(O)-, wherein R 9 and R 10 are independently selected from hydrogen, hydroxyl , Alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl or cycloalkyl.
  • sulfonyl refers herein to R 11 R 12 NS(O) 2 -, cycloalkyl-S(O) 2 -, cycloalkenyl-S(O) 2 -, aryl-S(O) 2 -, heteroaryl-S(O) 2 -, heterocycloalkyl-S(O) 2 -and alkyl-S(O) 2 -, wherein R 11 and R 12 are each independently selected from hydrogen , Hydroxy, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl or cycloalkyl.
  • sulfinyl refers herein to R 13 R 14 NS(O)-, cycloalkyl-S(O)-, cycloalkenyl-S(O)-, aryl-S(O)-, Heteroaryl-S(O)-, heterocycloalkyl-S(O)- or alkyl-S(O)-, wherein R 13 and R 14 are independently selected from hydrogen, hydroxyl, alkyl, Heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl or cycloalkyl.
  • acyloxy refers herein to -OC(O)-alkyl, -OC(O)-cycloalkyl, -OC(O)-cycloalkenyl, -OC(O)-aryl,- OC(O)-heteroaryl and -OC(O)-heterocycloalkyl, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycloalkyl groups are as described herein Defined in.
  • ester group refers herein to alkyl-OC(O)-, cycloalkyl-OC(O)-, cycloalkenyl-OC(O)-, heterocycloalkyl-OC(O)-, Aryl-OC(O)- and heteroaryl-OC(O)-, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl groups are as described herein As defined.
  • substituents refers herein to any group that is mono- or poly-substituted by the specified substituent to the extent that such mono- or poly-substitution (including multiple substitutions in the same part) is chemically allowed, each substituent may It is located at any available position on the group and can be connected by any available atom on the substituent.
  • Any available position refers to any position on the group of a molecule that is chemically available by methods known in the art or methods taught herein, and does not produce an excessively unstable molecule. When there are two or more substituents on any group, each substituent is defined independently of any other substituent, and therefore may be the same or different.
  • the substituents of the compounds of the present invention are disclosed in the form of groups or ranges. This specifically means that the present invention includes each member of such groups and ranges or a sub-combination of each individual in the member.
  • the term “C 1-6 alkyl” specifically means that methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl are individually disclosed.
  • the term "compounds of the invention” refers herein to compounds of formula (I) and formula (II) and all pure and mixed stereoisomers, geometric isomers, tautomers Body, solvates, prodrugs and isotopically labeled compounds and any pharmaceutically acceptable salts.
  • the solvate of the compound of the present invention refers to a compound or salt thereof combined with stoichiometric and non-stoichiometric solvents, such as hydrate, ethanolate, methanolate, acetoneate, and the like.
  • the compound may also exist in one or more crystalline states, i.e. as a eutectic, polymorph, or it may exist as an amorphous solid. All such forms are covered by the claims.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients constituting the formulation and/or the mammal being treated with it.
  • stereoisomer refers herein to compounds having one or more stereocenters with different chiralities, including the corresponding isomers and diastereomers.
  • tautomer means herein that structural isomers with different energies can cross the low energy barrier and thus convert to each other.
  • Valence tautomers include some bond-forming electronic recombination for interconversion.
  • prodrug herein refers to any derivative of the compound of the present invention capable of directly or indirectly providing the compound of the present invention, its active metabolite or residue when administered to a subject. Particularly preferred are those derivatives or prodrugs that increase the bioavailability of the compounds of the invention, improve metabolic stability and tissue targeting.
  • the compounds of the present invention can be used in the form of salts, such as "pharmaceutically acceptable salts" derived from inorganic or organic acids. These include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, ethanesulfonate, hydrogen sulfate Salt, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentane propionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerol phosphate, semi Sulfate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, mesylate, Ethylsulfonate, hydrochloride, 2-naphthalenesulf
  • the basic nitrogen-containing groups can be quaternized with the following reagents to form quaternary ammonium salts: such as lower alkyl halides, including methyl, ethyl, propyl and butyl chloride, bromide and iodine Compounds; such as dialkyl sulfates, including dimethyl, diethyl, dibutyl, and dipentyl sulfates; such as long-chain halides, including decyl, lauryl, myristyl, and stearyl Chloride, bromide and iodide; such as aralkyl halides, such as benzyl and phenethyl bromide.
  • lower alkyl halides including methyl, ethyl, propyl and butyl chloride, bromide and iodine Compounds
  • dialkyl sulfates including dimethyl, diethyl, dibutyl, and dipentyl s
  • the present invention also includes isotopically-labeled compounds of the present invention, that is, the same structure as disclosed above, but one or more atoms in the structure are replaced by atoms having the same number of protons but different numbers of neutrons.
  • isotopes incorporating the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl and 131 I etc.
  • the compounds of the present invention are all within the scope of the present invention.
  • Certain isotopically-labeled compounds of the present invention such as those labeled with 3 H or 14 C, can be used in pharmaceutical tissue distribution tests. Therefore, these 3 H or 14 C isotopes are particularly preferred because of their ease of preparation and detection.
  • the compound of formula (I) of the present invention can be prepared according to the following scheme 1.
  • a suitable solvent such as THF, DMF, acetonitrile, dioxane, NMP, DMSO and DMA, etc.
  • the compound SM is in an acid such as trifluoroacetic acid, phosphoric acid, methanesulfonic acid, etc., and a base such as diisopropylamine, di
  • a suitable solvent such as THF, DMF, acetonitrile, dioxane, NMP, DMSO and DMA, etc.
  • the compound SM is in an acid such as trifluoroacetic acid, phosphoric acid, methanesulfonic acid, etc.
  • a base such as diisopropylamine, di
  • ethylamine, dimethylamine, piperidine, tetrahydropyrrole, etc. it reacts with paraformaldehyde at a suitable temperature to generate intermediate M1.
  • R 1 and M2 in a suitable solvent, such as THF, acetonitrile, ethanol, methanol, dioxane, DMF, etc., in a base, such as K 2 CO 3 , Na 2 CO 3 , NaH, CsCO 3 , DBU, tert-butyl
  • a suitable solvent such as THF, acetonitrile, ethanol, methanol, dioxane, DMF, etc.
  • a base such as K 2 CO 3 , Na 2 CO 3 , NaH, CsCO 3 , DBU, tert-butyl
  • the compounds provided by the present invention can be prepared by standard synthetic methods well known in the art. This specification provides general methods for preparing the compounds of the present invention.
  • the starting materials are usually commercially available, for example by Alfa It can be purchased from other companies or prepared by methods well known to those skilled in the art.
  • the structures of the compounds of the following examples are characterized by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • reaction starting materials, intermediates and example compounds can be separated and purified by conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography (such as column chromatography, TLC separation and purification, etc.).
  • reaction conditions reaction temperature, reaction solvent, molar ratio of reactants or/and reaction duration
  • reaction temperature reaction temperature, reaction solvent, molar ratio of reactants or/and reaction duration
  • the progress of the reaction can be monitored by TLC, and an appropriate time can be selected to terminate the reaction and perform post-treatment accordingly.
  • the purification conditions of the compound may also change.
  • the appropriate column chromatography eluent is selected according to the R f value of TLC, or the corresponding compound is separated and purified by preparing TLC.
  • Toluene (300ml) and methylaluminum bis(2,6-di-tert-butyl-4-anisole) (66g) were added to the 2L reaction flask in turn, the temperature was lowered to 0°C, and 2.0M trimethylaluminum/toluene was added The solution (76 ml) was stirred at 20°C for 1 hour after the addition, and then the temperature was lowered to -80°C. Slowly add SA-B (16g) in 200ml toluene solution, and continue stirring for 1 hour after the addition.
  • compound 4 can also be prepared according to the following scheme:
  • Toluene (260g), ethyltriphenylphosphonium bromide (96g), potassium tert-butoxide (29g) were added to a 2L reaction flask in this order, and the temperature was raised to 60°C and stirred for 2 hours.
  • a toluene solution (100 g) of SAD-C (30 g) was added, and the temperature was raised to 90°C to react for 2 hours.
  • the reaction solution was cooled to room temperature, 390 g of saturated ammonium chloride solution was added to quench the reaction and stirred for 15 to 30 minutes. After standing, the layers were separated, and the aqueous layer was extracted once with 100 g of ethyl acetate.
  • N,N-dimethylacetamide (28g) and diisopropylamine (6g) in sequence, lower the temperature to below 10°C, and add N,N dimethylacetamide solution of trifluoroacetic acid (10g) (28g), after the addition is completed, the temperature is stopped and stirred for 30 minutes.
  • a solution of SAD-F (15g) in N,N-dimethylacetamide (80g) was added, followed by paraformaldehyde (6g). After the addition, the temperature was raised to 90°C and reacted for 20 hours.
  • reaction solution was cooled to room temperature, 200 g of ethyl acetate and 400 g of water were added, stirred for 10 minutes, and allowed to stand for liquid separation.
  • the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed twice with saturated sodium chloride, and anhydrous sulfuric acid Sodium was dried, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography to obtain 10g of light yellow solid.
  • the voltage clamp recording mode was used to clamp the cell membrane potential to -60mV. After stabilization, the first round of stimulation of GABA was given instantaneously; then the second round of stimulation with GABA and the compound was given under the same voltage mode.
  • the current value induced by 5 ⁇ M GABA acting on the cell is measured, and then the current value induced by 5 ⁇ M GABA and 10 ⁇ M test compound acting on the cell is measured, thereby calculating the combined effect of 5 ⁇ M GABA and 10 ⁇ M.
  • A 0 ⁇ E max ⁇ 200
  • B 200 ⁇ E max ⁇ 500
  • C E max >500.
  • SAGE-547 is an allosteric modulator of GABAA receptors and has shown significant therapeutic effects in a phase 3 clinical trial for the treatment of postpartum depression.
  • compound 4 (20 mg/kg) was administered by gavage, and no animal deaths were observed until 24 hours.
  • SAGE-217 is a steroid drug undergoing clinical trials.
  • 96 SD rats were randomly divided into 6 groups, 16 in each group, half male and female.
  • the 6 groups were given vehicle, compound 1 (2 mg/kg), compound 2 (2 mg/kg), compound 4 (1.5 mg/kg), compound 11 (2 mg/kg), paroxetine (20 mg/kg). Except for the paroxetine group, which was administered 3 times at 23.5h, 5h, and 1h before the test, the other groups were administered once a day for 3 consecutive days.
  • the compounds of the examples of the present invention showed a significant effect of reducing immobility time in the forced swimming test of rats.

Abstract

Provided in the present invention are compounds of formulae (I), (II), (III) and (IV), a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof. Disclosed are a method for preparing such compounds and the use of the compounds in the treatment of diseases, such as various nervous system diseases.

Description

一类类固醇化合物及其用途A class of steroid compounds and their uses 技术领域Technical field
本发明涉及新颖的结构式(I)和(II)化合物或其可药用盐，互变异构体或体内可水解的前体，它们的组合物和它们的使用方法，及这些新颖的化合物及其在医学上的用途。The present invention relates to novel compounds of formula (I) and (II) or pharmaceutically acceptable salts, tautomers or hydrolysable precursors in vivo, their compositions and methods of their use, and these novel compounds and Its use in medicine.
背景技术Background technique
γ-氨基丁酸(GABA)是中枢神经***中一种重要的抑制性氨基酸类神经介质，其传递作用由GABA受体介导。根据受体对***和拮抗剂敏感性的不同，可将GABA受体分为3个药理学亚型———GABA A，GABA B和GABA C。GABA A受体是三类受体中最重要的一种,它的功能障碍与神经和精神紊乱疾病如抑郁症，失眠，癫痫，焦虑，精神***症等密切相关。 Gamma-aminobutyric acid (GABA) is an important inhibitory amino acid nerve mediator in the central nervous system, and its transmission is mediated by GABA receptors. According to the different sensitivity of receptors to stimulants and antagonists, GABA receptors can be divided into three pharmacological subtypes-GABA A , GABA B and GABA C. GABA A receptor is the most important one of the three types of receptors. Its dysfunction is closely related to neurological and mental disorders such as depression, insomnia, epilepsy, anxiety, and schizophrenia.
GABA A受体是由5个不同亚基组成的五边形异质性多肽类寡聚体，其中心部位形成一个直径为0.5nm的GABA门控Cl -通道。GABA A受体中六个α，三个β，三个γ，一个δ，一个ε，一个θ，一个π和三个ρ亚基的存在及其在脑中的不同区域和细胞分布，产生具有不同亚基的多种GABA A受体亚型组成和不同的药理特性。在哺乳动物大脑中的天然GABA A受体主要是由α，β和γ亚基组成，2个α 1，2个β 2和1个γ 2亚基是最常见的组合形式。GABA A受体的结合位点包括GABA位点，苯并二氮杂卓位点，巴比妥盐位点，类固醇位点，印防己苦毒素位点和金属离子位点。 The GABA A receptor is a pentagonal heterogeneous polypeptide oligomer composed of 5 different subunits, and a GABA-gated Cl - channel with a diameter of 0.5 nm is formed in the central part. The presence of six α, three β, three γ, one δ, one ε, one θ, one π, and three ρ subunits in GABA A receptor and their distribution in different regions and cells in the brain produces The composition of multiple GABA A receptor subtypes with different subunits and different pharmacological properties. The natural GABA A receptor in the mammalian brain is mainly composed of α, β and γ subunits, and 2 α 1 , 2 β 2 and 1 γ 2 subunits are the most common combined forms. The binding sites of the GABA A receptor include GABA sites, benzodiazepine sites, barbiturate sites, steroid sites, tetrodotoxin sites and metal ion sites.
当GABA A受体与GABA结合时，GABA A受体开启氯离子通道，增加细胞膜对氯离子的通透性，氯离子内流，从而使神经元发生超极化，神经元兴奋性相应下降。 When the GABA A receptor binds to GABA, the GABA A receptor opens the chloride ion channel, increases the permeability of the cell membrane to chloride ions, and chloride ion influx, so that the neurons become hyperpolarized and the neuron excitability decreases accordingly.
分子研究，动物研究和临床研究表明，GABA A受体调节剂具有多种药理活性，包括抗焦虑，镇静，抗惊厥，抗抑郁，治疗癫痫等作用。 Molecular studies, animal studies, and clinical studies have shown that GABA A receptor modulators have a variety of pharmacological activities, including anti-anxiety, sedation, anti-convulsant, anti-depression, and treatment of epilepsy.
抑郁症又称抑郁障碍，是心境障碍的主要类型，主要临床特征是显著而持久的心境低落为，全球累计患病人数超过3.5亿。目前上市的治疗药物主要包括单胺氧化酶抑制剂，三环类抗抑郁药和5-HT再摄取抑制药。但传统药物存在起效慢，需要比较长的时间才能够使得症状逐渐消除；不能覆盖所有抑郁症症状或特征，效果不突出，如产后抑郁目前还没有上市药物；而且，有些药物治疗过程中会出现不良反应，很多患者甚至会出现性功能障碍的问题，影响到今后的生活质量。需要开发新型安全有效的的抗抑郁药物。Depression, also known as depressive disorder, is the main type of mood disorder. The main clinical feature is a significant and persistent mood depression. The cumulative number of patients worldwide exceeds 350 million. The therapeutic drugs currently on the market mainly include monoamine oxidase inhibitors, tricyclic antidepressants and 5-HT reuptake inhibitors. However, traditional drugs have a slow onset of action, and it takes a relatively long time to gradually eliminate the symptoms; they cannot cover all the symptoms or characteristics of depression, and the effect is not prominent, such as postpartum depression, there are currently no drugs on the market; and, some drugs will Adverse reactions occur, and many patients even experience sexual dysfunction, which affects the quality of life in the future. There is a need to develop new safe and effective antidepressants.
抗焦虑和辅助睡眠领域也迫切需要新型有效的治疗药物。The field of anti-anxiety and assisted sleep is also in urgent need of new and effective therapeutic drugs.
发明内容Summary of the invention
本发明提供一种式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，The present invention provides a compound of formula (I), its stereoisomer, tautomer or pharmaceutically acceptable salt,
Figure PCTCN2019128092-appb-000001
Figure PCTCN2019128092-appb-000001
其中，R 1选自-C 1-6烷基，-C 2-6烯基，-C 2-6炔基或-C 3-6碳环基，其中烷基，烯基，炔基或碳环基可被任意取代；包括氟，氯，溴，碘，氰基，羟基，氨基，氘原子取代； Wherein R 1 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or -C 3-6 carbocyclyl, wherein alkyl, alkenyl, alkynyl or carbon Cyclic groups can be optionally substituted; including fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, deuterium atoms;
环A为可被任意取代的含氮杂芳杂环。Ring A is a nitrogen-containing heteroaromatic heterocyclic ring which may be optionally substituted.
本发明所述的式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，其中包括通式(II)化合物，The compound of formula (I) according to the present invention, its stereoisomers, tautomers or pharmaceutically acceptable salts, including compounds of general formula (II),
Figure PCTCN2019128092-appb-000002
Figure PCTCN2019128092-appb-000002
其中，R 1选自-C 1-6烷基，-C 2-6烯基，-C 2-6炔基或-C 3-6碳环基，其中烷基，烯基，炔基或碳环基可被选自卤素，-C 1-6烷氧基，-C 1-6烷基的取代基取代；包括氟，氯，溴，碘，氰基，羟基，氨基，氘原子取代； Wherein R 1 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or -C 3-6 carbocyclyl, wherein alkyl, alkenyl, alkynyl or carbon The cyclic group may be substituted with a substituent selected from halogen, -C 1-6 alkoxy, -C 1-6 alkyl; including fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, deuterium atoms;
R 2，R 3和R 4独立地选自氢，卤素，-NO 2，-CN，-OR 5，-N(R 5) 2，-OH，-(CH 2) 0-6COOR 5，-NR 5R 6，-C(O)NR 5R 6，-OR 5，-O(CH 2) 1-4COOR 5，-Si(R 5) 3，-OC(O)R 5，-OC(O)OR 5，-OC(O)NR 5R 6，-OS(O) nR 5，-OS(O) nNR 5R 6，-S(O) mR 5，-OS(O) nNH(C＝O)NR 5R 6，-NHS(O) nR 5，炔基，烷基，杂烷基，烯基，环烷基，芳基，芳烷基，杂芳基或杂环基，其中，炔基，烷基，杂烷基，烯基，环烷基，芳基，芳烷基，杂芳基或杂环基可被任意取代； R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, -NO 2 , -CN, -OR 5 , -N(R 5 ) 2 , -OH, -(CH 2 ) 0-6 COOR 5 ,- NR 5 R 6 , -C(O)NR 5 R 6 , -OR 5 , -O(CH 2 ) 1-4 COOR 5 , -Si(R 5 ) 3 , -OC(O)R 5 , -OC( O)OR 5 , -OC(O)NR 5 R 6 , -OS(O) n R 5 , -OS(O) n NR 5 R 6 , -S(O) m R 5 , -OS(O) n NH(C=O)NR 5 R 6 , -NHS(O) n R 5 , alkynyl, alkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, aralkyl, heteroaryl or heterocyclic Group, wherein alkynyl, alkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, aralkyl, heteroaryl or heterocyclic group may be optionally substituted;
X为氮原子或者碳原子；X is a nitrogen atom or a carbon atom;
R 5和R 6独立地选自氢，-C 1-6烷基，-C 2-6烯基，-C 2-6炔基，-C 3-8环烷基，杂烷基，芳基，芳烷基，杂芳基或杂环基，其中，烷基，烯基，炔基，环烷基，杂烷基，芳基，芳烷基，杂芳基或杂环基可被任意取 代； R 5 and R 6 are independently selected from hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, heteroalkyl, aryl , Aralkyl, heteroaryl or heterocyclic group, wherein, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, aralkyl, heteroaryl or heterocyclic group may be optionally substituted ;
或者，R 5和R 6连同与它们相连的氮原子一起形成可被至少一个R 7取代的饱和或不饱和的杂环； Alternatively, R 5 and R 6 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring which may be substituted with at least one R 7 ;
每个R 7分别独立地选自-H，卤素，-C 1-6烷基或氧代； Each R 7 is independently selected from -H, halogen, -C 1-6 alkyl or oxo;
m选自0，1或2；m is selected from 0, 1 or 2;
n选自1，2或3。n is selected from 1, 2 or 3.
本发明所述的式(II)化合物，其中R 1选自-C 1-6烷基，-CF 3，-CHF 2，-CH 2F，-CH 2OCH 3或-CH 2OCH 2CH 3。 The compound of formula (II) according to the present invention, wherein R 1 is selected from -C 1-6 alkyl, -CF 3, -CHF 2, -CH 2 F, -CH 2 OCH 3 or -CH 2 OCH 2 CH 3 .
本发明所述的式(II)化合物，其中，R 2，R 3和R 4独立地选自氢，卤素，-NO 2，-CN，-OR 5，-N(R 5) 2，-OH，-(CH 2) 0-6COOR 5，-NR 5R 6，-C(O)NR 5R 6，-OR 5，-O(CH 2) 1-4COOR 5，-Si(R 5) 3，-OC(O)R 5，-OC(O)OR 5，-OC(O)NR 5R 6，-OS(O) nR 5，-OS(O) nNR 5R 6，-S(O) mR 5，-OS(O) nNH(C＝O)NR 5R 6，-NHS(O) nR 5，-C 2-6炔基，-C 1-6烷基，杂烷基，-C 2-6烯基，-C 3-8环烷基，芳基，芳烷基，杂芳基或3至8元杂环基，其中炔基，烷基，杂烷基，烯基，环烷基，芳基，芳烷基，杂芳基或杂环基可被选自-C 1-6烷基，卤素，-OH，氧代，-C 1-6烷氧基的取代基取代； The compound of formula (II) according to the present invention, wherein R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, -NO 2 , -CN, -OR 5 , -N(R 5 ) 2 , -OH , -(CH 2 ) 0-6 COOR 5 , -NR 5 R 6 , -C(O)NR 5 R 6 , -OR 5 , -O(CH 2 ) 1-4 COOR 5 , -Si(R 5 ) 3 , -OC(O)R 5 , -OC(O)OR 5 , -OC(O)NR 5 R 6 , -OS(O) n R 5 , -OS(O) n NR 5 R 6 , -S (O) m R 5 , -OS(O) n NH(C=O)NR 5 R 6 , -NHS(O) n R 5 , -C 2-6 alkynyl, -C 1-6 alkyl, hetero Alkyl, -C 2-6 alkenyl, -C 3-8 cycloalkyl, aryl, aralkyl, heteroaryl or 3 to 8 membered heterocyclic group, wherein alkynyl, alkyl, heteroalkyl, Alkenyl, cycloalkyl, aryl, aralkyl, heteroaryl or heterocyclic groups can be selected from -C 1-6 alkyl, halogen, -OH, oxo, -C 1-6 alkoxy Substituent substitution;
R 5和R 6独立地选自氢，-C 1-6烷基，-C 2-6烯基，-C 2-6炔基，-C 3-8环烷基，杂烷基，芳基，芳烷基，杂芳基或3至8元杂环基，其中，烷基，烯基，炔基，环烷基，杂烷基，芳基，芳烷基，杂芳基或杂环基可被选自-C 1-6烷基，卤素，-OH，氧代，-C 1-6烷氧基的取代基取代； R 5 and R 6 are independently selected from hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, heteroalkyl, aryl , Aralkyl, heteroaryl or 3 to 8 membered heterocyclic group, wherein, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, aralkyl, heteroaryl or heterocyclic group May be substituted by a substituent selected from -C 1-6 alkyl, halogen, -OH, oxo, -C 1-6 alkoxy;
或者，R 5和R 6连同与它们相连的氮原子一起形成可被至少一个R 7取代的饱和或不饱和的杂环； Alternatively, R 5 and R 6 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring which may be substituted with at least one R 7 ;
每个R 7分别独立地选自-H，卤素，-C 1-6烷基或氧代； Each R 7 is independently selected from -H, halogen, -C 1-6 alkyl or oxo;
m选自0，1或2；m is selected from 0, 1 or 2;
n选自1，2或3。n is selected from 1, 2 or 3.
本发明所述的式(II)化合物，其中
Figure PCTCN2019128092-appb-000003
选自以下结构， The compound of formula (II) according to the present invention, wherein
Figure PCTCN2019128092-appb-000003
Selected from the following structures,
Figure PCTCN2019128092-appb-000004
Figure PCTCN2019128092-appb-000004
本发明提供一种式(III)化合物，其立体异构体，互变异构体或药学上可接受的盐，The present invention provides a compound of formula (III), its stereoisomer, tautomer or pharmaceutically acceptable salt,
Figure PCTCN2019128092-appb-000005
Figure PCTCN2019128092-appb-000005
其中，R 1选自-C 1-6烷基，-C 2-6烯基，-C 2-6炔基或-C 3-6碳环基，其中烷基，烯基，炔基或碳环基可被任意取代，包括氟，氯，溴，碘，氰基，羟基，氨基，氘原子取代； Wherein R 1 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or -C 3-6 carbocyclyl, wherein alkyl, alkenyl, alkynyl or carbon The cyclic group can be optionally substituted, including fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, deuterium atoms;
环B为可被任意取代的含氮杂环。Ring B is a nitrogen-containing heterocyclic ring which may be optionally substituted.
本发明所述的式(I)，(II)和(III)化合物，其立体异构体，互变异构体或药学上可接受的盐，其选自下述化合物，The compounds of formula (I), (II) and (III) described in the present invention, their stereoisomers, tautomers or pharmaceutically acceptable salts, are selected from the following compounds,
Figure PCTCN2019128092-appb-000006
Figure PCTCN2019128092-appb-000006
本发明提供所述式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐的制备方法，包括如下步骤：The present invention provides a method for preparing the compound of formula (I), its stereoisomer, tautomer or pharmaceutically acceptable salt, which includes the following steps:
Figure PCTCN2019128092-appb-000007
Figure PCTCN2019128092-appb-000007
其中，R 1，环A的定义如上所述， Where R 1 and ring A are as defined above,
步骤1，在合适的溶剂中，在合适的温度下，化合物SM与多聚甲醛偶联成为化合物M1；Step 1. In a suitable solvent and at a suitable temperature, compound SM and paraformaldehyde are coupled to form compound M1;
步骤2，在合适的溶剂和合适的碱存在下，在合适的温度下，化合物M1与化合物M2反应得到式(I)化合物。Step 2. In the presence of a suitable solvent and a suitable base, at a suitable temperature, compound M1 is reacted with compound M2 to obtain a compound of formula (I).
本发明提供一种式(IV)化合物，其立体异构体，互变异构体或药学上可接受的盐，The present invention provides a compound of formula (IV), its stereoisomer, tautomer or pharmaceutically acceptable salt,
Figure PCTCN2019128092-appb-000008
Figure PCTCN2019128092-appb-000008
其中，R 1选自-C 1-6烷基，-C 2-6烯基，-C 2-6炔基或-C 3-6碳环基，其中烷基，烯基，炔基或碳环基可被任意取代；包括氟，氯，溴，碘，氰基，羟基，氨基，氘原子取代； Wherein R 1 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or -C 3-6 carbocyclyl, wherein alkyl, alkenyl, alkynyl or carbon Cyclic groups can be optionally substituted; including fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, deuterium atoms;
R a，R b选自氢，-C 1-6烷基，-C 2-6烯基，-C 2-6炔基，-C 3-8环烷基，杂烷基，芳基，芳烷基，杂芳基或3至8元杂环基，其中，烷基，烯基，炔基，环烷基，杂烷基，芳基，芳烷基，杂芳基或杂环基可被选自-C 1-6烷基，卤素，-OH，氧代，-C 1-6烷氧基的取代基取代。 R a , R b are selected from hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, heteroalkyl, aryl, aryl Alkyl, heteroaryl or 3- to 8-membered heterocyclic group, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, aralkyl, heteroaryl or heterocyclic group may be It is substituted with a substituent selected from -C 1-6 alkyl, halogen, -OH, oxo, and -C 1-6 alkoxy.
本发明包括下述化合物，其立体异构体，互变异构体或药学上可接受的盐，The present invention includes the following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
Figure PCTCN2019128092-appb-000009
Figure PCTCN2019128092-appb-000009
本发明提供一种药物组合物及其在制备用于预防和/或治疗与GABA功能有关的疾病的药物中的用途。The present invention provides a pharmaceutical composition and its use in the preparation of a medicament for preventing and/or treating diseases related to GABA function.
式(I)和式(II)化合物及其药学上可接受的盐在本文统称为“本发明化合物”。The compounds of formula (I) and formula (II) and their pharmaceutically acceptable salts are collectively referred to herein as "the compounds of the present invention".
本发明提供一种治疗和/或预防与GABA功能有关的疾病的方法，其包括向患者施用治疗有效量的本发明化合物及包含本发明化合物的药物组合物，其中所述与GABA功能有关的疾病为各种神经***疾病。The present invention provides a method for treating and/or preventing diseases related to GABA function, which comprises administering to a patient a therapeutically effective amount of a compound of the present invention and a pharmaceutical composition comprising the compound of the present invention, wherein the disease related to GABA function For various nervous system diseases.
本发明提供一种治疗和/或预防各种神经***疾病的方法，其包括向患者施用治疗有效量的本发明化合物及包含本发明化合物的药物组合物，其中所述的神经***疾病选自抑郁，睡眠障碍，精神***症，自闭症，人格障碍，情感障碍，焦虑，癫痫。The present invention provides a method for treating and/or preventing various neurological diseases, which comprises administering to a patient a therapeutically effective amount of a compound of the present invention and a pharmaceutical composition comprising the compound of the present invention, wherein the neurological disease is selected from depression , Sleep disorders, schizophrenia, autism, personality disorders, emotional disorders, anxiety, epilepsy.
发明详述Detailed description of the invention
如上文和本文其它地方所用，下列术语和缩写具有下面所定义的含义。如未定义，则本说明书所使用的所有技术和科学术语均具有本领域普通技术人员通常所理解的含义。As used above and elsewhere herein, the following terms and abbreviations have the meanings defined below. If not defined, all technical and scientific terms used in this specification have the meanings generally understood by those of ordinary skill in the art.
缩写abbreviation 含义meaning
GABAGABA γ-氨基丁酸γ-aminobutyric acid
THFTHF 四氢呋喃Tetrahydrofuran
DMFDMF N，N-二甲基甲酰胺N,N-dimethylformamide
NMPNMP N-甲基吡咯烷酮N-methylpyrrolidone
DMSODMSO 二甲亚砜Dimethyl sulfoxide
DMADMA 己二酸二甲酯Dimethyl adipate
DMPDMP Dess-Martin高价碘化合物Dess-Martin high-valent iodine compound
K 2CO 3 K 2 CO 3 碳酸钾Potassium carbonate
Na 2CO 3 Na 2 CO 3 碳酸钠Sodium carbonate
NaHNaH 氢化钠Sodium hydride
CsCO 3 CsCO 3 碳酸铯Cesium carbonate
DBUDBU 1,8-二氮杂二环[5.4.0]十一碳-7-烯1,8-diazabicyclo[5.4.0]undec-7-ene
TMSTMS 三甲基硅Trimethyl silicon
TLCTLC 薄层色谱TLC
R f R f 比移值Ratio shift
CDICDI 羰基二咪唑Carbonyldiimidazole
MADMAD 甲铝双(2,6-二叔丁基-4-苯甲醚)Methyl aluminum bis(2,6-di-tert-butyl-4-anisole)
DCMDCM 二氯甲烷Methylene chloride
NaHCO 3 NaHCO 3 碳酸氢钠Sodium bicarbonate
MTBEMTBE 甲基叔丁基醚Methyl tert-butyl ether
EAEA 乙酸乙酯Ethyl acetate
MSMS 质谱Mass spectrometry
术语“氢”在本文中是指-H。The term "hydrogen" refers herein to -H.
术语“卤素”在本文中是指-F，-Cl，-Br和-I。The term "halogen" refers herein to -F, -Cl, -Br and -I.
术语“氟”在本文中是指-F。The term "fluorine" refers herein to -F.
术语“氯”在本文中是指-Cl。The term "chlorine" refers herein to -Cl.
术语“溴”在本文中是指-Br。The term "bromine" refers herein to -Br.
术语“碘”在本文中是指-I。The term "iodine" refers herein to -I.
术语“氰基”在本文中是指-CN。The term "cyano" refers herein to -CN.
术语“氨基”在本文中是指-NH 2。 The term "amino" herein refers to -NH 2.
术语“羟基”在本文中是指-OH。The term "hydroxyl" refers herein to -OH.
术语“硝基”在本文中是指-NO 2。 The term "nitro" as used herein refers to -NO 2.
术语“羧基”在本文中是指-COOH。The term "carboxy" refers herein to -COOH.
术语“芳基”在本文中是指6至10元全碳单环或稠合多环(即共享相邻碳原子对的环)基团，具有共轭的π电子体系的多环(即带有相邻碳原子对的环)基团。芳基可以在产生稳定结构的任意碳原子上与所定义的化学结构共价连接。本文所述芳基可以任选地被一个或多个下列取代基所取代：氟，氯，溴，碘，氰基，硝基，羟基，羧基，氨基，烷基，烷氧基，酰基，酰胺基，酯基，胺基，磺酰基，亚磺酰基，环烷基，环烯基，杂环烷基，烯基，炔基和环烷氧基。The term "aryl" as used herein refers to a 6 to 10 membered all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) groups, a polycyclic (ie, with There are rings of adjacent pairs of carbon atoms. The aryl group can be covalently linked to the defined chemical structure on any carbon atom that results in a stable structure. The aryl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, acyl, amide Group, ester group, amine group, sulfonyl group, sulfinyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, alkenyl group, alkynyl group and cycloalkoxy group.
术语“杂芳基”在本文中是指由5至10个原子所组成的并且含有至少一个选自N，O或S等杂原子的芳香族基团。该术语可以具有单个环(非限制性实例包括呋喃，噻吩，咪唑，吡唑，吡啶，吡嗪，恶唑，噻唑等)或多个稠环(非限制性实例包括苯并噻吩，苯并呋喃，吲哚，异吲哚等)，其中稠环可以是或者可以不是包含杂原子的芳香族基团，假定连接点是通过芳族杂芳基基团的原子。本文所述杂芳基可以任选地被一个或多个下列取代基所取代：氟，氯，溴，碘，氰基，硝基，羟基，氨基，烷基，烷氧基，酰基，酰氧基，酰胺基，酯基，胺基，磺酰基，亚磺酰基，环烷基，环烯基，杂环烷基，烯基，炔基和环烷氧基。The term "heteroaryl" herein refers to an aromatic group composed of 5 to 10 atoms and containing at least one heteroatom selected from N, O, or S. The term may have a single ring (non-limiting examples include furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, oxazole, thiazole, etc.) or multiple condensed rings (non-limiting examples include benzothiophene, benzofuran , Indole, isoindole, etc.), where the fused ring may or may not be an aromatic group containing a heteroatom, assuming that the point of attachment is through an atom of an aromatic heteroaryl group. The heteroaryl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, amino, alkyl, alkoxy, acyl, acyloxy Group, amido group, ester group, amine group, sulfonyl group, sulfinyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, alkenyl group, alkynyl group and cycloalkoxy group.
术语“环烷基”在本文中是指具有3至10个碳原子，具有单环或多环(包括稠环，桥环及螺环***)的环状烷基。环烷基的非限制性实例包括环丙基，环丁基，环戊基，环己基等。本文所述环烷基可以任选地被一个或多个下列取代基所取代：氟，氯，溴，碘，氰基，硝基，羟基，羧基，氨基，烷基，氧代，烷氧基，酰基，酰氧基，酰胺基，酯基，胺基，环烷基，环烯基，杂环烷基，烯基，烯氧基，炔基，环烷氧基，芳基或杂芳基。The term "cycloalkyl" refers herein to cyclic alkyl groups having 3 to 10 carbon atoms and having monocyclic or polycyclic rings (including fused rings, bridged rings, and spiro ring systems). Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The cycloalkyl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, oxo, alkoxy , Acyl, acyloxy, amido, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, aryl or heteroaryl .
术语“杂环基”是指取代的或未取代的饱和或者不饱和且至少含有1至5个选自N，O或S杂原子的芳香环，非芳香环，芳香环，非芳香环可以是3至10元的单环，4至20元的螺环，并环或桥环，杂环基环中选择性取代的N，S可被氧化成各种氧化态。优选3至12元杂环。非限制性实施例包括氧杂环丙烷基，氧杂环丁基，氧杂环戊基，氧杂环己基，氧杂环己基，氧杂环辛基，氮杂环丙烷基，氮杂环丁基，氮杂环戊基，氮杂环己基，氮杂环丙烯基，1,3-二氧环戊基，1,4-二氧环戊基，1,3-二氧环戊基，1,3-二氧环己基，1,3-二硫环己基，氮杂环庚烯基，吗啉基，哌嗪基，吡啶基，呋喃基，噻吩基，吡咯基，吡喃基，N-烷基吡咯基，嘧啶基，吡嗪基，哒嗪基，咪唑基，哌啶基，硫代吗啉基，二氢吡喃，噻二唑基，噁唑基，噁二唑基，吡唑基，1,4-二氧杂环己二烯基等。The term "heterocyclic group" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring containing at least 1 to 5 heteroatoms selected from N, O or S, non-aromatic ring, aromatic ring, non-aromatic ring may be The 3 to 10 membered monocyclic ring, the 4 to 20 membered spiro ring, the bicyclic or bridged ring, and the N, S optionally substituted in the heterocyclic ring can be oxidized to various oxidation states. A 3 to 12-membered heterocyclic ring is preferred. Non-limiting examples include oxepanyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, aziridine, azetidine Group, azacyclopentyl, azacyclohexyl, azacyclopropenyl, 1,3-dioxacyclopentyl, 1,4-dioxacyclopentyl, 1,3-dioxacyclopentyl, 1 ,3-Dioxocyclohexyl, 1,3-dithiocyclohexyl, azepanyl, morpholinyl, piperazinyl, pyridyl, furyl, thienyl, pyrrolyl, pyranyl, N- Alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, thiomorpholinyl, dihydropyran, thiadiazolyl, oxazolyl, oxadiazolyl, pyrazole Group, 1,4-dioxacyclohexenyl and the like.
术语“杂环烷基”在本文中是指至少含有一个选自O，N和S等杂原子且任选含有一条或多条双键或三键的非芳族环烷基。杂环烷基作为整体可以具有3至10个环原子。杂环烷基可以在产生稳定结构的任意杂原子或碳原子上与所定义的化学结构共价连接。杂环烷基的非限制性实例包括：吡咯啉基，哌啶基，哌嗪基，四氢呋喃基，四氢吡喃基，吗啉基，吡喃基等。杂环烷基上的一个或多个N或S原子可以被氧化(例如吗啉N-氧化物，硫吗啉S-氧化物，硫吗啉S，S-二氧化物)。杂环烷基还可以含有一个或多个氧代基团，如邻苯二酰亚氨基，哌啶酮基，恶唑烷酮基，2,4(1H,3H)-二氧代-嘧啶基，吡啶-2(1H)-酮基等。本文所述杂环烷基可以任选地被一个或多个下列取代基所取代：氟，氯，溴，碘，氰基，硝基，羟基，羧基，氨基，烷基，烷氧基，氧代，酰基，酰氧基，酰胺基，酯基，胺基，环烷基，环烯基，杂环烷基，烯基，烯氧基，炔基，环烷氧基，芳基或杂芳基。The term "heterocycloalkyl" refers herein to a non-aromatic cycloalkyl group containing at least one heteroatom selected from O, N, and S, and optionally containing one or more double or triple bonds. The heterocycloalkyl group as a whole may have 3 to 10 ring atoms. The heterocycloalkyl group can be covalently linked to the defined chemical structure on any heteroatom or carbon atom that results in a stable structure. Non-limiting examples of heterocycloalkyl include: pyrrolinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyranyl, and the like. One or more N or S atoms on the heterocycloalkyl group can be oxidized (eg morpholine N-oxide, thiomorpholine S-oxide, thiomorpholine S, S-dioxide). Heterocycloalkyl can also contain one or more oxo groups, such as phthalimido, piperidone, oxazolidinyl, 2,4(1H,3H)-dioxo-pyrimidinyl , Pyridine-2(1H)-keto, etc. The heterocycloalkyl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, oxygen Substituted, acyl, acyloxy, amido, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, aryl or heteroaryl base.
术语“烯基”在本文中是指具有2至8个碳原子并且具有至少一个烯基不饱和位点的烯基基团。烯基的非限制性实例包括乙烯基，丙烯基，烯丙基，异丙烯基，丁烯基，异丁烯基等。本文所述烯基可以任选地被一个或多个下列取代基所取代：氟，氯，溴，碘，氰基，硝基，羟基，羧基，氨基，烷基，烷氧基，氧代，酰基，酰氧基，酰胺基，酯基，胺基，环烷基，环烯基，杂环烷基，烯基，烯氧基，炔基，炔氧基，环烷氧基，芳基或杂芳基。The term "alkenyl" refers herein to an alkenyl group having 2 to 8 carbon atoms and having at least one site of alkenyl unsaturation. Non-limiting examples of alkenyl groups include vinyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl and the like. The alkenyl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, oxo, Acyl, acyloxy, amido, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, cycloalkoxy, aryl or Heteroaryl.
术语“烷基”在本文中是指具有1至10个碳原子的饱和脂肪族烃基基团，该术语包括直链和支链烃基。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，仲丁基，叔丁基，正戊基，新戊基，正己基等。本文所述烷基可以任选地被一个或多个下列取代基所取代：氟，氯，溴，碘，氰基，硝基，羟基，羧基，氨基，烷基，烷氧基，酰基，酰氧基，氧代，酰胺基，酯基，胺基，环烷基，环烯基，杂环烷基，烯基，烯氧基，炔基，环烷氧基，杂环烷基氧基，芳氧基，杂芳氧基，芳基或杂芳基。上述烷基也包括一个或者多个氘原子取代的烷基。The term "alkyl" refers herein to a saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, and the term includes straight-chain and branched-chain hydrocarbon groups. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, and the like. The alkyl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, acyl, acyl Oxygen, oxo, amido, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, heterocycloalkyloxy, Aryloxy, heteroaryloxy, aryl or heteroaryl. The above-mentioned alkyl group also includes an alkyl group substituted with one or more deuterium atoms.
术语“杂烷基”在本文中是指包括至少一个杂原子的烷基。The term "heteroalkyl" refers herein to an alkyl group that includes at least one heteroatom.
术语“烷氧基”在本文中是指烷基基团通过氧原子与分子其余部分相连(-O-烷基)，其中所述烷基如本文中所定义。烷氧基的非限制性实例包括甲氧基，乙氧基，三氟甲氧基，二氟甲氧基，正丙氧基，异丙氧基，正丁氧基，叔丁氧基，正戊氧基等。The term "alkoxy" refers herein to an alkyl group attached to the rest of the molecule through an oxygen atom (-O-alkyl), where the alkyl group is as defined herein. Non-limiting examples of alkoxy groups include methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, n- Pentoxy etc.
术语“酰胺基”在本文中是指-NR 8-C(O)-烷基，-NR 8-C(O)-环烷基，-NR 8-C(O)-环烯基，-NR 8-C(O)-芳基，-NR 8-C(O)-杂芳基和-NR 8-C(O)-杂环烷基，其中R 8为氢，环烷基，环烯基，芳基，杂芳基，杂环烷基和烷基。其中所述氢，环烷基，环烯基，芳基，杂芳基，杂环烷基和烷基等基团如本文中所定义。 The term "amido" refers herein to -NR 8 -C(O)-alkyl, -NR 8 -C(O)-cycloalkyl, -NR 8 -C(O)-cycloalkenyl, -NR 8 -C(O)-aryl, -NR 8 -C(O)-heteroaryl and -NR 8 -C(O)-heterocycloalkyl, where R 8 is hydrogen, cycloalkyl, cycloalkenyl , Aryl, heteroaryl, heterocycloalkyl and alkyl. Wherein said hydrogen, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl and alkyl groups are as defined herein.
术语“酰基”在本文中是指H-C(O)-，R 9R 10N-C(O)-，烷基-C(O)-，环烷基-C(O)-，环烯基-C(O)-，杂环烷基-C(O)-，芳基-C(O)-和杂芳基-C(O)-，其中所述R 9和R 10分别独立地选自氢，羟基，烷基，杂环烷基，芳基，杂芳基，磺酰基，亚磺酰基，环烯基，酰基或环烷基。其中所述氢，羟基，烷基，杂环烷基，芳基， 杂芳基，磺酰基，亚磺酰基，环烯基，酰基和环烷基等基团如本文中所定义。 The term "acyl" refers herein to HC(O)-, R 9 R 10 NC(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, cycloalkenyl-C( O)-, heterocycloalkyl-C(O)-, aryl-C(O)- and heteroaryl-C(O)-, wherein R 9 and R 10 are independently selected from hydrogen, hydroxyl , Alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl or cycloalkyl. Wherein said hydrogen, hydroxyl, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl and cycloalkyl groups are as defined herein.
术语“磺酰基”在本文中是指R 11R 12N-S(O) 2-，环烷基-S(O) 2-，环烯基-S(O) 2-，芳基-S(O) 2-，杂芳基-S(O) 2-，杂环烷基-S(O) 2-和烷基-S(O) 2-，其中所述R 11和R 12分别独立地选自氢，羟基，烷基，杂环烷基，芳基，杂芳基，磺酰基，亚磺酰基，环烯基，酰基或环烷基。其中所述氢，羟基，烷基，杂环烷基，芳基，杂芳基，磺酰基，亚磺酰基，环烯基，酰基和环烷基等基团如本文中所定义。 The term "sulfonyl" refers herein to R 11 R 12 NS(O) 2 -, cycloalkyl-S(O) 2 -, cycloalkenyl-S(O) 2 -, aryl-S(O) 2 -, heteroaryl-S(O) 2 -, heterocycloalkyl-S(O) 2 -and alkyl-S(O) 2 -, wherein R 11 and R 12 are each independently selected from hydrogen , Hydroxy, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl or cycloalkyl. Wherein said hydrogen, hydroxyl, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl and cycloalkyl groups are as defined herein.
术语“亚磺酰基”在本文中是指R 13R 14N-S(O)-，环烷基-S(O)-，环烯基-S(O)-，芳基-S(O)-，杂芳基-S(O)-，杂环烷基-S(O)-或烷基-S(O)-，其中所述R 13和R 14分别独立地选自氢，羟基，烷基，杂环烷基，芳基，杂芳基，磺酰基，亚磺酰基，环烯基，酰基或环烷基。其中所述氢，羟基，烷基，杂环烷基，芳基，杂芳基，磺酰基，亚磺酰基，环烯基，酰基和环烷基等基团如本文中所定义。 The term "sulfinyl" refers herein to R 13 R 14 NS(O)-, cycloalkyl-S(O)-, cycloalkenyl-S(O)-, aryl-S(O)-, Heteroaryl-S(O)-, heterocycloalkyl-S(O)- or alkyl-S(O)-, wherein R 13 and R 14 are independently selected from hydrogen, hydroxyl, alkyl, Heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl or cycloalkyl. Wherein said hydrogen, hydroxyl, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl and cycloalkyl groups are as defined herein.
术语“酰氧基”在本文中是指-O-C(O)-烷基，-O-C(O)-环烷基，-O-C(O)-环烯基，-O-C(O)-芳基，-O-C(O)-杂芳基和-O-C(O)-杂环烷基，其中所述烷基，环烷基，环烯基，芳基，杂芳基和杂环烷基等基团如本文中所定义。The term "acyloxy" refers herein to -OC(O)-alkyl, -OC(O)-cycloalkyl, -OC(O)-cycloalkenyl, -OC(O)-aryl,- OC(O)-heteroaryl and -OC(O)-heterocycloalkyl, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycloalkyl groups are as described herein Defined in.
术语“酯基”在本文中是指烷基-O-C(O)-，环烷基-O-C(O)-，环烯基-O-C(O)-，杂环烷基-O-C(O)-，芳基-O-C(O)-和杂芳基-O-C(O)-，其中所述烷基，环烷基，环烯基，杂环烷基，芳基和杂芳基等基团如本文中所定义。The term "ester group" refers herein to alkyl-OC(O)-, cycloalkyl-OC(O)-, cycloalkenyl-OC(O)-, heterocycloalkyl-OC(O)-, Aryl-OC(O)- and heteroaryl-OC(O)-, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl groups are as described herein As defined.
术语“任选”或“任选地”是指随后描述的事件或情形可以但不一定出现，并且该描述包括其中所述事件或情形出现的情况以及其中它不出现的情况。The term "optional" or "optionally" means that the subsequently described event or circumstance can, but does not necessarily, occur, and the description includes the situation in which the described event or circumstance occurs and the situation in which it does not occur.
术语“任选被……所取代”是指所述结构是未取代的或者被一个或多个本发明所述的取代基取代。术语“取代”在本文中是指任何基团由指定取代基单取代或多取代至这种单取代或多取代(包括在相同部分的多重取代)在化学上允许的程度，每个取代基可以位于该基团上任何可利用的位置，且可以通过所述取代基上任何可利用的原子连接。“任何可利用的位置”是指通过本领域已知的方法或本文教导的方法可化学得到，并且不产生过度不稳定的分子的所述基团上的任何位置。当在任何基团上有两个或多个取代基时，每个取代基独立于任何其它取代基而定义，因此可以是相同或不同的。The term "optionally substituted" means that the structure is unsubstituted or substituted with one or more substituents described herein. The term "substituted" refers herein to any group that is mono- or poly-substituted by the specified substituent to the extent that such mono- or poly-substitution (including multiple substitutions in the same part) is chemically allowed, each substituent may It is located at any available position on the group and can be connected by any available atom on the substituent. "Any available position" refers to any position on the group of a molecule that is chemically available by methods known in the art or methods taught herein, and does not produce an excessively unstable molecule. When there are two or more substituents on any group, each substituent is defined independently of any other substituent, and therefore may be the same or different.
在本说明书的各个位置，本发明化合物的取代基以基团或范围的形式进行公开。这具体意味着本发明包括这样的基团和范围的每个成员或成员中的每个个体的亚组合。如术语“C 1-6烷基”具体意味着单独公开了甲基，乙基，C 3烷基，C 4烷基，C 5烷基和C 6烷基。 At various positions in this specification, the substituents of the compounds of the present invention are disclosed in the form of groups or ranges. This specifically means that the present invention includes each member of such groups and ranges or a sub-combination of each individual in the member. For example, the term “C 1-6 alkyl” specifically means that methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl are individually disclosed.
术语“本发明化合物”(除非另有具体指明)在本文中是指式(I)和式(II)化合物及其所有纯的和混合的立体异构体，几何异构体，互变异构体，溶剂合物，前药及同位素标记的化合物和任何药学上可接受的盐。本发明化合物的溶剂合物是指与化学计量和非化学计量的溶剂结合的化合物或其盐，如水合物，乙醇合物，甲醇合物，丙酮合物等。化合物也可以一种或多种结晶状态存在，即作为共晶体，多晶型物，或 其可以无定形固体存在。所有此种形式均被权利要求所涵盖。The term "compounds of the invention" (unless otherwise specified) refers herein to compounds of formula (I) and formula (II) and all pure and mixed stereoisomers, geometric isomers, tautomers Body, solvates, prodrugs and isotopically labeled compounds and any pharmaceutically acceptable salts. The solvate of the compound of the present invention refers to a compound or salt thereof combined with stoichiometric and non-stoichiometric solvents, such as hydrate, ethanolate, methanolate, acetoneate, and the like. The compound may also exist in one or more crystalline states, i.e. as a eutectic, polymorph, or it may exist as an amorphous solid. All such forms are covered by the claims.
术语“药学上可接受”表示物质或组合物在化学上和/或毒理学上必须与构成制剂的其它成分和/或用其治疗的哺乳动物相容。The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients constituting the formulation and/or the mammal being treated with it.
术语“立体异构体”在本文中是指具有一个或多个立体中心的手性不同的化合物，包括对应异构体和非对映异构体。The term "stereoisomer" refers herein to compounds having one or more stereocenters with different chiralities, including the corresponding isomers and diastereomers.
术语“互变异构体”在本文中是指具有不同能量的结构同分异构提可以越过低能垒，从而互相转化。诸如质子互变异构体包括通过质子迁移进行互变，如烯醇-酮互变异构体和亚胺-烯胺互变异构体，或者含有连接到环-NH-部分和环＝N-部分的环原子的杂芳基基团的互变异构形式，如吡唑，咪唑，苯并咪唑，***和四唑。化合价互变异构体包括一些成键电子重组而进行互变。The term "tautomer" means herein that structural isomers with different energies can cross the low energy barrier and thus convert to each other. Such as proton tautomers include interconversion through proton migration, such as enol-ketone tautomers and imine-enamine tautomers, or contain a ring-NH- moiety and ring=N -Tautomeric forms of heteroaryl groups of partial ring atoms, such as pyrazole, imidazole, benzimidazole, triazole and tetrazole. Valence tautomers include some bond-forming electronic recombination for interconversion.
术语“前药”在本文中是指在对受试者给药时，能够直接或间接地提供本发明的化合物，其活性代谢物或残基的本发明化合物的任何衍生物。尤其优选的是那些能增加本发明化合物生物利用度，提高代谢稳定性及组织靶向性的衍生物或前药。The term "prodrug" herein refers to any derivative of the compound of the present invention capable of directly or indirectly providing the compound of the present invention, its active metabolite or residue when administered to a subject. Particularly preferred are those derivatives or prodrugs that increase the bioavailability of the compounds of the invention, improve metabolic stability and tissue targeting.
本发明化合物可以以盐的形式被使用，如从无机酸或有机酸衍生得到的“医药上可接受的盐”。这些包括但并不限于下列所述：乙酸盐，己二酸盐，藻酸盐，柠檬酸盐，天冬氨酸盐，苯甲酸盐，苯磺酸盐，乙磺酸盐，硫酸氢盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，二葡萄糖酸盐，环戊烷丙酸盐，十二烷基硫酸盐，乙磺酸盐，葡糖庚酸盐，甘油磷酸盐，半硫酸盐，庚酸盐，己酸盐，延胡索酸盐，氢氯化物，氢溴酸盐，氢碘酸盐，2-羟基乙磺酸盐，乳酸盐，马来酸盐，甲磺酸盐，乙磺酸盐，盐酸盐，2-萘磺酸盐，草酸盐，果胶酯酸盐，硫酸盐，3-苯基丙酸盐，苦味酸盐，三甲基乙酸盐，丙酸盐，琥珀酸盐，酒石酸盐，硫氰酸盐，对甲苯磺酸盐和癸酸盐。另外，碱性含氮基团可以与以下试剂发生季铵化反应生成季铵盐：如低碳烷基卤化物，包括甲基，乙基，丙基和丁基的氯化物，溴化物和碘化物；如二烷基硫酸盐，包括二甲基，二乙基，二丁基和二戊基的硫酸盐；如长链卤化物，包括癸基，月桂基，肉豆蔻基和硬脂基的氯化物，溴化物和碘化物；如芳烷基卤化物，如苯甲基和苯乙基的溴化物等。The compounds of the present invention can be used in the form of salts, such as "pharmaceutically acceptable salts" derived from inorganic or organic acids. These include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, ethanesulfonate, hydrogen sulfate Salt, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentane propionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerol phosphate, semi Sulfate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, mesylate, Ethylsulfonate, hydrochloride, 2-naphthalenesulfonate, oxalate, pectinate, sulfate, 3-phenylpropionate, picrate, trimethylacetate, propionic acid Salt, succinate, tartrate, thiocyanate, p-toluenesulfonate and caprate. In addition, the basic nitrogen-containing groups can be quaternized with the following reagents to form quaternary ammonium salts: such as lower alkyl halides, including methyl, ethyl, propyl and butyl chloride, bromide and iodine Compounds; such as dialkyl sulfates, including dimethyl, diethyl, dibutyl, and dipentyl sulfates; such as long-chain halides, including decyl, lauryl, myristyl, and stearyl Chloride, bromide and iodide; such as aralkyl halides, such as benzyl and phenethyl bromide.
本发明还包括同位素标记的本发明化合物，即与上述所公开的结构相同，但该结构中一个或多个原子被与其具有相同质子数但不同中子数的原子所替代。结合本发明化合物的同位素实施例包括氢，碳，氮，氧，硫，氟，氯，碘的同位素，分别如 2H， 3H， 13C， 14C， 15N， 18O， 17O， 35S， 18F， 36Cl和 131I等。本发明的化合物，其立体异构体，互变异构体或医药上可接受的盐，以及含有上述同位素和/或其他原子同位素的所述以上形式的化合物，均在本发明范围内。某些同位素标记的本发明化合物，如被 3H或 14C所标记的那些化合物可以用于药物组织分布试验中，因此，这些 3H或 14C同位素由于其容易制备和检测是特别优选的。此外，被较重的同位素如 2H所替代的某些本发明化合物由于具有更好的代谢稳定性而具有某些治疗优势，如可以增加体内半衰期和较少剂量等，因此， 2H在某些情况下也是优选的。 The present invention also includes isotopically-labeled compounds of the present invention, that is, the same structure as disclosed above, but one or more atoms in the structure are replaced by atoms having the same number of protons but different numbers of neutrons. Examples of isotopes incorporating the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl and 131 I etc. The compounds of the present invention, their stereoisomers, tautomers or pharmaceutically acceptable salts, and the above-mentioned compounds containing the above-mentioned isotopes and/or other atomic isotopes are all within the scope of the present invention. Certain isotopically-labeled compounds of the present invention, such as those labeled with 3 H or 14 C, can be used in pharmaceutical tissue distribution tests. Therefore, these 3 H or 14 C isotopes are particularly preferred because of their ease of preparation and detection. Further, substitution with heavier isotopes such as 2 H Certain compounds of the present invention as an alternative due to better metabolic stability have certain therapeutic advantages such as increased in vivo half-life may be fewer doses and the like, and therefore, in a 2 H It is also preferable in some cases.
具体实施方式：detailed description:
下面用实施例来进一步说明本发明，但本发明并不受其限制。贯穿本申请，本文提及本发明的化合物和方法的多个实施例。所述的多个实施例旨在提供多个说明性实例，不应将其解释为替代物的描述。同时应注意，本文中所论述的实施例(包括各种方法和参数)仅为了说明本发明，并不以任何方式限制本发明的保护范围。为描述本发明，以下列出了具体实施例。但需要理解，本发明不限于这些实施例，以下实施例只是提供实践本发明的方法，并不以任何方式限制本发明的范畴。The following examples further illustrate the present invention, but the present invention is not limited thereto. Throughout this application, various examples of compounds and methods of the invention are mentioned herein. The multiple embodiments described are intended to provide multiple illustrative examples and should not be interpreted as alternative descriptions. At the same time, it should be noted that the embodiments (including various methods and parameters) discussed herein are only for illustrating the present invention, and do not limit the protection scope of the present invention in any way. To describe the present invention, specific examples are listed below. However, it should be understood that the present invention is not limited to these embodiments. The following embodiments merely provide a method for practicing the present invention, and do not limit the scope of the present invention in any way.
本发明式(I)化合物可以按照以下流程1加以制备。在合适的溶剂如THF，DMF，乙腈，二氧六环，NMP，DMSO和DMA等中，化合物SM在酸如三氟乙酸，磷酸，甲磺酸等，和碱如二异丙基胺，二乙胺，二甲胺，哌啶，四氢吡咯等的作用下，与多聚甲醛在合适的温度下反应，生成中间体M1。M1和M2在合适的溶剂中，如THF，乙腈，乙醇，甲醇，二氧六环，DMF等中，在碱，如K 2CO 3，Na 2CO 3，NaH，CsCO 3，DBU，叔丁醇钾，三乙胺等作用下，生成式(I)化合物。其中，R 1和环A的定义如本发明所述的定义。 The compound of formula (I) of the present invention can be prepared according to the following scheme 1. In a suitable solvent such as THF, DMF, acetonitrile, dioxane, NMP, DMSO and DMA, etc., the compound SM is in an acid such as trifluoroacetic acid, phosphoric acid, methanesulfonic acid, etc., and a base such as diisopropylamine, di Under the action of ethylamine, dimethylamine, piperidine, tetrahydropyrrole, etc., it reacts with paraformaldehyde at a suitable temperature to generate intermediate M1. M1 and M2 in a suitable solvent, such as THF, acetonitrile, ethanol, methanol, dioxane, DMF, etc., in a base, such as K 2 CO 3 , Na 2 CO 3 , NaH, CsCO 3 , DBU, tert-butyl Under the action of potassium alkoxide and triethylamine, the compound of formula (I) is formed. The definitions of R 1 and ring A are as defined in the present invention.
流程1Process 1
Figure PCTCN2019128092-appb-000010
Figure PCTCN2019128092-appb-000010
本发明提供的化合物可以通过本领域公知的标准合成方法来制备，本说明书提供了制备本发明化合物的一般方法。起始原料通常可通过商业化获得，例如通过Alfa
Figure PCTCN2019128092-appb-000011
等公司购买得到，或者通过本领域技术人员所熟知的方法进行制备。 The compounds provided by the present invention can be prepared by standard synthetic methods well known in the art. This specification provides general methods for preparing the compounds of the present invention. The starting materials are usually commercially available, for example by Alfa
Figure PCTCN2019128092-appb-000011
It can be purchased from other companies or prepared by methods well known to those skilled in the art.
下文通过实施例与制备进一步解释并列举本发明化合物及相应的制备方法。应了解，尽管具体实施例中给出了典型或优选的反应条件(如反应温度，时间，反应物的摩尔比，反应溶剂以及压力等)，但是本领域技术人员也可以使用其它反应条件。最佳反应条件可随所用的特定反应底物或溶剂而发生改变，但所述条件可由所属领域的技术人员通过常规优化而确定。The following examples and preparations are used to further explain and list the compounds of the present invention and corresponding preparation methods. It should be understood that although typical or preferred reaction conditions (such as reaction temperature, time, molar ratio of reactants, reaction solvent and pressure, etc.) are given in the specific examples, those skilled in the art may also use other reaction conditions. The optimal reaction conditions may vary with the specific reaction substrate or solvent used, but the conditions can be determined by those skilled in the art through routine optimization.
下述实施例化合物的结构通过核磁共振(NMR)和/或质谱(MS)来表征。使用NMR波谱仪，将化合物溶于适当的氘代试剂中，环境温度下以TMS为内标进行 1H-NMR分析。NMR化学位移(δ)以ppm为单位，并使用以下简称：s，单峰；d，双重峰；t，三重峰；q，四重峰；m，多重峰；brs，宽单峰。MS通过质谱仪(ESI)测定。 The structures of the compounds of the following examples are characterized by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). Using an NMR spectrometer, the compound was dissolved in an appropriate deuterated reagent, and 1 H-NMR analysis was performed using TMS as an internal standard at ambient temperature. The NMR chemical shift (δ) is in ppm and uses the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; brs, broad singlet. MS was determined by mass spectrometry (ESI).
反应起始原料，中间体以及实施例化合物可以通过沉淀，过滤，结晶，蒸发，蒸馏以及色谱法(如柱层析法，TLC分离纯化等)等常规技术进行分离与纯化。The reaction starting materials, intermediates and example compounds can be separated and purified by conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography (such as column chromatography, TLC separation and purification, etc.).
参考其它实施例或合成方法时，反应条件(反应温度，反应溶剂，反应物摩尔比或/和反应持续时间) 可能不同。一般而言，可通过TLC监测反应进程，据此选择合适的时间终止反应并进行后处理。化合物的纯化条件也可能发生变化，一般而言，依据TLC的R f值选择合适柱层析洗脱剂，或通过制备TLC分离纯化相应化合物。 When referring to other embodiments or synthesis methods, the reaction conditions (reaction temperature, reaction solvent, molar ratio of reactants or/and reaction duration) may be different. In general, the progress of the reaction can be monitored by TLC, and an appropriate time can be selected to terminate the reaction and perform post-treatment accordingly. The purification conditions of the compound may also change. Generally speaking, the appropriate column chromatography eluent is selected according to the R f value of TLC, or the corresponding compound is separated and purified by preparing TLC.
实施例1：制备化合物1Example 1: Preparation of compound 1
Figure PCTCN2019128092-appb-000012
Figure PCTCN2019128092-appb-000012
步骤1：制备SA-BStep 1: Preparation of SA-B
向反应瓶中依次加入SA-A(200.0克，736mmol)，钯碳(20.0克)，四氢呋喃(1000ml)，浓氢溴酸(0.4ml)，氢气置换后，于1-3atm氢气压25℃搅拌过夜。向体系中加入适量NaHCO 3，搅拌5min，将反应液垫硅藻土过滤，滤饼用适量DCM洗涤，滤液浓缩得到约200g类白色粗品。将粗品于乙醇和水(1600ml/1600ml)的混合溶剂中结晶得白色粉末固体166g，收率83％。 To the reaction flask, add SA-A (200.0 g, 736 mmol), palladium on carbon (20.0 g), tetrahydrofuran (1000 ml), concentrated hydrobromic acid (0.4 ml) in sequence, and after hydrogen replacement, stir at 1-3 atm hydrogen pressure at 25°C overnight. Add an appropriate amount of NaHCO 3 to the system, stir for 5 min, filter the reaction liquid pad of celite, wash the filter cake with an appropriate amount of DCM, and concentrate the filtrate to obtain about 200 g of off-white crude product. The crude product was crystallized in a mixed solvent of ethanol and water (1600ml/1600ml) to obtain 166g of white powder solid with a yield of 83%.
步骤2：制备SA-CStep 2: Preparation of SA-C
于50L反应釜中依次加入甲铝双(2,6-二叔丁基-4-苯甲醚)(666.0克，3022mmol)，甲苯(3000ml)，降温至0℃，加入2.0M三甲基铝/甲苯溶液(760ml，1520mmol)，加毕后20℃搅拌1小时，然后降温至-80℃。缓慢加入SA-B(166.0g，606mmol)的2000ml甲苯溶液，加完后继续搅拌1小时。将1.0M MeMgBr/THF(1220ml，1220mmol)于-80℃缓慢加至反应瓶中，-80℃下搅拌4小时。加入饱和氯化铵水溶液1000ml淬灭反应(加入时无块状，小颗粒)，升温到0℃以上，加入6L水搅拌分液，有机层用饱和食盐水洗，无水硫酸钠干燥，减压浓缩。柱层析纯化(石油醚：乙酸乙酯：二氯甲烷＝5:1:1)得白色固体SA-C 155克，收率88％。In a 50L reactor, add methylaluminum bis(2,6-di-tert-butyl-4-anisole) (666.0g, 3022mmol), toluene (3000ml), cool to 0℃, add 2.0M trimethylaluminum /Toluene solution (760ml, 1520mmol), stirred at 20℃ for 1 hour after addition, and then cooled to -80℃. A solution of SA-B (166.0 g, 606 mmol) in 2000 ml of toluene was slowly added, and stirring was continued for 1 hour after the addition was completed. 1.0M MeMgBr/THF (1220ml, 1220mmol) was slowly added to the reaction flask at -80°C and stirred at -80°C for 4 hours. 1000ml of saturated ammonium chloride aqueous solution was added to quench the reaction (no lumps, small particles when added), the temperature was raised to above 0°C, 6L of water was added to stir and separate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure . Column chromatography purification (petroleum ether: ethyl acetate: dichloromethane = 5:1:1) to obtain 155 g of white solid SA-C, yield 88%.
步骤3：制备SA-DStep 3: Preparation of SA-D
于5L反应瓶中依次加入PPh 3EtBr(500.0克，1346.8mmol)，叔丁醇钾(150.0克，1336.8mmol)，1500ml甲苯，60℃下搅拌2小时，然后加入SA-C(155.0克，534.5mmol)的400ml甲苯溶液，90℃反应2小时。将反应液冷却至室温，加入饱和氯化铵溶液500ml淬灭反应，补加1L水分液。有机层用饱和食盐水洗涤， 无水硫酸钠干燥，真空浓缩，所得油状物用柱层析纯化(石油醚：乙酸乙酯＝5:1)，得白色粉末状固体SA-D151.5克，收率94％。 In a 5L reaction flask, add PPh 3 EtBr (500.0 g, 1346.8 mmol), potassium tert-butoxide (150.0 g, 1336.8 mmol), 1500 ml of toluene, stir at 60°C for 2 hours, then add SA-C (155.0 g, 534.5 400ml of toluene solution at 90°C for 2 hours. The reaction solution was cooled to room temperature, 500 ml of saturated ammonium chloride solution was added to quench the reaction, and 1 L of water solution was added. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting oil was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 151.5 g of white powdery solid SA-D, The yield is 94%.
步骤4：制备SA-EStep 4: Preparation of SA-E
向5L反应瓶中依次加入SA-D(151.5克，501.7mmol)，1515ml四氢呋喃，搅拌下充分溶解，氮气置换。0℃下缓慢加入1.0M BH 3/THF(1515ml，1515mmol)，加毕后20℃搅拌3小时。将反应液降温至0℃，缓慢加入3M的氢氧化钠溶液517ml，有大量气泡产生，无气泡后继续加入210ml 30％H 2O 2水溶液，加毕后20℃下搅拌2小时。向体系中加入200g的硫代硫酸钠溶液2000ml，减压浓缩除去四氢呋喃，加入乙酸乙酯2000ml搅拌10min分液，有机相用1M氢氧化钠溶液搅拌洗涤3次(每次1000ml)，饱和食盐水1000ml洗涤，将有机相干燥浓缩得到白色粉末状固体SA-E粗品165.0克，直接作为下一步原料使用。 Into a 5L reaction flask, sequentially add SA-D (151.5 g, 501.7 mmol) and 1515 ml of tetrahydrofuran, and dissolve it with stirring, and replace with nitrogen. 1.0M BH 3 /THF (1515ml, 1515mmol) was slowly added at 0°C, and stirred at 20°C for 3 hours after the addition was completed. The reaction solution was cooled to 0°C, and 517 ml of 3M sodium hydroxide solution was slowly added. A large amount of bubbles were generated. After no bubbles, 210 ml of 30% H 2 O 2 aqueous solution was added, and the mixture was stirred at 20° C. for 2 hours. Add 200g of sodium thiosulfate solution 2000ml to the system, concentrate under reduced pressure to remove tetrahydrofuran, add ethyl acetate 2000ml and stir for 10min to separate the liquid, the organic phase was washed with 1M sodium hydroxide solution with stirring 3 times (1000ml each time), saturated brine After washing with 1000 ml, the organic phase was dried and concentrated to obtain 165.0 g of white powdery solid SA-E crude product, which was directly used as the next raw material.
步骤5：制备SA-FStep 5: Preparation of SA-F
于1000ml反应瓶中依次加入SA-E粗品(165.0克)，2000ml二氯甲烷，室温搅拌溶解，加入250.0克硅胶。冰浴降温至0℃，分批加入氯铬酸吡啶盐(165.0克，765.7mmol)，加毕后20℃搅拌2小时。反应液浓缩至干，柱层析(石油醚：乙酸乙酯＝1:1)，洗脱液依次用饱和硫代硫酸钠，饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，得类白色粉末状固体SA-F粗品160.0克。将粗品(160.0克)于2000ml正己烷中加热至70℃回流打浆3小时，冷却至25℃，过滤，干燥得白色粉末状固体SA-F(112.0克，步骤4和步骤5两步收率70％)。In a 1000ml reaction flask, sequentially add crude SA-E (165.0g), 2000ml of dichloromethane, stir and dissolve at room temperature, and add 250.0g of silica gel. The temperature was lowered to 0°C in an ice bath, pyridinium chlorochromate (165.0 g, 765.7 mmol) was added in portions, and stirred at 20°C for 2 hours after the addition was completed. The reaction solution was concentrated to dryness, column chromatography (petroleum ether: ethyl acetate = 1:1), the eluent was washed with saturated sodium thiosulfate, saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give off-white 160.0 grams of powdered solid SA-F crude. The crude product (160.0g) was heated to 70°C in 2000ml of n-hexane and beaten by refluxing for 3 hours, cooled to 25°C, filtered and dried to obtain white powdery solid SA-F (112.0g, step 4 and step 5 two steps yield 70 %).
步骤6：制备SA-GStep 6: Preparation of SA-G
于2000ml反应瓶中依次加入SA-F(112.0克，352.2mmol)，三氟乙酸的二异丙胺盐(1：1；80.0克，372.1mmol)，三氟乙酸(10.0克，87.72mmol)，多聚甲醛(32克，1066.7mmol)，DMA1120ml，90℃下搅拌15h。将反应液溶于MTBE 1.5L和乙酸乙酯1.5L，搅拌中加入5L水，搅拌10min分液，水相用MTBE和EA各1.5L萃取分液。合并有机相，用5L水洗2次，柱层析(MTBE:EA＝1:1)，洗脱液加入10克活性炭搅拌1h过滤。滤液浓缩得到白色固体SA-G粗品110.0克。将粗品(110.0克)于550ml乙腈和550ml水中析晶，得到白色固体SA-G(79.3克，收率68％)。In a 2000ml reaction flask, add SA-F (112.0 g, 352.2 mmol), diisopropylamine salt of trifluoroacetic acid (1:1; 80.0 g, 372.1 mmol), trifluoroacetic acid (10.0 g, 87.72 mmol), and more Polyoxymethylene (32g, 1066.7mmol), DMA1120ml, stirred at 90°C for 15h. The reaction solution was dissolved in MTBE 1.5L and ethyl acetate 1.5L, 5L water was added to the stirring, and stirred for 10 minutes to separate the liquid, and the aqueous phase was extracted and separated with 1.5L each of MTBE and EA. The organic phases were combined, washed twice with 5 L of water, column chromatography (MTBE:EA=1:1), the eluent was added with 10 g of activated carbon and stirred for 1 h and filtered. The filtrate was concentrated to give 110.0 g of crude SA-G as a white solid. The crude product (110.0 g) was crystallized in 550 ml of acetonitrile and 550 ml of water to obtain white solid SA-G (79.3 g, yield 68%).
步骤7：制备化合物1Step 7: Preparation of compound 1
于2000ml的反应瓶中依次加入SA-G(79.3克，240.3mmol)，碳酸钾(49.8克，360.9mmol)，4-甲腈吡唑(31.5克，338.7mmol)，乙腈760ml，50℃搅拌反应2h。加入1200ml水，冷却至室温搅拌1h，过滤，滤饼依次用200ml乙腈：水＝1:1，1000ml水洗涤。45℃鼓风干燥，得到化合物1(白色固体，90.5克，收率89％)。 1H NMR(CDCl 3,400MHz,ppm):δ＝7.92(s,1H),7.76(s,1H),4.52-4.45(m,1H),4.40-4.33(m,1H),3.10-3.03(m,1H),2.93-2.85(m,1H),2.50-2.46(t,J＝8.8Hz,1H),2.16-2.09(m,1H),1.85-1.79(m,4H),1.71-1.58(m，5H),1.48-0.95(m,17H),0.40(s,3H). 13C NMR(CDCl 3,100MHz,ppm):δ＝13.4,22.8,24.2,25.4,25.6,26.0,26.5,31.3,34.5,34.7,37.6,39.0,40.2,41.1,41.6,43.3,44.9,47.0,55.8,63.2,72.0,91.8,113.4,135.8,142.4,208.4.MS：m/z 424.5[M+H] +。 In a 2000ml reaction flask, add SA-G (79.3g, 240.3mmol), potassium carbonate (49.8g, 360.9mmol), 4-carbonitrile pyrazole (31.5g, 338.7mmol), acetonitrile 760ml, stir at 50℃ 2h. Add 1200ml of water, cool to room temperature and stir for 1h, filter. The filter cake is washed with 200ml of acetonitrile: water = 1:1 and 1000ml of water in turn. Dry at 45°C with air blow to obtain compound 1 (white solid, 90.5 g, yield 89%). 1 H NMR (CDCl 3 , 400 MHz, ppm): δ = 7.92 (s, 1H), 7.76 (s, 1H), 4.52-4.45 (m, 1H), 4.40-4.33 (m, 1H), 3.10-3.03 ( m,1H),2.93-2.85(m,1H),2.50-2.46(t,J=8.8Hz,1H),2.16-2.09(m,1H),1.85-1.79(m,4H),1.71-1.58( m, 5H), 1.48-0.95 (m, 17H), 0.40 (s, 3H). 13 C NMR (CDCl 3 , 100MHz, ppm): δ=13.4, 22.8, 24.2, 25.4, 25.6, 26.0, 26.5, 31.3 ,34.5,34.7,37.6,39.0,40.2,41.1,41.6,43.3,44.9,47.0,55.8,63.2,72.0,91.8,113.4,135.8,142.4,208.4.MS: m/z 424.5[M+H] + .
实施例2：制备化合物2Example 2: Preparation of compound 2
Figure PCTCN2019128092-appb-000013
Figure PCTCN2019128092-appb-000013
参考实施例1的制备方案，得到化合物2，MS:m/z 424.5[M+H] +。 Referring to the preparation scheme of Example 1, compound 2 was obtained, MS: m/z 424.5 [M+H] + .
Figure PCTCN2019128092-appb-000014
Figure PCTCN2019128092-appb-000014
于反应瓶中依次加入SA-G(2.0g，6.1mmol)，碳酸钾(1.25g，9.0mmol)，3-氰基吡唑(0.73g，7.8mmol)，乙腈(30ml)，加完后升温至50℃搅拌2小时至原料反应完全。向反应瓶中加入水，析出固体，过滤，烘干后再经乙酸乙酯重结晶得白色固体1.9g，收率74％。 1H NMR(400MHz,CDCl 3):δ7.56(d,J＝2.4Hz,1H),6.60(d,J＝2.4Hz,1H),4.55-4.48(m,1H),4.42-4.35(m,1H),3.14-3.06(m,1H),2.95-2.88(m,1H),2.50(t,J＝8.8Hz,1H),2.16-2.05(m,1H),1.90-1.79(m,4H),1.74-1.58(m,4H),1.48-1.34(m,6H),1.30-1.14(m,8H),1.08-0.97(m,3H),0.41(s,3H). 13C NMR(100MHz,CDCl 3):δ208.5,132.1,124.6,114.1,111.1,72.0,63.2,55.8,47.3,44.9,43.5,41.6,41.1,40.2,39.0,37.6,34.7,34.5,31.3,26.5,26.0,25.6,25.4,24.2,22.8,13.4。 Add SA-G (2.0g, 6.1mmol), potassium carbonate (1.25g, 9.0mmol), 3-cyanopyrazole (0.73g, 7.8mmol), and acetonitrile (30ml) to the reaction bottle in sequence, and warm up after the addition Stir at 50°C for 2 hours until the reaction of the raw materials is complete. Water was added to the reaction bottle to precipitate a solid, which was filtered, dried, and then recrystallized from ethyl acetate to obtain a white solid 1.9g, with a yield of 74%. 1 H NMR (400 MHz, CDCl 3 ): δ 7.56 (d, J=2.4 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 4.55-4.48 (m, 1H), 4.42-4.35 (m ,1H),3.14-3.06(m,1H),2.95-2.88(m,1H),2.50(t,J=8.8Hz,1H),2.16-2.05(m,1H),1.90-1.79(m,4H ), 1.74-1.58 (m, 4H), 1.48-1.34 (m, 6H), 1.30-1.14 (m, 8H), 1.08-0.97 (m, 3H), 0.41 (s, 3H). 13 C NMR (100MHz , CDCl 3 ): δ 208.5, 132.1, 124.6, 114.1, 111.1, 72.0, 63.2, 55.8, 47.3, 44.9, 43.5, 41.6, 41.1, 40.2, 39.0, 37.6, 34.7, 34.5, 31.3, 26.5, 26.0, 25.6, 25.4 , 24.2, 22.8, 13.4.
实施例3：制备化合物3Example 3: Preparation of compound 3
Figure PCTCN2019128092-appb-000015
Figure PCTCN2019128092-appb-000015
参照实施例1的制备方案，得到化合物3，ESI-MS：400.2[M+H] +。 Referring to the preparation scheme of Example 1, compound 3 is obtained, ESI-MS: 400.2 [M+H] + .
实施例4：制备化合物4Example 4: Preparation of compound 4
Figure PCTCN2019128092-appb-000016
Figure PCTCN2019128092-appb-000016
参照实施例1的制备方案，得到化合物4，MS:m/z 427.2[M+H] +。具体实施如下： Referring to the preparation scheme of Example 1, compound 4 was obtained, MS: m/z 427.2 [M+H] + . The specific implementation is as follows:
Figure PCTCN2019128092-appb-000017
Figure PCTCN2019128092-appb-000017
步骤1：制备SAD-CStep 1: Preparation of SAD-C
于2L反应瓶中依次加入甲苯(300ml)，甲铝双(2,6-二叔丁基-4-苯甲醚)(66克)，降温至0℃，加入2.0M三甲基铝/甲苯溶液(76ml)，加毕后20℃搅拌1小时，然后降温至-80℃。缓慢加入SA-B(16g)的200ml甲苯溶液，加完后继续搅拌1小时。将1.0M CD 3-MgBr/THF(120ml)于-80℃缓慢加至反应瓶中，-80℃下搅拌4小时。加入饱和氯化铵水溶液100ml淬灭反应，升温到0℃以上，缓慢加入600m水搅拌分液，有机层用饱和氯化钠水洗，无水硫酸钠干燥，减压浓缩。柱层析纯化得白色固体SAD-C共计15克。 Toluene (300ml) and methylaluminum bis(2,6-di-tert-butyl-4-anisole) (66g) were added to the 2L reaction flask in turn, the temperature was lowered to 0°C, and 2.0M trimethylaluminum/toluene was added The solution (76 ml) was stirred at 20°C for 1 hour after the addition, and then the temperature was lowered to -80°C. Slowly add SA-B (16g) in 200ml toluene solution, and continue stirring for 1 hour after the addition. The 1.0M CD 3 -MgBr / THF (120ml ) at -80 ℃ was slowly added to the reaction flask and stirred at -80 ℃. 4 hours. 100ml of saturated aqueous ammonium chloride solution was added to quench the reaction, and the temperature was raised to above 0°C. 600m of water was slowly added to stir and separate the liquid. The organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography purified 15 g of white solid SAD-C.
步骤2：制备SAD-DStep 2: Preparation of SAD-D
于500mL反应瓶中依次加入叔丁醇钾(15克)，PPh 3EtBr(50克)，150ml甲苯，60℃下搅拌2小时，然后加入SAD-C(15克)的400ml甲苯溶液，90℃反应2小时。将反应液冷却至室温，加入饱和氯化铵溶液50ml淬灭反应。有机层用饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，所得油状物，柱层析纯化，得白色粉末状固体SAD-D共计15克。 In a 500mL reaction flask, add potassium tert-butoxide (15g), PPh 3 EtBr (50g), 150ml toluene, stir at 60℃ for 2 hours, then add 400ml toluene solution of SAD-C (15g), 90℃ React for 2 hours. The reaction solution was cooled to room temperature, and 50 ml of saturated ammonium chloride solution was added to quench the reaction. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting oil was purified by column chromatography to obtain a total of 15 g of white powdery solid SAD-D.
步骤3：制备SAD-EStep 3: Preparation of SAD-E
向1L反应瓶中依次加入SAD-D(15克)，150ml四氢呋喃，搅拌下充分溶解，氮气置换。0℃下缓慢加入1.0M BH 3/THF(150ml)，加毕后20℃搅拌3小时。将反应液降温至0℃，缓慢加入3M的氢氧化钠溶液50ml，有大量气泡产生，无气泡后继续加入20ml 30％H 2O 2水溶液，加毕后20℃下搅拌2小时。向体系中加入20g的硫代硫酸钠溶液200ml，减压浓缩除去四氢呋喃，加入乙酸乙酯200ml搅拌10min分液，有机相用1M氢氧化钠溶液搅拌洗涤3次(每次100ml)，饱和食盐水100ml洗涤，将有机相干燥浓缩得到白色粉末状固体SAD-E粗品16克，直接作为下一步原料使用。 Into a 1 L reaction bottle, sequentially add SAD-D (15 g), 150 ml of tetrahydrofuran, dissolve it with stirring, and replace with nitrogen. 1.0M BH 3 /THF (150ml) was slowly added at 0°C, and stirred at 20°C for 3 hours after the addition was completed. The reaction solution was cooled to 0°C, and 50 ml of 3M sodium hydroxide solution was slowly added. A large number of bubbles were generated. After no bubbles were added, 20 ml of 30% H 2 O 2 aqueous solution was added, and the mixture was stirred at 20° C. for 2 hours. Add 200g of sodium thiosulfate solution 200ml to the system, concentrate under reduced pressure to remove tetrahydrofuran, add ethyl acetate 200ml and stir for 10min to separate, the organic phase was washed with 1M sodium hydroxide solution with stirring 3 times (100ml each time), saturated brine Wash 100 ml, dry and concentrate the organic phase to obtain 16 g of white powdery solid SAD-E crude product, which is used directly as the next raw material.
步骤4：制备SAD-FStep 4: Preparation of SAD-F
于500ml反应瓶中依次加入SAD-E粗品(16克)，200ml二氯甲烷，室温搅拌溶解，加入25克硅胶。冰浴降温至0℃，分批加入氯铬酸吡啶盐(16克)，加毕后20℃搅拌2小时。反应液浓缩至干，柱层析， 洗脱液依次用饱和硫代硫酸钠，饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，得类白色粉末状固体SAD-F粗品16克。柱层析得到白色粉末状固体SAD-F(11克)。In a 500ml reaction flask, sequentially add crude SAD-E (16g), 200ml of dichloromethane, stir and dissolve at room temperature, and add 25g of silica gel. The temperature was lowered to 0°C in an ice bath, pyridine chlorochromate (16 g) was added in portions, and the mixture was stirred at 20°C for 2 hours after the addition. The reaction solution was concentrated to dryness, column chromatography, the eluent was washed with saturated sodium thiosulfate, saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain 16 g of crude SAD-F as a white powdery solid. Column chromatography gave SAD-F (11 g) as a white powdery solid.
步骤5：制备SAD-GStep 5: Preparation of SAD-G
于200ml反应瓶中依次加入SAD-F(11克)，三氟乙酸的二异丙胺盐(1：1；8克)，三氟乙酸(1克)，多聚甲醛(3.2克)，DMA110ml，90℃下搅拌15h。将反应液溶于叔丁基甲醚150mL和乙酸乙酯150mL，搅拌中加入500mL水，搅拌10min分液，水相用叔丁基甲醚和乙酸乙酯各150mL萃取分液。合并有机相，用500mL水洗2次，柱层析，洗脱液加入1克活性炭搅拌1h过滤。滤液浓缩得到白色固体SAD-G粗品11克。将粗品重结晶(乙腈：水＝1:1)，得到白色固体SAD-G(7.5克)。In a 200ml reaction bottle, add SAD-F (11g), diisopropylamine salt of trifluoroacetic acid (1:1; 8g), trifluoroacetic acid (1g), paraformaldehyde (3.2g), DMA 110ml, Stir at 90°C for 15h. The reaction solution was dissolved in 150 mL of tert-butyl methyl ether and 150 mL of ethyl acetate, 500 mL of water was added to the stirring, and the mixture was stirred for 10 min. The aqueous phase was extracted and separated with 150 mL of tert-butyl methyl ether and ethyl acetate. The organic phases were combined, washed twice with 500 mL of water, column chromatography, and 1 g of activated carbon was added to the eluent and stirred for 1 h and filtered. The filtrate was concentrated to give 11 g of crude SAD-G as a white solid. The crude product was recrystallized (acetonitrile: water = 1:1) to obtain SAD-G (7.5 g) as a white solid.
步骤6：制备化合物4Step 6: Preparation of compound 4
于200ml的反应瓶中依次加入SAD-G(7.5克)，碳酸钾(5克)，4-甲腈吡唑(3.1克)，乙腈70ml，50℃搅拌反应2h。加入120ml水，冷却至室温搅拌1h，过滤，滤饼依次用20ml乙腈：水＝1:1，100ml水洗涤。45℃鼓风干燥，得到化合物4(白色固体，3克)。In a 200ml reaction bottle, add SAD-G (7.5g), potassium carbonate (5g), 4-carbonitrile pyrazole (3.1g), acetonitrile 70ml, and stir at 50°C for 2h. Add 120ml of water, cool to room temperature and stir for 1h, filter. The filter cake is washed successively with 20ml of acetonitrile: water = 1:1 and 100ml of water. Dry at 45°C with air blow to obtain compound 4 (white solid, 3 g).
另，化合物4也可以按照以下的方案进行制备：In addition, compound 4 can also be prepared according to the following scheme:
Figure PCTCN2019128092-appb-000018
Figure PCTCN2019128092-appb-000018
步骤1：制备SAD-CStep 1: Preparation of SAD-C
于5L干燥反应瓶中依次加入2,6-二叔丁基-4-甲基酚(321g)，甲苯(1L)，降温至0℃，加入2.0M三甲基铝的甲苯溶液(360mL)，加毕后20～25℃搅拌1小时，然后降温至-80℃。缓慢加入SA-B(80g)的甲苯溶液(800mL)，加完后继续搅拌1小时。将1.0M氘代甲基碘化镁的***溶液(580mL)于-80～-70℃缓慢加至反应瓶中，加完后于-80～-70℃下搅拌4小时。加入1.6L饱和氯化铵水溶液淬灭反应，加完后搅拌30分钟，将反应液转入配制有1L 1M氢氧化钠溶液的10L双层玻璃反应釜中，控温20℃左右搅拌15～30分钟，静置分液，水层于5L双层玻璃反应釜中用甲苯萃取三次(800mL×3)，合并有机层，饱和氯化钠溶液洗涤两次(2L×2)，有机相用400g无水硫酸钠干燥，过滤，滤液于60℃减压浓缩至干。 柱层析纯化，得白色固体SAD-C 53克。In a 5L dry reaction bottle, add 2,6-di-tert-butyl-4-methylphenol (321g), toluene (1L), cool to 0℃, add 2.0M trimethylaluminum toluene solution (360mL), After the addition, the mixture was stirred at 20-25°C for 1 hour, and then cooled to -80°C. A toluene solution (800 mL) of SA-B (80 g) was slowly added, and stirring was continued for 1 hour after the addition was completed. A 1.0 M ether solution of deuterated methyl magnesium iodide (580 mL) was slowly added to the reaction bottle at -80 to -70°C, and after the addition was completed, it was stirred at -80 to -70°C for 4 hours. Add 1.6L of saturated ammonium chloride aqueous solution to quench the reaction. Stir for 30 minutes after the addition. Transfer the reaction solution into a 10L double-layer glass reactor equipped with 1L of 1M sodium hydroxide solution. Stir at a temperature of about 20°C and stir for 15-30 The liquid layer was left still for 3 minutes, and the aqueous layer was extracted three times with toluene (800 mL×3) in a 5L double-layer glass reactor. The organic layers were combined and washed twice with saturated sodium chloride solution (2L×2). Dry over sodium sulfate and filter. The filtrate is concentrated to dryness under reduced pressure at 60°C. Purified by column chromatography to obtain 53 g of white solid SAD-C.
步骤2：制备SAD-DStep 2: Preparation of SAD-D
于2L反应瓶中依次加入甲苯(260g)，乙基三苯基溴化膦(96g)，叔丁醇钾(29g)，升温至60℃搅拌2小时。加入SAD-C(30g)的甲苯溶液(100g)，升温至90℃反应2小时。将反应液冷却至室温，加入390g饱和氯化铵溶液淬灭反应并搅拌15～30分钟，静置后分液，水层用100g乙酸乙酯萃取一次，合并有机相，400g饱和氯化钠水溶液洗涤一次，无水硫酸钠干燥，过滤，减压浓缩至干，硅胶柱层析纯化，得浅黄色油状物28g。Toluene (260g), ethyltriphenylphosphonium bromide (96g), potassium tert-butoxide (29g) were added to a 2L reaction flask in this order, and the temperature was raised to 60°C and stirred for 2 hours. A toluene solution (100 g) of SAD-C (30 g) was added, and the temperature was raised to 90°C to react for 2 hours. The reaction solution was cooled to room temperature, 390 g of saturated ammonium chloride solution was added to quench the reaction and stirred for 15 to 30 minutes. After standing, the layers were separated, and the aqueous layer was extracted once with 100 g of ethyl acetate. The organic phases were combined and 400 g of saturated sodium chloride aqueous solution Washed once, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography to obtain 28g of light yellow oil.
步骤3：制备SAD-EStep 3: Preparation of SAD-E
向1L反应瓶中依次加入SAD-D(28g)，四氢呋喃(250g)，搅拌下充分溶解，氮气置换。降温至0℃，缓慢加入1.0M硼烷四氢呋喃溶液(250g)，加毕后室温搅拌3小时。将反应液降温至0℃，缓慢加入3M的氢氧化钠溶液(100g)，有大量气泡产生，加毕于0～10℃搅拌30分钟，继续加入30％过氧化氢水溶液(43g)，加毕后室温搅拌2小时。向体系中加入硫代硫酸钠(40g)的水溶液(400g)，搅拌30分钟，减压浓缩除去大量四氢呋喃，浓缩物用乙酸乙酯萃取2次(125g×2)，合并有机相，饱和氯化钠洗涤2次(300g×2)，无水硫酸钠干燥，过滤，减压浓缩至干，得33g浅黄色粗品，直接用于下一步反应。Into a 1 L reaction bottle, sequentially add SAD-D (28 g) and tetrahydrofuran (250 g), dissolve it under stirring, and replace with nitrogen. The temperature was lowered to 0°C, and a 1.0 M borane tetrahydrofuran solution (250 g) was slowly added, and the mixture was stirred at room temperature for 3 hours after the addition. The reaction solution was cooled to 0°C, and 3M sodium hydroxide solution (100g) was slowly added, a large amount of bubbles were generated, and the mixture was stirred at 0～10°C for 30 minutes, and then 30% aqueous hydrogen peroxide solution (43g) was added. After stirring at room temperature for 2 hours. An aqueous solution (400 g) of sodium thiosulfate (40 g) was added to the system, stirred for 30 minutes, concentrated under reduced pressure to remove a large amount of tetrahydrofuran, the concentrate was extracted twice with ethyl acetate (125 g×2), the organic phases were combined, and saturated chlorination Sodium was washed twice (300g×2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain 33g of pale yellow crude product, which was directly used in the next reaction.
步骤4：制备SAD-FStep 4: Preparation of SAD-F
于1L反应瓶中依次加入SAD-E粗品(33g)，二氯甲烷(600g)，室温搅拌溶解，冰浴降温至0℃，分批加入戴斯-马丁氧化剂(79g)，加毕后室温搅拌24小时。降温至0～10℃，缓慢加入含有亚硫酸钠(47g)和碳酸钠(39g)的水溶液(600g)，加完后搅拌30分钟，静置分液，水相用200g二氯甲烷萃取一次，合并有机相，350g饱和氯化钠溶液洗涤一次，无水硫酸钠干燥，过滤，减压浓缩至干，得褐色油状物SAD-F，柱层析纯化，得黄色固体SAD-F 18g。In a 1L reaction bottle, add crude SAD-E (33g), dichloromethane (600g), stir and dissolve at room temperature, cool to 0°C in an ice bath, add Dess-Martin oxidant (79g) in batches, and stir at room temperature after addition 24 hours. Reduce the temperature to 0～10℃, slowly add an aqueous solution (600g) containing sodium sulfite (47g) and sodium carbonate (39g), stir for 30 minutes after the addition is complete, let stand for liquid separation, extract the aqueous phase once with 200g dichloromethane, combine organic The phase was washed once with 350g of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain brown oil SAD-F. Purification by column chromatography gave 18g of yellow solid SAD-F.
步骤5：制备SAD-GStep 5: Preparation of SAD-G
于500mL反应瓶中依次加入N,N-二甲基乙酰胺(28g)，二异丙胺(6g)，降温至10℃以下，加入三氟乙酸(10g)的N,N二甲基乙酰胺溶液(28g)，加完后停止降温，搅拌30分钟。加入SAD-F(15g)的N,N-二甲基乙酰胺溶液(80g)，再加入多聚甲醛(6g)，加完后升温至90℃反应20小时。将反应液降至室温，加入200g乙酸乙酯和400g水，搅拌10分钟，静置分液，水相用乙酸乙酯萃取2次，合并有机相，饱和氯化钠洗涤2次，无水硫酸钠干燥，过滤，减压浓缩至干，硅胶柱层析纯化得浅黄色固体10g。In a 500mL reaction flask, add N,N-dimethylacetamide (28g) and diisopropylamine (6g) in sequence, lower the temperature to below 10℃, and add N,N dimethylacetamide solution of trifluoroacetic acid (10g) (28g), after the addition is completed, the temperature is stopped and stirred for 30 minutes. A solution of SAD-F (15g) in N,N-dimethylacetamide (80g) was added, followed by paraformaldehyde (6g). After the addition, the temperature was raised to 90°C and reacted for 20 hours. The reaction solution was cooled to room temperature, 200 g of ethyl acetate and 400 g of water were added, stirred for 10 minutes, and allowed to stand for liquid separation. The aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed twice with saturated sodium chloride, and anhydrous sulfuric acid Sodium was dried, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography to obtain 10g of light yellow solid.
步骤6：制备化合物4Step 6: Preparation of compound 4
于2L的反应瓶中依次加入SAD-G(9g)，碳酸钾(6g)，4-氰基吡唑(3g)，乙腈(88g)，加完后升温至50℃搅拌2小时。向反应体系中加入200g水，析出固体，加完后搅拌1小时，过滤，滤饼用200ml乙腈：水＝1：1的混合溶剂洗涤，再用500ml水洗涤，50℃鼓风干燥，得到浅黄色固体8g。In a 2L reaction bottle, add SAD-G (9g), potassium carbonate (6g), 4-cyanopyrazole (3g), and acetonitrile (88g) in succession. After addition, the temperature was raised to 50°C and stirred for 2 hours. 200g of water was added to the reaction system to precipitate a solid. After the addition, the mixture was stirred for 1 hour and filtered. The filter cake was washed with a mixed solvent of 200ml of acetonitrile: water = 1:1, then washed with 500ml of water, and dried at 50°C by air blowing to obtain a shallow Yellow solid 8g.
实施例5：制备化合物5Example 5: Preparation of compound 5
Figure PCTCN2019128092-appb-000019
Figure PCTCN2019128092-appb-000019
于反应瓶中依次加入SA-G(1.0g，3.0mmol)，碳酸钾(0.62g，4.5mmol)，吗啉(0.39ml，4.5mmol)，乙腈(10ml)，加完后升温至50℃搅拌2小时。向反应瓶中加入水，乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩后经硅胶柱层析纯化(二氯甲烷：甲醇＝20：1)，得化合物5(0.58g，收率46％)。 1H NMR(400MHz,CDCl 3):δ3.65(t,J＝4.6Hz,4H),2.64-2.58(m,2H),2.54-2.48(m,3H),2.41-2.39(m,4H),2.16-2.08(m,1H),1.94(dt,J＝3.1,12.2Hz,1H),1.81-1.75(m,3H),1.69-1.55(m,4H),1.43-1.14(m,14H),1.08-0.96(m,3H),0.56(s,3H). 13C NMR(100MHz,CDCl 3):δ210.2,71.7,66.8,63.5,55.8,53.6,53.1,44.7,41.6,41.4,41.1,40.3,39.2,37.6,34.6,34.4,31.4,26.5,26.0,25.6,25.4,24.3,22.9,13.6.MS:m/z 418.3,[M+H] +。 Add SA-G (1.0g, 3.0mmol), potassium carbonate (0.62g, 4.5mmol), morpholine (0.39ml, 4.5mmol), acetonitrile (10ml) to the reaction bottle in sequence, and warm to 50°C after stirring 2 hours. Water was added to the reaction flask, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to give compound 5 (0.58g, yield Rate 46%). 1 H NMR (400 MHz, CDCl 3 ): δ 3.65 (t, J=4.6 Hz, 4H), 2.64-2.58 (m, 2H), 2.54-2.48 (m, 3H), 2.41-2.39 (m, 4H) , 2.16-2.08 (m, 1H), 1.94 (dt, J = 3.1, 12.2 Hz, 1H), 1.81-1.75 (m, 3H), 1.69-1.55 (m, 4H), 1.43-1.14 (m, 14H) , 1.08-0.96 (m, 3H), 0.56 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 210.2, 71.7, 66.8, 63.5, 55.8, 53.6, 53.1, 44.7, 41.6, 41.4, 41.1 , 40.3, 39.2, 37.6, 34.6, 34.4, 31.4, 26.5, 26.0, 25.6, 25.4, 24.3, 22.9, 13.6. MS: m/z 418.3, [M+H] + .
实施例6：制备化合物6Example 6: Preparation of compound 6
Figure PCTCN2019128092-appb-000020
Figure PCTCN2019128092-appb-000020
于反应瓶中依次加入SA-G(1.0g，3.0mmol)，碳酸钾(0.62g，4.5mmol)，5-羟基-1,2,3,4-四氢异喹啉盐酸盐(0.84g，4.5mmol)，乙腈(10ml)，水(1ml)，加完后升温至50℃反应过夜。向反应瓶中加入水，乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩后经硅胶柱层析纯化(二氯甲烷：甲醇＝10：1)，得化合物6(0.79g，收率54％)。 1H NMR(400MHz,CDCl 3):δ6.93(t,J＝7.8Hz,1H),6.56(d,J＝7.6Hz,1H),6.52(d,J＝7.9Hz,1H),3.63(s,2H),2.84(t,J＝7.3Hz,2H),2.81-2.64(m,6H),2.56(t,J＝8.7Hz,1H),2.19-2.13(m,1H),1.97-1.94(m,1H),1.87-1.81(m,3H),1.69-1.61(m,4H),1.49-1.35(m,6H),1.34-1.20(m,8H),1.14-1.02(m,3H),0.60(s,3H). 13C NMR(100MHz,CDCl 3):δ210.7,154.1,135.4,126.4,121.2,118.2,112.7,72.3,63.6,55.9,55.8,52.2,50.7,44.8,41.8,41.7,41.1,40.3,39.1,37.6,34.7,34.5,31.4,26.5,26.1,25.7,25.4,24.3,23.1,22.9,13.6.MS:m/z 480.3,[M+H] +。 Add SA-G (1.0g, 3.0mmol), potassium carbonate (0.62g, 4.5mmol), 5-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.84g) , 4.5mmol), acetonitrile (10ml), water (1ml), after addition, warmed to 50 ℃ overnight. Water was added to the reaction flask, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to give compound 6 (0.79g, yield Rate 54%). 1 H NMR (400 MHz, CDCl 3 ): δ 6.93 (t, J=7.8 Hz, 1H), 6.56 (d, J=7.6 Hz, 1H), 6.52 (d, J=7.9 Hz, 1H), 3.63 ( s, 2H), 2.84 (t, J = 7.3Hz, 2H), 2.81-2.64 (m, 6H), 2.56 (t, J = 8.7Hz, 1H), 2.19-2.13 (m, 1H), 1.97-1.94 (m,1H),1.87-1.81(m,3H),1.69-1.61(m,4H),1.49-1.35(m,6H),1.34-1.20(m,8H),1.14-1.02(m,3H) ,0.60(s,3H). 13 C NMR(100MHz,CDCl 3 ):δ210.7,154.1,135.4,126.4,121.2,118.2,112.7,72.3,63.6,55.9,55.8,52.2,50.7,44.8,41.8,41.7, 41.1, 40.3, 39.1, 37.6, 34.7, 34.5, 31.4, 26.5, 26.1,25.7, 25.4, 24.3, 23.12.9, 13.6. MS: m/z 480.3, [M+H] + .
实施例7：制备化合物7Example 7: Preparation of compound 7
Figure PCTCN2019128092-appb-000021
Figure PCTCN2019128092-appb-000021
于反应瓶中依次加入SA-G(1.0g，3.0mmol)，碳酸钾(0.62g，4.5mmol)，哌啶(0.41ml，4.5mmol)，乙腈(10ml)，加完后升温至50℃搅拌2小时。向反应瓶中加入水，乙酸乙酯萃取，无水硫酸钠干燥，过 滤，减压浓缩后经硅胶柱层析纯化(石油醚：乙酸乙酯＝1：1)，得化合物7(0.56g，收率45％)。 1H NMR(400MHz,CDCl 3):δ2.67-2.50(m,4H),2.48-2.26(brs,4H),2.21-2.13(m,1H),2.00(dt,J＝3.3,12.3Hz,1H),1.88-1.81(m,3H),1.77-1.55(m,9H),1.46-1.41(m,8H),1.34-1.18(m,8H),1.13-1.01(m,3H),0.61(s,3H). 13C NMR(100MHz,CDCl 3):δ210.8,72.0,63.6,55.8,54.6,53.5,44.7,41.9,41.7,41.2,40.3,39.2,37.7,34.7,34.5,31.4,26.5,26.1,26.0,25.7,25.4,24.3,22.9,13.6.MS:m/z 416.3,[M+H] +。 Add SA-G (1.0g, 3.0mmol), potassium carbonate (0.62g, 4.5mmol), piperidine (0.41ml, 4.5mmol), and acetonitrile (10ml) to the reaction bottle in sequence, and warm up to 50°C after stirring 2 hours. Water was added to the reaction flask, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give compound 7 (0.56g, Yield 45%). 1 H NMR (400 MHz, CDCl 3 ): δ 2.67-2.50 (m, 4H), 2.48-2.26 (brs, 4H), 2.21-2.13 (m, 1H), 2.00 (dt, J=3.3, 12.3 Hz, 1H), 1.88-1.81(m, 3H), 1.77-1.55(m, 9H), 1.46-1.41(m, 8H), 1.34-1.18(m, 8H), 1.13-1.01(m, 3H), 0.61( s, 3H). 13 C NMR (100MHz, CDCl 3 ): δ210.8, 72.0, 63.6, 55.8, 54.6, 53.5, 44.7, 41.9, 41.7, 41.2, 40.3, 39.2, 37.7, 34.7, 34.5, 31.4, 26.5 , 26.1,26.0, 25.7, 25.4, 24.3, 22.9, 13.6. MS: m/z 416.3, [M+H] + .
实施例8：制备化合物8Example 8: Preparation of compound 8
Figure PCTCN2019128092-appb-000022
Figure PCTCN2019128092-appb-000022
参照实施例1的制备方案，将氘代氢气作为相应的试剂，得到化合物8，MS:m/z 426.5[M+H] +。 Referring to the preparation scheme of Example 1, using deuterated hydrogen as the corresponding reagent, compound 8 was obtained, MS: m/z 426.5 [M+H] + .
实施例9：制备化合物9Example 9: Preparation of compound 9
Figure PCTCN2019128092-appb-000023
Figure PCTCN2019128092-appb-000023
于反应瓶中依次加入SA-G(1.0g，3.0mmol)，碳酸钾(0.62g，4.5mmol)，N-甲基炔丙基胺(0.31g，4.5mmol)，乙腈(10ml)，加完后升温至50℃搅拌2小时。向反应瓶中加入水，乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩后经硅胶柱层析纯化(二氯甲烷：甲醇＝40：1)，得化合物9(0.75g，收率62％)。 1H NMR(400MHz,CDCl 3):δ3.34(d,J＝2.4Hz,2H),2.75-2.72(m,2H),2.58-2.53(m,3H),2.32(s,3H),2.24(t,J＝2.4Hz,1H),2.20-2.15(m,1H),2.00(dt,J＝3.3,12.2Hz,1H),1.88-1.78(m,3H),1.75-1.61(m,4H),1.52-1.38(m,7H),1.35-1.20(m,8H),1.14-1.02(m,3H),0.62(s,3H). 13C NMR(100MHz,CDCl 3):δ210.2,78.4,73.2,72.0,63.5,55.8,50.2,45.7,44.7,42.5,41.8,41.7,41.2,40.3,39.2,37.6,34.7,34.5,31.4,26.5,26.1,25.7,25.4,24.3,22.9,13.6.MS:m/z 400.3,[M+H] +。 Add SA-G (1.0g, 3.0mmol), potassium carbonate (0.62g, 4.5mmol), N-methylpropargylamine (0.31g, 4.5mmol), and acetonitrile (10ml) to the reaction bottle in sequence. After heating to 50 ℃ and stirring for 2 hours. Water was added to the reaction flask, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane: methanol = 40: 1) to give compound 9 (0.75g, yield Rate 62%). 1 H NMR (400 MHz, CDCl 3 ): δ 3.34 (d, J=2.4 Hz, 2H), 2.75-2.72 (m, 2H), 2.58-2.53 (m, 3H), 2.32 (s, 3H), 2.24 (t, J=2.4Hz, 1H), 2.20-2.15(m, 1H), 2.00(dt, J=3.3, 12.2Hz, 1H), 1.88-1.78(m, 3H), 1.75-1.61(m, 4H) ), 1.52-1.38 (m, 7H), 1.35-1.20 (m, 8H), 1.14-1.02 (m, 3H), 0.62 (s, 3H). 13 C NMR (100MHz, CDCl 3 ): δ210.2, 78.4, 73.2, 72.0, 63.5, 55.8, 50.2, 45.7, 44.7, 42.5, 41.8, 41.7, 41.2, 40.3, 39.2, 37.6, 34.7, 34.5, 31.4, 26.5, 26.1,25.7, 25.4, 24.3, 22.9, 13.6. MS: m/z 400.3, [M+H] + .
实施例10：制备化合物10Example 10: Preparation of compound 10
Figure PCTCN2019128092-appb-000024
Figure PCTCN2019128092-appb-000024
于反应瓶中依次加入SA-G(1.0g，3.0mmol)，碳酸钾(0.62g，4.5mmol)，二甲胺水溶液(0.75ml，4.5mmol)，乙腈(10ml)，加完后升温至50℃搅拌2小时。向反应瓶中加入水，乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩后经硅胶柱层析纯化(二氯甲烷：甲醇＝40：1)，得化合物10(0.71g，收率63％)。 1H NMR(400MHz,CDCl 3):δ2.59-2.51(m,4H),2.23(s,6H),1.99(dt,J＝3.2,12.2Hz,1H),1.87-1.59(m,8H),1.49-1.15(m,15H),1.12-1.01(m,3H),0.60(s,3H). 13C NMR(100MHz,CDCl 3):δ210.4,71.9,63.5,55.8,53.9,45.5,44.7,42.5,41.7,41.1,40.3,39.2,37.6,34.7,34.5,31.4,26.5,26.1,25.7,25.4,24.3,22.9,13.6.MS:m/z 376.3,[M+H] +。 Add SA-G (1.0g, 3.0mmol), potassium carbonate (0.62g, 4.5mmol), dimethylamine aqueous solution (0.75ml, 4.5mmol), and acetonitrile (10ml) to the reaction bottle in sequence, and increase the temperature to 50 Stir at 2°C for 2 hours. Water was added to the reaction flask, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane: methanol = 40: 1) to give compound 10 (0.71g, yield Rate 63%). 1 H NMR (400 MHz, CDCl 3 ): δ 2.59-2.51 (m, 4H), 2.23 (s, 6H), 1.99 (dt, J=3.2, 12.2 Hz, 1H), 1.87-1.59 (m, 8H) , 1.49-1.15 (m, 15H), 1.12-1.01 (m, 3H), 0.60 (s, 3H). 13 C NMR (100MHz, CDCl 3 ): δ 210.4, 71.9, 63.5, 55.8, 53.9, 45.5, 44.7, 42.5, 41.7, 41.1, 40.3, 39.2, 37.6, 34.7, 34.5, 31.4, 26.5, 26.1,25.7, 25.4, 24.3, 22.9, 13.6. MS: m/z 376.3, [M+H] + .
实施例11：制备化合物11Example 11: Preparation of compound 11
Figure PCTCN2019128092-appb-000025
Figure PCTCN2019128092-appb-000025
于反应瓶中依次加入SA-G(1.0g，3.0mmol)，碳酸钾(0.62g，4.5mmol)，苄胺(0.50ml，4.5mmol)，乙腈(10ml)，加完后升温至50℃搅拌2小时。向反应瓶中加入水，乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩后经硅胶柱层析纯化(石油醚：乙酸乙酯＝2：1-1：1)，得化合物11(0.68g，收率52％)。 1H NMR(400MHz,CDCl 3):δ7.34-7.33(m,4H),7.28-7.24(m,1H),3.80(d,J＝1.4Hz,2H),2.86(t,J＝6.2Hz,2H),2.63(t,J＝6.2Hz,2H),2.53(t,J＝8.9Hz,1H),2.23-2.13(m,1H),2.00(dt,J＝3.3,12.2Hz,1H),1.89-1.81(m,3H),1.74-1.61(m,6H),1.50-1.38(m,6H),1.33-1.19(m,8H),1.13-1.02(m,3H),0.62(s,3H). 13C NMR(100MHz,CDCl 3):δ211.4,140.2,128.4,128.1,126.9,72.0,63.4,55.8,54.2,44.7,44.4,44.0,41.7,41.2,40.3,39.1,37.6,34.7,34.5,31.4,26.5,26.1,25.7,25.4,24.3,22.9,13.6.MS:m/z 438.3,[M+H] +。 Add SA-G (1.0g, 3.0mmol), potassium carbonate (0.62g, 4.5mmol), benzylamine (0.50ml, 4.5mmol), acetonitrile (10ml) to the reaction bottle in sequence, and warm to 50°C after stirring 2 hours. Water was added to the reaction flask, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1-1:1) to give compound 11 (0.68g, 52% yield). 1 H NMR (400 MHz, CDCl 3 ): δ7.34-7.33 (m, 4H), 7.28-7.24 (m, 1H), 3.80 (d, J = 1.4 Hz, 2H), 2.86 (t, J = 6.2 Hz , 2H), 2.63 (t, J = 6.2Hz, 2H), 2.53 (t, J = 8.9Hz, 1H), 2.23-2.13 (m, 1H), 2.00 (dt, J = 3.3, 12.2Hz, 1H) , 1.89-1.81(m, 3H), 1.74-1.61(m, 6H), 1.50-1.38(m, 6H), 1.33-1.19(m, 8H), 1.13-1.02(m, 3H), 0.62(s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 211.4, 140.2, 128.4, 128.1, 126.9, 72.0, 63.4, 55.8, 54.2, 44.7, 44.4, 44.0, 41.7, 41.2, 40.3, 39.1, 37.6, 34.7, 34.5 , 31.4, 26.5, 26.1,25.7, 25.4, 24.3, 22.9, 13.6. MS: m/z 438.3, [M+H] + .
实施例12：制备化合物12Example 12: Preparation of compound 12
Figure PCTCN2019128092-appb-000026
Figure PCTCN2019128092-appb-000026
参照实施例4和实施例11的制备方案，得到化合物12，MS:m/z 441.6[M+H] +。 Referring to the preparation schemes of Example 4 and Example 11, compound 12 was obtained, MS: m/z 441.6 [M+H] + .
生物测试Biological test
1，对重组人GABAA4(α4β3δ)通道的作用1. Effect on recombinant human GABAA4 (α4β3δ) channel
采用全细胞膜片钳技术测定化合物对GABA A4(α4β3δ)通道的作用。用α4β3δ亚基瞬时转染HEK293 细胞，转染后24小时换成完全培养基，孵育细胞48小时后进行电生理检测。用细胞外液将测试的化合储液以及激动剂GABA储液稀释至工作液浓度，加于灌流***中。将细胞从培养箱中取出，放置于盛有外液的记录小室中，在显微镜下寻找状态良好的细胞进行封接。将内液注入拉制好的玻璃电极中，在显微镜下操作使电极轻轻接触细胞，给予负压，形成高阻封接，持续给予负压，将封接好的细胞破膜，补偿。实验采用电压钳记录模式，将细胞膜电位钳制于-60mV,待稳定后，瞬间给予GABA第一轮刺激；然后在相同的电压模式下给与GABA以及化合物混合的第二轮刺激。 Whole-cell patch-clamp technique was used to determine the effect of compounds on GABA A 4 (α4β3δ) channels. Transfect HEK293 cells with α4β3δ subunit transiently, change to complete medium 24 hours after transfection, and conduct electrophysiological detection after incubating the cells for 48 hours. Dilute the test compound stock solution and agonist GABA stock solution to the working solution concentration with extracellular fluid and add it to the perfusion system. Remove the cells from the incubator, place them in a recording chamber filled with external fluid, and look for cells in good condition under the microscope for sealing. Inject the internal fluid into the drawn glass electrode. Operate under the microscope to make the electrode lightly contact the cells and give negative pressure to form a high-resistance seal. Continue to give negative pressure to break the sealed cells and compensate. In the experiment, the voltage clamp recording mode was used to clamp the cell membrane potential to -60mV. After stabilization, the first round of stimulation of GABA was given instantaneously; then the second round of stimulation with GABA and the compound was given under the same voltage mode.
首先测量出由5μM GABA作用于细胞诱导出的电流值，然后测量5μM GABA与10μM待测化合物共同作用于细胞诱导的电流值，由此计算出5μM GABA与10μM共同作用的效应。First, the current value induced by 5 μM GABA acting on the cell is measured, and then the current value induced by 5 μM GABA and 10 μM test compound acting on the cell is measured, thereby calculating the combined effect of 5 μM GABA and 10 μM.
将化合物对GABAA4(α4β3δ)通道的作用结果列于表1中。The results of the compounds on GABAA4 (α4β3δ) channel are listed in Table 1.
化合物编号Compound number α4β3δ通道(Emax)α4β3δ channel (Emax)
11 CC
44 CC
SAGE-547SAGE-547 AA
表1中，A表示0≤E max≤200，B表示200<E max≤500，C表示E max>500。 In Table 1, A represents 0≤E max ≤200, B represents 200<E max ≤500, and C represents E max >500.
试验结果表明，化合物1和化合物4对GABAA4(α4β3δ)通道的调节作用显著强于SAGE-547。SAGE-547是GABAA受体的变构调节剂，已在治疗产后抑郁的临床3期试验中显示了显著的治疗效果。The test results show that the modulation effect of compound 1 and compound 4 on GABAA4 (α4β3δ) channel is significantly stronger than that of SAGE-547. SAGE-547 is an allosteric modulator of GABAA receptors and has shown significant therapeutic effects in a phase 3 clinical trial for the treatment of postpartum depression.
2，大鼠试验12. Rat test 1
雄性SD大鼠8只，灌胃给予化合物1(20mg/kg)，观察至24h，没有出现动物死亡。Eight male SD rats were given compound 1 (20 mg/kg) by gavage, and no animal death occurred until 24 hours.
采用同样的试验方案，灌胃给予化合物4(20mg/kg)，观察至24h，没有出现动物死亡。Using the same test protocol, compound 4 (20 mg/kg) was administered by gavage, and no animal deaths were observed until 24 hours.
3，大鼠试验23. Rat test 2
雄性SD大鼠24只，随机分为两组，每组12只。通过静脉注射给药，给予化合物1或SAGE-217 5mg/kg。化合物SAGE-217组有5只动物在给药后5-15min内死亡。化合物1组，观察至24小时，没有出现动物死亡。表明化合物1的安全性优于SAGE-217。Twenty-four male SD rats were randomly divided into two groups, 12 in each group. By intravenous injection, Compound 1 or SAGE-217 5 mg/kg was administered. Five animals in the compound SAGE-217 group died within 5-15 minutes after administration. In the compound 1 group, no animal death occurred until 24 hours. It shows that the safety of compound 1 is better than that of SAGE-217.
雄性SD大鼠36只，随机分为三组，每组12只。通过静脉注射给药，给予化合物2、4或SAGE-2175mg/kg，观察至24小时，化合物2和4给药组均没有出现动物死亡；SAGE-217组有4只动物在20min内死亡。表明化合物2和4的安全性优于SAGE-217。SAGE-217是正在进行临床试验的类固醇类药物。36 male SD rats were randomly divided into three groups, 12 in each group. By intravenous administration, compound 2, 4 or SAGE-2175 mg/kg was administered. It was observed that no animals died in the compound 2 and 4 administration groups until 24 hours; 4 animals in the SAGE-217 group died within 20 minutes. It shows that the safety of compounds 2 and 4 is better than that of SAGE-217. SAGE-217 is a steroid drug undergoing clinical trials.
4、SD大鼠强迫游泳试验4. Forced swimming test of SD rats
96只SD大鼠，随机分为6组，每组16只，雌雄各半。6个组分别给予溶媒、化合物1(2mg/kg)、化合物2(2mg/kg)、化合物4(1.5mg/kg)、化合物11(2mg/kg)、帕罗西汀(20mg/kg)。除帕罗西汀组在 试验前23.5h、5h和1h分别给药3次外，其余组每天给药一次，连续给药3天。96 SD rats were randomly divided into 6 groups, 16 in each group, half male and female. The 6 groups were given vehicle, compound 1 (2 mg/kg), compound 2 (2 mg/kg), compound 4 (1.5 mg/kg), compound 11 (2 mg/kg), paroxetine (20 mg/kg). Except for the paroxetine group, which was administered 3 times at 23.5h, 5h, and 1h before the test, the other groups were administered once a day for 3 consecutive days.
在正式游泳试验的前一天，进行预游泳试验。将大鼠放入游泳缸内，开始计时，15min后，将大鼠从水中取出并擦干，放回原笼内。The day before the formal swimming test, a pre-swimming test was conducted. Place the rat in the swimming tank and start timing. After 15 minutes, remove the rat from the water and dry it, and put it back in the original cage.
除帕罗西汀外，其余组在第三天给药后0.5h，将动物放入强迫游泳装置(水深30厘米，水温23-25℃)中，游泳6分钟，分析最后4分钟的大鼠动和不动时间。Except for paroxetine, the remaining groups were placed in a forced swimming device (water depth 30 cm, water temperature 23-25°C) for 0.5 minutes after the third day of dosing, swimming for 6 minutes. Don't move time.
化合物编号Compound number 不动时间(s)Fixed time (s)
VehicleVehicle 44.244.2
11 24.224.2
22 27.927.9
44 18.118.1
1111 30.230.2
帕罗西汀Paroxetine 35.335.3
本发明实施例化合物在大鼠强迫游泳试验中显示了显著的减少不动时间的效果。The compounds of the examples of the present invention showed a significant effect of reducing immobility time in the forced swimming test of rats.
5、行为学观察5. Behavioral observation
行为学观察表明，化合物9和10在SD大鼠中，在一定给药剂量下，相对于溶媒组，均出现那了药物作用于中枢神经***的相关行为学现象，且安全性良好，提示此类化合物在睡眠障碍、焦虑等中枢神经***疾病中具有治疗潜力。Behavioral observations show that, in SD rats, at a certain dose, compounds 9 and 10 exhibited behavioral phenomena related to the drug acting on the central nervous system relative to the vehicle group, and the safety was good, suggesting that this Compounds have therapeutic potential in central nervous system diseases such as sleep disorders and anxiety.

Claims (16)

  1. 一种式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，A compound of formula (I), its stereoisomers, tautomers or pharmaceutically acceptable salts,
    Figure PCTCN2019128092-appb-100001
    Figure PCTCN2019128092-appb-100001
    其中，R 1选自-C 1-6烷基，-C 2-6烯基，-C 2-6炔基或-C 3-6碳环基，其中烷基，烯基，炔基或碳环基可被任意取代，包括氟，氯，溴，碘，氰基，羟基，氨基，氘原子取代； Wherein R 1 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or -C 3-6 carbocyclyl, wherein alkyl, alkenyl, alkynyl or carbon The cyclic group can be optionally substituted, including fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, deuterium atoms;
    环A为可被任意取代的含氮杂芳环。Ring A is a nitrogen-containing heteroaromatic ring which may be optionally substituted.
  2. 如权利要求1所述的式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，其中包括通式(II)化合物，The compound of formula (I) according to claim 1, its stereoisomer, tautomer or pharmaceutically acceptable salt, which includes a compound of general formula (II),
    Figure PCTCN2019128092-appb-100002
    Figure PCTCN2019128092-appb-100002
    其中，R 1选自-C 1-6烷基，-C 2-6烯基，-C 2-6炔基或-C 3-6碳环基，其中烷基，烯基，炔基或碳环基可被选自氘，卤素，-C 1-6烷氧基，-C 1-6烷基的取代基取代； Wherein R 1 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or -C 3-6 carbocyclyl, wherein alkyl, alkenyl, alkynyl or carbon The cyclic group may be substituted with a substituent selected from deuterium, halogen, -C 1-6 alkoxy, -C 1-6 alkyl;
    R 2，R 3和R 4独立地选自氢，卤素，-NO 2，-CN，-OR 5，-N(R 5) 2，-OH，-(CH 2) 0-6COOR 5，-NR 5R 6，-C(O)NR 5R 6，-OR 5，-O(CH 2) 1-4COOR 5，-Si(R 5) 3，-OC(O)R 5，-OC(O)OR 5，-OC(O)NR 5R 6，-OS(O) nR 5，-OS(O) nNR 5R 6，-S(O) mR 5，-OS(O) nNH(C＝O)NR 5R 6，-NHS(O) nR 5，炔基，烷基，杂烷基，烯基，环烷基，芳基，芳烷基，杂芳基或杂环基，其中，炔基，烷基，杂烷基，烯基，环烷基，芳基，芳烷基，杂芳基或杂环基可被任意取代； R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, -NO 2 , -CN, -OR 5 , -N(R 5 ) 2 , -OH, -(CH 2 ) 0-6 COOR 5 ,- NR 5 R 6 , -C(O)NR 5 R 6 , -OR 5 , -O(CH 2 ) 1-4 COOR 5 , -Si(R 5 ) 3 , -OC(O)R 5 , -OC( O)OR 5 , -OC(O)NR 5 R 6 , -OS(O) n R 5 , -OS(O) n NR 5 R 6 , -S(O) m R 5 , -OS(O) n NH(C=O)NR 5 R 6 , -NHS(O) n R 5 , alkynyl, alkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, aralkyl, heteroaryl or heterocyclic Group, wherein alkynyl, alkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, aralkyl, heteroaryl or heterocyclic group may be optionally substituted;
    X为氮原子或者碳原子；X is a nitrogen atom or a carbon atom;
    R 5和R 6独立地选自氢，-C 1-6烷基，-C 2-6烯基，-C 2-6炔基，-C 3-8环烷基，杂烷基，芳基，芳烷基，杂芳基或杂环基；其中，烷基，烯基，炔基，环烷基，杂烷基，芳基，芳烷基，杂芳基或杂环基可被任意取代； R 5 and R 6 are independently selected from hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, heteroalkyl, aryl , Aralkyl, heteroaryl or heterocyclic group; wherein, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, aralkyl, heteroaryl or heterocyclic group may be optionally substituted ;
    或者，R 5和R 6连同与它们相连的氮原子一起形成可被至少一个R 7取代的饱和或不饱和的杂环； Alternatively, R 5 and R 6 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring which may be substituted with at least one R 7 ;
    每个R 7分别独立地选自-H，卤素，-C 1-6烷基或氧代； Each R 7 is independently selected from -H, halogen, -C 1-6 alkyl or oxo;
    m选自0，1或2；m is selected from 0, 1 or 2;
    n选自1，2或3。n is selected from 1, 2 or 3.
  3. 如权利要求2所述的式(II)化合物，其中R 1选自-C 1-6烷基，-CD 3，-CF 3，-CHF 2，-CH 2F，-CH 2OCH 3或-CH 2OCH 2CH 3。 The compound of formula (II) according to claim 2, wherein R 1 is selected from -C 1-6 alkyl, -CD 3 , -CF 3, -CHF 2, -CH 2 F, -CH 2 OCH 3 or- CH 2 OCH 2 CH 3 .
  4. 如权利要求2所述的式(II)化合物，其中，R 2，R 3和R 4独立地选自氢，卤素，-NO 2，-CN，-OR 5，-N(R 5) 2，-OH，-(CH 2) 0-6COOR 5，-NR 5R 6，-C(O)NR 5R 6，-OR 5，-O(CH 2) 1-4COOR 5，-Si(R 5) 3，-OC(O)R 5，-OC(O)OR 5，-OC(O)NR 5R 6，-OS(O) nR 5，-OS(O) nNR 5R 6，-S(O) mR 5，-OS(O) nNH(C＝O)NR 5R 6，-NHS(O) nR 5，-C 2-6炔基，-C 1-6烷基，杂烷基，-C 2-6烯基，-C 3-8环烷基，芳基，芳烷基，杂芳基或3至8元杂环基，其中，炔基，烷基，杂烷基，烯基，环烷基，芳基，芳烷基，杂芳基或杂环基可被选自-C 1-6烷基，卤素，-OH，氧代，-C 1-6烷氧基的取代基取代； The compound of formula (II) according to claim 2, wherein R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, -NO 2 , -CN, -OR 5 , -N(R 5 ) 2 , -OH, -(CH 2 ) 0-6 COOR 5 , -NR 5 R 6 , -C(O)NR 5 R 6 , -OR 5 , -O(CH 2 ) 1-4 COOR 5 , -Si(R 5 ) 3 , -OC(O)R 5 , -OC(O)OR 5 , -OC(O)NR 5 R 6 , -OS(O) n R 5 , -OS(O) n NR 5 R 6 , -S(O) m R 5 , -OS(O) n NH(C=O)NR 5 R 6 , -NHS(O) n R 5 , -C 2-6 alkynyl, -C 1-6 alkyl , Heteroalkyl, -C 2-6 alkenyl, -C 3-8 cycloalkyl, aryl, aralkyl, heteroaryl or 3 to 8 membered heterocyclic group, wherein, alkynyl, alkyl, hetero Alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heteroaryl or heterocyclyl can be selected from -C 1-6 alkyl, halogen, -OH, oxo, -C 1-6 alkyl Oxygen substituent substitution;
    R 5和R 6独立地选自氢，-C 1-6烷基，-C 2-6烯基，-C 2-6炔基，-C 3-8环烷基，杂烷基，芳基，芳烷基，杂芳基或3至8元杂环基，其中，烷基，烯基，炔基，环烷基，杂烷基，芳基，芳烷基，杂芳基或杂环基可被选自-C 1-6烷基，卤素，-OH，氧代，-C 1-6烷氧基的取代基取代； R 5 and R 6 are independently selected from hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, heteroalkyl, aryl , Aralkyl, heteroaryl or 3 to 8 membered heterocyclic group, wherein, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, aralkyl, heteroaryl or heterocyclic group May be substituted by a substituent selected from -C 1-6 alkyl, halogen, -OH, oxo, -C 1-6 alkoxy;
    或者，R 5和R 6连同与它们相连的氮原子一起形成可被至少一个R 7取代的饱和或不饱和的杂环； Alternatively, R 5 and R 6 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring which may be substituted with at least one R 7 ;
    每个R 7分别独立地选自-H，卤素，-C 1-6烷基或氧代； Each R 7 is independently selected from -H, halogen, -C 1-6 alkyl or oxo;
    m选自0，1或2；m is selected from 0, 1 or 2;
    n选自1，2或3。n is selected from 1, 2 or 3.
  5. 如权利要求2所述的式(II)化合物，其中
    Figure PCTCN2019128092-appb-100003
    选自以下结构，     The compound of formula (II) according to claim 2, wherein
    Figure PCTCN2019128092-appb-100003
    Selected from the following structures,
    Figure PCTCN2019128092-appb-100004
    Figure PCTCN2019128092-appb-100004
  6. 一种式(III)化合物，其立体异构体，互变异构体或药学上可接受的盐，A compound of formula (III), its stereoisomer, tautomer or pharmaceutically acceptable salt,
    Figure PCTCN2019128092-appb-100005
    Figure PCTCN2019128092-appb-100005
    其中，R 1选自-C 1-6烷基，-C 2-6烯基，-C 2-6炔基或-C 3-6碳环基，其中烷基，烯基，炔基或碳环基可被任意取代，包括氟，氯，溴，碘，氰基，羟基，氨基，氘原子取代； Wherein R 1 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or -C 3-6 carbocyclyl, wherein alkyl, alkenyl, alkynyl or carbon The cyclic group can be optionally substituted, including fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, deuterium atoms;
    环B为可被任意取代的含氮杂环。Ring B is a nitrogen-containing heterocyclic ring which may be optionally substituted.
  7. 如权利要求1至6所述的式(I)，(II)和(III)化合物，其立体异构体，互变异构体或药学上可接受的盐，其选自下述化合物，The compounds of formulae (I), (II) and (III) as claimed in claims 1 to 6, their stereoisomers, tautomers or pharmaceutically acceptable salts selected from the following compounds,
    Figure PCTCN2019128092-appb-100006
    Figure PCTCN2019128092-appb-100006
  8. 一种如权利要求1至7中任一项所述式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐的制备方法，包括如下步骤：A method for preparing a compound of formula (I) according to any one of claims 1 to 7, its stereoisomer, tautomer or pharmaceutically acceptable salt, comprising the following steps:
    Figure PCTCN2019128092-appb-100007
    Figure PCTCN2019128092-appb-100007
    其中，R 1，环A的定义如权利要求1， Where R 1 and ring A are as defined in claim 1,
    步骤1，在合适的溶剂中，在合适的温度下，化合物SM与多聚甲醛偶联成为化合物M1；Step 1. In a suitable solvent and at a suitable temperature, compound SM and paraformaldehyde are coupled to form compound M1;
    步骤2，在合适的溶剂和合适的碱存在下，在合适的温度下，化合物M1与化合物M2反应得到式(I)化合物。Step 2. In the presence of a suitable solvent and a suitable base, at a suitable temperature, compound M1 is reacted with compound M2 to obtain a compound of formula (I).
  9. 一种式(IV)化合物，其立体异构体，互变异构体或药学上可接受的盐，A compound of formula (IV), its stereoisomer, tautomer or pharmaceutically acceptable salt,
    Figure PCTCN2019128092-appb-100008
    Figure PCTCN2019128092-appb-100008
    其中，R 1选自-C 1-6烷基，-C 2-6烯基，-C 2-6炔基或-C 3-6碳环基，其中烷基，烯基，炔基或碳环基可被任意取代，包括氟，氯，溴，碘，氰基，羟基，氨基，氘原子取代； Wherein R 1 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or -C 3-6 carbocyclyl, wherein alkyl, alkenyl, alkynyl or carbon The cyclic group can be optionally substituted, including fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, deuterium atoms;
    R a，R b选自氢，-C 1-6烷基，-C 2-6烯基，-C 2-6炔基，-C 3-8环烷基，杂烷基，芳基，芳烷基，杂芳基或3至8元杂环基，其中，烷基，烯基，炔基，环烷基，杂烷基，芳基，芳烷基，杂芳基或杂环基可被选自-C 1-6烷基，卤素，-OH，氧代，-C 1-6烷氧基的取代基取代。 R a , R b are selected from hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, heteroalkyl, aryl, aryl Alkyl, heteroaryl or 3- to 8-membered heterocyclic group, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, aralkyl, heteroaryl or heterocyclic group may be It is substituted with a substituent selected from -C 1-6 alkyl, halogen, -OH, oxo, -C 1-6 alkoxy.
  10. 下述化合物，其立体异构体，互变异构体或药学上可接受的盐，The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
    Figure PCTCN2019128092-appb-100009
    Figure PCTCN2019128092-appb-100009
  11. 一种药物组合物，其包括治疗有效剂量的权利要求1至10中任一项所述化合物或其立体异构体，互变异构体或药学上可接受的盐及可药用的载体。A pharmaceutical composition comprising a therapeutically effective dose of a compound according to any one of claims 1 to 10 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  12. 根据权利要求1-10中任意一项所述的化合物或其可药用的盐或根据权利要求10所述的药物组合物在制备用于预防和/或治疗与GABA功能有关的疾病的药物中的用途。The compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 10 in the preparation of a medicament for preventing and/or treating diseases related to GABA function the use of.
  13. 根据权利要求12中的用途，其中所述与GABA功能有关的疾病为各种神经***疾病。The use according to claim 12, wherein the diseases related to GABA function are various neurological diseases.
  14. 一种治疗和/或预防与GABA功能有关的疾病的方法，其包括向患者施用治疗有效量的权利要求1-10中任意一项所述的化合物或其可药用盐或根据权利要求11所述的药物组合物，其中所述与GABA功能有关的疾病为各种神经***疾病。A method for treating and/or preventing diseases related to GABA function, which comprises administering to a patient a therapeutically effective amount of a compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof or according to claim 11 The pharmaceutical composition, wherein the diseases related to GABA function are various neurological diseases.
  15. 一种治疗和/或预防各种神经***疾病的方法，其包括向患者施用治疗有效量的权利要求1-10中任意一项所述的化合物或其可药用盐或根据权利要求11所述的药物组合物，其中所述的神经***疾病选自睡眠障碍，精神***症，抑郁，自闭症，人格障碍，情感障碍，焦虑，癫痫。A method for treating and/or preventing various neurological diseases, which comprises administering to a patient a therapeutically effective amount of the compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof or according to claim 11 The pharmaceutical composition, wherein the neurological diseases are selected from sleep disorders, schizophrenia, depression, autism, personality disorders, emotional disorders, anxiety, epilepsy.
  16. 根据权利要求1-10中任意一项所述的化合物或其可药用的盐或根据权利要求11所述的药物组合物在制备用于治疗焦虑，经前综合症，抑郁，产后抑郁的药物以及用于镇静，催眠，麻醉的药物中的用途。The compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 11 is prepared for the treatment of anxiety, premenstrual syndrome, depression, postpartum depression And the use in medicine for sedation, hypnosis, anesthesia.
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