WO2018228476A1 - Benzimidazole compounds and application thereof - Google Patents

Benzimidazole compounds and application thereof Download PDF

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Publication number
WO2018228476A1
WO2018228476A1 PCT/CN2018/091270 CN2018091270W WO2018228476A1 WO 2018228476 A1 WO2018228476 A1 WO 2018228476A1 CN 2018091270 W CN2018091270 W CN 2018091270W WO 2018228476 A1 WO2018228476 A1 WO 2018228476A1
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group
mmol
etoac
pharmaceutically acceptable
acceptable salt
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PCT/CN2018/091270
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French (fr)
Chinese (zh)
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王大海
钱文远
刘世岚
陈曙辉
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南京明德新药研发股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline

Definitions

  • the present invention relates to a series of benzimidazoles and their use as inhibitors of IDH mutants, and in particular to compounds of the formula ( ⁇ ), tautomers thereof or pharmaceutically acceptable salts thereof.
  • Isocitrate dehydrogenase is an important enzyme in the citric acid cycle, catalyzing the oxidative decarboxylation of isocitrate to 2-oxoglutaric acid (ie 2- ⁇ -ketoglutarate, ⁇ -KG).
  • the protein encoded by IDH 1 is a NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes, which contains a PTS-1 peroxidase targeting signal sequence. The presence of this enzyme in the oxidase body suggests an effect in the regeneration of the internal NADPH.
  • Non-mutation such as wild-type IDH, catalyzes the oxidative decarboxylation of isocitrate while reducing NAD + (NADP + ) to NADP (NADPH):
  • IDH 1/2 mutation has been found in a variety of tumors, including glioma, acute myeloid leukemia (AML), chondrosarcoma, intrahepatic cholangiocarcinoma, melanoma, prostate cancer, and angioimmunoblastic T-cell lymphoma. Protein (IDH 1/2m). In gliomas, more than 70% of non-primary glioblastomas have IDH1 mutations, and 92.7% of IDH1 mutant tumors are arginine replaced by histidine (ie, IDH1 R132H).
  • the IDH mutein has a novel protein function, namely catalytic reduction of ⁇ -KG to produce the oncogenic metabolite 2-hydroxyglutaric acid (2-HG), which is believed to contribute to the formation and progression of cancer.
  • the level of 2-HG produced in normal cells is very low, but cells with IDH mutations can produce high levels of 2-HG. High levels of 2-HG can also be found in tumors with IDH mutations.
  • the inhibition of mutant IDH and its novel activity is a potential method for cancer treatment, and there is a new effect of requiring an inhibitor of IDH mutant to inhibit its production of 2-HG.
  • the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof,
  • T 1 and T 2 are each independently selected from: N or CH;
  • R 1 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, or selected from C 1 1-6 alkyl, C 1-6 heteroalkane optionally substituted by 1, 2 or 3 R Base, C 3-6 cycloalkyl;
  • R 2 are each independently selected from H, F, Cl, Br, I, OH, NH 2 or independently selected from: C 1-6 alkyl optionally substituted by 1, 2 or 3 R;
  • R 3 is selected from C 1 1-6 alkyl, C 1-6 heteroalkyl optionally substituted by 1, 2 or 3 R;
  • L 1 is selected from the group consisting of: 1, 2 or 3 R substituted: -C 1-6 alkyl-, -C 1-6 heteroalkyl-, -3 to 6-membered heterocycloalkyl-, -C 3 -6 cycloalkyl-C 1-6 alkyl-;
  • R is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, or selected from the group consisting of 1, 2 or 3 R's substituted: C 1-6 alkyl, C 1-6 hetero alkyl;
  • R' is selected from the group consisting of: F, Cl, Br, I, OH, NH 2 , CN, Me;
  • hetero of the C 1-6 heteroalkyl group and the 3-6 membered heterocycloalkyl group is selected from the group consisting of N, -O-, -S-, -NH-;
  • the number of the above heteroatoms or heteroatoms is independently selected from 1, 2, 3 or 4.
  • the above R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from: C 1-3 alkane optionally substituted by 1, 2 or 3 R' Base, C 1-3 alkoxy.
  • R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from the group consisting of 1, 2 or 3 R' substitutions: Me, Et,
  • the above R is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Et,
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from: C 1-3 alkane optionally substituted by 1, 2 or 3 R Base, C 1-3 alkoxy, cyclopropyl.
  • R 1 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Et,
  • R 2 are each independently selected from H, F, Cl, Br, I, OH, NH 2 or independently selected from, optionally substituted by 1, 2 or 3 R: C 1-3 alkyl.
  • R 2 is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , Me.
  • R 3 above is selected from C 1 - 3 alkyl, C 1-3 alkoxy optionally substituted by 1, 2 or 3 R.
  • R 3 is selected from the group consisting of: 1, 2 or 3 R: Me, Et,
  • R 3 is selected from the group consisting of Me, CF 3 , Et, CH(CH 3 ) 2 ,
  • the above L 1 is selected from optionally substituted with 1, 2 or 3 R is: -C 1-3 alkyl -, - C 1-3 alkyl -O -, - 4-membered heterocycle Alkyl-, -cyclopropyl-C 1-3 alkyl-.
  • the above L 1 is selected from the group consisting of: 1, (or 2 or 3) R substituted: -(CH 2 ) 2 -, -CH 2 -O-, -azetidinyl-, -cyclopropyl- CH 2 -.
  • the above L 1 is selected from the group consisting of: -(CH 2 ) 2 -, -CH 2 C(CH 3 ) 2 -, -CH 2 -O-,
  • the structural unit From:
  • the structural unit From:
  • the above R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from: C 1-3 alkane optionally substituted by 1, 2 or 3 R'
  • the group, C 1-3 alkoxy, other variables are as defined in the present invention.
  • R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from the group consisting of 1, 2 or 3 R' substitutions: Me, Et, Other variables are as defined by the present invention.
  • the above R is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Et, Other variables are as defined by the present invention.
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from: C 1-3 alkane optionally substituted by 1, 2 or 3 R Base, C 1-3 alkoxy, cyclopropyl, other variables are as defined herein.
  • R 1 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Et, Other variables are as defined by the present invention.
  • R 2 are each independently selected from H, F, Cl, Br, I, OH, NH 2 or independently selected from, optionally substituted by 1, 2 or 3 R: C 1-3 alkyl, other variables are as defined herein.
  • R 2 is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , Me, and other variables are as defined herein.
  • R 3 above is selected from C 1 1-3 alkyl, C 1-3 alkoxy optionally substituted by 1, 2 or 3 R, and other variables are as defined herein.
  • R 3 is selected from the group consisting of: 1, 2 or 3 R: Me, Et, Other variables are as defined by the present invention.
  • R 3 is selected from the group consisting of Me, CF 3 , Et, CH(CH 3 ) 2 , Other variables are as defined by the present invention.
  • L 1 is selected from optionally substituted with 1, 2 or 3 R is: -C 1-3 alkyl -, - C 1-3 alkyl -O -, - 4-membered heterocycle Alkyl-, -cyclopropyl-C 1-3 alkyl-, other variables are as defined herein.
  • the above L 1 is selected from the group consisting of: 1, (or 2 or 3) R substituted: -(CH 2 ) 2 -, -CH 2 -O-, -azetidinyl-, -cyclopropyl- CH 2 -, other variables are as defined by the present invention.
  • the above L 1 is selected from the group consisting of: -(CH 2 ) 2 -, -CH 2 C(CH 3 ) 2 -, -CH 2 -O-, Other variables are as defined by the present invention.
  • the above compound, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • n is selected from: 0, 1 or 2;
  • n is selected from: 1, 2 or 3;
  • T 1 , T 2 , T 3 are each independently selected from: N or CH;
  • L 2 is selected from the group consisting of: 1, 2 or 3, R: -C 1-3 alkyl-, -C 1-3 alkoxy-;
  • R, R 1 , R 2 , R 3 are as defined in the present invention.
  • the above compound, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • n is selected from: 0, 1 or 2;
  • n is selected from: 1, 2 or 3;
  • T 1 , T 2 , T 3 are each independently selected from: N or CH;
  • L 2 is selected from the group consisting of: -(CH 2 ) 2 -, -CH 2 C(CH 3 ) 2 -, -CH 2 -O-;
  • R, R 1 , R 2 , R 3 are as defined by the claims.
  • the present invention also provides a compound of the formula: or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above composition for the preparation of a drug related to an IDH mutant inhibitor.
  • pharmaceutically acceptable as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • Wedge and dashed keys unless otherwise stated Represents the absolute configuration of a stereocenter, using wavy lines Indicates a wedge or dashed key use Indicates the relative configuration of the stereocenter.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Ketone substitution does not occur on the aryl group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • the medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B. It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic.
  • the hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons) , C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .).
  • C 1-12 is selected from C 1
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • hydrocarbyl means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy). By customary expression, those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents attached through an oxygen bridge
  • C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), they are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • aryl or heteroaryl groups include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isomerism Azyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, indolyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl, 1 -naphthyl, 2-naphthyl, 4-biphenylyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • the compounds of the present invention have significant IDH1 mutant inhibition and good selectivity, while having a better distribution ratio in brain tumors and paracranial tissues, which can reduce potential side effects on normal brain tissue.
  • Example 1 inhibits the level of 2-HG in brain tumor, plasma and paracancerous brain tissue of Balb/c mice
  • Example 1B (1.00 g, 2.80 mmol), (E)-3-(4,4,5,5-tetramethyl-1,3,2-oxaboran-2-yl)ethyl acrylate (949.28 Mg, 4.20 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (204.82 mg, 279.92 ⁇ mol), potassium carbonate (1.16 g, 8.40 mmol) of dioxane The mixed solution of (15.00 ml) and water (1.50 ml) was replaced with nitrogen three times, then heated to 95 ° C and stirred for 4 hours. The reaction mixture was concentrated to dryness vacuol.
  • Example 1C A solution of Example 1C (750.00 mg, 1.99 mmol) and palladium carbon (130.00 mg, 10% purity) in methanol (20.00 mL) was used to displace hydrogen three times and then stirred at 20 ° C for 16 hours under a hydrogen (15 psi) atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give a residue.
  • Example 1E To a solution of Example 1D (200.00 mg, 573.92 ⁇ mol) in tetrahydrofuran (3.00 mL) was added 1-isothiocyano-4-(trifluoromethoxy)benzene (125.79 mg, 573.92 ⁇ mol, 93.18 ⁇ l), stirring for three hours, then adding EDCI (220.04 mg, 1.15 mmol), the reaction solution was heated to 70 ° C for 3 hours, and the reaction solution was concentrated under reduced pressure to give a residue. Purification gave Example 1E.
  • Example 1D To a solution of Example 1D (300.00 mg, 562.24 ⁇ mol) of tetrahydrofuran (5.00 ml) and water (5.00 ml) was added lithium hydroxide monohydrate (117.96 mg, 2.81 mmol), and the reaction mixture was stirred at 70 ° C for 16 hours. The mixture was concentrated under reduced pressure to remove tetrahydrofuran, and the residue was diluted with water (10.00 ml), then acidified with 1N hydrochloric acid to adjust pH 6 and filtered and collected to give Example 1.
  • Example 2A 122.09 mg, 688.70 ⁇ mol was added to a solution of 344.35 ⁇ mol of tetrahydrofuran (3.00 ml), stirred for 2 hours, then EDCI (132.02 mg, 688.70 ⁇ mol) was added, and the reaction was stirred at 70 ° C. hour. The reaction mixture was concentrated under reduced pressure to give a crystallite.
  • Example 3B (120.00 mg, 231.85 micromoles) and lithium hydroxide monohydrate (24.32 mg, 579.63 micromoles) were dissolved in methanol (5.00 mL) and water (1.00 mL). The mixed solution was reacted at 15 ° C for 16 hours. After completion of the reaction, the crude product was concentrated under reduced pressure.
  • Example 4A 600 mg was dissolved in 30 ml of tetrahydrofuran, and 995 mg of potassium carbonate and 755 mg of 2,2,6,6-tetramethyltetrahydropyran-4-amine were added. The reaction solution was stirred at 60 ° C for 16 hours. The reaction mixture was diluted with water and EtOAc (EtOAc m.
  • Example 4B was obtained by flash silica gel column chromatography.
  • Example 4B (800 mg, 2.07 mmol), ethyl-(E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Ethyl acrylate (1.4 g, 6.20 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (302 mg, 0.42 mmol), cesium carbonate (1.35 g) , 4.13 mmol) was added to dioxane (8 ml) and water (2 ml), and the mixture was degassed with nitrogen for 3 times, and then the reaction mixture was reacted at 90 ° C for 16 hours under nitrogen atmosphere. The reaction mixture was filtered, washed with EtOAc EtOAc. Purification by flash silica gel column chromatography gave Example 4C.
  • Example 4C (900 mg, 2.21 mmol) was dissolved in 30 ml of methanol, and 0.6 g of 10% palladium carbon was added under a nitrogen atmosphere. The reaction solution was replaced with H 2 for 3 times and stirred at 10 ° C in a hydrogen atmosphere. hour. The reaction solution was concentrated by filtration to give Example 4D.
  • Example 4E (500 mg, 0.89 mmol) was added to 15 ml of tetrahydrofuran and 15 ml of water, and lithium hydroxide monohydrate (186.12 mg, 4.44 mmol) was added, and the mixture was stirred at 40 ° C for 16 hours. The reaction mixture was adjusted to pH 3-4, and extracted with 100 ml of ethyl acetate, obtained in Example 4.
  • Example 5A (870 mg, 2.34 mmol), ethyl-(E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Ethyl acrylate (1.59 g, 7.03 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (343 mg, 0.469 mmol), cesium carbonate (1.53 g) , 4.69 mmol), dissolved in 8 ml of dioxane and 2 ml of water, and replaced with nitrogen three times. The reaction solution was stirred at 90 ° C for 16 hours under a nitrogen atmosphere.
  • Example 5B was obtained by flash column chromatography on silica gel.
  • Example 5B (600 mg, 1.54 mmol) was dissolved in 30 ml of methanol, and 10 g of 0.6 g of palladium carbon was added under a nitrogen atmosphere. The reaction solution was replaced with H 2 for 3 times and stirred at 10 ° C in a hydrogen atmosphere. hour. The reaction solution was concentrated by filtration to give Example 5C.
  • Example 5D (350 mg, 0.64 mmol) was dissolved in 15 mL of tetrahydrofuran and 15 mL water, and lithium hydroxide monohydrate (134.09 mg, 3.2 mmol) was added. The reaction solution was stirred at 40 ° C for 16 hours. The pH of the reaction mixture was adjusted to 3-4. Example 5 was obtained by high performance liquid chromatography.
  • Example 6A A solution of Example 6A (1.00 g, 3.69 mmol) in tetrahydrofuran (10.00 mL) was added potassium carbonate (1.02 g, 7.38 mmol) and 2,2,6,6-tetramethyltetrahydropyran-4-amine ( 580.26 mg, 3.69 mmol), the mixture was stirred at 50 ° C for 16 hours, then 2,2,6,6-tetramethyltetrahydropyran-4-amine (580.26 mg, 3.69 mmol) was added to make the reaction The solution was stirred at 70 ° C for 16 hr.
  • Example 6C (200.00 mg, 528.40 micromol) of tetrahydrofuran (4.00 ml) was added 1-isothiocyano-4-(trifluoromethoxy)benzene (115.82 mg, 528.40 micromoles, 85.79 microliters), mixture After stirring at 30 ° C for 2 hours, additional EDCI (202.59 mg, 1.06 mmol) was added, and the mixture was stirred at 70 ° C for 3 hours. The reaction mixture was diluted with ethyl acetate (10 ml), water (2 ml ⁇ 3) and brine It was washed with 10 ml), dried over anhydrous sodium sulfate, filtered, and evaporated.
  • Example 7A (0.775 g, 2.51 mmol), EtOAc (EtOAc) And the precipitate was collected by filtration to give Example 7B.
  • Example 7B (0.82 g, 1.39 mmol), (E)-3-(4,4,5,5-tetramethyl-1,3,2-oxaboran-2-yl)ethyl acrylate (472.70 Mg, 2.09 mmol, 1,1,-bis(diphenylphosphino)ferrocene palladium dichloride (101.99 mg, 139.39 ⁇ mol), potassium carbonate (577.96 mg, 4.18 mmol) of dioxane A mixture of (10.00 ml) and water (1.00 ml) was replaced with nitrogen three times, then heated to 90 ° C and stirred for 16 hours. The reaction mixture was diluted with EtOAc EtOAc EtOAc. The residue was purified by column chromatography to give Example 7C.
  • Example 7E was obtained.
  • Example 7E To a solution of Example 7E (0.5 g, 888.70 ⁇ mol) of tetrahydrofuran (8.00 ml) and water (8.00 ml) was added lithium hydroxide monohydrate (186.45 mg, 4.44 mmol), and the reaction mixture was stirred at 15 ° C for 16 hours. The mixture was concentrated under reduced pressure to remove EtOAc. EtOAc (EtOAc) (EtOAc) The residue was dried with EtOAc (EtOAc).
  • Example 8B An insurance powder (1.23 g, 7.06 mmol) and sodium carbonate (1.07 g, 10.08 mmol) were added to a mixed solution of Example 8B (790.00 mg, 2.02 mmol) in ethanol (10 ml) and water (10 ml). The mixture was stirred at 70 ° C for 16 hours. The reaction mixture was separated with EtOAc EtOAc EtOAc.
  • Example 8E To a solution of Example 8E (300 mg, 530.03 micromoles) in methanol (4 ml) was added to a solution of EtOAc (40. , 1.06 mmol) in DMF (2 mL). Stir at room temperature for 16 hours. Ethyl acetate (15 ml) and water (15 ml) were added toEtOAc. Washing, drying, filtration and concentration under reduced pressure afforded Example 8F.
  • Lithium hydroxide monohydrate (110.81 mg, 2.64 mmol) was added to a mixed solution of Example 8F (300 mg, 528.14 ⁇ mol) in tetrahydrofuran (3 ml) and water (3 ml). Stir at 40 ° C for 16 hours. The pH was adjusted to 5 with 1 mol of hydrochloric acid, and dried to give a residue.
  • Example 9A To a solution of Example 9A (1 g, 4.14 mmol) and 2,2,6,6-tetramethyltetrahydropyran-4-amine (976.51 mg, 6.21 mmol) in dioxane (20 mL) Potassium carbonate (1.72 g, 12.42 mmol) was added, and the reaction solution was stirred at 95 ° C for 16 hours. The reaction mixture was concentrated to drynessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss
  • Example 9C (0.45 g, 673.10 ⁇ mol), (E)-3-(4,4,5,5-tetramethyl-1,3,2-oxaboran-2-yl)ethyl acrylate (228.26 Mg, 1.01 mmol, 1,1,-bis(diphenylphosphino)ferrocene palladium dichloride (49.25 mg, 67.31 ⁇ mol), potassium carbonate (279.09
  • Example 9D Palladium carbon (0.03 g, 10% purity) was added to a solution of Example 9D (0.16 g, 347.49 micromoles) in methanol (2 mL) and DCM (2 mL). The mixture was stirred several times at 15 ° C under a hydrogen (15 psi) atmosphere for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced vacuo.
  • Example 9F To a solution of Example 9F (3.00 ml) and water (3.00 ml), lithium hydroxide monohydrate (54.36 mg, 1.30 mmol) was added, and the reaction mixture was stirred at 15 ° C for 16 hours, and the reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. It was diluted with water (5 ml), and then adjusted to pH 3 with a 1N hydrochloric acid solution, and the precipitate was collected by filtration to obtain Example 9.
  • Example 10C 1-Isothiocyanato-4-(trifluoromethoxy)benzene (152.56 mg, 696.02 ⁇ mol) was added to a solution of Example 10C (230 mg, 632.75 micromoles) in tetrahydrofuran (8 mL), 40 Stir at °C for 16 hours. Further, EDCI (145.56 mg, 759.30 ⁇ mol) was added to the reaction solution, and the mixture was stirred at 80 ° C for 3 hours. The reaction mixture was separated with EtOAc EtOAc (EtOAc m. Example 10D was obtained.
  • Example 10D To a mixed solution of Example 10D (220 mg, 401.02 ⁇ mol) in tetrahydrofuran (2 ml) and water (2 ml) was added. Stir at 40 ° C for 16 hours. The pH was adjusted to 5 with 1 mol of hydrochloric acid, and dried to give a residue.
  • Example 11B A solution of Example 11B (0.75 g, 1.9 mmol) in methanol was added 20% wet Pd / C (1.01 g, 1.9 mmol). The reaction solution was stirred for half an hour in an atmosphere of a hydrogen balloon at 20 °C. Thin sheet chromatography showed complete reaction of the starting material. After the reaction solution was filtered, the mother liquid was spun dry to obtain Example 11C, which was directly used for the next reaction.
  • Example 12C Hexahydrate and nickel dichloride (470.63 mg, 1.98 mmol) were added to a solution of Example 12C (220.00 mg, 495.00 micromoles) in methanol (5 ml), then sodium borohydride (37.45 mg, 999.00) A solution of micromolar) in DMF (2 mL). Stir at room temperature for 16 hours. The reaction mixture was poured with EtOAc EtOAc (EtOAc m. Filtration and concentration under reduced pressure gave Example 12D.
  • Example 12D 1-Isothiocyanato-4-(trifluoromethoxy)benzene (109.99 mg, 501.33 ⁇ mol) was added to a solution of Example 12D (190 mg, 450.21 micromoles) in tetrahydrofuran (3 ml), 40 ° C Stir under 16 hours. Further, EDCI (104.95 mg, 547.45 ⁇ mol) was added to the reaction solution, and the mixture was stirred at 80 ° C for 2 hours. The reaction mixture was separated with EtOAc EtOAc (EtOAc m. Example 12E was obtained.
  • Lithium hydroxide monohydrate (69.76 mg, 1.66 mmol) was added to a mixed solution of Example 12E (200 mg, 332.46 ⁇ mol) of tetrahydrofuran (2 ml) and water (2 ml). Stir at 40 ° C for 16 hours. The pH was adjusted to 5 with 1 mol of hydrochloric acid, and dried to give a residue.
  • N-(4-Bromo-2-nitrophenyl)-4,4,6,6-tetramethyltetrahydropyran-2-amine (0.4 g, 1.12 mmol), azetidine-3 -Methylcarboxylate (203.68 mg, 1.34 mmol, hydrochloride), [2-(dicyclohexylphosphino)-3,6-methoxy-2',4',6'-triisopropyl- a mixed solution of 1,1'-biphenyl][2-(2-aminoethyl)benzene]palladium chloride (44.72 mg, 55.98 ⁇ mol), potassium carbonate (619.01 mg, 4.48 mmol) in toluene (8 ml) It was replaced with nitrogen three times, and then heated to 100 ° C and stirred for 16 hours.
  • Example 13C To a solution of Example 13C (0.12 g, 214.72 ⁇ mol) of tetrahydrofuran (2.00 ml) and water (2.00 ml), lithium hydroxide monohydrate (27.03 mg, 644.15 ⁇ mol) was added, and the reaction mixture was stirred at 20 ° C for 16 hours. The mixture was acidified with EtOAc (EtOAc) (EtOAc)EtOAc. The residue was purified by high performance liquid chromatography to give Example 13.
  • EtOAc EtOAc
  • EtOAc EtOAc
  • Example 14A To a solution of 4-fluorobenzoic acid (9 g, 64.23 mmol) in tetrahydrofuran (120 ml) was added imidazole (874.58 mg, 12.85 mmol) and carbonyldiimidazole (11.46 g, 70.66 mmol). Stir for 16 hours. The reaction solution was directly beaten by acetone:water to 1:1 to obtain Example 14A.
  • Example 14A To a solution of Example 14A (12.2 g, 64.15 mmol) in EtOAc (EtOAc) 128.30 mmol), the reaction solution was stirred at 55 ° C for 16 hours. The reaction was poured into EtOAc (EtOAc) (EtOAc (EtOAc) Example 14B was obtained by water 1:1 with water: acetone.
  • 1 H NMR (400 MHz, CHLOROFORM-d) ⁇ 8.00 (br s, 2H), 7.16 (br s, 2H), 4.23 (br s, 2H), 3.97 (br s, 2H), 1.27 (br s, 3H) ).
  • Triethylsilane (7.75 g, 66.67 mmol, 10.65 mL) was added to a solution of Example 14C (6.3 g, 26.67 mmol) in trifluoroacetic acid (60 mL). The reaction solution was stirred at 15 ° C for 16 hours. The reaction mixture was poured into ice water (200 ml), and then ethyl acetate (200 ml) was added, and the mixture was basified with sodium carbonate and adjusted to pH 9. The combined organic layers were washed with brine (200 ml x 2).
  • Example 14F Potassium carbonate (116.36 mg, 841.90 micromoles) and 2,2,6,6-tetramethyltetrahydropyran-4-amine (132.39 mg, 841.90 micromoles) were added to a solution of Example 14D in DMF (3 mL). The mixture was stirred at 90 ° C for 16 hours. The mixture was poured into water (20 ml), EtOAc (EtOAc m. The residue obtained was purified by column chromatography to give Example 14F.
  • Example 14F 160 mg, 395.55 [mu] mol in methanol (3 mL) was added NiCl 2 .6H 2 O (376.07 mg, 1.58 mol), followed by addition of NaBH 4 (29.93 mg, 791.10 micro
  • EtOAc 3 mL
  • EtOAc EtOAc
  • EtOAc EtOAc
  • MS-ESI m/z
  • Example 14G was added a solution of 1-isothiocyanato-4-(trifluoromethoxy)benzene (90.13 mg, 411.20 ⁇ mol) in a solution of Example 14G (140 mg, 373.81 mmol) in tetrahydrofuran (5 mL) at 40 ° C Stir for 16 hours. Then EDCI (85.99 mg, 448.58 micromoles) was added and the reaction was stirred at 80 ° C for 2 hours. The mixture was poured into water (15 ml), EtOAc (EtOAc m. Example 14H was isolated by TLC plate. MS-ESI (m/z): 560 (M+H) + .
  • Example 15A (2.5 g, 7.00 mmol), cyclopropylboronic acid (721.34 mg, 8.40 mmol), Pd (dppf) Cl 2 (1.02 g, 1.04 mmol) and cesium carbonate (4.56 g, 14.00 mmol) It was dissolved in a mixed solution of dioxane (25 ml) and water (2.5 ml), and reacted at 90 ° C for 16 hours under the protection of an inert gas. After the reaction was completed, the reaction mixture was filtered, evaporated, evaporated, evaporated, evaporated, evaporated. The mixture was dried with sodium sulfate, filtered, evaporated, evaporated, evaporated
  • Example 15B (2.5 g, 7.00 mmol) was dissolved in DMF (15 mL), and then a mixture of N-bromosuccinimide (1.17 g, 6.60 mmol) was reacted at 20 ° C for 16 hours. After the completion of the reaction, water (50 ml) was added, and then ethyl acetate (20 ml ⁇ 3) was evaporated. Drying, filtration and concentration under reduced pressure afforded Example 15C.
  • Example 15D (1.11 g, 2.67 mmol) was dissolved in MeOH (12 mL). EtOAc (EtOAc: EtOAc. ). After the mixture was reacted at 0 ° C for 10 minutes, a mixture of sodium borohydride (403.3 mg, 10.66 mmol) was added and reacted at 20 ° C for 16 hours. After the reaction was completed, the reaction mixture was evaporated, evaporated, evaporated, evaporated, evaporated. The residue was dried over anhydrous sodium sulfate, filtered and evaporated.
  • Example 15E (200.00 mg, 514.74 ⁇ mol) and 1-isothiocyanato-4-(trifluoromethoxy)benzene (124.11 mg, 566.22 ⁇ mol) in tetrahydrofuran (5.00 ml) mixed solution stirred at 30 ° C After 3 hours, EDCI (197.35 mg, 71.03 mmol) was further added, and the reaction solution was reacted at 70 ° C for 3 hours. After the completion of the reaction, water (5 ml) was added to the mixture, and the aqueous phase was extracted with ethyl acetate (10 ml ⁇ 3), and the combined organic phases were washed with water (10 ml) and brine (10 ml ⁇ 1). The residue was dried over anhydrous sodium sulfate, filtered and evaporated.
  • Example 15F (170 mg, 296.35 ⁇ mol) and lithium hydroxide monohydrate (62.18 mg, 1.48 mmol) were dissolved in a mixture of methanol (5.00 ml) and water (1.00 ml). The mixed solution was reacted at 20 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a crude material.
  • Example 16B Lithium chloride (271.07 mg, 6.39 mmol, 130.95 ml) and water (300.00 mg, 16.65 mmol, 0.3 ml) were added to a solution of Example 16A (1 g, 3.20 mmol) in dimethyl sulfoxide (10 ml). The reaction mixture was stirred at 180 ° C for 12 hours, the reaction mixture was diluted with water (40 ml), and then extracted with ethyl acetate (30 ml ⁇ 2), and the combined organic layer was washed with brine (30 ml ⁇ 1) The sodium was dried, filtered, and concentrated under reduced pressure to give Example 16B.
  • Example 16C Potassium nitrate (255.78 mg, 2.53 mmol) was added to a solution of Example 16B (0.58 g, 2.41 mmol). The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. Filtration and concentration under reduced pressure gave Example 16C.
  • Example 16C To a solution of Example 16C (0.47 g, 1.64 mmol) in dimethyl sulfoxide (8 mL), potassium carbonate (682.05 mg, 4.93 mmol) and 2,2,6,6-tetramethyltetrahydropyran. 4-Amine (310.41 mg, 1.97 mmol). The reaction solution was stirred at 130 ° C for 24 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc)EtOAc. The residue obtained by concentration was purified by chromatography to afford Example 16D.
  • EtOAc EtOAc
  • Example 16F To a solution of Example 16F (134 mg, 238.59 ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ /RTI> ⁇ /RTI> ⁇ /RTI> ⁇ /RTI> ⁇ /RTIgt;
  • the reaction mixture was acidified with hydrochloric acid (1N) to adjust pH to 3 and then the precipitate was collected by filtration.
  • the IDH1 mutant catalyzes the reduction of NADPH-dependent ⁇ -KG to 2-HG, and the consumed NADPH can be read by fluorescence.
  • IDH1 wt wild type: 65 ⁇ M isocitric acid + 50 ⁇ M NADP
  • IDH1 (R132H): 1500 ⁇ M ⁇ -KG+15 ⁇ M NADPH
  • IDH1 (R132C): 500 ⁇ M ⁇ -KG+15 ⁇ M NADPH
  • 1.33X enzyme (not added in the control well), buffer and NADP or NADPH (control well) were added to the wells of the reaction plate, and the test compound was dissolved in 100% DMSO and added to the enzyme mixture (Echo550, Nanoscale). After simple centrifugation, the cells were incubated for 60 minutes, and a mixture of 4X substrate and cofactor was added to start the reaction. After simple centrifugation, the mixture was shaken and incubated at room temperature for 45 minutes.
  • IDH1 catalyzes the reduction of isocitrate to alpha-ketoglutarate ( ⁇ -KG) in vivo, while the IDH1 mutant further catalyzes the reduction of ⁇ -KG to 2-hydroxyglutarate (2HG).
  • the U87MG-IDH1-R132H cell line is a stable cell line stably expressing the IDH1-R132H mutant by transfecting U87MG cells with IDH1-R132H, and the HT1080 cell line contains an endogenous IDH1-R132C mutant.
  • the compound was diluted with DMSO in a 3-fold gradient and added to the cell culture plate for a total of 10 concentrations, each with double duplicate wells.
  • the negative control wells contained only DMSO and the positive control wells contained AGI-5198 at a final concentration of 5 [mu]M.
  • the final concentration of DMSO in all wells was 0.5%.
  • the IDH1 mutant cell strain was seeded at a density of 40,000 cells/well into a cell culture plate containing the compound. The cells were incubated with the compounds for 3 days at 37 ° C in a 5% CO 2 incubator.
  • cytotoxicity % (1-CPD/ZPE) ⁇ 100% *
  • HPE Mean value of positive control well signal, containing 5uM AGI-5198
  • a U87 stable cell line expressing exogenous expression of IDH1R132H was established, and a brain orthotopic tumor model of the cell line was constructed to detect the reduction effect of IDH1 inhibitor on the level of carcinogenic metabolite 2-HG. And compared with BAY1436032 (BAY032).
  • mice bearing U87-IDH1R132H brain orthotopic tumors were divided into three groups and administered to 100 mg/kg BAY032 or Example 1, administered twice daily for 3 times, and the other group was not. Do any treatment as a negative control. After 0.25 hours, 2 hours, and 8 hours of administration, the brain tumor, paracancerous brain tissue, and plasma of 3 mice were separately measured for 2-HG content, and the corresponding tissues of the negative control mice were used as controls.
  • Example 1 The total exposure (AUC) of Example 1 in brain tumors and paracranial tissues was 540777 nM ⁇ hr, 58872 nM ⁇ hr, respectively, while the total exposure (AUC) of BAY032 in brain tumors and paracranial tissues was 219710 nM ⁇ hr, respectively. , 102336nM ⁇ hr.
  • the compounds of the present invention have significant IDH1 mutant inhibition and good selectivity, and have a better distribution ratio in brain tumors and paracranial tissues, which can reduce potential side effects on normal brain tissues.
  • test compound was dissolved in DMSO to prepare a 10 mmol/L stock solution. Dilute to a theoretical concentration of 200 ⁇ M (containing 2% DMSO) with phosphate buffer. The mixture was shaken at room temperature for 24 hours, suction filtered, and the supernatant was taken and detected by HPLC-UV analysis. 980 ⁇ L of dissolution medium was pipetted into a 2 mL screw-capped glass vial using a pipette (Eppendorf Research). 20 ⁇ L of the stock solution of each test compound and the QC sample were added to a buffer solution corresponding to a kinetic detection solution of pH 6.5. The final concentrations of test compound and DMSO solution were 200 ⁇ M and 2%, respectively. Pill cover.
  • the theoretical maximum concentration is 200 ⁇ M.
  • the mixture was shaken at 880 rpm for 24 hours at room temperature.
  • the vial was centrifuged for 30 minutes at 13,000 rpm.
  • 200 ⁇ L of the supernatant was added to a 96-well plate using a digital pipette.
  • the solubility of the test compound was determined by high performance liquid chromatography.
  • Example 1 of the present invention exhibited excellent water solubility (at three different pH conditions) compared to BAY032.
  • the compounds of the invention are clearly more soluble in water than the prior art.
  • mice The purpose of this study was to determine the pharmacokinetic parameters of the compound and calculate its oral bioavailability in male CD-1 mice.
  • the project used six male CD-1 mice, three mice were administered intravenously at a dose of 1 mg/kg, and 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8 were collected after administration.
  • 24h plasma samples three other mice were orally administered by intragastric administration at a dose of 20 mg/kg, collected for 0 h (before administration) and 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8 after administration.
  • 24h plasma samples, then LC/MS/MS analysis and data collection of the collected samples, and the collected analytical data were calculated using Phoenix WinNonlin 6.3 software.
  • the compounds of the invention have better bioavailability and exposure compared to BAY032.

Abstract

The present invention relates to a series of benzimidazole compounds and application thereof as IDH mutant inhibitors, in particular, to a compound as represented by formula (I), tautomers thereof, or pharmaceutically-acceptable salts thereof.

Description

苯并咪唑类化合物及其应用Benzimidazole compounds and their applications
相关申请的引用Reference to related application
本申请主张于2017年06月15日提交的中国专利申请CN201710452439.1的优先权，其内容在此并入本申请。The present application claims priority to Chinese Patent Application No. CN.
技术领域Technical field
本发明涉及一系列苯并咪唑类化合物及其作为IDH突变体抑制剂的应用，具体涉及式(Ι)所示化合物、其互变异构体或其药学上可接受的盐。The present invention relates to a series of benzimidazoles and their use as inhibitors of IDH mutants, and in particular to compounds of the formula (Ι), tautomers thereof or pharmaceutically acceptable salts thereof.
技术背景technical background
异柠檬酸脱氢酶(Isocitrate dehydrogenase)是柠檬酸循环过程中的重要酶，催化异柠檬酸氧化脱羧成2-氧代戊二酸(即2-α-酮戊二酸，α-KG)。IDH 1这种基因编码的蛋白是在细胞质和过氧化物酶体中发现的NADP(+)-依赖性异柠檬酸脱氢酶，其中含有PTS-1过氧化物酶靶向信号序列。该酶在氧化物酶体中的存在暗示在用于内部NADPH再生中的作用。Isocitrate dehydrogenase is an important enzyme in the citric acid cycle, catalyzing the oxidative decarboxylation of isocitrate to 2-oxoglutaric acid (ie 2-α-ketoglutarate, α-KG). The protein encoded by IDH 1 is a NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes, which contains a PTS-1 peroxidase targeting signal sequence. The presence of this enzyme in the oxidase body suggests an effect in the regeneration of the internal NADPH.
非突变例如野生型IDH催化异柠檬酸氧化脱羧的同时，还原NAD +(NADP +)至NADP(NADPH): Non-mutation, such as wild-type IDH, catalyzes the oxidative decarboxylation of isocitrate while reducing NAD + (NADP + ) to NADP (NADPH):
异柠檬酸酯+NAD +(NADP +)→α-KG+CO 2+NADP(NADPH)+H + Isocitrate + NAD + (NADP + ) → α-KG + CO 2 + NADP (NADPH) + H +
已经在多种肿瘤，包括胶质瘤、急性髓性白血病(AML)、软骨肉瘤、肝内胆管瘤、黑色素瘤、***癌、血管免疫母细胞性T细胞淋巴瘤中，发现IDH 1/2突变蛋白(IDH 1/2m)。胶质瘤中，非原发性胶质母细胞瘤中70％以上具有IDH1突变，IDH1突变肿瘤中92.7％是精氨酸被组氨酸替代(即IDH1 R132H)。IDH 1/2 mutation has been found in a variety of tumors, including glioma, acute myeloid leukemia (AML), chondrosarcoma, intrahepatic cholangiocarcinoma, melanoma, prostate cancer, and angioimmunoblastic T-cell lymphoma. Protein (IDH 1/2m). In gliomas, more than 70% of non-primary glioblastomas have IDH1 mutations, and 92.7% of IDH1 mutant tumors are arginine replaced by histidine (ie, IDH1 R132H).
IDH突变蛋白具有新的蛋白功能，即催化还原α-KG生成致癌代谢物2-羟基戊二酸(2-HG)，2-HG的产生据信有助于癌症的形成和发展。正常细胞中产生2-HG的水平非常低，但是具有IDH突变的细胞能产生高水平的2-HG。在具有IDH突变的肿瘤中同样能够发现高水平的2-HG。The IDH mutein has a novel protein function, namely catalytic reduction of α-KG to produce the oncogenic metabolite 2-hydroxyglutaric acid (2-HG), which is believed to contribute to the formation and progression of cancer. The level of 2-HG produced in normal cells is very low, but cells with IDH mutations can produce high levels of 2-HG. High levels of 2-HG can also be found in tumors with IDH mutations.
因此突变IDH及其新活性的抑制是用于癌症治疗的潜在方法，也就存在需要获得IDH突变体的抑制剂来抑制其产生2-HG的新作用。Therefore, the inhibition of mutant IDH and its novel activity is a potential method for cancer treatment, and there is a new effect of requiring an inhibitor of IDH mutant to inhibit its production of 2-HG.
Acta Neuropathol(2017,Vol(133),Issue 4,629–644)公开了化合物BAY1436032的具体结构。Acta Neuropathol (2017, Vol (133), Issue 4, 629-644) discloses the specific structure of compound BAY 1436032.
Figure PCTCN2018091270-appb-000001
Figure PCTCN2018091270-appb-000001
发明内容Summary of the invention
本发明提供了式(Ⅰ)所示化合物或其药学上可接受的盐，The present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2018091270-appb-000002
Figure PCTCN2018091270-appb-000002
其中，among them,
T 1、T 2分别独立地选自：N或CH； T 1 and T 2 are each independently selected from: N or CH;
R 1选自H、F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6杂烷基、C 3-6环烷基； R 1 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, or selected from C 1 1-6 alkyl, C 1-6 heteroalkane optionally substituted by 1, 2 or 3 R Base, C 3-6 cycloalkyl;
R 2分别独立地选自H、F、Cl、Br、I、OH、NH 2，或分别独立地选自任选被1、2或3个R取代的：C 1-6烷基； R 2 are each independently selected from H, F, Cl, Br, I, OH, NH 2 or independently selected from: C 1-6 alkyl optionally substituted by 1, 2 or 3 R;
R 3选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6杂烷基； R 3 is selected from C 1 1-6 alkyl, C 1-6 heteroalkyl optionally substituted by 1, 2 or 3 R;
L 1选自任选被1、2或3个R取代的：-C 1-6烷基-、-C 1-6杂烷基-、-3～6元杂环烷基-、-C 3-6环烷基-C 1-6烷基-； L 1 is selected from the group consisting of: 1, 2 or 3 R substituted: -C 1-6 alkyl-, -C 1-6 heteroalkyl-, -3 to 6-membered heterocycloalkyl-, -C 3 -6 cycloalkyl-C 1-6 alkyl-;
R选自：H、F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：C 1-6烷基、C 1-6杂烷基； R is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, or selected from the group consisting of 1, 2 or 3 R's substituted: C 1-6 alkyl, C 1-6 hetero alkyl;
R’选自：F、Cl、Br、I、OH、NH 2、CN、Me； R' is selected from the group consisting of: F, Cl, Br, I, OH, NH 2 , CN, Me;
所述C 1-6杂烷基、3～6元杂环烷基之“杂”选自N、-O-、-S-、-NH-； The "hetero" of the C 1-6 heteroalkyl group and the 3-6 membered heterocycloalkyl group is selected from the group consisting of N, -O-, -S-, -NH-;
上述杂原子或杂原子团的数目分别独立地选自1、2、3或4。The number of the above heteroatoms or heteroatoms is independently selected from 1, 2, 3 or 4.
本发明的一些方案中，上述R选自H、F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：C 1-3烷基、C 1-3烷氧基。 In some embodiments of the invention, the above R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from: C 1-3 alkane optionally substituted by 1, 2 or 3 R' Base, C 1-3 alkoxy.
本发明的一些方案中，上述R选自H、F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：Me、Et、
Figure PCTCN2018091270-appb-000003
In some embodiments of the invention, the above R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from the group consisting of 1, 2 or 3 R' substitutions: Me, Et,
Figure PCTCN2018091270-appb-000003
本发明的一些方案中，上述R选自：H、F、Cl、Br、I、OH、NH 2、CN、Me、CF 3、Et、
Figure PCTCN2018091270-appb-000004
In some aspects of the invention, the above R is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Et,
Figure PCTCN2018091270-appb-000004
本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基、环丙基。 In some embodiments of the invention, the above R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from: C 1-3 alkane optionally substituted by 1, 2 or 3 R Base, C 1-3 alkoxy, cyclopropyl.
本发明的一些方案中，上述R 1选自：H、F、Cl、Br、I、OH、NH 2、CN、Me、CF 3、Et、
Figure PCTCN2018091270-appb-000005
Figure PCTCN2018091270-appb-000006
In some aspects of the invention, the above R 1 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Et,
Figure PCTCN2018091270-appb-000005
Figure PCTCN2018091270-appb-000006
本发明的一些方案中，上述R 2分别独立地选自H、F、Cl、Br、I、OH、NH 2，或分别独立地选自任选被1、2或3个R取代的：C 1-3烷基。 In some embodiments of the invention, the above R 2 are each independently selected from H, F, Cl, Br, I, OH, NH 2 or independently selected from, optionally substituted by 1, 2 or 3 R: C 1-3 alkyl.
本发明的一些方案中，上述R 2分别独立地选自H、F、Cl、Br、I、OH、NH 2、Me。 In some aspects of the invention, R 2 is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , Me.
本发明的一些方案中，上述R 3选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基。 In some embodiments of the invention, R 3 above is selected from C 1 - 3 alkyl, C 1-3 alkoxy optionally substituted by 1, 2 or 3 R.
本发明的一些方案中，上述R 3选自任选被1、2或3个R取代的：Me、Et、
Figure PCTCN2018091270-appb-000007
In some embodiments of the invention, the above R 3 is selected from the group consisting of: 1, 2 or 3 R: Me, Et,
Figure PCTCN2018091270-appb-000007
本发明的一些方案中，上述R 3选自：Me、CF 3、Et、
Figure PCTCN2018091270-appb-000008
CH(CH 3) 2、
Figure PCTCN2018091270-appb-000009
In some aspects of the invention, the above R 3 is selected from the group consisting of Me, CF 3 , Et,
Figure PCTCN2018091270-appb-000008
CH(CH 3 ) 2 ,
Figure PCTCN2018091270-appb-000009
本发明的一些方案中，上述L 1选自任选被1、2或3个R取代的：-C 1-3烷基-、-C 1-3烷基-O-、-4元杂环烷基-、-环丙基-C 1-3烷基-。 Some aspects of the present invention, the above L 1 is selected from optionally substituted with 1, 2 or 3 R is: -C 1-3 alkyl -, - C 1-3 alkyl -O -, - 4-membered heterocycle Alkyl-, -cyclopropyl-C 1-3 alkyl-.
本发明的一些方案中，上述L 1选自任选被1、2或3个R取代的：-(CH 2) 2-、-CH 2-O-、-吖丁啶基-、-环丙基-CH 2-。 In some embodiments of the invention, the above L 1 is selected from the group consisting of: 1, (or 2 or 3) R substituted: -(CH 2 ) 2 -, -CH 2 -O-, -azetidinyl-, -cyclopropyl- CH 2 -.
本发明的一些方案中，上述L 1选自：-(CH 2) 2-、-CH 2C(CH 3) 2-、-CH 2-O-、
Figure PCTCN2018091270-appb-000010
In some aspects of the invention, the above L 1 is selected from the group consisting of: -(CH 2 ) 2 -, -CH 2 C(CH 3 ) 2 -, -CH 2 -O-,
Figure PCTCN2018091270-appb-000010
本发明的一些方案中，上述结构单元
Figure PCTCN2018091270-appb-000011
选自：
Figure PCTCN2018091270-appb-000012
In some aspects of the invention, the structural unit
Figure PCTCN2018091270-appb-000011
From:
Figure PCTCN2018091270-appb-000012
本发明的一些方案中，上述结构单元
Figure PCTCN2018091270-appb-000013
选自：
Figure PCTCN2018091270-appb-000014
Figure PCTCN2018091270-appb-000015
In some aspects of the invention, the structural unit
Figure PCTCN2018091270-appb-000013
From:
Figure PCTCN2018091270-appb-000014
Figure PCTCN2018091270-appb-000015
本发明的一些方案中，上述R选自H、F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：C 1-3烷基、C 1-3烷氧基，其他变量如本发明所定义。 In some embodiments of the invention, the above R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from: C 1-3 alkane optionally substituted by 1, 2 or 3 R' The group, C 1-3 alkoxy, other variables are as defined in the present invention.
本发明的一些方案中，上述R选自H、F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：Me、Et、
Figure PCTCN2018091270-appb-000016
其他变量如本发明所定义。 In some embodiments of the invention, the above R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from the group consisting of 1, 2 or 3 R' substitutions: Me, Et,
Figure PCTCN2018091270-appb-000016
Other variables are as defined by the present invention.
本发明的一些方案中，上述R选自：H、F、Cl、Br、I、OH、NH 2、CN、Me、CF 3、Et、
Figure PCTCN2018091270-appb-000017
其他变量如本发明所定义。 In some aspects of the invention, the above R is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Et,
Figure PCTCN2018091270-appb-000017
Other variables are as defined by the present invention.
本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基、环丙基，其他变量如本发明所定义。 In some embodiments of the invention, the above R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from: C 1-3 alkane optionally substituted by 1, 2 or 3 R Base, C 1-3 alkoxy, cyclopropyl, other variables are as defined herein.
本发明的一些方案中，上述R 1选自：H、F、Cl、Br、I、OH、NH 2、CN、Me、CF 3、Et、
Figure PCTCN2018091270-appb-000018
Figure PCTCN2018091270-appb-000019
其他变量如本发明所定义。 In some aspects of the invention, the above R 1 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Et,
Figure PCTCN2018091270-appb-000018
Figure PCTCN2018091270-appb-000019
Other variables are as defined by the present invention.
本发明的一些方案中，上述R 2分别独立地选自H、F、Cl、Br、I、OH、NH 2，或分别独立地选自任选被1、2或3个R取代的：C 1-3烷基，其他变量如本发明所定义。 In some embodiments of the invention, the above R 2 are each independently selected from H, F, Cl, Br, I, OH, NH 2 or independently selected from, optionally substituted by 1, 2 or 3 R: C 1-3 alkyl, other variables are as defined herein.
本发明的一些方案中，上述R 2分别独立地选自H、F、Cl、Br、I、OH、NH 2、Me，其他变量如本发明所定义。 In some aspects of the invention, R 2 is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , Me, and other variables are as defined herein.
本发明的一些方案中，上述R 3选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基，其他变量如本发明所定义。 In some embodiments of the invention, R 3 above is selected from C 1 1-3 alkyl, C 1-3 alkoxy optionally substituted by 1, 2 or 3 R, and other variables are as defined herein.
本发明的一些方案中，上述R 3选自任选被1、2或3个R取代的：Me、Et、
Figure PCTCN2018091270-appb-000020
其他变量如本发明所定义。 In some embodiments of the invention, the above R 3 is selected from the group consisting of: 1, 2 or 3 R: Me, Et,
Figure PCTCN2018091270-appb-000020
Other variables are as defined by the present invention.
本发明的一些方案中，上述R 3选自：Me、CF 3、Et、
Figure PCTCN2018091270-appb-000021
CH(CH 3) 2、
Figure PCTCN2018091270-appb-000022
其他变量如本发明所定义。 In some aspects of the invention, the above R 3 is selected from the group consisting of Me, CF 3 , Et,
Figure PCTCN2018091270-appb-000021
CH(CH 3 ) 2 ,
Figure PCTCN2018091270-appb-000022
Other variables are as defined by the present invention.
本发明的一些方案中，上述L 1选自任选被1、2或3个R取代的：-C 1-3烷基-、-C 1-3烷基-O-、-4元杂环烷基-、-环丙基-C 1-3烷基-，其他变量如本发明所定义。 Some aspects of the present invention, the above L 1 is selected from optionally substituted with 1, 2 or 3 R is: -C 1-3 alkyl -, - C 1-3 alkyl -O -, - 4-membered heterocycle Alkyl-, -cyclopropyl-C 1-3 alkyl-, other variables are as defined herein.
本发明的一些方案中，上述L 1选自任选被1、2或3个R取代的：-(CH 2) 2-、-CH 2-O-、-吖丁啶基-、-环丙基-CH 2-，其他变量如本发明所定义。 In some embodiments of the invention, the above L 1 is selected from the group consisting of: 1, (or 2 or 3) R substituted: -(CH 2 ) 2 -, -CH 2 -O-, -azetidinyl-, -cyclopropyl- CH 2 -, other variables are as defined by the present invention.
本发明的一些方案中，上述L 1选自：-(CH 2) 2-、-CH 2C(CH 3) 2-、-CH 2-O-、
Figure PCTCN2018091270-appb-000023
其他变量如本发明所定义。 In some aspects of the invention, the above L 1 is selected from the group consisting of: -(CH 2 ) 2 -, -CH 2 C(CH 3 ) 2 -, -CH 2 -O-,
Figure PCTCN2018091270-appb-000023
Other variables are as defined by the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2018091270-appb-000024
选自：
Figure PCTCN2018091270-appb-000025
其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2018091270-appb-000024
From:
Figure PCTCN2018091270-appb-000025
Other variables are as defined by the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2018091270-appb-000026
选自：
Figure PCTCN2018091270-appb-000027
Figure PCTCN2018091270-appb-000028
其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2018091270-appb-000026
From:
Figure PCTCN2018091270-appb-000027
Figure PCTCN2018091270-appb-000028
Other variables are as defined by the present invention.
本发明还有一些方案是由上述各变量任意组合而来。Still other aspects of the invention are arbitrarily combined from the above variables.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自：In some embodiments of the invention, the above compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of
Figure PCTCN2018091270-appb-000029
Figure PCTCN2018091270-appb-000029
其中，among them,
n选自：0、1或2；n is selected from: 0, 1 or 2;
m选自：1、2或3；m is selected from: 1, 2 or 3;
T 1、T 2、T 3分别独立地选自：N或CH； T 1 , T 2 , T 3 are each independently selected from: N or CH;
L 2选自任选被1、2或3个R取代的：-C 1-3烷基-、-C 1-3烷氧基-； L 2 is selected from the group consisting of: 1, 2 or 3, R: -C 1-3 alkyl-, -C 1-3 alkoxy-;
R、R 1、R 2、R 3如本发明所定义。 R, R 1 , R 2 , R 3 are as defined in the present invention.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自：In some embodiments of the invention, the above compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of
Figure PCTCN2018091270-appb-000030
Figure PCTCN2018091270-appb-000030
其中，among them,
n选自：0、1或2；n is selected from: 0, 1 or 2;
m选自：1、2或3；m is selected from: 1, 2 or 3;
T 1、T 2、T 3分别独立地选自：N或CH； T 1 , T 2 , T 3 are each independently selected from: N or CH;
L 2选自：-(CH 2) 2-、-CH 2C(CH 3) 2-、-CH 2-O-； L 2 is selected from the group consisting of: -(CH 2 ) 2 -, -CH 2 C(CH 3 ) 2 -, -CH 2 -O-;
R、R 1、R 2、R 3如权利要求本发明所定义。 R, R 1 , R 2 , R 3 are as defined by the claims.
本发明还提供了下式所示化合物或其药学上可接受的盐，其选自：The present invention also provides a compound of the formula: or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:
Figure PCTCN2018091270-appb-000031
Figure PCTCN2018091270-appb-000031
Figure PCTCN2018091270-appb-000032
Figure PCTCN2018091270-appb-000032
本发明还提供了一种药物组合物，包括治疗有效量的上述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.
本发明还提供了上述的化合物或其药学上可接受的盐或者上述组合物在制备IDH突变体抑制剂相关药物上的应用。The present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above composition for the preparation of a drug related to an IDH mutant inhibitor.
定义和说明Definition and description
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered undefined or unclear without a particular definition, but should be understood in the ordinary sense. When a trade name appears in this document, it is intended to refer to its corresponding commodity or its active ingredient.
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成 盐。The term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base. When a relatively acidic functional group is contained in the compound of the present invention, a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When a relatively basic functional group is contained in the compound of the present invention, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine, etc.) And salts of organic acids such as glucuronic acid. Certain specific compounds of the invention contain both basic and acidic functional groups which can be converted to any base or acid addition salt.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
除非另有说明，用楔形键和虚线键
Figure PCTCN2018091270-appb-000033
表示一个立体中心的绝对构型，用波浪线
Figure PCTCN2018091270-appb-000034
表示楔形键或虚线键
Figure PCTCN2018091270-appb-000035
用
Figure PCTCN2018091270-appb-000036
表示立体中心的相对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。 Wedge and dashed keys unless otherwise stated
Figure PCTCN2018091270-appb-000033
Represents the absolute configuration of a stereocenter, using wavy lines
Figure PCTCN2018091270-appb-000034
Indicates a wedge or dashed key
Figure PCTCN2018091270-appb-000035
use
Figure PCTCN2018091270-appb-000036
Indicates the relative configuration of the stereocenter. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the invention.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。The optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer. Alternatively, when a molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art. The diastereomers are resolved and the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。"Optional" or "optionally" means that the subsequently described event or condition may, but is not necessarily, to occur, and that the description includes instances in which the event or condition occurs and instances in which the event or condition does not occur.
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非 另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of. When the substituent is a keto group (ie, =0), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on the aryl group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with at most two R, and each case has an independent option. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。 When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2018091270-appb-000037
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2018091270-appb-000038
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2018091270-appb-000039
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。 When the listed linking group does not indicate its direction of attachment, its connection direction is arbitrary, for example,
Figure PCTCN2018091270-appb-000037
The medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B.
Figure PCTCN2018091270-appb-000038
It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right.
Figure PCTCN2018091270-appb-000039
Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-或-S(＝O)N(H)-。 Unless otherwise specified, the term "hetero" denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O). ), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, =O, =S, -C (= O) O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) 2 -, and optionally substituted -C(=O)N (H)-, -N(H)-, -C(=NH)-, -S(=O) 2 N(H)- or -S(=O)N(H)-.
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。Unless otherwise specified, "ring" means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring" means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms. Thus, "5- to 7-membered ring" includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term "5- to 7-membered heterocycloalkyl ring" includes pyridyl and piperidinyl, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, each of which "ring" independently conforms to the above definition.
除非另有规定，术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的，本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优 选方案是，当杂环中S及O原子的总数超过1时，这些杂原子彼此不相邻。另一个优选方案是，杂环中S及O原子的总数不超过1。如本文所用，术语“芳族杂环基团”或“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环，它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。值得注意的是，芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring. The nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein). The heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites. The nitrogen atom in the heterocycle is optionally quaternized. A preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one. The term "aromatic heterocyclic group" or "heteroaryl" as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein). The nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed one. Bridged rings are also included in the definition of heterocycles. A bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms. Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
杂环化合物的实例包括但不限于：吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并***基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-***基、1,2,4-***基、1,2,5-***基、1,3,4-***基和呫吨基。还包括稠环和螺环化合物。Examples of heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl, indanyl, mesoindolyl, fluorenyl, 3H-indole Mercapto, isobenzofuranyl, isodecyl, isoindoline, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl , octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, hydroxymethyl, pyrimidinyl, phenanthryl, phenanthroline, phenazine, phenothiazine , benzoxanthyl, phenoloxazinyl, pyridazinyl, piperazinyl, piperidinyl, piperidinone, 4-piperidinone, piperonyl, pteridinyl, fluorenyl, pyranyl, Pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridylthiazole, pyridyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl , pyrrolyl, quinazolinyl, quinolyl, 4H-quinazinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, tetrazolyl, 6H -1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4 -thiadiazolyl, thiazolidine, thiazolyl, isothiazolylthiophenyl, thienooxazolyl, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazole Base, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthene. Also included are fused ring and spiro compounds.
除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、芳基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基)，可以是单取代或多取代的，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，可以包括二价或多价原子团，具有指定数量的碳原子(如C 1-C 12表示1至12个碳，C 1-12选自C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12；C 3-12选自C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12。)。“烃基”包括但不限于脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烃基”表示直链的或支链的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和 的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烃基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构体。 Unless otherwise specified, the term "hydrocarbyl" or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic. The hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons) , C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .). "Hydrocarbyl" includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members. An aromatic hydrocarbon group such as benzene, naphthalene or the like. In some embodiments, the term "hydrocarbyl" means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl). A homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl. The unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合，有一定数目的碳原子和至少一个杂原子组成。在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子或杂原子团可以位于杂烃基的任何内部位置，包括该烃基附着于分子其余部分的位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。实例包括但不限于-CH 2-CH 2-O-CH 3、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(O)-CH 3、-CH 2-CH 2-S(O) 2-CH 3、-CH＝CH-O-CH 3、-CH 2-CH＝N-OCH 3和–CH＝CH-N(CH 3)-CH 3。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。 Unless otherwise specified, the term "heterohydrocarbyl" or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom. In some embodiments, the term "heteroalkyl" by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom. In a typical embodiment, the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized. The hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy). By customary expression, those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively. Examples include, but are not limited to, -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 , -CH 2 -S -CH 2 -CH 3 , -CH 2 -CH 2 , -S(O)-CH 3 , -CH 2 -CH 2 -S(O) 2 -CH 3 , -CH=CH-O-CH 3 ,- CH 2 -CH=N-OCH 3 and -CH=CH-N(CH 3 )-CH 3 . Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
除非另有规定，术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外，就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言，杂原子可以占据该杂环附着于分子其余部分的位置。环烃基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。Unless otherwise specified, the term "cycloalkyl", "heterocycloalkyl" or its subordinate concept (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl) A heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized "hydrocarbyl group" or "heterohydrocarbyl group", respectively. Further, in the case of a heterohydrocarbyl group or a heterocycloalkyl group (such as a heteroalkyl group or a heterocycloalkyl group), a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule. Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH 2F)或多取代的(如-CF 3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等。 Unless otherwise specified, the term "alkyl" is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of the alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
除非另有规定，环烷基包括任何稳定的环状或多环烃基，任何碳原子都是饱和的，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。Unless otherwise specified, a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent. Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C 1-C 4)烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定，卤代烷基的实例包括但不 仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。 Unless otherwise specified, the term "halo" or "halogen", by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom. Further, the term "haloalkyl" is intended to include both monohaloalkyl and polyhaloalkyl. For example, the term "halo(C 1 -C 4 )alkyl" is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait. Unless otherwise specified, examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基，除非另有规定，C 1-6烷氧基包括C 1、C 2、C 3、C 4、C 5和C 6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。 The above-described alkyl groups having the specified number of carbon atoms, "alkoxy" represents attached through an oxygen bridge, unless otherwise specified, C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代或多取代的，可以是一价、二价或者多价，它可以是单环或多环(比如1至3个环；其中至少一个环是芳族的)，它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、萘基、联苯基、吡咯基、吡唑基、咪唑基、吡嗪基、恶唑基、苯基-恶唑基、异恶唑基、噻唑基、呋喃基、噻吩基、吡啶基、嘧啶基、苯并噻唑基、嘌呤基、苯并咪唑基、吲哚基、异喹啉基、喹喔啉基、喹啉基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。Unless otherwise specified, the term "aryl" denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), they are fused together or covalently linked. The term "heteroaryl" refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl or heteroaryl groups include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isomerism Azyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, indolyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl, 1 -naphthyl, 2-naphthyl, 4-biphenylyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, fluorenyl, 2-benzimidazolyl, 5-indenyl, 1-isoquinolinyl, 5-isoquinolinyl, 2-quina Porphyrin, 5-quinoxalinyl, 3-quinolyl and 6-quinolinyl. The substituents of any of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并***-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁基羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂；EDCI代表1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐。 The solvent used in the present invention is commercially available. The present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyloxycarbonyl, an amine protecting group; BOC for t-butylcarbonyl is an amine protecting group; HOAc for acetic acid; NaCNBH 3 for sodium cyanoborohydride ; rt stands for room temperature; O/N stands for overnight; THF stands for tetrahydrofuran; Boc 2 O stands for di-tert-butyl dicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl 2 stands for chloride Sulfone; CS 2 represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI stands for N-fluoro-N-(phenylsulfonyl)benzenesulfonamide; NCS stands for 1-chloropyrrolidine-2,5-dione; n-Bu 4 NF stands for fluorine Tetrabutylammonium; iPrOH stands for 2-propanol; mp stands for melting point; LDA stands for diisopropylamino lithium; EDCI stands for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride salt.
化合物经手工或者
Figure PCTCN2018091270-appb-000040
软件命名，市售化合物采用供应商目录名称。 Compound by hand or
Figure PCTCN2018091270-appb-000040
Software naming, commercially available compounds using the supplier catalog name.
本发明化合物具有显著的IDH1突变体抑制作用和良好的选择性，同时在脑瘤和脑旁组织中的具有更 好的分布比例，可降低对正常脑组织的潜在副作用。The compounds of the present invention have significant IDH1 mutant inhibition and good selectivity, while having a better distribution ratio in brain tumors and paracranial tissues, which can reduce potential side effects on normal brain tissue.
附图说明DRAWINGS
图1：实施例1抑制Balb/c小鼠脑瘤、血浆和癌旁脑组织中2-HG的水平Figure 1: Example 1 inhibits the level of 2-HG in brain tumor, plasma and paracancerous brain tissue of Balb/c mice
a)给药0.25小时、2小时和8小时后，小鼠脑瘤内2-HG含量；a) 2-HG content in mouse brain tumors after 0.25 hours, 2 hours and 8 hours of administration;
b)给药0.25、2小时和8小时后，小鼠血浆内2-HG含量；b) 2-HG content in mouse plasma after 0.25, 2 hours and 8 hours of administration;
c)给药0.25、2小时和8小时后，小鼠癌旁脑组织内2-HG含量。c) 2-HG content in mouse paracancerous brain tissue after 0.25, 2 hours and 8 hours of administration.
具体实施方式detailed description
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The invention is described in detail below by the examples, but is not intended to limit the invention. The present invention has been described in detail herein, the embodiments of the present invention are disclosed herein, and various modifications and changes may be made to the embodiments of the present invention without departing from the spirit and scope of the invention. It will be obvious.
流程AProcess A
Figure PCTCN2018091270-appb-000041
Figure PCTCN2018091270-appb-000041
实施例1Example 1
Figure PCTCN2018091270-appb-000042
Figure PCTCN2018091270-appb-000042
实施例1AExample 1A
Figure PCTCN2018091270-appb-000043
Figure PCTCN2018091270-appb-000043
向2,2,6,6-四甲基四氢-2H-吡喃-4-酮(2.00克，12.80毫摩尔)的甲醇(60.00毫升)和水(6.00毫升)溶液中加入甲酸铵(8.07克，128.00毫摩尔)。在完全溶解后加入钯碳(1.00克，10％的纯度)，反应液在20℃下搅拌32小时。对反应液进行过滤，对滤液进行减压浓缩得到一个残余物。用甲醇(30毫升)溶解残余物，然后加入37％的盐酸(3毫升)。将混合物减压浓缩得到一个粗产物实施例1A。直接用于下一步，没有进一步纯化。To a solution of 2,2,6,6-tetramethyltetrahydro-2H-pyran-4-one (2.00 g, 12.80 mmol) in methanol (60.00 mL) and water (6.00 mL) Gram, 128.00 mmol). After complete dissolution, palladium on carbon (1.00 g, 10% purity) was added, and the reaction solution was stirred at 20 ° C for 32 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was dissolved in MeOH (30 mL) then EtOAc (EtOAc) The mixture was concentrated under reduced pressure to give a crude product Example 1A. Used directly in the next step without further purification.
实施例1BExample 1B
Figure PCTCN2018091270-appb-000044
Figure PCTCN2018091270-appb-000044
向4-溴-1-氟-2-硝基苯(2.80克，12.72毫摩尔，1.56毫升)和实施例1A(2.00克，12.72毫摩尔)的四氢呋喃(30.00毫升)溶液中加入碳酸钾(3.52克，25.44毫摩尔)，反应液在50℃搅拌16小时。反应液用水(100毫升)稀释，然后用乙酸乙酯(60毫升×2)萃取，合并的有机层用盐水(80毫升×1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到实施例1B。 1H NMR(400MHz,CHLOROFORM-d)δ＝1.06-1.32(m,6H)1.32-1.43(m,8H)2.03(dd,J＝12.90,3.48Hz,2H)3.87-4.02(m,1H)6.78(d,J＝9.29Hz,1H)7.49(dd,J＝9.17,2.32Hz,1H)7.91(br d,J＝7.09Hz,1H)8.31(d,J＝2.45Hz,1H). To a solution of 4-bromo-1-fluoro-2-nitrobenzene (2.80 g, 12.72 mmol, 1.56 ml) and THF (3. Grams, 25.44 mmol), the reaction was stirred at 50 ° C for 16 hours. The reaction mixture was diluted with H.sub.2 (EtOAc (EtOAc) 1B. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 1.06-1.32 (m, 6H) 1.32-1.43 (m, 8H) 2.03 (dd, J = 12.90, 3.48 Hz, 2H) 3.87-4.02 (m, 1H) 6.78 (d, J = 9.29 Hz, 1H) 7.49 (dd, J = 9.17, 2.32 Hz, 1H) 7.91 (br d, J = 7.09 Hz, 1H) 8.31 (d, J = 2.45 Hz, 1H).
实施例1CExample 1C
Figure PCTCN2018091270-appb-000045
Figure PCTCN2018091270-appb-000045
实施例1B(1.00克，2.80毫摩尔)，(E)-3-(4,4,5,5-四甲基-1,3,2-氧硼烷-2-基)丙烯酸乙酯(949.28毫克,4.20毫摩尔)，1,1’-二(二苯膦基)二茂铁二氯化钯(204.82毫克，279.92微摩尔)，碳酸钾(1.16克，8.40毫摩尔)的二氧六环(15.00毫升)和水(1.50毫升)混合溶液用氮气置换三次，然后加热到95℃搅拌4小时，反应液减压浓缩干燥，残余物用水(100毫升)稀释，然后用乙酸乙酯(50毫升×2)萃取，合并的有机层用盐水(60毫升×1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到的残余物，残余物通过柱色谱纯化 得到实施例1C。 1H NMR(400MHz,CHLOROFORM-d)δ＝1.20-1.26(m,2H)1.29(s,6H)1.34(t,J＝7.15Hz,3H)1.38-1.45(m,6H)2.06(dd,J＝12.86,3.70Hz,2H)3.96-4.10(m,1H)4.26(q,J＝7.15Hz,2H)6.31(d,J＝15.94Hz,1H)6.91(d,J＝9.16Hz,1H)7.58(d,J＝15.94Hz,1H)7.64(dd,J＝8.91,2.01Hz,1H)8.17(br d,J＝7.15Hz,1H)8.35(d,J＝1.88Hz,1H). Example 1B (1.00 g, 2.80 mmol), (E)-3-(4,4,5,5-tetramethyl-1,3,2-oxaboran-2-yl)ethyl acrylate (949.28 Mg, 4.20 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (204.82 mg, 279.92 μmol), potassium carbonate (1.16 g, 8.40 mmol) of dioxane The mixed solution of (15.00 ml) and water (1.50 ml) was replaced with nitrogen three times, then heated to 95 ° C and stirred for 4 hours. The reaction mixture was concentrated to dryness vacuol. The mixture was extracted with EtOAc (EtOAc)EtOAc. 1 H NMR (400 MHz, CHLOROFORM-d) δ=1.20-1.26 (m, 2H) 1.29 (s, 6H) 1.34 (t, J = 7.15 Hz, 3H) 1.38-1.45 (m, 6H) 2.06 (dd, J =12.86, 3.70 Hz, 2H) 3.96-4.10 (m, 1H) 4.26 (q, J = 7.15 Hz, 2H) 6.31 (d, J = 15.94 Hz, 1H) 6.91 (d, J = 9.16 Hz, 1H) 7.58 (d, J = 15.94 Hz, 1H) 7.64 (dd, J = 8.91, 2.01 Hz, 1H) 8.17 (br d, J = 7.15 Hz, 1H) 8.35 (d, J = 1.88 Hz, 1H).
实施例1D
Figure PCTCN2018091270-appb-000046
Example 1D
Figure PCTCN2018091270-appb-000046
实施例1C(750.00毫克，1.99毫摩尔)和钯碳(130.00毫克，10％纯度)的甲醇(20.00毫升)溶液置换氢气三次然后在氢气(15psi)氛围下20℃搅拌16小时。对反应液进行过滤，对滤液进行减压浓缩得到一个残余物，残余物通过柱色谱纯化得到实施例1D。A solution of Example 1C (750.00 mg, 1.99 mmol) and palladium carbon (130.00 mg, 10% purity) in methanol (20.00 mL) was used to displace hydrogen three times and then stirred at 20 ° C for 16 hours under a hydrogen (15 psi) atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give a residue.
实施例1EExample 1E
Figure PCTCN2018091270-appb-000047
Figure PCTCN2018091270-appb-000047
在30℃下，实施例1D(200.00毫克,573.92微摩尔)的四氢呋喃(3.00毫升)溶液中加入1-异硫氰基-4-(三氟甲氧基)苯(125.79毫克，573.92微摩尔，93.18微升)，搅拌三小时，然后再加入EDCI(220.04毫克，1.15毫摩尔)，使反应液升温到70℃搅拌3小时，对反应液进行减压浓缩得到一个残余物，残余物通过柱色谱纯化得到实施例1E。 1H NMR(400MHz,CHLOROFORM-d)δppm 1.11(s,6H)1.20-1.31(m,9H)1.74(br dd,J＝12.61,3.20Hz,2H)2.19(t,J＝12.80Hz,2H)2.68(t,J＝7.84Hz,2H)3.06(t,J＝7.78Hz,2H)4.08-4.25(m,2H)4.63(br t,J＝12.80Hz,1H)6.99-7.20(m,5H)7.37(d,J＝8.28Hz,1H)7.45(s,1H)7.81(br s,1H). To a solution of Example 1D (200.00 mg, 573.92 μmol) in tetrahydrofuran (3.00 mL) was added 1-isothiocyano-4-(trifluoromethoxy)benzene (125.79 mg, 573.92 μmol, 93.18 μl), stirring for three hours, then adding EDCI (220.04 mg, 1.15 mmol), the reaction solution was heated to 70 ° C for 3 hours, and the reaction solution was concentrated under reduced pressure to give a residue. Purification gave Example 1E. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.11 (s, 6H) 1.20-1.31 (m, 9H) 1.74 (br dd, J = 12.61, 3.20 Hz, 2H) 2.19 (t, J = 12.80 Hz, 2H) 2.68 (t, J = 7.84 Hz, 2H) 3.06 (t, J = 7.78 Hz, 2H) 4.08 - 4.25 (m, 2H) 4.63 (br t, J = 12.80 Hz, 1H) 6.99 - 7.20 (m, 5H) 7.37 (d, J = 8.28 Hz, 1H) 7.45 (s, 1H) 7.81 (br s, 1H).
实施例1Example 1
Figure PCTCN2018091270-appb-000048
Figure PCTCN2018091270-appb-000048
实施例1D(300.00毫克，562.24微摩尔)的四氢呋喃(5.00毫升)和水(5.00毫升)溶液中加入一水合氢氧化锂(117.96毫克，2.81毫摩尔)，反应液在70℃搅拌16小时，反应混合物减压浓缩去除四氢呋喃，残余物再用水(10.00毫升)稀释，然后用1N盐酸酸化调节pH值为6，过滤并收集沉淀物，得到实施例1。 1H NMR(400MHz,CHLOROFORM-d)δppm 0.86(s,6H)1.20(s,6H)1.65(dd,J＝12.42,2.76Hz,2H)2.10(br t,J＝12.74Hz,2H)2.66-2.81(m,2H)3.03-3.18(m,2H)4.46(br t,J＝12.80Hz,1H)7.02(d,J＝8.91Hz,2H)7.08(d,J＝8.28Hz,1H)7.17(d,J＝8.53Hz,2H)7.37(d,J＝8.28Hz,1H)7.82(s,1H). To a solution of Example 1D (300.00 mg, 562.24 μmol) of tetrahydrofuran (5.00 ml) and water (5.00 ml) was added lithium hydroxide monohydrate (117.96 mg, 2.81 mmol), and the reaction mixture was stirred at 70 ° C for 16 hours. The mixture was concentrated under reduced pressure to remove tetrahydrofuran, and the residue was diluted with water (10.00 ml), then acidified with 1N hydrochloric acid to adjust pH 6 and filtered and collected to give Example 1. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.86 (s, 6H) 1.20 (s, 6H) 1.65 (dd, J = 12.42, 2.76 Hz, 2H) 2.10 (br t, J = 12.74 Hz, 2H) 2.66- 2.81(m,2H)3.03-3.18(m,2H)4.46(br t,J=12.80Hz,1H)7.02(d,J=8.91Hz,2H)7.08(d,J=8.28Hz,1H)7.17( d, J = 8.53 Hz, 2H) 7.37 (d, J = 8.28 Hz, 1H) 7.82 (s, 1H).
实施例2Example 2
Figure PCTCN2018091270-appb-000049
Figure PCTCN2018091270-appb-000049
实施例2AExample 2A
Figure PCTCN2018091270-appb-000050
Figure PCTCN2018091270-appb-000050
0℃下，向硫光气(215.01毫克,1.87毫摩尔,143.34微升)的DCM(3.00毫升)和水(3.00毫克)溶液中加入碳酸钙(425.38毫克,4.25毫摩尔)，搅拌10分钟，在0℃下再加入4-异丙基苯胺(230.00毫克,1.70毫摩尔,242.11微升)，然后再升温到20℃搅拌20分钟。反应液用水(20毫升)稀释，然后用乙酸乙酯(20毫升×2)萃取，合并的有机层用盐水(20毫升×1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到实施例2A。 1H NMR(400MHz,CHLOROFORM-d)δ＝1.25(d,J＝6.90Hz,6H)2.92(dt,J＝13.80,6.90Hz,1H)7.13-7.25(m,4H). Calcium carbonate (425.38 mg, 4.25 mmol) was added to a solution of thiophosgene (215.01 mg, 1.87 mmol, 143.34 μL) in DCM (3.00 mL) and water (3.00 mg). Further, 4-isopropylaniline (230.00 mg, 1.70 mmol, 242.11 μl) was added at 0 ° C, and then the mixture was further heated to 20 ° C and stirred for 20 minutes. The reaction mixture was diluted with EtOAc EtOAc (EtOAc m. 2A. 1 H NMR (400MHz, CHLOROFORM- d) δ = 1.25 (d, J = 6.90Hz, 6H) 2.92 (dt, J = 13.80,6.90Hz, 1H) 7.13-7.25 (m, 4H).
实施例2BExample 2B
Figure PCTCN2018091270-appb-000051
Figure PCTCN2018091270-appb-000051
在20℃下，向乙基-3-[3-氨基-4-[(2,2,6,6-四甲基四氢吡喃-4-基)氨基]苯基]丙酸(120.00毫克,344.35微摩尔)的四氢呋喃(3.00毫升)溶液中加入实施例2A(122.09毫克,688.70微摩尔)，搅拌2小时，然后再加入EDCI(132.02毫克,688.70微摩尔)，反应液在70℃搅拌2小时。反应液通过减压浓缩得到残余物，残余物通过柱色谱纯化得到实施例2B。To ethyl-3-[3-amino-4-[(2,2,6,6-tetramethyltetrahydropyran-4-yl)amino]phenyl]propanoic acid (120.00 mg at 20 ° C) Example 2A (122.09 mg, 688.70 μmol) was added to a solution of 344.35 μmol of tetrahydrofuran (3.00 ml), stirred for 2 hours, then EDCI (132.02 mg, 688.70 μmol) was added, and the reaction was stirred at 70 ° C. hour. The reaction mixture was concentrated under reduced pressure to give a crystallite.
实施例2Example 2
Figure PCTCN2018091270-appb-000052
Figure PCTCN2018091270-appb-000052
实施例2B(35.00毫克,71.19微摩尔)的四氢呋喃(2.00毫升)和水(2.00毫升)溶液中加入一水合氢氧化锂(14.94毫克，355.95微摩尔)，反应液在70℃搅拌16小时，反应混合物减压浓缩得到残余物，残余物通过高效液相色谱纯化得到实施例2。 1H NMR(400MHz,CHLOROFORM-d)δppm 0.77(s,6H)1.10-1.24(m,13H)1.63(dd,J＝12.49,2.95Hz,2H)2.06(br t,J＝12.74Hz,2H)2.63-2.74(m,2H)2.85(spt,J＝6.82Hz,1H)3.03-3.15(m,2H)4.49(br t,J＝12.92Hz,1H)7.01(d,J＝8.28Hz,2H)7.06(dd,J＝8.41,1.25Hz,1H)7.17(d,J＝8.41Hz,2H)7.33(d,J＝8.41Hz,1H)7.80(s,1H). To a solution of THF (25.00 mg, 71. The mixture was concentrated under reduced pressure to give a crystallite. 1 H NMR (400MHz, CHLOROFORM- d) δppm 0.77 (s, 6H) 1.10-1.24 (m, 13H) 1.63 (dd, J = 12.49,2.95Hz, 2H) 2.06 (br t, J = 12.74Hz, 2H) 2.63-2.74(m,2H)2.85(spt,J=6.82Hz,1H)3.03-3.15(m,2H)4.49(br t,J=12.92Hz,1H)7.01(d,J=8.28Hz,2H) 7.06 (dd, J = 8.41, 1.25 Hz, 1H) 7.17 (d, J = 8.41 Hz, 2H) 7.33 (d, J = 8.41 Hz, 1H) 7.80 (s, 1H).
实施例3Example 3
Figure PCTCN2018091270-appb-000053
Figure PCTCN2018091270-appb-000053
实施例3AExample 3A
Figure PCTCN2018091270-appb-000054
Figure PCTCN2018091270-appb-000054
在0℃下，向硫光气(157.00毫克,1.37毫摩尔,104.67微升)和碳酸钙(310.61毫克,3.10毫摩尔)的DCM(10.00毫升)和水(10.00毫升)的混合溶液中加入4-(三氟甲基)苯胺(200.00毫克,1.24毫摩尔,153.85微升),反应逐渐升温到15℃搅拌10分钟，向反应液加入水(5毫升)，然后用DCM(10毫升×2)萃取，合并有机相并依次用水(10毫升)、盐水(10毫升×1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到实施例3A。产物直接用于下一步，不需要进一步纯化。To a mixed solution of thiophosgene (157.00 mg, 1.37 mmol, 104.67 μl) and calcium carbonate (310.61 mg, 3.10 mmol) in DCM (10.00 mL) and water (10.00 mL) at 0 ° C -(Trifluoromethyl)aniline (200.00 mg, 1.24 mmol, 153.85 μL), the reaction was gradually warmed to 15 ° C and stirred for 10 min, then water (5 mL) was added to the reaction mixture, then DCM (10 mL × 2) The organic phase was combined, washed with water (10 ml), brine The product was used directly in the next step without further purification.
实施例3BExample 3B
Figure PCTCN2018091270-appb-000055
Figure PCTCN2018091270-appb-000055
3-[3-氨基-4-[(2,2,6,6-四甲基四氢吡喃-4-基)氨基]苯基]丙酸乙酯(130.00毫克，373.05微摩尔)和实施例3A(90.96毫克,447.66微摩尔)溶于四氢呋喃(5.00毫升)，混合溶液在30℃搅拌30小时,然后再加入EDCI(143.03毫克,746.10微摩尔)，反应液在70℃反应3小时。反应完毕后，向反应液中加入水(5毫升)，水相再用乙酸乙酯(10毫升×3)萃取，合并的有机相依次用水(10毫升)和盐水(10毫升×1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到的粗产物，粗产物通过柱色谱纯化得到实施例3B。3-[3-Amino-4-[(2,2,6,6-tetramethyltetrahydropyran-4-yl)amino]phenyl]propanoic acid ethyl ester (130.00 mg, 373.05 μmol) and carried out Example 3A (90.96 mg, 447.66 μmol) was dissolved in tetrahydrofuran (5.00 ml), and the mixture was stirred at 30 ° C for 30 hours, then EDCI (143.03 mg, 746.10 μmol) was added, and the reaction mixture was reacted at 70 ° C for 3 hours. After the completion of the reaction, water (5 ml) was added to the mixture, and the aqueous phase was extracted with ethyl acetate (10 ml × 3), and the combined organic phases were washed with water (10 ml) and brine (10 ml × 1). The residue was dried over anhydrous sodium sulfate, filtered, and then evaporated
实施例3Example 3
Figure PCTCN2018091270-appb-000056
Figure PCTCN2018091270-appb-000056
实施例3B(120.00毫克,231.85微摩尔)和一水合氢氧化锂(24.32毫克,579.63微摩尔)溶于甲醇(5.00毫升)和水(1.00毫升)。混合溶液在15℃反应16小时后。反应完毕后，减压浓缩得到粗产物，粗产物通过高效液相色谱纯化得到实施例3。 1H NMR(400MHz,METHANOL-d4)δ＝7.59(d,J＝8.5Hz,2H),7.52(d, J＝8.4Hz,1H),7.42-7.30(m,3H),7.11(d,J＝7.5Hz,1H),3.01(t,J＝7.6Hz,2H),2.64(br t,J＝7.5Hz,2H),2.34(br t,J＝12.7Hz,2H),1.88(dd,J＝3.4,12.8Hz,2H),1.31(d,J＝7.9Hz,12H). Example 3B (120.00 mg, 231.85 micromoles) and lithium hydroxide monohydrate (24.32 mg, 579.63 micromoles) were dissolved in methanol (5.00 mL) and water (1.00 mL). The mixed solution was reacted at 15 ° C for 16 hours. After completion of the reaction, the crude product was concentrated under reduced pressure. 1 H NMR (400MHz, METHANOL- d4) δ = 7.59 (d, J = 8.5Hz, 2H), 7.52 (d, J = 8.4Hz, 1H), 7.42-7.30 (m, 3H), 7.11 (d, J = 7.5 Hz, 1H), 3.01 (t, J = 7.6 Hz, 2H), 2.64 (br t, J = 7.5 Hz, 2H), 2.34 (br t, J = 12.7 Hz, 2H), 1.88 (dd, J =3.4, 12.8 Hz, 2H), 1.31 (d, J = 7.9 Hz, 12H).
实施例4Example 4
Figure PCTCN2018091270-appb-000057
Figure PCTCN2018091270-appb-000057
实施例4AExample 4A
Figure PCTCN2018091270-appb-000058
Figure PCTCN2018091270-appb-000058
冰水浴中将1-溴-4氟-2-甲氧基苯(2.5克，12.19毫摩尔)溶于30mL浓硫酸中，缓慢滴加HNO 3(0.806克，12.8毫摩尔)和H 2SO 4(2.21克，22.55毫摩尔)的混合物。反应液在0℃继续搅拌30分钟。反应液缓慢倒入冰水中，用150毫升的乙酸乙酯萃取，100毫升饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。通过快速硅胶柱层析纯化得到实施例4A。 1H NMR(400MHz,DMSO-d6)δ＝8.40(d,J＝8.0Hz,1H),7.43(d,J＝13.6Hz,1H),4.00(s,3H). 1-Bromo-4-fluoro-2-methoxybenzene (2.5 g, 12.19 mmol) was dissolved in 30 mL of concentrated sulfuric acid in an ice water bath, and HNO 3 (0.806 g, 12.8 mmol) and H 2 SO 4 were slowly added dropwise. A mixture of (2.21 g, 22.55 mmol). The reaction solution was stirred at 0 ° C for further 30 minutes. The reaction mixture was poured into EtOAc (EtOAc)EtOAc. Purification by flash silica gel column chromatography gave Example 4A. 1 H NMR (400 MHz, DMSO-d6) δ = 8.40 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 13.6 Hz, 1H), 4.00 (s, 3H).
实施例4BExample 4B
Figure PCTCN2018091270-appb-000059
Figure PCTCN2018091270-appb-000059
将600毫克实施例4A溶于30毫升四氢呋喃中，加入995毫克碳酸钾和755毫克2,2,6,6-四甲基四氢吡喃-4-胺。反应液在60℃搅拌16小时。反应液加水稀释，用150毫升(50毫升*3)萃取，合并有机层，有机层用50毫升饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩。通过快速硅胶柱色谱纯化得到实施例4B。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.42(s,1H),8.21(br d,J＝6.8Hz,1H),6.22(s,1H),4.00-3.90(m,4H),2.07(dd,J＝3.5,12.8Hz,2H),1.55(s,2H),1.40(s,6H),1.30(s,6H). 600 mg of Example 4A was dissolved in 30 ml of tetrahydrofuran, and 995 mg of potassium carbonate and 755 mg of 2,2,6,6-tetramethyltetrahydropyran-4-amine were added. The reaction solution was stirred at 60 ° C for 16 hours. The reaction mixture was diluted with water and EtOAc (EtOAc m. Example 4B was obtained by flash silica gel column chromatography. 1 H NMR (400MHz, CHLOROFORM- d) δ = 8.42 (s, 1H), 8.21 (br d, J = 6.8Hz, 1H), 6.22 (s, 1H), 4.00-3.90 (m, 4H), 2.07 ( Dd, J=3.5, 12.8 Hz, 2H), 1.55 (s, 2H), 1.40 (s, 6H), 1.30 (s, 6H).
实施例4CExample 4C
Figure PCTCN2018091270-appb-000060
Figure PCTCN2018091270-appb-000060
将实施例4B(800毫克，2.07毫摩尔)，乙基-(E)-3-(4,4,5,5-四甲基-1,3,2-二氧杂已硼烷-2-基)丙烯酸乙酯(1.4克，6.20毫摩尔)，[1,1’-双(二苯基膦基)二茂铁]二氯化钯(302毫克，0.42毫摩尔)，碳酸铯(1.35克，4.13毫摩尔)加入二氧六环(8ml)和水(2ml)中，用氮气脱气保护3次，然后反应液在氮气保护下90℃反应16小时。反应液过滤，用50毫升水稀释，用150毫升(50毫升*3)萃取，合并有机层，有机层用100毫升饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩。通过快速硅胶柱色谱纯化得到实施例4C.Example 4B (800 mg, 2.07 mmol), ethyl-(E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Ethyl acrylate (1.4 g, 6.20 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (302 mg, 0.42 mmol), cesium carbonate (1.35 g) , 4.13 mmol) was added to dioxane (8 ml) and water (2 ml), and the mixture was degassed with nitrogen for 3 times, and then the reaction mixture was reacted at 90 ° C for 16 hours under nitrogen atmosphere. The reaction mixture was filtered, washed with EtOAc EtOAc. Purification by flash silica gel column chromatography gave Example 4C.
实施例4DExample 4D
Figure PCTCN2018091270-appb-000061
Figure PCTCN2018091270-appb-000061
实施例4C(900毫克，2.21毫摩尔)溶于30毫升甲醇中，在氮气保护下加入0.6克10％含量的钯碳，反应液用H 2置换3次，并在氢气环境中10℃搅拌16小时。反应液过滤浓缩得到实施例4D。 Example 4C (900 mg, 2.21 mmol) was dissolved in 30 ml of methanol, and 0.6 g of 10% palladium carbon was added under a nitrogen atmosphere. The reaction solution was replaced with H 2 for 3 times and stirred at 10 ° C in a hydrogen atmosphere. hour. The reaction solution was concentrated by filtration to give Example 4D.
实施例4EExample 4E
Figure PCTCN2018091270-appb-000062
Figure PCTCN2018091270-appb-000062
实施例4D(400毫克，1.06毫摩尔)溶于15毫升四氢呋喃中，加入1-异硫氰酸酯基-4-(三氟甲氧基)苯(255.56毫克，1.17毫摩尔)。反应液在15℃搅拌2小时。然后加入EDCI(243.84毫克，1.27毫摩尔)。反应液在70℃搅拌16小时。反应液减压浓缩，通过快速硅胶柱色谱纯化得到实施例4E.Example 4D (400 mg, 1.06 mmol) was dissolved in 15 mL of THF. <EMI ID=9.1>> The reaction solution was stirred at 15 ° C for 2 hours. Then EDCI (243.84 mg, 1.27 mmol) was added. The reaction solution was stirred at 70 ° C for 16 hours. The reaction solution was concentrated under reduced pressure and purified by flash column chromatography.
实施例4Example 4
Figure PCTCN2018091270-appb-000063
Figure PCTCN2018091270-appb-000063
实施例4E(500毫克，0.89毫摩尔)加入15毫升四氢呋喃和15毫升水中，加入一水合氢氧化锂(186.12毫克，4.44毫摩尔)，反应液在40℃搅拌16小时。将反应液pH调节到3-4，用100毫升乙酸乙酯萃取，通过制备分离得到实施例4. 1H NMR(400MHz,DMSO-d6)δ＝12.12(s,1H),7.59(br d,J＝9.0Hz,2H),7.48(br s,2H),7.21(s,1H),7.08(s,1H),4.88(br s,1H),3.90(s,3H),2.84(br t,J＝7.5Hz,2H),2.67(s,1H),2.33(br,s,1H),2.22(br t,J＝12.7Hz,2H),1.92(br d,J＝9.5Hz,2H),1.35(s,6H),1.27(s,6H). Example 4E (500 mg, 0.89 mmol) was added to 15 ml of tetrahydrofuran and 15 ml of water, and lithium hydroxide monohydrate (186.12 mg, 4.44 mmol) was added, and the mixture was stirred at 40 ° C for 16 hours. The reaction mixture was adjusted to pH 3-4, and extracted with 100 ml of ethyl acetate, obtained in Example 4. 1 H NMR (400MHz, DMSO -d6) δ = 12.12 (s, 1H) prepared by separating, 7.59 (br d, J=9.0 Hz, 2H), 7.48 (br s, 2H), 7.21 (s, 1H), 7.08 (s, 1H), 4.88 (br s, 1H), 3.90 (s, 3H), 2.84 (br t, J=7.5 Hz, 2H), 2.67 (s, 1H), 2.33 (br, s, 1H), 2.22 (br t, J = 12.7 Hz, 2H), 1.92 (br d, J = 9.5 Hz, 2H), 1.35(s,6H), 1.27(s,6H).
实施例5Example 5
Figure PCTCN2018091270-appb-000064
Figure PCTCN2018091270-appb-000064
实施例5AExample 5A
Figure PCTCN2018091270-appb-000065
Figure PCTCN2018091270-appb-000065
将1-溴-4-氟-2-甲基-5-硝基苯(600毫克，2.56毫摩尔)溶于20毫升DMF中，加入碳酸钾(884.54毫克，6.4毫摩尔)和2,2,6,6-四甲基四氢吡喃-4-胺(805.12毫克，5.12毫摩尔)。反应液在60℃搅拌16小时。反应液用50毫升水稀释，用150毫升(50毫升*3)萃取3次，合并有机层，用50毫升饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。通过快速硅胶柱色谱纯化得到实施例5A。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.36(s,1H),7.89(br d,J＝7.0Hz,1H),6.74(s,1H),3.96(tdt,J＝3.8,7.7,11.6Hz,1H),2.42(s,3H),2.06-2.01(m,2H),1.44(d,J＝4.8Hz,2H),1.40(s,6H),1.29(s,6H)。 1-Bromo-4-fluoro-2-methyl-5-nitrobenzene (600 mg, 2.56 mmol) was dissolved in 20 mL of DMF and potassium carbonate (884.54 mg, 6.4 mmol) and 2,2, 6,6-Tetramethyltetrahydropyran-4-amine (805.12 mg, 5.12 mmol). The reaction solution was stirred at 60 ° C for 16 hours. The reaction mixture was diluted with 50 ml of EtOAc. Example 5A was obtained by flash silica gel column chromatography. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.36 (s, 1H), 7.89 (brd, J = 7.0 Hz, 1H), 6.74 (s, 1H), 3.96 (tdt, J = 3.8, 7.7, 11.6 Hz, 1H), 2.42 (s, 3H), 2.06-2.01 (m, 2H), 1.44 (d, J = 4.8 Hz, 2H), 1.40 (s, 6H), 1.29 (s, 6H).
实施例5BExample 5B
Figure PCTCN2018091270-appb-000066
Figure PCTCN2018091270-appb-000066
将实施例5A(870毫克，2.34毫摩尔)，乙基-(E)-3-(4,4,5,5-四甲基-1,3,2-二氧杂已硼烷-2-基)丙烯酸乙酯(1.59克，7.03毫摩尔)，[1,1’-双(二苯基膦基)二茂铁]二氯化钯(343毫克，0.469毫摩尔)，碳酸铯(1.53克，4.69毫摩尔)溶于8毫升二氧六环和2毫升水中，用氮气置换3次。反应液在氮气保护下90℃搅拌16小时。反应液过滤，加50毫升水稀释，用150毫升(50毫升*3)乙酸乙酯萃取3次。合并有机相，用100毫升食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。通过快速硅胶柱色谱层析得到实施例5B。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.48(s,1H),8.07(br d,J＝7.3Hz,1H),7.78(d,J＝15.8Hz,1H),6.67(s,1H),6.36(d,J＝15.8Hz,1H),4.27(q,J＝7.1Hz,2H),4.02(dtd,J＝3.5,7.8,11.6Hz,1H),2.46(s,3H),2.10-2.01(m,2H),1.56(s,1H),1.41(s,6H),1.38(s,1H),1.35(t,J＝7.2Hz,3H),1.29(s,6H)。 Example 5A (870 mg, 2.34 mmol), ethyl-(E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Ethyl acrylate (1.59 g, 7.03 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (343 mg, 0.469 mmol), cesium carbonate (1.53 g) , 4.69 mmol), dissolved in 8 ml of dioxane and 2 ml of water, and replaced with nitrogen three times. The reaction solution was stirred at 90 ° C for 16 hours under a nitrogen atmosphere. The reaction mixture was filtered, diluted with water (50 ml) The combined organic layers were washed with EtOAc EtOAc m. Example 5B was obtained by flash column chromatography on silica gel. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.48 (s, 1H), 8.07 (brd, J = 7.3 Hz, 1H), 7.78 (d, J = 15.8 Hz, 1H), 6.67 (s, 1H) , 6.36 (d, J = 15.8 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 4.02 (dtd, J = 3.5, 7.8, 11.6 Hz, 1H), 2.46 (s, 3H), 2.10- 2.01 (m, 2H), 1.56 (s, 1H), 1.41 (s, 6H), 1.38 (s, 1H), 1.35 (t, J = 7.2 Hz, 3H), 1.29 (s, 6H).
实施例5CExample 5C
Figure PCTCN2018091270-appb-000067
Figure PCTCN2018091270-appb-000067
实施例5B(600毫克，1.54毫摩尔)溶于30毫升甲醇中，在氮气环境下，加入10％含量0.6克钯碳，反应液用H 2置换3次，并在氢气环境中10℃搅拌16小时。反应液过滤浓缩得到实施例5C。 Example 5B (600 mg, 1.54 mmol) was dissolved in 30 ml of methanol, and 10 g of 0.6 g of palladium carbon was added under a nitrogen atmosphere. The reaction solution was replaced with H 2 for 3 times and stirred at 10 ° C in a hydrogen atmosphere. hour. The reaction solution was concentrated by filtration to give Example 5C.
实施例5DExample 5D
Figure PCTCN2018091270-appb-000068
Figure PCTCN2018091270-appb-000068
实施例5C(300毫克，0.828毫摩尔)溶于15毫升四氢呋喃中，加入1-异硫氰酸酯基-4-(三氟甲氧基)苯(199.53毫克，0.91毫摩尔)。反应液在15℃搅拌2小时。加入EDCI(190.38毫克，0.99毫摩尔)，反应液在70℃搅拌16小时。反应液减压浓缩，通过快速硅胶柱色谱层析得到实施例5D。Example 5C (300 mg, 0.828 mmol) was dissolved in 15 mL of THF. <EMI ID=9.1>> The reaction solution was stirred at 15 ° C for 2 hours. EDCI (190.38 mg, 0.99 mmol) was added and the reaction was stirred at 70 ° C for 16 h. The reaction mixture was concentrated under reduced pressure and purified to silica gel column chromatography.
实施例5Example 5
Figure PCTCN2018091270-appb-000069
Figure PCTCN2018091270-appb-000069
实施例5D(350毫克，0.64毫摩尔)溶于15毫升四氢呋喃和15毫升水中，加入一水合氢氧化锂(134.09毫克，3.2毫摩尔)。反应液在40℃搅拌16小时。将反应液pH调节到3-4，用100毫升乙酸乙酯萃取，有机相减压浓缩。通过高效液相柱色谱分离得到实施例5。 1H NMR(400MHz,DMSO-d6)δ＝12.76-11.65(m,1H),10.20-10.50(m,1H),7.62(d,J＝8.8Hz,2H),7.56(s,1H),7.50(br d,J＝8.5Hz,2H),7.18(s,1H),4.88(br t,J＝12.7Hz,1H),2.87(br t,J＝7.4Hz,2H),2.52(br s,2H),2.41(s,3H),2.23(br t,J＝12.5Hz,2H),1.91(br d,J＝9.3Hz,2H),1.36(s,6H),1.26(s,6H)。 Example 5D (350 mg, 0.64 mmol) was dissolved in 15 mL of tetrahydrofuran and 15 mL water, and lithium hydroxide monohydrate (134.09 mg, 3.2 mmol) was added. The reaction solution was stirred at 40 ° C for 16 hours. The pH of the reaction mixture was adjusted to 3-4. Example 5 was obtained by high performance liquid chromatography. 1 H NMR (400 MHz, DMSO-d6) δ=12.76-11.65 (m, 1H), 10.20-10.50 (m, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.56 (s, 1H), 7.50 (br d, J = 8.5 Hz, 2H), 7.18 (s, 1H), 4.88 (br t, J = 12.7 Hz, 1H), 2.87 (br t, J = 7.4 Hz, 2H), 2.52 (br s, 2H), 2.41 (s, 3H), 2.23 (br t, J = 12.5 Hz, 2H), 1.91 (br d, J = 9.3 Hz, 2H), 1.36 (s, 6H), 1.26 (s, 6H).
实施例6Example 6
Figure PCTCN2018091270-appb-000070
Figure PCTCN2018091270-appb-000070
实施例6AExample 6A
Figure PCTCN2018091270-appb-000071
Figure PCTCN2018091270-appb-000071
向4-氟-3-硝基酚(3.00克，19.10毫摩尔)的二甲基甲酰胺(30.00毫升)溶液中加入氢化钠(840.40毫克，21.01毫摩尔，60％纯度)，混合物在10℃搅拌30分钟，然后在10℃下再加入2-溴乙酸叔丁酯(3.73克，19.10毫摩尔，2.82毫升)搅拌16小时，反应液减压浓缩去除二甲基甲酰胺，残余物再用水(20.00毫升)稀释，然后用乙酸乙酯(20毫升×4)萃取，合并的有机层用盐水(30毫升×1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到的残余物通过柱色谱纯化得到实施例6A。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.51-7.38(m,1H),7.19-7.07(m,2H),4.57-4.38(m,2H),1.47-1.36(m,9H)。 To a solution of 4-fluoro-3-nitrophenol (3.00 g, 19.10 mmol) in dimethylformamide (30.00 mL), sodium hydride (840.40 mg, 21.01 mmol, 60% purity), mixture at 10 ° C Stir for 30 minutes, then add 2-bromoacetic acid tert-butyl ester (3.73 g, 19.10 mmol, 2.82 ml) at 10 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove dimethylformamide. The mixture was diluted with EtOAc (EtOAc (EtOAc) (EtOAc) Purification gave Example 6A. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.51 - 7.38 (m, 1H), 7.19 - 7.07 (m, 2H), 4.57 - 4.38 (m, 2H), 1.47-1.36 (m, 9H).
实施例6BExample 6B
Figure PCTCN2018091270-appb-000072
Figure PCTCN2018091270-appb-000072
实施例6A(1.00克，3.69毫摩尔)的四氢呋喃(10.00毫升)溶液加入碳酸钾(1.02克，7.38毫摩尔)和2,2,6,6-四甲基四氢吡喃-4-胺(580.26毫克，3.69毫摩尔)，混合物在50℃下搅拌16小时，然后再加入2,2,6,6-四甲基四氢吡喃-4-胺(580.26毫克，3.69毫摩尔)，使反应液在70℃搅拌16小时，反应液用乙酸乙酯(50毫升)稀释，再用盐水(20毫升×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到实施例6B。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.90(br d,J＝7.3Hz,1H),7.61(d,J＝3.1Hz,1H),6.88(d,J＝9.4Hz,1H),4.51(s,2H),3.98(tdt,J＝3.7,7.6,11.5Hz,1H),2.05(dd,J＝3.3,13.2Hz,2H),1.79(dd,J＝3.8,12.8Hz,2H),1.53(s,9H),1.40(s,6H),1.29(s,6H)。 A solution of Example 6A (1.00 g, 3.69 mmol) in tetrahydrofuran (10.00 mL) was added potassium carbonate (1.02 g, 7.38 mmol) and 2,2,6,6-tetramethyltetrahydropyran-4-amine ( 580.26 mg, 3.69 mmol), the mixture was stirred at 50 ° C for 16 hours, then 2,2,6,6-tetramethyltetrahydropyran-4-amine (580.26 mg, 3.69 mmol) was added to make the reaction The solution was stirred at 70 ° C for 16 hr. EtOAc (EtOAc) 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.90 (br d, J = 7.3 Hz, 1H), 7.61 (d, J = 3.1 Hz, 1H), 6.88 (d, J = 9.4 Hz, 1H), 4.51 (s, 2H), 3.98 (tdt, J = 3.7, 7.6, 11.5 Hz, 1H), 2.05 (dd, J = 3.3, 13.2 Hz, 2H), 1.79 (dd, J = 3.8, 12.8 Hz, 2H), 1.53 (s, 9H), 1.40 (s, 6H), 1.29 (s, 6H).
实施例6CExample 6C
Figure PCTCN2018091270-appb-000073
Figure PCTCN2018091270-appb-000073
氮气的保护下，实施例6B(1.50克，3.67毫摩尔)的乙酸乙酯(20.00毫升)溶液中加入钯碳(10％,0.5克)。这悬浮物在抽真空用氢气置换多次，混合物在氢气(15psi)氛围下15℃搅拌24小时。反应液过滤，并将滤液减压浓缩得到实施例6C。粗产物直接用于下一步，不需要进一步纯化。Palladium on carbon (10%, 0.5 g) was added to a solution of EXAMPLE 6B (1.50 g, 3.67 mmol This suspension was replaced several times with hydrogen under vacuum, and the mixture was stirred at 15 ° C for 24 hours under a hydrogen (15 psi) atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced vacuo. The crude product was used directly in the next step without further purification.
实施例6DExample 6D
Figure PCTCN2018091270-appb-000074
Figure PCTCN2018091270-appb-000074
实施例6C(200.00毫克,528.40微摩尔)的四氢呋喃(4.00毫升)溶液加入1-异硫氰基-4-(三氟甲氧基)苯(115.82毫克,528.40微摩尔,85.79微升)，混合物在30℃搅拌2小时之后，再加入EDCI(202.59毫克,1.06毫摩尔)，混合物在70℃搅拌3小时，反应混合物用乙酸乙酯(10毫升)稀释，用水(2毫升×3)和盐水(10毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到的残余物通过板分离纯化和高效液相色谱纯化得到实施例6D。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.38(d,J＝9.0Hz,1H),7.25-7.19(m,4H),7.02(d,J＝2.3 Hz,1H),6.97(dd,J＝2.2,9.0Hz,1H),4.54-4.43(m,3H),2.06-1.98(m,2H),1.67-1.57(m,2H),1.45(s,9H),1.15(s,6H),0.77(s,6H)。 Example 6C (200.00 mg, 528.40 micromol) of tetrahydrofuran (4.00 ml) was added 1-isothiocyano-4-(trifluoromethoxy)benzene (115.82 mg, 528.40 micromoles, 85.79 microliters), mixture After stirring at 30 ° C for 2 hours, additional EDCI (202.59 mg, 1.06 mmol) was added, and the mixture was stirred at 70 ° C for 3 hours. The reaction mixture was diluted with ethyl acetate (10 ml), water (2 ml × 3) and brine It was washed with 10 ml), dried over anhydrous sodium sulfate, filtered, and evaporated. 1 H NMR (400MHz, CHLOROFORM- d) δ = 7.38 (d, J = 9.0Hz, 1H), 7.25-7.19 (m, 4H), 7.02 (d, J = 2.3 Hz, 1H), 6.97 (dd, J =2.2, 9.0 Hz, 1H), 4.54-4.43 (m, 3H), 2.06-1.98 (m, 2H), 1.67-1.57 (m, 2H), 1.45 (s, 9H), 1.15 (s, 6H), 0.77 (s, 6H).
实施例6Example 6
Figure PCTCN2018091270-appb-000075
Figure PCTCN2018091270-appb-000075
实施例6C(70.00毫克,124.20微摩尔)的盐酸/二氧六环(4M,2.80毫升)溶液在15℃搅拌16小时。反应混合物通过减压浓缩得到一个残余物，残余物通过高效液相色谱纯化得到实施例6。 1H NMR(400MHz,METHANOL-d4)δ＝7.73(d,J＝9.2Hz,1H),7.67-7.57(m,2H),7.56-7.45(m,2H),7.04(dd,J＝2.4,9.1Hz,1H),6.98(d,J＝2.4Hz,1H),5.04-4.96(m,1H),4.73(s,2H),2.38(br t,J＝12.8Hz,2H),2.08(br dd,J＝3.7,12.7Hz,2H),1.47(s,6H),1.37(s,6H)。 A solution of the hydrochloride / dioxane (4M, 2. <RTI ID=0.0></RTI></RTI><RTIgt; The reaction mixture was concentrated under reduced pressure to give a residue. 1 H NMR (400MHz, METHANOL- d4) δ = 7.73 (d, J = 9.2Hz, 1H), 7.67-7.57 (m, 2H), 7.56-7.45 (m, 2H), 7.04 (dd, J = 2.4, 9.1 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 5.04-4.96 (m, 1H), 4.73 (s, 2H), 2.38 (br t, J = 12.8 Hz, 2H), 2.08 (br Dd, J = 3.7, 12.7 Hz, 2H), 1.47 (s, 6H), 1.37 (s, 6H).
实施例7Example 7
Figure PCTCN2018091270-appb-000076
Figure PCTCN2018091270-appb-000076
实施例7AExample 7A
Figure PCTCN2018091270-appb-000077
Figure PCTCN2018091270-appb-000077
向2-氯-6-甲氧基-3-硝基吡啶(0.5克,2.65毫摩尔)和2,2,6,6-四甲基四氢吡喃-4-胺(625.08毫克,3.98毫摩尔)的四氢呋喃(10毫升)溶液加入碳酸钾(1.10克,7.95毫摩尔)，反应液在60-70℃搅拌16小时。反应混合物减压浓缩去除四氢呋喃，残余物用水(30毫升)稀释，然后用乙酸乙酯(20毫升×2)萃取，合并的有机层用盐水(40毫升×1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到实施例7A。产物直接用于下一步，没有进一步纯化。To 2-chloro-6-methoxy-3-nitropyridine (0.5 g, 2.65 mmol) and 2,2,6,6-tetramethyltetrahydropyran-4-amine (625.08 mg, 3.98 m) A solution of the molar solution of tetrahydrofuran (10 ml) was added potassium carbonate (1.10 g, 7.95 mmol), and the mixture was stirred at 60-70 ° C for 16 hours. The reaction mixture was concentrated under reduced EtOAc (EtOAc m. Filtration and concentration under reduced pressure gave Example 7A. The product was used directly in the next step without further purification.
实施例7BExample 7B
Figure PCTCN2018091270-appb-000078
Figure PCTCN2018091270-appb-000078
实施例7A(0.775克,2.51毫摩尔)的二甲基甲酰胺(10毫升)加入NBS(490.47毫克,2.76毫摩尔)，反应液在40℃搅拌16小时，反应混合物用水(30毫升)稀释，并且通过过滤收集沉淀物得到实施例7B。 1H NMR(400MHz,CHLOROFORM-d)δ＝1.28(s,6H),1.35-1.45(m,8H),2.06(dd,J＝12.59,3.67Hz,2H),3.99-4.12(m,3H),4.53-4.75(m,1H),8.36(br d,J＝6.72Hz,1H),8.55(s,1H). Example 7A (0.775 g, 2.51 mmol), EtOAc (EtOAc) And the precipitate was collected by filtration to give Example 7B. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 1.28 (s, 6H), 1.35-1.45 (m, 8H), 2.06 (dd, J = 12.59, 3.67 Hz, 2H), 3.99 - 4.12 (m, 3H) , 4.53-4.75 (m, 1H), 8.36 (br d, J = 6.72 Hz, 1H), 8.55 (s, 1H).
实施例7CExample 7C
Figure PCTCN2018091270-appb-000079
Figure PCTCN2018091270-appb-000079
实施例7B(0.82克,1.39毫摩尔)，(E)-3-(4,4,5,5-四甲基-1,3，2-氧硼烷-2-基)丙烯酸乙酯(472.70毫克,2.09毫摩尔)，1,1，-二(二苯膦基)二茂铁二氯化钯(101.99毫克,139.39微摩尔)，碳酸钾(577.96毫克,4.18毫摩尔)的二氧六环(10.00毫升)和水(1.00毫升)混合物用氮气置换三次，然后加热到90℃搅拌16小时。反应液用水(60毫升)稀释，然后用乙酸乙酯(30毫升×2)萃取，合并的有机层用盐水(30毫升×1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到的残余物，残余物通过柱色谱纯化得到实施例7C。 1H NMR(400MHz,CHLOROFORM-d)δ＝1.25-1.41(m,17H),2.07(dd,J＝12.59,3.67Hz,2H),4.04-4.10(m,3H),4.25(q,J＝7.09Hz,2H),4.71(ddt,J＝11.72,7.99,4.14,4.14Hz,1H),6.48(d,J＝16.02Hz,1H),7.64(d,J＝16.02Hz,1H),8.47-8.57(m,2H). Example 7B (0.82 g, 1.39 mmol), (E)-3-(4,4,5,5-tetramethyl-1,3,2-oxaboran-2-yl)ethyl acrylate (472.70 Mg, 2.09 mmol, 1,1,-bis(diphenylphosphino)ferrocene palladium dichloride (101.99 mg, 139.39 μmol), potassium carbonate (577.96 mg, 4.18 mmol) of dioxane A mixture of (10.00 ml) and water (1.00 ml) was replaced with nitrogen three times, then heated to 90 ° C and stirred for 16 hours. The reaction mixture was diluted with EtOAc EtOAc EtOAc. The residue was purified by column chromatography to give Example 7C. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 1.25-1.41 (m, 17H), 2.07 (dd, J = 12.59, 3.67 Hz, 2H), 4.04 - 4.10 (m, 3H), 4.25 (q, J = 7.09 Hz, 2H), 4.71 (ddt, J = 11.72, 7.99, 4.14, 4.14 Hz, 1H), 6.48 (d, J = 16.02 Hz, 1H), 7.64 (d, J = 16.02 Hz, 1H), 8.47- 8.57 (m, 2H).
实施例7DExample 7D
Figure PCTCN2018091270-appb-000080
Figure PCTCN2018091270-appb-000080
氮气的保护下，实施例7C(0.55克,1.35毫摩尔)的甲醇(12毫升)溶液中加入钯碳(100.00毫克,10％纯度)，把悬浮液抽真空置换氢气多次然后在氢气(15psi)氛围下25℃搅拌1小时。对反应液进行过滤，对滤液进行减压浓缩得到实施例7D，产物直接用于下一步，不需要进一步纯化。Palladium on carbon (100.00 mg, 10% purity) was added to a solution of EXAMPLE 7C (0.55 g, 1.35 mmol) in MeOH (12 mL). N.sub. Stir at 25 ° C for 1 hour under the atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced vacuo.
实施例7EExample 7E
Figure PCTCN2018091270-appb-000081
Figure PCTCN2018091270-appb-000081
25℃下，实施例7D(0.51克，1.34毫摩尔)的四氢呋喃(10.00毫升)溶液中加入1-异硫氰基-4-(三氟甲氧基)苯(294.56毫克,1.34毫摩尔,218.19微升)，搅拌2小时，然后再加入EDCI(515.25毫克，2.69毫摩尔)，使反应液升温到70℃搅拌2小时，对反应液进行减压浓缩得到一个残余物，残余物通过柱色谱纯化得到实施例7E。 1H NMR(400MHz,CHLOROFORM-d)δ＝1.07(s,6H),1.14-1.24(m,9H),1.63(dd,J＝12.72,3.42Hz,2H),2.51-2.69(m,4H),2.90(t,J＝7.58Hz,2H),3.90(s,3H),3.98-4.14(m,2H),4.54(tt,J＝12.61,3.29Hz,1H),7.00-7.11(m,4H),7.33(br s,1H),7.54(s,1H). To a solution of Example 7D (0.51 g, 1.34 mmol) in tetrahydrofuran (10.00 mL), EtOAc (EtOAc: EtOAc. The mixture was stirred for 2 hours, then EDCI (515.25 mg, 2.69 mmol) was added. The reaction mixture was warmed to 70 ° C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. Example 7E was obtained. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 1.07 (s, 6H), 1.14-1.24 (m, 9H), 1.63 (dd, J = 12.72, 3.42 Hz, 2H), 2.51-2.69 (m, 4H) , 2.90 (t, J = 7.58 Hz, 2H), 3.90 (s, 3H), 3.98-4.14 (m, 2H), 4.54 (tt, J = 12.61, 3.29 Hz, 1H), 7.00-7.11 (m, 4H) ), 7.33 (br s, 1H), 7.54 (s, 1H).
实施例7Example 7
Figure PCTCN2018091270-appb-000082
Figure PCTCN2018091270-appb-000082
实施例7E(0.5克,888.70微摩尔)的四氢呋喃(8.00毫升)和水(8.00毫升)溶液中加入一水合氢氧化锂(186.45毫克，4.44毫摩尔)，反应液在15℃搅拌16小时，反应混合物减压浓缩去除四氢呋喃，残余物再用1N盐酸酸化调节pH值为4，然后用乙酸乙酯(40毫升×2)萃取，合并的有机层用盐水(40毫升×1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到的残余物通过高效液相色谱纯化得到实施例7。 1H NMR(400MHz,METHANOL-d4)δ＝1.22-1.41(m,12H),1.81(dd,J＝12.72,3.67Hz,2H),2.59(t,J＝7.52Hz,2H),2.77-2.97(m,4H),3.35(s,1H),3.99(s,3H),7.23(d,J＝8.44Hz,2H),7.33-7.42(m,2H),7.54(s,1H)。 To a solution of Example 7E (0.5 g, 888.70 μmol) of tetrahydrofuran (8.00 ml) and water (8.00 ml) was added lithium hydroxide monohydrate (186.45 mg, 4.44 mmol), and the reaction mixture was stirred at 15 ° C for 16 hours. The mixture was concentrated under reduced pressure to remove EtOAc. EtOAc (EtOAc) (EtOAc) The residue was dried with EtOAc (EtOAc). 1 H NMR (400MHz, METHANOL- d4) δ = 1.22-1.41 (m, 12H), 1.81 (dd, J = 12.72,3.67Hz, 2H), 2.59 (t, J = 7.52Hz, 2H), 2.77-2.97 (m, 4H), 3.35 (s, 1H), 3.99 (s, 3H), 7.23 (d, J = 8.44 Hz, 2H), 7.33 - 7.42 (m, 2H), 7.54 (s, 1H).
实施例8Example 8
Figure PCTCN2018091270-appb-000083
Figure PCTCN2018091270-appb-000083
实施例8AExample 8A
Figure PCTCN2018091270-appb-000084
Figure PCTCN2018091270-appb-000084
将碳酸钾(472.38毫克,3.42毫摩尔)和2,2,6,6-四甲基四氢-2H-吡喃-4-胺(671.85毫克,4.27毫摩尔)加入到4-氯-2-氟-1-硝基-苯(500.00毫克,2.85毫摩尔)的四氢呋喃(10毫升)溶液中，室温下搅拌1小时。反应液用乙酸乙酯(15毫升×2)和水(50毫升)分层，有机相用盐水(20.00毫升×2)洗涤，干燥，过滤，减压浓缩得到残余物，残余物通过柱色谱纯化得到实施例8A。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.14(d,J＝9.0Hz,1H),7.99(br d,J＝6.5Hz,1H),6.84(d,J＝2.0Hz,1H),6.62(dd,J＝2.1,9.2Hz,1H),3.93(tdt,J＝3.6,7.6,11.5Hz,1H),2.05(dd,J＝3.6,12.9Hz,2H),1.41(s,6H),1.37(s,1H),1.35-1.32(m,1H),1.29(s,6H). Potassium carbonate (472.38 mg, 3.42 mmol) and 2,2,6,6-tetramethyltetrahydro-2H-pyran-4-amine (671.85 mg, 4.27 mmol) were added to 4-chloro-2- A solution of fluoro-1-nitro-benzene (500.00 mg, 2.85 mmol) in tetrahydrofuran (10 ml) was stirred at room temperature for one hour. The reaction mixture was separated with EtOAc EtOAc (EtOAc m. Example 8A was obtained. 1 H NMR (400MHz, CHLOROFORM- d) δ = 8.14 (d, J = 9.0Hz, 1H), 7.99 (br d, J = 6.5Hz, 1H), 6.84 (d, J = 2.0Hz, 1H), 6.62 (dd, J = 2.1, 9.2 Hz, 1H), 3.93 (tdt, J = 3.6, 7.6, 11.5 Hz, 1H), 2.05 (dd, J = 3.6, 12.9 Hz, 2H), 1.41 (s, 6H), 1.37 (s, 1H), 1.35 - 1.32 (m, 1H), 1.29 (s, 6H).
实施例8BExample 8B
Figure PCTCN2018091270-appb-000085
Figure PCTCN2018091270-appb-000085
将NBS(381.24毫克，2.14毫摩尔)加入到实施例8A(670.00毫克，2.14毫摩尔)的乙腈(20毫升)溶液中，70℃下搅拌16小时。反应液用乙酸乙酯(20毫升×2)和水(50毫升)分层，有机相用盐水(20.00毫升×2)洗涤，干燥，过滤，减压浓缩得到实施例8B。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.45(s,1H),7.87(br d,J＝6.8Hz,1H),6.98(s,1H),3.91(tdt,J＝3.7,7.6,11.5Hz,1H),2.03(dd,J＝3.5,12.8Hz,2H),1.40(s,6H),1.38-1.32(m,2H),1.29(s,6H). NBS (381.24 mg, 2.14 mmol) was added to EtOAc (EtOAc m. The reaction mixture was separated with EtOAc EtOAc EtOAc. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.45 (s, 1H), 7.87 (brd, J = 6.8 Hz, 1H), 6.98 (s, 1H), 3.91 (tdt, J = 3.7, 7.6, 11.5) Hz, 1H), 2.03 (dd, J=3.5, 12.8 Hz, 2H), 1.40 (s, 6H), 1.38-1.32 (m, 2H), 1.29 (s, 6H).
实施例8CExample 8C
Figure PCTCN2018091270-appb-000086
Figure PCTCN2018091270-appb-000086
将保险粉(1.23克,7.06毫摩尔)和碳酸钠(1.07克,10.08毫摩尔)加入到实施例8B(790.00毫克,2.02毫摩尔)的乙醇(10毫升)和水(10毫升)的混合溶液中，70℃下搅拌16小时。反应液用乙酸乙酯(50毫升×2)和水(50毫升)分层，有机相用盐水(50.00毫升×2)洗涤，干燥，过滤，减压浓缩得到实施例8C。 1H NMR(400MHz,CHLOROFORM-d)δ＝6.94(s,1H),6.69(s,1H),3.70(br t,J＝11.8Hz,1H),3.29(br s,2H),2.01(br dd,J＝3.6,12.7Hz,2H),1.38(s,6H),1.28-1.24(m,8H). An insurance powder (1.23 g, 7.06 mmol) and sodium carbonate (1.07 g, 10.08 mmol) were added to a mixed solution of Example 8B (790.00 mg, 2.02 mmol) in ethanol (10 ml) and water (10 ml). The mixture was stirred at 70 ° C for 16 hours. The reaction mixture was separated with EtOAc EtOAc EtOAc. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 6.94 (s, 1H), 6.69 (s, 1H), 3.70 (brt, J = 11.8 Hz, 1H), 3.29 (br s, 2H), 2.01 (br) Dd, J = 3.6, 12.7 Hz, 2H), 1.38 (s, 6H), 1.28-1.24 (m, 8H).
实施例8DExample 8D
Figure PCTCN2018091270-appb-000087
Figure PCTCN2018091270-appb-000087
将1-异硫氰基-4-(三氟甲氧基)苯(413.27毫克,1.89毫摩尔)加入到实施例8C(620毫克，1.71毫摩尔)的四氢呋喃(15毫升)的溶液中，40℃下搅拌16小时。再将EDCI(394.32毫克,2.06毫摩尔)加入到反应液中，80℃下搅拌4小时。反应液用乙酸乙酯(15毫升×2)和水(15毫升)分层，有机相用盐水(20.00毫升×2)洗涤，干燥，过滤，减压浓缩得到残余物，残余物经过柱色谱分离得到实施例8D。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.81(br s,1H),7.50(s,1H),7.24-7.18(m,4H),7.02(br s,1H),4.62-4.47(m,1H),2.11(br t,J＝12.8Hz,2H),1.79(dd,J＝3.3,12.8Hz,2H),1.30(s,6H),1.17(s,6H). 1-Isothiocyanato-4-(trifluoromethoxy)benzene (413.27 mg, 1.89 mmol) was added to a solution of EXAMPLE 8C (620 mg, 1.71 mmol) in tetrahydrofuran (15 mL), 40 Stir at °C for 16 hours. Further, EDCI (394.32 mg, 2.06 mmol) was added to the reaction mixture, and the mixture was stirred at 80 ° C for 4 hours. The reaction mixture was separated with EtOAc EtOAc (EtOAc m. Example 8D was obtained. 1 H NMR (400MHz, CHLOROFORM- d) δ = 7.81 (br s, 1H), 7.50 (s, 1H), 7.24-7.18 (m, 4H), 7.02 (br s, 1H), 4.62-4.47 (m, 1H), 2.11 (br t, J = 12.8 Hz, 2H), 1.79 (dd, J = 3.3, 12.8 Hz, 2H), 1.30 (s, 6H), 1.17 (s, 6H).
实施例8EExample 8E
Figure PCTCN2018091270-appb-000088
Figure PCTCN2018091270-appb-000088
将(E)-3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)丙烯酸酯(310.09毫克,1.37毫摩尔)和碳酸钾(284.34毫克,2.06毫摩尔)加入到实施例8D(375毫克,685.80微摩尔)的1,4-二氧六环(12毫升)和 水(3毫升)的混合溶液中，再在氮气保护下加入Pd(dppf)Cl 2(50.18毫克,68.58微摩尔)。在氮气保护，100℃下搅拌4小时。反应液用乙酸乙酯(20毫升×2)和水(30毫升)分层，有机相用盐水(20.00毫升×2)洗涤，干燥，过滤，减压浓缩得到残余物，残余物经过柱色谱分离得到实施例8E。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.20(br d,J＝16.1Hz,1H),7.86(br s,1H),7.42(br s,1H),7.31(br s,1H),7.23(br d,J＝8.8Hz,3H),6.43(br d,J＝15.6Hz,2H),4.30(q,J＝6.9Hz,2H),4.13(q,J＝7.3Hz,1H),2.20-2.07(m,2H),1.83(br d,J＝12.3Hz,2H),1.37(br t,J＝7.2Hz,3H),1.32(s,6H),1.27(s,6H). (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (310.09 mg, 1.37 mmol) and potassium carbonate (284.34 mg, 2.06 mmol) was added to a mixture of 1,4-dioxane (12 ml) and water (3 ml) of Example 8D (375 mg, 685. Pd(dppf)Cl 2 (50.18 mg, 68.58 μmol) was added. Stir under nitrogen for 10 hours at 100 °C. The reaction mixture was separated with EtOAc EtOAc (EtOAc m. Example 8E was obtained. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.20 (br d, J = 16.1 Hz, 1H), 7.86 (br s, 1H), 7.42 (br s, 1H), 7.31 (br s, 1H), 7.23 (br d, J = 8.8 Hz, 3H), 6.43 (br d, J = 15.6 Hz, 2H), 4.30 (q, J = 6.9 Hz, 2H), 4.13 (q, J = 7.3 Hz, 1H), 2.20 -2.07 (m, 2H), 1.83 (br d, J = 12.3 Hz, 2H), 1.37 (br t, J = 7.2 Hz, 3H), 1.32 (s, 6H), 1.27 (s, 6H).
实施例8FExample 8F
Figure PCTCN2018091270-appb-000089
Figure PCTCN2018091270-appb-000089
将六水合二氯化镍(503.93毫克,2.12毫摩尔)加入到实施例8E(300毫克，530.03微摩尔)的甲醇(4毫升)的溶液中，再在零度下滴加硼氢化钠(40.10毫克,1.06毫摩尔)的DMF(2毫升)溶液。在室温下搅拌16小时。向反应液中加入用乙酸乙酯(15毫升)和水(15毫升)，用硅藻土过滤，滤液用乙酸乙酯(150毫升×2)分层，有机相用盐水(20.00毫升×2)洗涤，干燥，过滤，减压浓缩得到，实施例8F。To a solution of Example 8E (300 mg, 530.03 micromoles) in methanol (4 ml) was added to a solution of EtOAc (40. , 1.06 mmol) in DMF (2 mL). Stir at room temperature for 16 hours. Ethyl acetate (15 ml) and water (15 ml) were added toEtOAc. Washing, drying, filtration and concentration under reduced pressure afforded Example 8F.
实施例8Example 8
Figure PCTCN2018091270-appb-000090
Figure PCTCN2018091270-appb-000090
将一水合氢氧化锂(110.81毫克，2.64毫摩尔)加入到实施例8F(300毫克，528.14微摩尔)的四氢呋喃(3毫升)和水(3毫升)的混合溶液中。在40℃下搅拌16小时。用1摩尔的盐酸调pH到5，旋干得到残余物，残余物通过制备分离得到实施例8。 1H NMR(400MHz,DMSO-d6)δ＝7.69(br d,J＝8.8Hz,3H),7.43(br d,J＝7.5Hz,2H),7.35(s,1H),4.87(br t,J＝12.8Hz,1H),2.97(br t,J＝7.3Hz,2H),2.59-2.56(m,2H),2.16(br t,J＝12.5Hz,2H),1.86(br d,J＝9.0Hz,2H),1.36(s,6H),1.25(s,6H)。 Lithium hydroxide monohydrate (110.81 mg, 2.64 mmol) was added to a mixed solution of Example 8F (300 mg, 528.14 μmol) in tetrahydrofuran (3 ml) and water (3 ml). Stir at 40 ° C for 16 hours. The pH was adjusted to 5 with 1 mol of hydrochloric acid, and dried to give a residue. 1 H NMR (400 MHz, DMSO-d6) δ = 7.69 (brd, J = 8.8 Hz, 3H), 7.43 (brd, J = 7.5 Hz, 2H), 7.35 (s, 1H), 4.87 (br t, J = 12.8 Hz, 1H), 2.97 (br t, J = 7.3 Hz, 2H), 2.59 - 2.56 (m, 2H), 2.16 (br t, J = 12.5 Hz, 2H), 1.86 (br d, J = 9.0 Hz, 2H), 1.36 (s, 6H), 1.25 (s, 6H).
实施例9Example 9
Figure PCTCN2018091270-appb-000091
Figure PCTCN2018091270-appb-000091
实施例9AExample 9A
Figure PCTCN2018091270-appb-000092
Figure PCTCN2018091270-appb-000092
在-10℃下，向1-氯-3-(三氟甲氧基)苯(3克，15.26毫摩尔)的硫酸(8毫升)溶液中用注射器滴加硝酸(2.80克，44.44毫摩尔,2毫升)，反应液降温-10℃搅拌1小时，通过另外加入水(100毫升)对反应液进行淬灭，然后用乙酸乙酯(50毫升×2)萃取，合并的有机层用盐水(50毫升×1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到的残余物通过柱色谱纯化得到实施例9A。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.96-8.05(m,1H)7.99(br s,1H)7.99(s,1H)。 To a solution of 1-chloro-3-(trifluoromethoxy)benzene (3 g, 15.26 mmol) in sulphuric acid (8 mL), nitric acid (2.80 g, 44.44 mmol, 2 ml), the reaction solution was cooled at -10 ° C for 1 hour, the reaction solution was quenched by additional water (100 ml), and then extracted with ethyl acetate (50 ml × 2). The mixture was washed with EtOAc (1 mL). 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.96 - 8.05 (m, 1H) 7.79 (br s, 1H) 7.99 (s, 1H).
实施例9BExample 9B
Figure PCTCN2018091270-appb-000093
Figure PCTCN2018091270-appb-000093
向实施例9A(1克，4.14毫摩尔)和2,2,6,6-四甲基四氢吡喃-4-胺(976.51毫克，6.21毫摩尔)的二氧六环(20毫升)溶液中加入碳酸钾(1.72克，12.42毫摩尔)，反应液在95℃搅拌16小时。反应混合物减压浓缩去除二氧六环，残余物用水(100毫升)稀释，然后用乙酸乙酯(40毫升×2)萃取，合并的有机层用盐水(40毫升×1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到的残余物通过柱色谱纯化得到实施例9B。To a solution of Example 9A (1 g, 4.14 mmol) and 2,2,6,6-tetramethyltetrahydropyran-4-amine (976.51 mg, 6.21 mmol) in dioxane (20 mL) Potassium carbonate (1.72 g, 12.42 mmol) was added, and the reaction solution was stirred at 95 ° C for 16 hours. The reaction mixture was concentrated to drynessnessnessnessnessnessnessnessnessnessssssssssssssssssssssssssssssssssssssssssssssssssss The residue was dried with EtOAc (EtOAc m.
实施例9CExample 9C
Figure PCTCN2018091270-appb-000094
Figure PCTCN2018091270-appb-000094
实施例9B(0.4克,1.10毫摩尔)的二甲基甲酰胺(10毫升)加入NBS(216.13毫克,1.21毫摩尔)，反应液在 15℃搅拌16小时，反应液用水(50毫升)稀释，然后用乙酸乙酯(20毫升×2)萃取，合并的有机层用盐水(20毫升×1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到实施例9C。 1H NMR(400MHz,CHLOROFORM-d)δ＝1.21(s,6H),1.27-1.37(m,8H),1.96(dd,J＝12.72,3.79Hz,2H),3.82(dtd,J＝14.90,7.56,7.56,3.48Hz,1H),6.74(s,1H)7.87(br d,J＝6.85Hz,1H),8.41(s,1H). Example 9B (0.4 g, 1.10 mmol) of dimethylformamide (10 ml) was added NBS (216.13 mg, 1.21 mmol), and the mixture was stirred at 15 ° C for 16 hours, and the reaction mixture was diluted with water (50 ml). The mixture was extracted with EtOAc (EtOAc m. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 1.21. (s, 6H), 1.27.37 (m, 8H), 1.96 (dd, J = 12.72, 3.79 Hz, 2H), 3.82 (dtd, J = 14.90, 7.56, 7.56, 3.48 Hz, 1H), 6.74 (s, 1H) 7.87 (br d, J = 6.85 Hz, 1H), 8.41 (s, 1H).
实施例9DExample 9D
Figure PCTCN2018091270-appb-000095
Figure PCTCN2018091270-appb-000095
实施例9C(0.45克，673.10微摩尔)，(E)-3-(4,4,5,5-四甲基-1,3，2-氧硼烷-2-基)丙烯酸乙酯(228.26毫克,1.01毫摩尔)，1,1,-二(二苯膦基)二茂铁二氯化钯(49.25毫克，67.31微摩尔)，碳酸钾(279.09Example 9C (0.45 g, 673.10 μmol), (E)-3-(4,4,5,5-tetramethyl-1,3,2-oxaboran-2-yl)ethyl acrylate (228.26 Mg, 1.01 mmol, 1,1,-bis(diphenylphosphino)ferrocene palladium dichloride (49.25 mg, 67.31 μmol), potassium carbonate (279.09
克，1.01毫摩尔)的二氧六环(10.00毫升)和水(1.00毫升)混合溶液用氮气置换三次，然后加热到a mixture of dioxane (10.00 ml) and water (1.00 ml) was replaced with nitrogen three times and then heated to
90℃搅拌16小时，反应混合物减压浓缩去除二氧六环，残余物用水(50毫升)稀释，然后用乙酸乙酯(30毫升×2)萃取，合并的有机层用盐水(40毫升×1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到的残余物通过板分离纯化得到实施例9D。After stirring at 90 ° C for 16 hours, the reaction mixture was evaporated to dryness crystals crystals crystalssssssssssssssssssssssssssssssssss The mixture was washed with anhydrous sodium sulfate, filtered, and then evaporated.
实施例9EExample 9E
Figure PCTCN2018091270-appb-000096
Figure PCTCN2018091270-appb-000096
在氮气的保护下，实施例9D(0.16克，347.49微摩尔)的甲醇(2毫升)和DCM(2毫升)溶液中加入钯碳(0.03克，10％纯度)，把悬浮液抽真空置换氢气多次然后在氢气(15psi)氛围下15℃搅拌16小时。对反应液进行过滤，对滤液进行减压浓缩得到实施例9E，产物直接用于下一步，不需要进一步纯化。Palladium carbon (0.03 g, 10% purity) was added to a solution of Example 9D (0.16 g, 347.49 micromoles) in methanol (2 mL) and DCM (2 mL). The mixture was stirred several times at 15 ° C under a hydrogen (15 psi) atmosphere for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced vacuo.
实施例9FExample 9F
Figure PCTCN2018091270-appb-000097
Figure PCTCN2018091270-appb-000097
在30℃下，实施例9E(0.15克，346.84微摩尔)的四氢呋喃(5.00毫升)溶液中加入1-异硫氰基-4-(三氟甲氧基)苯(83.62毫克，381.52微摩尔，61.94微升)，搅拌1小时，然后再加入EDCI(132.98毫克，693.68微摩尔)，使反应液升温到70℃搅拌1小时，对反应液进行减压浓缩得到一个残余物，残余物通过柱色谱纯化得到实施例9F。To a solution of the THF (5. 61.94 μl), stirring for 1 hour, then adding EDCI (132.98 mg, 693.68 μmol), the reaction solution was heated to 70 ° C and stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to give a residue. Purification gave Example 9F.
实施例9Example 9
Figure PCTCN2018091270-appb-000098
Figure PCTCN2018091270-appb-000098
实施例9F(3.00毫升)和水(3.00毫升)溶液中加入一水合氢氧化锂(54.36毫克，1.30毫摩尔)，反应液在15℃搅拌16小时，反应混合物减压浓缩去除四氢呋喃，残余物再用水(5毫升)稀释，然后再用1N盐酸溶液调节pH值为3，通过过滤收集沉淀物得到实施例9。 1H NMR(400MHz,DMSO-d6)δ＝1.23(s,6H),1.37(s,6H),1.80-1.98(m,2H),2.10(br t,J＝12.55Hz,2H),2.55-2.60(m,2H),2.92(br t,J＝7.47Hz,2H),4.86-5.05(m,1H),4.92-4.98(m,1H),7.32-7.45(m,3H),7.51(br s,1H),7.72(br d,J＝8.66Hz,2H),12.25(br s,1H). To a solution of Example 9F (3.00 ml) and water (3.00 ml), lithium hydroxide monohydrate (54.36 mg, 1.30 mmol) was added, and the reaction mixture was stirred at 15 ° C for 16 hours, and the reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. It was diluted with water (5 ml), and then adjusted to pH 3 with a 1N hydrochloric acid solution, and the precipitate was collected by filtration to obtain Example 9. 1 H NMR (400MHz, DMSO- d6) δ = 1.23 (s, 6H), 1.37 (s, 6H), 1.80-1.98 (m, 2H), 2.10 (br t, J = 12.55Hz, 2H), 2.55- 2.60 (m, 2H), 2.92 (br t, J = 7.47 Hz, 2H), 4.86-5.05 (m, 1H), 4.92-4.98 (m, 1H), 7.32-7.45 (m, 3H), 7.51 (br) s, 1H), 7.72 (br d, J = 8.66 Hz, 2H), 12.25 (br s, 1H).
实施例10Example 10
Figure PCTCN2018091270-appb-000099
Figure PCTCN2018091270-appb-000099
实施例10AExample 10A
Figure PCTCN2018091270-appb-000100
Figure PCTCN2018091270-appb-000100
将碳酸钾(329.76毫克,2.39毫摩尔)和2,2,6,6-四甲基四氢-2H-吡喃-4-胺(469.01毫克,2.98毫摩尔)加入到5-溴-2-氯-6-甲基-3-硝基-吡啶(500.00毫克，1.99毫摩尔)的THF(10毫升)溶液中，70℃搅拌16小时。反应液用乙酸乙酯(15毫升×2)和水(15毫升)分层，有机相用盐水(20.00毫升×2)洗涤，干燥，过滤，减压浓缩得到残余物，残余物通过柱色谱纯化得到实施例10A。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.50(s,1H),7.97(br d,J＝6.8Hz,1H),4.73(tdt,J＝3.7,7.9,11.8Hz,1H),2.60(s,3H),2.04(dd,J＝3.6,12.4Hz,2H),1.39(s,6H),1.37-1.31(m,2H),1.27(s,6H). Potassium carbonate (329.76 mg, 2.39 mmol) and 2,2,6,6-tetramethyltetrahydro-2H-pyran-4-amine (469.01 mg, 2.98 mmol) were added to 5-bromo-2- A solution of chloro-6-methyl-3-nitro-pyridine (500.00 mg, 1.99 mmol) in THF (10 mL). The reaction mixture was separated with EtOAc EtOAc EtOAc. Example 10A was obtained. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.50 (s, 1H), 7.97 (brd, J = 6.8 Hz, 1H), 4.73 (tdt, J = 3.7, 7.9, 11.8 Hz, 1H), 2.60 ( s, 3H), 2.04 (dd, J = 3.6, 12.4 Hz, 2H), 1.39 (s, 6H), 1.37-1.31 (m, 2H), 1.27 (s, 6H).
实施例10BExample 10B
Figure PCTCN2018091270-appb-000101
Figure PCTCN2018091270-appb-000101
将(E)-3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)丙烯酸酯(273.29毫克,1.21毫摩尔)和碳酸钾(334.14毫克,2.42毫摩尔)加入到实施例10A(300毫克,805.89微摩尔)的1,4-二氧六环(8毫升)和水(2毫升)的混合溶液中，再在氮气保护下加入Pd(dppf)Cl 2(58.97毫克,80.59微摩尔)。在氮气保护，90℃下搅拌5小时。反应液用乙酸乙酯(30毫升×2)和水(30毫升)分层，有机相用盐水(30.00毫升×2)洗涤，干燥，过滤，减压浓缩得到残余物，残余物经过柱色谱分离得到实施例10B。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.61(s,1H),8.15(br d,J＝7.3Hz,1H),7.78(d,J＝15.8Hz,1H),6.33(d,J＝15.8Hz,1H),4.81(dtd,J＝3.9,8.1,11.9Hz,1H),4.28(q,J＝7.3Hz,2H),2.61(s,3H),2.06(dd,J＝3.8,12.5Hz,2H),1.40(s,6H),1.38-1.31(m,5H),1.28(s,6H). (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (273.29 mg, 1.21 mmol) and potassium carbonate (334.14 mg, 2.42 mmol) was added to a mixed solution of 1,4-dioxane (8 ml) and water (2 ml) of Example 10A (300 mg, 805.89 micromoles) under nitrogen Pd(dppf)Cl 2 (58.97 mg, 80.59 μmol) was added. Stir under nitrogen for 5 hours at 90 °C. The reaction mixture was separated with EtOAc EtOAc (EtOAc m. Example 10B was obtained. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.61 (s, 1H), 8.15 (brd, J = 7.3 Hz, 1H), 7.78 (d, J = 15.8 Hz, 1H), 6.33 (d, J = 15.8 Hz, 1H), 4.81 (dtd, J = 3.9, 8.1, 11.9 Hz, 1H), 4.28 (q, J = 7.3 Hz, 2H), 2.61 (s, 3H), 2.06 (dd, J = 3.8, 12.5) Hz, 2H), 1.40 (s, 6H), 1.38-1.31 (m, 5H), 1.28 (s, 6H).
实施例10CExample 10C
Figure PCTCN2018091270-appb-000102
Figure PCTCN2018091270-appb-000102
将钯炭(26毫克)加入到实施例10B(210.00毫克，557.84微摩尔)的甲醇(20毫升)的溶液中，用氢气球置换三次，在氢气气氛下室温搅拌16小时。反应液用硅藻土过滤，用乙醇(10mL)洗涤四次。滤液旋干得到实施例10C。 1H NMR(400MHz,CHLOROFORM-d)δ＝6.68(s,1H),4.53-4.42(m,1H),4.14(q,J＝7.2Hz,2H),3.07-2.94(m,2H),2.78(t,J＝7.9Hz,2H),2.55-2.48(m,2H),2.35(s,3H),2.08(dd,J＝3.5,12.3Hz,2H),1.39(s,6H),1.27(s,2H),1.24(s,6H),1.22-1.11(m,3H). Palladium on carbon (26 mg) was added to a solution of EtOAc (EtOAc m. The reaction solution was filtered through Celite, and washed four times with ethyl alcohol (10 mL). The filtrate was spun dry to give Example 10C. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 6.68 (s, 1H), 4.53-4.42 (m, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.07-2.94 (m, 2H), 2.78 (t, J = 7.9 Hz, 2H), 2.55-2.48 (m, 2H), 2.35 (s, 3H), 2.08 (dd, J = 3.5, 12.3 Hz, 2H), 1.39 (s, 6H), 1.27 ( s, 2H), 1.24 (s, 6H), 1.22-1.11 (m, 3H).
实施例10DExample 10D
Figure PCTCN2018091270-appb-000103
Figure PCTCN2018091270-appb-000103
将1-异硫氰基-4-(三氟甲氧基)苯(152.56毫克，696.02微摩尔)加入到实施例10C(230毫克,632.75微摩尔)的四氢呋喃(8毫升)的溶液中，40℃下搅拌16小时。再将EDCI(145.56毫克,759.30微摩尔)加入到反应液中，80℃下搅拌3小时。反应液用乙酸乙酯(15毫升×2)和水(15毫升)分层，有机相用盐水(20.00毫升×2)洗涤，干燥，过滤，减压浓缩得到残余物，残余物经过柱色谱分离得到实施例10D。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.54(br s,1H),7.40(br d,J＝8.3Hz,2H),7.22(br,d,J＝8.5Hz,1H),7.24-7.18(m,1H),6.43(br s,1H),4.82(br t,J＝12.5Hz,1H),4.21-4.14(m,2H),3.02(br,t,J＝7.8Hz,2H),2.64(s,2H),2.61(s,3H),1.78(dd,J＝3.3,12.5Hz,2H),1.32(s,6H),1.29(s,6H),1.28-1.27(m,1H),1.27(s,2H),1.26(br s,2H). 1-Isothiocyanato-4-(trifluoromethoxy)benzene (152.56 mg, 696.02 μmol) was added to a solution of Example 10C (230 mg, 632.75 micromoles) in tetrahydrofuran (8 mL), 40 Stir at °C for 16 hours. Further, EDCI (145.56 mg, 759.30 μmol) was added to the reaction solution, and the mixture was stirred at 80 ° C for 3 hours. The reaction mixture was separated with EtOAc EtOAc (EtOAc m. Example 10D was obtained. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.54 (br s, 1H), 7.40 (br d, J = 8.3 Hz, 2H), 7.22 (br, d, J = 8.5 Hz, 1H), 7.24 - 7.18 (m, 1H), 6.43 (br s, 1H), 4.82 (br t, J = 12.5 Hz, 1H), 4.21-4.14 (m, 2H), 3.02 (br, t, J = 7.8 Hz, 2H), 2.64 (s, 2H), 2.61 (s, 3H), 1.78 (dd, J = 3.3, 12.5 Hz, 2H), 1.32 (s, 6H), 1.29 (s, 6H), 1.28-1.27 (m, 1H) , 1.27 (s, 2H), 1.26 (br s, 2H).
实施例10Example 10
Figure PCTCN2018091270-appb-000104
Figure PCTCN2018091270-appb-000104
将一水合氢氧化锂(84.14毫克,2.01毫摩尔)加入到实施例10D(220毫克,401.02微摩尔)的四氢呋喃(2毫升)和水(2毫升)的混合溶液中。在40℃下搅拌16小时。用1摩尔的盐酸调pH到5，旋干得到残余物，残余物用制备分离得到实施例10。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.80(s,1H),7.26-7.19(m,4H),4.48(br t,J＝12.4Hz,1H),3.07(br t,J＝6.8Hz,2H),2.83-2.68(m,4H),2.63(s,3H),1.59(br,dd,J＝2.8,12.3Hz,2H),1.23(s,6H),0.88(s,6H). To a mixed solution of Example 10D (220 mg, 401.02 μmol) in tetrahydrofuran (2 ml) and water (2 ml) was added. Stir at 40 ° C for 16 hours. The pH was adjusted to 5 with 1 mol of hydrochloric acid, and dried to give a residue. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.80 (s, 1H), 7.26-7.19 (m, 4H), 4.48 (brt, J = 12.4 Hz, 1H), 3.07 (brt, J = 6.8 Hz) , 2H), 2.83-2.68 (m, 4H), 2.63 (s, 3H), 1.59 (br, dd, J = 2.8, 12.3 Hz, 2H), 1.23 (s, 6H), 0.88 (s, 6H).
实施例11Example 11
Figure PCTCN2018091270-appb-000105
Figure PCTCN2018091270-appb-000105
实施例11AExample 11A
Figure PCTCN2018091270-appb-000106
Figure PCTCN2018091270-appb-000106
20℃下，1-溴-2,4-二氟-5-硝基苯(2克,8.4毫摩尔)的四氢呋喃溶液中加入碳酸钾(1.74克，12.61毫摩尔)及2,2,6,6-四甲基四氢吡喃-4-胺(2.64克，16.81毫摩尔).然后反应液在60℃下搅拌1小时。薄板层析显示反应有一部分原料未反应完。反应液旋干后硅胶柱层析(石油醚：乙酸乙酯20/1-10/1)纯化得到实施例11A. 1H NMR(400MHz,CHLOROFORM-d)δ＝8.46(d,J＝7.3Hz,1H),8.03(br d,J＝5.3Hz,1H),6.60(d,J＝10.8Hz,1H),3.94-3.82(m,1H),2.03(dd,J＝3.6,12.9Hz,2H),1.40(s,6H),1.35-1.32(m,2H),1.29(s,6H). Potassium carbonate (1.74 g, 12.61 mmol) and 2,2,6 were added to a solution of 1-bromo-2,4-difluoro-5-nitrobenzene (2 g, 8.4 mmol) in tetrahydrofuran at 20 °C. 6-Tetramethyltetrahydropyran-4-amine (2.64 g, 16.81 mmol). The reaction solution was then stirred at 60 ° C for 1 hour. Thin plate chromatography showed that some of the starting materials were not reacted. The reaction solution was spin-dry silica gel column chromatography (petroleum ether: ethyl acetate 20 / 1-10 / 1) to give Example 11A 1 H NMR (400MHz, CHLOROFORM -d) δ = 8.46 (d, J = 7.3Hz. , 1H), 8.03 (br d, J = 5.3 Hz, 1H), 6.60 (d, J = 10.8 Hz, 1H), 3.94 - 3.82 (m, 1H), 2.03 (dd, J = 3.6, 12.9 Hz, 2H ), 1.40 (s, 6H), 1.35 - 1.32 (m, 2H), 1.29 (s, 6H).
实施例11BExample 11B
Figure PCTCN2018091270-appb-000107
Figure PCTCN2018091270-appb-000107
20℃下，实施例11A(1克,2.67毫摩尔)的1,4-二氧六环溶液中分别加入乙基-(E)-3-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)丙-2-烯酸酯(903.75毫克,4毫摩尔)，Pd(dppf)Cl 2(195.0毫克,266.5毫摩尔)和氟化钾(232.24毫克,4毫摩尔)。反应液在80℃下搅拌1小时，薄板层析显示原料反应完全。反应液旋干后柱层析(石油醚：乙酸乙酯10/1-5/1)得到实施例11B。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.48(d,J＝7.8Hz,1H),8.18(br d,J＝7.0Hz,1H),7.63(d,J＝16.1Hz,1H),6.54(d,J＝13.3Hz,1H),6.46(d,J＝16.1Hz,1H),4.28(q,J＝7.2Hz,2H),3.99-3.85(m,1H),2.05(dd,J＝3.5,12.8Hz,2H),1.41(s,6H),1.35(t,J＝7.0Hz,3H),1.29(s,6H),1.25-1.21(m,2H). Ethyl-(E)-3-(4,4,5,5-tetramethyl-) was added to a solution of Example 11A (1 g, 2.67 mmol) in 1,4-dioxane at 20 °C. 1,3,2-dioxaboron-2-yl)prop-2-enoate (903.75 mg, 4 mmol), Pd(dppf)Cl 2 (195.0 mg, 266.5 mmol) and potassium fluoride (232.24) Mg, 4 mmol). The reaction solution was stirred at 80 ° C for 1 hour, and thin plate chromatography showed that the starting material was completely reacted. After the reaction mixture was dried to dryness (m.j. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.48 (d, J = 7.8 Hz, 1H), 8.18 (brd, J = 7.0 Hz, 1H), 7.63 (d, J = 16.1 Hz, 1H), 6.54 (d, J = 13.3 Hz, 1H), 6.46 (d, J = 16.1 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H), 3.99 - 3.85 (m, 1H), 2.05 (dd, J = 3.5, 12.8 Hz, 2H), 1.41 (s, 6H), 1.35 (t, J = 7.0 Hz, 3H), 1.29 (s, 6H), 1.25-1.21 (m, 2H).
实施例11CExample 11C
Figure PCTCN2018091270-appb-000108
Figure PCTCN2018091270-appb-000108
实施例11B(0.75克，1.9毫摩尔)的甲醇溶液中加入20％湿Pd/C(1.01克，1.9毫摩尔)。反应液在20℃下氢气球的气氛中搅拌半小时。薄板层析显示原料反应完全。反应液过滤后母液旋干得到实施例11C，直接用于下一步反应。 1H NMR(400MHz,CHLOROFORM-d)δ＝6.55(d,J＝7.5Hz,1H),6.35(d,J＝11.8Hz,1H),4.20-4.07(m,3H),3.68(tt,J＝3.6,11.7Hz,1H),2.87-2.77(m,2H),2.62-2.51(m,2H),2.08-1.97(m,2H),1.37(s,6H),1.25(s,6H),1.24-1.23(m,2H),1.22(s,3H). A solution of Example 11B (0.75 g, 1.9 mmol) in methanol was added 20% wet Pd / C (1.01 g, 1.9 mmol). The reaction solution was stirred for half an hour in an atmosphere of a hydrogen balloon at 20 °C. Thin sheet chromatography showed complete reaction of the starting material. After the reaction solution was filtered, the mother liquid was spun dry to obtain Example 11C, which was directly used for the next reaction. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 6.55 (d, J = 7.5 Hz, 1H), 6.35 (d, J = 11.8 Hz, 1H), 4.20 - 4.07 (m, 3H), 3.68 (tt, J = 3.6, 11.7 Hz, 1H), 2.87-2.77 (m, 2H), 2.62-2.51 (m, 2H), 2.08-1.97 (m, 2H), 1.37 (s, 6H), 1.25 (s, 6H), 1.24-1.23 (m, 2H), 1.22 (s, 3H).
实施例11DExample 11D
Figure PCTCN2018091270-appb-000109
Figure PCTCN2018091270-appb-000109
20℃下，往含有乙基-(E)-3-[5-氨基-2-氟-4-[(2,2,6,6-四甲基四氢吡喃-4-基)氨基苯基]丙酸酯(0.7克，1.91毫摩尔)的四氢呋喃溶液中加入4-三氟甲氧基苯异硫氰酸酯(0.418克，2.87毫摩尔)。反应液在40℃下搅拌一小时后加入EDCI(0.549克，2.87毫摩尔)，80℃下继续搅拌一小时。薄板层析显示原料反应完全。反应液旋干后柱层析(石油醚：乙酸乙酯10/1-5/1)得到实施例11D。 1H NMR(400MHz,CHLOROFORM-d)δ＝ 7.41(br s,1H),7.22-7.09(m,5H),6.30(br s,1H),4.59(br s,1H),4.20-4.10(m,2H),3.07(br t,J＝7.7Hz,2H),2.67(t,J＝7.9Hz,2H),2.13(t,J＝12.8Hz,2H),1.76(dd,J＝3.3,12.5Hz,2H),1.29(s,6H),1.27-1.24(m,3H),1.16(s,6H). To ethyl-(E)-3-[5-amino-2-fluoro-4-[(2,2,6,6-tetramethyltetrahydropyran-4-yl)aminobenzene at 20 ° C To a solution of propionate (0.7 g, 1.91 mmol) in tetrahydrofuran was added 4-trifluoromethoxyphenyl isothiocyanate (0.418 g, 2.87 mmol). After the reaction mixture was stirred at 40 ° C for one hour, EDCI (0.549 g, 2.87 mmol) was added, and stirring was continued at 80 ° C for one hour. Thin sheet chromatography showed complete reaction of the starting material. After the reaction mixture was dried to dryness (m.j. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.41 (br s, 1H), 7.22-7.09 (m, 5H), 6.30 (br s, 1H), 4.59 (br s, 1H), 4.20-4.10 (m) , 2H), 3.07 (br t, J = 7.7 Hz, 2H), 2.67 (t, J = 7.9 Hz, 2H), 2.13 (t, J = 12.8 Hz, 2H), 1.76 (dd, J = 3.3, 12.5) Hz, 2H), 1.29 (s, 6H), 1.27-1.24 (m, 3H), 1.16 (s, 6H).
实施例11Example 11
Figure PCTCN2018091270-appb-000110
Figure PCTCN2018091270-appb-000110
20℃下，实施例11D的甲醇水(4毫升/4毫升)溶液中加入LiOH·H 2O(0.266克，6.35毫摩尔)。然后在40℃下搅拌一小时，薄板层析显示原料反应完全。反应液旋干后柱层析(二氯甲烷：乙酸乙酯10/1-1/1)得到实施例11。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.74(d,J＝6.8Hz,1H),7.18(br,d,J＝8.5Hz,2H),7.13(d,J＝10.3Hz,1H),7.00(br,d,J＝8.8Hz,2H),4.44(br t,J＝12.7Hz,1H),3.12(br,d,J＝5.0Hz,2H),2.80-2.68(m,2H),2.04(br,d,J＝13.6Hz,2H),1.63(br,d,J＝9.8Hz,2H),1.21(s,6H),0.85(s,6H). LiOH.H 2 O (0.266 g, 6.35 mmol) was added to a solution of the solution of methanol (4 ml / 4 ml). It was then stirred at 40 ° C for one hour, and thin plate chromatography showed that the starting material was completely reacted. After the reaction mixture was dried to dryness (m.j. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.74 (d, J = 6.8 Hz, 1H), 7.18 (br, d, J = 8.5 Hz, 2H), 7.13 (d, J = 10.3 Hz, 1H), 7.00 (br, d, J = 8.8 Hz, 2H), 4.44 (br t, J = 12.7 Hz, 1H), 3.12 (br, d, J = 5.0 Hz, 2H), 2.80-2.68 (m, 2H), 2.04 (br, d, J = 13.6 Hz, 2H), 1.63 (br, d, J = 9.8 Hz, 2H), 1.21 (s, 6H), 0.85 (s, 6H).
实施例12Example 12
Figure PCTCN2018091270-appb-000111
Figure PCTCN2018091270-appb-000111
实施例12AExample 12A
Figure PCTCN2018091270-appb-000112
Figure PCTCN2018091270-appb-000112
将碳酸钾(735.29毫克,5.32毫摩尔)和2,2,6,6-四甲基四氢-2H-吡喃-4-胺(1.05克,6.65毫摩尔)加入到2-氯-1-硝基-4-(三氟甲基)苯(1.0克,4.43毫摩尔)的THF(20毫升)溶液中，70℃搅拌16小时。反应液 用乙酸乙酯(60毫升×2)和水(60毫升)分层，有机相用盐水(50.00毫升×2)洗涤，干燥，过滤，减压浓缩得到残余物，残余物通过柱色谱纯化得到实施例12A。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.31(d,J＝9.0Hz,1H),7.97(br d,J＝6.3Hz,1H),7.13(s,1H),6.87(dd,J＝1.5,8.8Hz,1H),4.01(dtd,J＝3.6,7.8,11.5Hz,1H),2.06(dd,J＝3.6,12.9Hz,2H),1.41(s,6H),1.33(d,J＝1.5Hz,2H),1.30(s,6H). Potassium carbonate (735.29 mg, 5.32 mmol) and 2,2,6,6-tetramethyltetrahydro-2H-pyran-4-amine (1.05 g, 6.65 mmol) were added to 2-chloro-1- A solution of nitro-4-(trifluoromethyl)benzene (1.0 g, 4.43 mmol) in THF (20 mL). The reaction mixture was separated with EtOAc EtOAc EtOAc. Example 12A was obtained. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.31 (d, J = 9.0 Hz, 1H), 7.97 (brd, J = 6.3 Hz, 1H), 7.13 (s, 1H), 6.87 (dd, J = 1.5, 8.8 Hz, 1H), 4.01 (dtd, J = 3.6, 7.8, 11.5 Hz, 1H), 2.06 (dd, J = 3.6, 12.9 Hz, 2H), 1.41 (s, 6H), 1.33 (d, J) =1.5 Hz, 2H), 1.30 (s, 6H).
实施例12BExample 12B
Figure PCTCN2018091270-appb-000113
Figure PCTCN2018091270-appb-000113
将NBS(30.83毫克,173.24微摩尔)加入到实施例12A(50毫克，144.37微摩尔)的DMF(2毫升)溶液中，50℃搅拌16小时。反应液用乙酸乙酯(15毫升×2)和水(15毫升)分层，有机相用饱和碳酸氢钠(20.00毫升×2)，盐水(20.00毫升×2)洗涤，干燥，过滤，减旋干得到实施例12B。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.50(s,1H),7.90(br d,J＝5.8Hz,1H),7.26(br s,1H),4.06-3.92(m,1H),2.04(dd,J＝2.8,12.0Hz,2H),1.72-1.66(m,2H),1.40(s,6H),1.30(s,6H). NBS (30.83 mg, 173.24 μmol) was added to a solution of EtOAc (EtOAc m. The reaction mixture was separated with EtOAc (EtOAc m.). Example 12B was obtained dry. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.50 (s, 1H), 7.90 (brd, J = 5.8 Hz, 1H), 7.26 (br s, 1H), 4.06-3.92 (m, 1H), 2.04 (dd, J = 2.8, 12.0 Hz, 2H), 1.72-1.66 (m, 2H), 1.40 (s, 6H), 1.30 (s, 6H).
实施例12CExample 12C
Figure PCTCN2018091270-appb-000114
Figure PCTCN2018091270-appb-000114
将(E)-3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)丙烯酸酯(398.73毫克,1.76毫摩尔)和碳酸钾(487.51毫克,3.53毫摩尔)加入到实施例12B(500毫克，1.18毫摩尔)的1,4-二氧六环(12毫升)和水(3毫升)的混合溶液中，再在氮气保护下加入Pd(dppf)Cl 2(86.03毫克,117.58微摩尔)。在氮气保护，90℃下搅拌5小时。反应液用乙酸乙酯(30毫升×2)和水(30毫升)分层，有机相用盐水(30.00毫升×2)洗涤，干燥，过滤，减压浓缩得到残余物，残余物经过柱色谱分离得到实施例12C。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.61(s,1H),8.07(br,d,J＝6.8Hz,1H),7.86(br,d,J＝13.8Hz,1H),7.23(s,1H),6.41(d,J＝15.6Hz,1H),4.29(q,J＝7.0Hz,2H),4.11-3.97(m,1H),2.06(dd,J＝3.5,12.8Hz,2H),1.45(s,1H),1.41(s,6H),1.39(s,1H),1.35(t,J＝7.2Hz,3H),1.30(s,6H). (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (398.73 mg, 1.76 mmol) and potassium carbonate (487.51 mg, 3.53 mmol) was added to a mixture of 1,4-dioxane (12 ml) and water (3 ml) of Example 12B (500 mg, 1.18 mmol). Pd(dppf)Cl 2 (86.03 mg, 117.58 μmol) was added. Stir under nitrogen for 5 hours at 90 °C. The reaction mixture was separated with EtOAc EtOAc (EtOAc m. Example 12C was obtained. 1 H NMR (400MHz, CHLOROFORM- d) δ = 8.61 (s, 1H), 8.07 (br, d, J = 6.8Hz, 1H), 7.86 (br, d, J = 13.8Hz, 1H), 7.23 (s , 1H), 6.41 (d, J = 15.6 Hz, 1H), 4.29 (q, J = 7.0 Hz, 2H), 4.11-3.97 (m, 1H), 2.06 (dd, J = 3.5, 12.8 Hz, 2H) , 1.45 (s, 1H), 1.41 (s, 6H), 1.39 (s, 1H), 1.35 (t, J = 7.2 Hz, 3H), 1.30 (s, 6H).
实施例12DExample 12D
Figure PCTCN2018091270-appb-000115
Figure PCTCN2018091270-appb-000115
将六水和二氯化镍(470.63毫克,1.98毫摩尔)加入到实施例12C(220.00毫克,495.00微摩尔)的甲醇(5毫升)的溶液中，再滴加硼氢化钠(37.45毫克,999.00微摩尔)的DMF(2毫升)的溶液。在室温下搅拌16小时。反应液加入水(15毫升)和乙酸乙酯(15毫升)，用硅藻土过滤，用乙酸乙酯(5mL)洗涤两次，分层有机相用盐水(20.00毫升×2)洗涤，干燥，过滤，减压浓缩得到实施例12D。 1H NMR(400MHz,CHLOROFORM-d)δ＝6.91(s,1H),6.65(s,1H),4.18-4.12(m,2H),3.74(br t,J＝11.5Hz,1H),3.58(br s,2H),3.03-2.95(m,2H),2.95-2.82(m,1H),2.62-2.51(m,2H),2.01(dd,J＝3.5,12.5Hz,2H),1.37(s,6H),1.27-1.24(m,9H),1.21-1.15(m,2H). Hexahydrate and nickel dichloride (470.63 mg, 1.98 mmol) were added to a solution of Example 12C (220.00 mg, 495.00 micromoles) in methanol (5 ml), then sodium borohydride (37.45 mg, 999.00) A solution of micromolar) in DMF (2 mL). Stir at room temperature for 16 hours. The reaction mixture was poured with EtOAc EtOAc (EtOAc m. Filtration and concentration under reduced pressure gave Example 12D. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 6.91 (s, 1H), 6.65 (s, 1H), 4.18 - 4.12 (m, 2H), 3.74 (brt, J = 11.5 Hz, 1H), 3.58 ( Br s, 2H), 3.03-2.95 (m, 2H), 2.95-2.82 (m, 1H), 2.62-2.51 (m, 2H), 2.01 (dd, J = 3.5, 12.5 Hz, 2H), 1.37 (s , 6H), 1.27-1.24 (m, 9H), 1.21-1.15 (m, 2H).
实施例12EExample 12E
Figure PCTCN2018091270-appb-000116
Figure PCTCN2018091270-appb-000116
1-异硫氰基-4-(三氟甲氧基)苯(109.99毫克，501.83微摩尔)加入到实施例12D(190毫克，450.21微摩尔)的四氢呋喃(3毫升)的溶液中，40℃下搅拌16小时。再将EDCI(104.95毫克，547.45微摩尔)加入到反应液中，80℃下搅拌2小时。反应液用乙酸乙酯(15毫升×2)和水(15毫升)分层，有机相用盐水(20.00毫升×2)洗涤，干燥，过滤，减压浓缩得到残余物，残余物经过柱色谱分离得到实施例12E。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.62(br s,1H),7.53(br s,1H),7.33(br d,J＝8.8Hz,2H),7.26-7.21(m,2H),6.45(br s,1H),4.63(br s,1H),4.26-4.15(m,2H),3.21(br t,J＝8.0Hz,2H),2.71-2.61(m,2H),2.21-2.10(m,2H),1.84(dd,J＝3.4,12.7Hz,2H),1.32(s,6H),1.29-1.27(m,3H),1.24(s,6H). 1-Isothiocyanato-4-(trifluoromethoxy)benzene (109.99 mg, 501.33 μmol) was added to a solution of Example 12D (190 mg, 450.21 micromoles) in tetrahydrofuran (3 ml), 40 ° C Stir under 16 hours. Further, EDCI (104.95 mg, 547.45 μmol) was added to the reaction solution, and the mixture was stirred at 80 ° C for 2 hours. The reaction mixture was separated with EtOAc EtOAc (EtOAc m. Example 12E was obtained. 1 H NMR (400MHz, CHLOROFORM- d) δ = 7.62 (br s, 1H), 7.53 (br s, 1H), 7.33 (br d, J = 8.8Hz, 2H), 7.26-7.21 (m, 2H), 6.45 (br s, 1H), 4.63 (br s, 1H), 4.26-4.15 (m, 2H), 3.21 (br t, J = 8.0 Hz, 2H), 2.71-2.61 (m, 2H), 2.21-2.10 (m, 2H), 1.84 (dd, J = 3.4, 12.7 Hz, 2H), 1.32 (s, 6H), 1.29-1.27 (m, 3H), 1.24 (s, 6H).
实施例12Example 12
Figure PCTCN2018091270-appb-000117
Figure PCTCN2018091270-appb-000117
将一水合氢氧化锂(69.76毫克，1.66毫摩尔)加入到实施例12E(200毫克，332.46微摩尔)的四氢呋喃(2毫升)和水(2毫升)的混合溶液中。在40℃下搅拌16小时。用1摩尔的盐酸调pH到5，旋干得到残余物，残余物用制备分离得到实施例12。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.72(br d,J＝16.8Hz,2H),7.29(br s,4H),4.63(br s,1H),3.26(br s,2H),2.75(br s,2H),2.06(br d,J＝9.8Hz,2H),1.73(br d,J＝9.3Hz,2H),1.26(br s,6H),0.88(br s,6H)。 Lithium hydroxide monohydrate (69.76 mg, 1.66 mmol) was added to a mixed solution of Example 12E (200 mg, 332.46 μmol) of tetrahydrofuran (2 ml) and water (2 ml). Stir at 40 ° C for 16 hours. The pH was adjusted to 5 with 1 mol of hydrochloric acid, and dried to give a residue. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.72 (br d, J = 16.8 Hz, 2H), 7.29 (br s, 4H), 4.63 (br s, 1H), 3.26 (br s, 2H), 2.75 (br s, 2H), 2.06 (br d, J = 9.8 Hz, 2H), 1.73 (br d, J = 9.3 Hz, 2H), 1.26 (br s, 6H), 0.88 (br s, 6H).
实施例13Example 13
Figure PCTCN2018091270-appb-000118
Figure PCTCN2018091270-appb-000118
实施例13AExample 13A
Figure PCTCN2018091270-appb-000119
Figure PCTCN2018091270-appb-000119
N-(4-溴-2-硝基苯基)-4,4,6,6-四甲基四氢吡喃-2-胺(0.4克，1.12毫摩尔)，氮杂环丁烷-3-羧酸甲酯(203.68毫克，1.34毫摩尔，盐酸盐),[2-(二环己基磷)-3,6-甲氧基-2',4',6'-三异丙基-1,1'-联苯][2-(2-氨基乙基)苯]氯化钯(44.72毫克,55.98微摩尔)，碳酸钾(619.01毫克，4.48毫摩尔)的甲苯(8毫升)混合溶液用氮气置换三次，然后加热到100℃搅拌16小时。反应混合物减压浓缩去除甲苯，残余物用水(50毫升)稀释，然后用乙酸乙酯(20毫升×2)萃取，合并的有机层用盐水(30毫升×1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到的残余物通过柱色谱纯化得到实施例13A。 1H NMR(400MHz,CHLOROFORM-d)δ＝1.27(s,6H), 1.32-1.44(m,8H),1.97-2.11(m,2H),3.51-3.63(m,1H),3.77(s,3H),3.89-4.10(m,5H),6.78-6.91(m,2H),7.23(d,J＝2.13Hz,1H),7.73(br d,J＝7.15Hz,1H). N-(4-Bromo-2-nitrophenyl)-4,4,6,6-tetramethyltetrahydropyran-2-amine (0.4 g, 1.12 mmol), azetidine-3 -Methylcarboxylate (203.68 mg, 1.34 mmol, hydrochloride), [2-(dicyclohexylphosphino)-3,6-methoxy-2',4',6'-triisopropyl- a mixed solution of 1,1'-biphenyl][2-(2-aminoethyl)benzene]palladium chloride (44.72 mg, 55.98 μmol), potassium carbonate (619.01 mg, 4.48 mmol) in toluene (8 ml) It was replaced with nitrogen three times, and then heated to 100 ° C and stirred for 16 hours. The reaction mixture was concentrated to drynessnessnessnessnessnessnessnesssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss Filtration and concentration under reduced pressure were purified by column chromatography to afford Example 13A. 1 H NMR (400MHz, CHLOROFORM- d) δ = 1.27 (s, 6H), 1.32-1.44 (m, 8H), 1.97-2.11 (m, 2H), 3.51-3.63 (m, 1H), 3.77 (s, 3H), 3.89-4.10 (m, 5H), 6.78-6.91 (m, 2H), 7.23 (d, J = 2.13 Hz, 1H), 7.73 (br d, J = 7.15 Hz, 1H).
实施例13BExample 13B
Figure PCTCN2018091270-appb-000120
Figure PCTCN2018091270-appb-000120
在氮气的保护下，向实施例13A(0.39克，996.27微摩尔)的甲醇(10.00毫升)溶液中加入钯碳(0.1克，10％纯度)。把悬浮液抽真空用氢气多次置换，然后在氢气(15psi)氛围下20℃搅拌2小时。对反应液进行过滤，对滤液进行减压浓缩得到实施例13B，产物直接用于下一步，不需要进一步纯化。Palladium on carbon (0.1 g, 10% purity) was added to a solution of EXAMPLE 13A (0.39 g, 996.27 micromoles) in methanol (10.00 mL). The suspension was evacuated and replaced with hydrogen several times, and then stirred at 20 ° C for 2 hours under a hydrogen (15 psi) atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced vacuo.
实施例13CExample 13C
Figure PCTCN2018091270-appb-000121
Figure PCTCN2018091270-appb-000121
在25℃下，实施例13B(0.32克，885.26微摩尔)的四氢呋喃(10.00毫升)溶液中加入1-异硫氰基-4-(三氟甲氧基)苯(213.44毫克，973.78微摩尔，158.10微升)，搅拌1小时，然后再加入EDCI(339.41毫克，1.77微摩尔)，使反应液升温到70℃搅拌1小时，对反应液进行减压浓缩得到一个残余物，残余物通过柱色谱纯化得到实施例13C。 1H NMR(400MHz,METHANOL-d4)δ＝1.30(d,J＝10.79Hz,12H),1.83(dd,J＝12.74,3.58Hz,2H),2.29(t,J＝12.80Hz,2H),3.50-3.66(m,1H),3.75(s,3H),3.95(t,J＝6.59Hz,2H),4.01-4.09(m,2H),4.81(br d,J＝3.64Hz,1H),6.43(dd,J＝8.66,2.13Hz,1H),6.60(d,J＝1.38Hz,1H),7.17-7.31(m,4H),7.37-7.44(m,1H),7.40(d,J＝8.66Hz,1H). To a solution of the THF (1. 158.10 μl), stirring for 1 hour, then adding EDCI (339.41 mg, 1.77 μmol), and heating the reaction mixture to 70 ° C for 1 hour. The reaction solution was concentrated under reduced pressure to give a residue. Purification gave Example 13C. 1 H NMR (400MHz, METHANOL- d4) δ = 1.30 (d, J = 10.79Hz, 12H), 1.83 (dd, J = 12.74,3.58Hz, 2H), 2.29 (t, J = 12.80Hz, 2H), 3.50-3.66 (m, 1H), 3.75 (s, 3H), 3.95 (t, J = 6.59 Hz, 2H), 4.01-4.09 (m, 2H), 4.81 (br d, J = 3.64 Hz, 1H), 6.43 (dd, J = 8.66, 2.13 Hz, 1H), 6.60 (d, J = 1.38 Hz, 1H), 7.17 - 7.31 (m, 4H), 7.37-7.44 (m, 1H), 7.40 (d, J = 8.66Hz, 1H).
实施例13Example 13
Figure PCTCN2018091270-appb-000122
Figure PCTCN2018091270-appb-000122
实施例13C(0.12克,214.72微摩尔)的四氢呋喃(2.00毫升)和水(2.00毫升)溶液中加入一水合氢氧化锂(27.03毫克，644.15微摩尔)，反应液在20℃搅拌16小时，反应混合物用1N盐酸酸化调节pH值为3，然后用乙酸乙酯(20毫升×2)萃取，合并的有机层用盐水(20毫升×1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到的残余物，残余物通过高效液相色谱纯化得到实施例13。 1H NMR(400MHz,CHLOROFORM-d)δ＝0.87(s,6H),1.21(s,6H),1.68(br d,J＝9.66Hz,2H),2.08(br t,J＝12.74Hz,2H),3.61(quin,J＝7.47Hz,1H),4.11-4.24(m,5H),4.47(br t,J＝12.74Hz,2H),6.43(dd,J＝8.72,1.69Hz,1H),6.67(d,J＝1.51Hz,1H),7.10-7.25(m,4H),7.30(d,J＝8.78Hz,1H). To a solution of Example 13C (0.12 g, 214.72 μmol) of tetrahydrofuran (2.00 ml) and water (2.00 ml), lithium hydroxide monohydrate (27.03 mg, 644.15 μmol) was added, and the reaction mixture was stirred at 20 ° C for 16 hours. The mixture was acidified with EtOAc (EtOAc) (EtOAc)EtOAc. The residue was purified by high performance liquid chromatography to give Example 13. 1 H NMR (400MHz, CHLOROFORM- d) δ = 0.87 (s, 6H), 1.21 (s, 6H), 1.68 (br d, J = 9.66Hz, 2H), 2.08 (br t, J = 12.74Hz, 2H ), 3.61 (quin, J = 7.47 Hz, 1H), 4.11-4.24 (m, 5H), 4.47 (br t, J = 12.74 Hz, 2H), 6.43 (dd, J = 8.72, 1.69 Hz, 1H), 6.67 (d, J = 1.51 Hz, 1H), 7.10-7.25 (m, 4H), 7.30 (d, J = 8.78 Hz, 1H).
实施例14Example 14
Figure PCTCN2018091270-appb-000123
Figure PCTCN2018091270-appb-000123
实施例14AExample 14A
Figure PCTCN2018091270-appb-000124
Figure PCTCN2018091270-appb-000124
向4-氟苯甲酸(9克,64.23毫摩尔)的四氢呋喃(120毫升)溶液中加入咪唑(874.58毫克,12.85毫摩尔)和羰基二咪唑(11.46克,70.66毫摩尔)，反应液在15℃搅拌16小时。反应液直接通过丙酮：水为1:1打浆得到实施例14A。To a solution of 4-fluorobenzoic acid (9 g, 64.23 mmol) in tetrahydrofuran (120 ml) was added imidazole (874.58 mg, 12.85 mmol) and carbonyldiimidazole (11.46 g, 70.66 mmol). Stir for 16 hours. The reaction solution was directly beaten by acetone:water to 1:1 to obtain Example 14A.
实施例14BExample 14B
Figure PCTCN2018091270-appb-000125
Figure PCTCN2018091270-appb-000125
向实施例14A(12.2克，64.15毫摩尔)的四氢呋喃(200毫升)溶液中加入氯化镁(7.33克，76.98毫摩尔,3.16毫升)和3-乙氧基-3-氧丙酸钾(21.84克，128.30毫摩尔)，反应液在55℃搅拌16小时。将反应物倾倒水(500毫升)中，然后用乙酸乙酯(200毫升×2)萃取，合并的有机层用盐水(200毫升×2)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过水：丙酮为1:1打浆得到实施例14B。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.00(br s,2H),7.16(br s,2H),4.23(br s,2H),3.97(br s,2H),1.27(br s,3H). To a solution of Example 14A (12.2 g, 64.15 mmol) in EtOAc (EtOAc (EtOAc) 128.30 mmol), the reaction solution was stirred at 55 ° C for 16 hours. The reaction was poured into EtOAc (EtOAc) (EtOAc (EtOAc) Example 14B was obtained by water 1:1 with water: acetone. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.00 (br s, 2H), 7.16 (br s, 2H), 4.23 (br s, 2H), 3.97 (br s, 2H), 1.27 (br s, 3H) ).
实施例14CExample 14C
Figure PCTCN2018091270-appb-000126
Figure PCTCN2018091270-appb-000126
向实施例14B(11.5克,54.71毫摩尔)的二甲基亚砜(150毫升)溶液中加入碳酸钾(15.12克，109.42毫摩尔)和甲醇(7.01克，218.84毫摩尔，8.86毫升)，混合物在10℃下搅拌30分钟，然后再加入1,2-二溴乙烷(41.11克，218.84毫摩尔，16.51毫升)，反应液在60℃下搅拌两天，向反应液加入水(800毫升)淬灭，然后用DCM(100毫升×3)萃取，合并的有机层用盐水(200毫升×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到的残余物，残余物通过柱色谱纯化得到实施例14C。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.97-7.87(m,2H),7.12(t,J＝8.7Hz,2H),4.09-4.01(m,2H),1.64-1.58(m,2H),1.54-1.47(m,2H),1.00(t,J＝7.0Hz,3H). To a solution of EtOAc (11.5 g, 54.71 mmol After stirring at 10 ° C for 30 minutes, 1,2-dibromoethane (41.11 g, 218.84 mmol, 16.51 ml) was further added, and the reaction mixture was stirred at 60 ° C for two days, and water (800 ml) was added to the reaction mixture. After quenching, it was extracted with EtOAc EtOAc EtOAc. Example 14C was obtained. 1 H NMR (400MHz, CHLOROFORM- d) δ = 7.97-7.87 (m, 2H), 7.12 (t, J = 8.7Hz, 2H), 4.09-4.01 (m, 2H), 1.64-1.58 (m, 2H) , 1.54-1.47 (m, 2H), 1.00 (t, J = 7.0 Hz, 3H).
实施例14DExample 14D
Figure PCTCN2018091270-appb-000127
Figure PCTCN2018091270-appb-000127
在0℃和氮气的保护下，用注射器将三乙基硅烷(7.75克,66.67毫摩尔,10.65毫升)加入实施例14C(6.3克，26.67毫摩尔)的三氟乙酸(60毫升)溶液中，反应液在15℃搅拌16小时。将反应液倒入冰水(200毫升)中，之后再加入乙酸乙酯(200毫升)，混合液加入碳酸钠碱化调节pH为9，合并的有机层用盐水(200毫升×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到的残余物通过柱色谱纯化得到实施例14D。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.21(dd,J＝5.5,8.3Hz,2H),6.96(t,J＝8.8Hz,2H),4.08(q,J＝7.0Hz,2H),2.94(s,2H),1.32-1.27(m,2H),1.18(t,J＝7.2Hz,3H),0.83-0.76(m,2H). Triethylsilane (7.75 g, 66.67 mmol, 10.65 mL) was added to a solution of Example 14C (6.3 g, 26.67 mmol) in trifluoroacetic acid (60 mL). The reaction solution was stirred at 15 ° C for 16 hours. The reaction mixture was poured into ice water (200 ml), and then ethyl acetate (200 ml) was added, and the mixture was basified with sodium carbonate and adjusted to pH 9. The combined organic layers were washed with brine (200 ml x 2). The residue was dried over anhydrous sodium sulfate, filtered and evaporated 1 H NMR (400MHz, CHLOROFORM- d) δ = 7.21 (dd, J = 5.5,8.3Hz, 2H), 6.96 (t, J = 8.8Hz, 2H), 4.08 (q, J = 7.0Hz, 2H), 2.94 (s, 2H), 1.32-1.27 (m, 2H), 1.18 (t, J = 7.2 Hz, 3H), 0.83-0.76 (m, 2H).
实施例14EExample 14E
Figure PCTCN2018091270-appb-000128
Figure PCTCN2018091270-appb-000128
在0℃下,硝酸钾(1.90克,18.81毫摩尔)滴加到1-[(4-氟苯基)甲基]环丙基羧酸乙酯的硫酸(40毫升)溶液 中，混合物在0℃下搅拌2小时。反应液用饱和碳酸氢钠溶液调pH＝11，然后用乙酸乙酯(50毫升)萃取两次，合并的有机相用饱和食盐水(50毫升×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到的残余物通过柱色谱纯化得到实施例14E。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.98(dd,J＝2.1,7.2Hz,1H),7.56(ddd,J＝2.1,4.2,8.5Hz,1H),7.20(dd,J＝8.7,10.7Hz,1H),4.10-4.03(m,2H),2.96(s,2H),1.40-1.35(m,1H),1.40-1.35(m,1H),1.19(t,J＝7.0Hz,3H),0.91-0.86(m,2H). Potassium nitrate (1.90 g, 18.81 mmol) was added dropwise to a solution of ethyl 1-[(4-fluorophenyl)methyl]cyclopropylcarboxylate in sulfuric acid (40 ml) at 0 ° C. Stir at ° C for 2 hours. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) The residue obtained by concentration under reduced pressure was purified by column chromatography. 1 H NMR (400MHz, CHLOROFORM- d) δ = 7.98 (dd, J = 2.1,7.2Hz, 1H), 7.56 (ddd, J = 2.1,4.2,8.5Hz, 1H), 7.20 (dd, J = 8.7, 10.7Hz,1H),4.10-4.03(m,2H),2.96(s,2H),1.40-1.35(m,1H),1.40-1.35(m,1H), 1.19(t,J=7.0Hz,3H ), 0.91-0.86 (m, 2H).
实施例14FExample 14F
Figure PCTCN2018091270-appb-000129
Figure PCTCN2018091270-appb-000129
实施例14D的DMF(3毫升)溶液中加入碳酸钾(116.36毫克，841.90微摩尔)和2,2,6,6-四甲基四氢吡喃-4-胺(132.39毫克，841.90微摩尔)，混合物在90℃下搅拌16小时。混合物倒入水(20毫升)中，再用然后用乙酸乙酯(20毫升×2)萃取.合并的有机相用饱和食盐水(20毫升×2)洗涤，无水硫酸钠干燥，减压浓缩得到的残余物通过柱色谱纯化得到实施例14F。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.07(d,J＝1.8Hz,1H),7.87(br d,J＝7.3Hz,1H),7.42(dd,J＝1.8,8.8Hz,1H),6.81(d,J＝8.8Hz,1H),4.10(q,J＝7.0Hz,2H),4.02-3.92(m,1H),2.86(s,2H),2.05(dd,J＝3.5,12.8Hz,2H),1.39(s,6H),1.36(s,1H),1.32(d,J＝3.3Hz,1H),1.30(d,J＝2.5Hz,2H),1.28(s,6H),1.22(t,J＝7.2Hz,3H),0.87-0.81(m,2H). Potassium carbonate (116.36 mg, 841.90 micromoles) and 2,2,6,6-tetramethyltetrahydropyran-4-amine (132.39 mg, 841.90 micromoles) were added to a solution of Example 14D in DMF (3 mL). The mixture was stirred at 90 ° C for 16 hours. The mixture was poured into water (20 ml), EtOAc (EtOAc m. The residue obtained was purified by column chromatography to give Example 14F. 1 H NMR (400MHz, CHLOROFORM- d) δ = 8.07 (d, J = 1.8Hz, 1H), 7.87 (br d, J = 7.3Hz, 1H), 7.42 (dd, J = 1.8,8.8Hz, 1H) , 6.81 (d, J = 8.8 Hz, 1H), 4.10 (q, J = 7.0 Hz, 2H), 4.02-3.92 (m, 1H), 2.86 (s, 2H), 2.05 (dd, J = 3.5, 12.8) Hz, 2H), 1.39 (s, 6H), 1.36 (s, 1H), 1.32 (d, J = 3.3 Hz, 1H), 1.30 (d, J = 2.5 Hz, 2H), 1.28 (s, 6H), 1.22 (t, J = 7.2 Hz, 3H), 0.87-0.81 (m, 2H).
实施例14GExample 14G
Figure PCTCN2018091270-appb-000130
Figure PCTCN2018091270-appb-000130
在10℃下，实施例14F(160毫克,395.55微摩尔)的甲醇(3毫升)溶液中加入NiCl 2.6H 2O(376.07毫克，1.58微摩尔)，然后加入NaBH 4(29.93毫克，791.10微摩尔)的DMF(0.5毫升)溶液，反应液在10℃下搅拌1小时，混合物倒入水(15毫升)，乙酸乙酯(15毫升)中，用硅藻土过滤，滤饼用乙酸乙酯(5毫升×2)洗涤，合并的有机相用饱和食盐水(20毫升×2)洗涤，无水硫酸钠干燥，减压浓缩得到实施例14G。MS-ESI(m/z):375(M+H) +. At 10 ℃, embodiments Example 14F (160 mg, 395.55 [mu] mol) in methanol (3 mL) was added NiCl 2 .6H 2 O (376.07 mg, 1.58 mol), followed by addition of NaBH 4 (29.93 mg, 791.10 micro To a solution of EtOAc (3 mL), EtOAc (EtOAc)EtOAc. (5 ml × 2) was washed, and the combined organic layer was washed with sat. MS-ESI (m/z): 375 (M+H) + .
实施例14HExample 14H
Figure PCTCN2018091270-appb-000131
Figure PCTCN2018091270-appb-000131
实施例14G(140毫克，373.81毫摩尔)的四氢呋喃(5毫升)溶液中加入1-异硫氰基-4-(三氟甲氧基)苯(90.13毫克，411.20微摩尔)后在40℃下搅拌16小时。然后加入EDCI(85.99毫克，448.58微摩尔)，该反应液在80℃下搅拌2小时。混合物倒入水(15毫升)，用乙酸乙酯(15毫升×2)萃取，合并的有机相用饱和食盐水(20毫升×2)洗涤，无水硫酸钠干燥，减压浓缩得到的残留物，通过TLC板分离得到实施例14H。MS-ESI(m/z):560(M+H) +. Add a solution of 1-isothiocyanato-4-(trifluoromethoxy)benzene (90.13 mg, 411.20 μmol) in a solution of Example 14G (140 mg, 373.81 mmol) in tetrahydrofuran (5 mL) at 40 ° C Stir for 16 hours. Then EDCI (85.99 mg, 448.58 micromoles) was added and the reaction was stirred at 80 ° C for 2 hours. The mixture was poured into water (15 ml), EtOAc (EtOAc m. Example 14H was isolated by TLC plate. MS-ESI (m/z): 560 (M+H) + .
实施例14Example 14
Figure PCTCN2018091270-appb-000132
Figure PCTCN2018091270-appb-000132
实施例14H(170毫克,303.78微摩尔)的四氢呋喃(2毫升)和水(2毫升)溶液中加入NaOH(60.75毫克，1.52毫摩尔)。混合物在80℃下16小时。反应混合物用1摩尔的盐酸溶液调pH＝3,然后用乙酸乙酯(15毫升×2)萃取。合并的有机相用饱和食盐水(20毫升×2)洗涤，无水硫酸钠干燥，减压浓缩得到的残留物，通过高效液相色谱法分离得到实施例14。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.53(br s,1H),7.45(d,J＝8.5Hz,1H),7.27-7.25(m,1H),7.24(s,4H),4.62(br t,J＝12.8Hz,1H),3.02(s,2H),2.14(br t,J＝12.7Hz,2H),1.72(br dd,J＝2.9,12.4Hz,2H),1.40(br s,2H),1.23(s,6H),0.96-0.92(m,2H),0.90(s,6H).MS-ESI(m/z):532(M+H) +. To a solution of THF (60.75 mg, 1.52 mmol). The mixture was at 80 ° C for 16 hours. The reaction mixture was adjusted to pH = 3 with 1 mol of a hydrochloric acid solution, and then extracted with ethyl acetate (15 ml × 2). The combined organic layers were washed with brine (20 mL EtOAc) 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.53 (br s, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.27-7.25 (m, 1H), 7.24 (s, 4H), 4.62 ( Br t, J = 12.8 Hz, 1H), 3.02 (s, 2H), 2.14 (br t, J = 12.7 Hz, 2H), 1.72 (br dd, J = 2.9, 12.4 Hz, 2H), 1.40 (br s , 2H), 1.23 (s, 6H), 0.96-0.92 (m, 2H), 0.90 (s, 6H). MS-ESI (m/z): 532 (M+H) + .
实施例15Example 15
Figure PCTCN2018091270-appb-000133
Figure PCTCN2018091270-appb-000133
实施例15AExample 15A
Figure PCTCN2018091270-appb-000134
Figure PCTCN2018091270-appb-000134
4-溴-2-氟-1-硝基苯(2克,9.09毫摩尔)和2,2,6,6四甲基四氢吡喃盐酸盐(1.76克，9.09毫摩尔)的DMF(20.00毫升)的混合溶液中加入碳酸钾(2.51克,18.18毫摩尔),混合液在80℃反应16小时后，向反应液加入水(40毫升)，然后用乙酸乙酯(20毫升×2)萃取，合并有机相并依次用水(20毫升)、盐水(20毫升×1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到实施例15A。产物直接用于下一步，不需要进一步纯化。4-bromo-2-fluoro-1-nitrobenzene (2 g, 9.09 mmol) and 2,2,6,6 tetramethyltetrahydropyran hydrochloride (1.76 g, 9.09 mmol) of DMF ( Potassium carbonate (2.51 g, 18.18 mmol) was added to a mixed solution of 20.00 ml), and the mixture was reacted at 80 ° C for 16 hours, and then water (40 ml) was added to the reaction mixture, followed by ethyl acetate (20 ml × 2). The organic phase was combined and washed with EtOAc EtOAc m. The product was used directly in the next step without further purification.
实施例15BExample 15B
Figure PCTCN2018091270-appb-000135
Figure PCTCN2018091270-appb-000135
实施例15A(2.5克,7.00毫摩尔)，环丙基硼酸(721.34毫克，8.40毫摩尔)，Pd(dppf)Cl 2(1.02克，1.04毫摩尔)和碳酸铯(4.56克，14.00毫摩尔)溶于二氧六环(25毫升)和水(2.5毫升)的混合溶液中,并在惰性气体的保护下90℃反应16小时。反应完毕后，将反应液过滤，浓缩后加入水(40毫升)，然后用乙酸乙酯(20毫升×3)萃取，合并有机相并依次用水(20毫升)、盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩，并通过柱色谱纯化得到实施例15B。 Example 15A (2.5 g, 7.00 mmol), cyclopropylboronic acid (721.34 mg, 8.40 mmol), Pd (dppf) Cl 2 (1.02 g, 1.04 mmol) and cesium carbonate (4.56 g, 14.00 mmol) It was dissolved in a mixed solution of dioxane (25 ml) and water (2.5 ml), and reacted at 90 ° C for 16 hours under the protection of an inert gas. After the reaction was completed, the reaction mixture was filtered, evaporated, evaporated, evaporated, evaporated, evaporated. The mixture was dried with sodium sulfate, filtered, evaporated, evaporated
实施例15CExample 15C
Figure PCTCN2018091270-appb-000136
Figure PCTCN2018091270-appb-000136
实施例15B(2.5克,7.00毫摩尔)溶于DMF(15毫升)中，并加入N-溴代琥珀酰亚胺(1.17克，6.60毫摩 尔)混合液在20℃反应16小时。反应完毕后，向反应液中加入水(50毫升)，然后用乙酸乙酯(20毫升×3)萃取，合并有机相并依次用水(20毫升)、盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到实施例15C，粗产品不需要进一点纯化，直接用于下一步反应。Example 15B (2.5 g, 7.00 mmol) was dissolved in DMF (15 mL), and then a mixture of N-bromosuccinimide (1.17 g, 6.60 mmol) was reacted at 20 ° C for 16 hours. After the completion of the reaction, water (50 ml) was added, and then ethyl acetate (20 ml × 3) was evaporated. Drying, filtration and concentration under reduced pressure afforded Example 15C.
实施例15DExample 15D
Figure PCTCN2018091270-appb-000137
Figure PCTCN2018091270-appb-000137
实施例15C(1.8克，4.53毫摩尔)，乙基-(E)-3-(4,4,5,5-四甲基-1,3,2-氧硼烷-2-基)丙烯酸-2-乙酸甲酯(1.23克，5.44毫摩尔),Pd(dppf)Cl 2(663毫克，906.1微摩尔)和碳酸铯(2.95克，9.06毫摩尔)溶于二氧六环(20毫升)和水(2毫升)的混合溶液中,并在惰性气体的保护下90℃反应16小时。反应完毕后，将反应液过滤，浓缩后加入水(20毫升)，然后用乙酸乙酯(20毫升×3)萃取，合并有机相并依次用水(20毫升)、盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩，并通过柱色谱纯化得到实施例15D。 Example 15C (1.8 g, 4.53 mmol), ethyl-(E)-3-(4,4,5,5-tetramethyl-1,3,2-oxaboran-2-yl)acrylic acid- 2-ethyl acetate (1.23 g, 5.44 mmol), Pd(dppf)Cl 2 (663 mg, 906.1 μmol) and cesium carbonate (2.95 g, 9.06 mmol) were dissolved in dioxane (20 mL) and A mixed solution of water (2 ml) was reacted at 90 ° C for 16 hours under the protection of an inert gas. After the reaction was completed, the reaction mixture was filtered, evaporated, evaporated, evaporated,,,,,,,,,,,,,, The mixture was dried with sodium sulfate, filtered, evaporated and evaporated
实施例15EExample 15E
Figure PCTCN2018091270-appb-000138
Figure PCTCN2018091270-appb-000138
实施例15D(1.11克，2.67毫摩尔)溶于甲醇(12毫升)中，在0℃下加入六水合氯化镍(2.53克，10.66毫摩尔)和DMF(973.98毫克，13.33毫摩尔，1.03毫升)。混合液在0℃反应10分钟后，加入硼氢化钠(403.3毫克，10.66毫摩尔)混合液在20℃反应16小时。反应完毕后，反应液过滤浓缩，并向残渣中加入水(10毫升)，然后用乙酸乙酯(20毫升×3)萃取，合并有机相并依次用水(20毫升)、盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到实施例15E，粗产品不需要进一步纯化，直接用于下一步反应。Example 15D (1.11 g, 2.67 mmol) was dissolved in MeOH (12 mL). EtOAc (EtOAc: EtOAc. ). After the mixture was reacted at 0 ° C for 10 minutes, a mixture of sodium borohydride (403.3 mg, 10.66 mmol) was added and reacted at 20 ° C for 16 hours. After the reaction was completed, the reaction mixture was evaporated, evaporated, evaporated, evaporated, evaporated. The residue was dried over anhydrous sodium sulfate, filtered and evaporated.
实施例15FExample 15F
Figure PCTCN2018091270-appb-000139
Figure PCTCN2018091270-appb-000139
实施例15E(200.00毫克，514.74微摩尔)和1-异硫氰基-4-(三氟甲氧基)苯(124.11毫克,566.22微摩尔)溶于四氢呋喃(5.00毫升)混合溶液在30℃搅拌3小时,然后再加入EDCI(197.35毫克,71.03毫摩尔)，反应液在70℃反应3小时。反应完毕后，向反应液中加入水(5毫升)，水相再用乙酸乙酯(10毫升×3)萃取，合并的有机相依次用水(10毫升)和盐水(10毫升×1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到的粗产物，粗产物通过柱色谱纯化得到实施例15F。Example 15E (200.00 mg, 514.74 μmol) and 1-isothiocyanato-4-(trifluoromethoxy)benzene (124.11 mg, 566.22 μmol) in tetrahydrofuran (5.00 ml) mixed solution stirred at 30 ° C After 3 hours, EDCI (197.35 mg, 71.03 mmol) was further added, and the reaction solution was reacted at 70 ° C for 3 hours. After the completion of the reaction, water (5 ml) was added to the mixture, and the aqueous phase was extracted with ethyl acetate (10 ml × 3), and the combined organic phases were washed with water (10 ml) and brine (10 ml × 1). The residue was dried over anhydrous sodium sulfate, filtered and evaporated.
实施例15Example 15
Figure PCTCN2018091270-appb-000140
Figure PCTCN2018091270-appb-000140
实施例15F(170毫克，296.35微摩尔)和一水合氢氧化锂(62.18毫克，1.48毫摩尔)溶于甲醇(5.00毫升)和水(1.00毫升)混合溶液中。混合溶液在20℃反应16小时后。反应液减压浓缩得到粗产物，粗产物通过高效液相色谱纯化得到实施例15。 1H NMR(400MHz,METHANOL-d4)δ＝8.27(s,1H),7.34-7.30(m,3H),7.28-7.24(m,2H),7.19(s,1H),3.22(t,J＝7.8Hz,2H),2.68(t,J＝7.8Hz,2H),2.28(t,J＝12.8Hz,2H),2.14-2.05(m,1H),1.89(dd,J＝3.7,12.8Hz,2H),1.33(d,J＝11.6Hz,12H),1.09-1.03(m,2H),0.69-0.63(m,2H). Example 15F (170 mg, 296.35 μmol) and lithium hydroxide monohydrate (62.18 mg, 1.48 mmol) were dissolved in a mixture of methanol (5.00 ml) and water (1.00 ml). The mixed solution was reacted at 20 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a crude material. 1 H NMR (400 MHz, METHANOL-d4) δ = 8.27 (s, 1H), 7.34-7.30 (m, 3H), 7.28-7.24 (m, 2H), 7.19 (s, 1H), 3.22 (t, J = 7.8 Hz, 2H), 2.68 (t, J = 7.8 Hz, 2H), 2.28 (t, J = 12.8 Hz, 2H), 2.14 - 2.05 (m, 1H), 1.89 (dd, J = 3.7, 12.8 Hz, 2H), 1.33 (d, J = 11.6 Hz, 12H), 1.09-1.03 (m, 2H), 0.69-0.63 (m, 2H).
实施例16Example 16
Figure PCTCN2018091270-appb-000141
Figure PCTCN2018091270-appb-000141
实施例16AExample 16A
Figure PCTCN2018091270-appb-000142
Figure PCTCN2018091270-appb-000142
溴-(4-氯苯基)镁(1M)的四氢呋喃(10.99毫升)溶液中加入氯化亚铜(19.78毫克,199.77微摩尔,4.78微升)，反应液在20℃搅拌30分钟，然后在0℃下用注射器加入2-亚异丙基丙二酸二乙酯(2克，9.99毫摩尔)，反应液升温到40℃搅拌3小时，反应混合物缓慢加入盐酸(1N，10毫升)淬灭，然后用水(40毫升)稀释，然后用乙酸乙酯(30毫升×2)萃取，合并的有机层用盐水(30毫升×1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到的残余物通过柱色谱纯化得到实施例16A。 1H NMR(400MHz,CHLOROFORM-d)δ＝1.16(t,J＝7.09Hz,6H),1.57(s,6H),3.77(s,1H),4.08(q,J＝7.13Hz,4H),7.25-7.37(m,4H). To a solution of bromo-(4-chlorophenyl)magnesium (1M) in tetrahydrofuran (10.99 ml) was added cuprous chloride (19.78 mg, 199.77 μmol, 4.78 μL), and the mixture was stirred at 20 ° C for 30 minutes, then Add 2-isopropylidenemalonate (2 g, 9.99 mmol) with a syringe at 0 ° C, and warm the reaction mixture to 40 ° C for 3 hours. The reaction mixture was slowly added with hydrochloric acid (1 N, 10 mL). It was then diluted with water (40 ml), EtOAc (EtOAc (EtOAc) Purification by column chromatography gave Example 16A. 1 H NMR (400MHz, CHLOROFORM- d) δ = 1.16 (t, J = 7.09Hz, 6H), 1.57 (s, 6H), 3.77 (s, 1H), 4.08 (q, J = 7.13Hz, 4H), 7.25-7.37 (m, 4H).
实施例16BExample 16B
Figure PCTCN2018091270-appb-000143
Figure PCTCN2018091270-appb-000143
实施例16A(1克,3.20毫摩尔)的二甲基亚砜(10毫升)溶液中加入氯化锂(271.07毫克，6.39毫摩尔，130.95毫升)和水(300.00毫克，16.65毫摩尔，0.3毫升)，反应液在180℃搅拌12小时，反应混合物用水(40毫升)稀释，然后用乙酸乙酯(30毫升×2)萃取，合并的有机层用盐水(30毫升×1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到实施例16B。 1H NMR(400MHz,CHLOROFORM-d)δ＝1.12(t,J＝7.15Hz,3H),1.46(s,6H),2.59-2.65(m,2H),4.00(q,J＝7.15Hz,2H),7.27-7.34(m,4H). Lithium chloride (271.07 mg, 6.39 mmol, 130.95 ml) and water (300.00 mg, 16.65 mmol, 0.3 ml) were added to a solution of Example 16A (1 g, 3.20 mmol) in dimethyl sulfoxide (10 ml). The reaction mixture was stirred at 180 ° C for 12 hours, the reaction mixture was diluted with water (40 ml), and then extracted with ethyl acetate (30 ml × 2), and the combined organic layer was washed with brine (30 ml × 1) The sodium was dried, filtered, and concentrated under reduced pressure to give Example 16B. 1 H NMR (400 MHz, CHLOROFORM-d) δ=1.12 (t, J = 7.15 Hz, 3H), 1.46 (s, 6H), 2.59-2.65 (m, 2H), 4.00 (q, J = 7.15 Hz, 2H) ), 7.27-7.34 (m, 4H).
实施例16CExample 16C
Figure PCTCN2018091270-appb-000144
Figure PCTCN2018091270-appb-000144
在0℃下，实施例16B(0.58克,2.41毫摩尔)的硫酸(8毫升)溶液中加入硝酸钾(255.78毫克,2.53毫摩尔)，搅拌30分钟。在0℃下向反应液加入冰水(40毫升)淬灭，然后用乙酸乙酯(30毫升×2)萃取，合并的有机层用盐水(30毫升×1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到实施例16C。 1H NMR(400MHz,CHLOROFORM-d)δ＝1.12(t,J＝7.15Hz,3H),1.48(s,6H),2.65(s,2H),4.00(q,J＝7.15Hz,2H),7.45-7.55(m,2H),7.87(d,J＝2.13Hz,1H). Potassium nitrate (255.78 mg, 2.53 mmol) was added to a solution of Example 16B (0.58 g, 2.41 mmol). The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. Filtration and concentration under reduced pressure gave Example 16C. 1 H NMR (400MHz, CHLOROFORM- d) δ = 1.12 (t, J = 7.15Hz, 3H), 1.48 (s, 6H), 2.65 (s, 2H), 4.00 (q, J = 7.15Hz, 2H), 7.45-7.55 (m, 2H), 7.87 (d, J = 2.13 Hz, 1H).
实施例16DExample 16D
Figure PCTCN2018091270-appb-000145
Figure PCTCN2018091270-appb-000145
实施例16C(0.47克，1.64毫摩尔)的二甲基亚砜(8毫升)溶液中加入碳酸钾(682.05毫克，4.93毫摩尔)和2,2,6,6-四甲基四氢吡喃-4-胺(310.41毫克，1.97毫摩尔)。反应液在130℃搅拌24小时。反应液加入氯化铵(20毫升)淬灭，然后用乙酸乙酯(30毫升×2)萃取，合并的有机层用盐水(30毫升×1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到的残余物通过板分离纯化得到实施例16D。 1H NMR(400MHz,CHLOROFORM-d)δ＝1.11-1.19(m,3H),1.25-1.30(m,6H),1.31-1.42(m,7H),1.42-1.47(m,6H),2.05(dd,J＝12.78,3.36Hz,2H),2.60(s,2H),3.92-4.08(m,3H),6.87(d,J＝9.05Hz,1H),7.46-7.57(m,1H),7.88(br d,J＝7.46Hz,1H),8.16(d,J＝2.32Hz,1H). To a solution of Example 16C (0.47 g, 1.64 mmol) in dimethyl sulfoxide (8 mL), potassium carbonate (682.05 mg, 4.93 mmol) and 2,2,6,6-tetramethyltetrahydropyran. 4-Amine (310.41 mg, 1.97 mmol). The reaction solution was stirred at 130 ° C for 24 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc)EtOAc. The residue obtained by concentration was purified by chromatography to afford Example 16D. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 1.11-1.19 (m, 3H), 1.25-1.30 (m, 6H), 1.31-1.42 (m, 7H), 1.42-1.47 (m, 6H), 2.05 ( Dd, J = 12.78, 3.36 Hz, 2H), 2.60 (s, 2H), 3.92-4.08 (m, 3H), 6.87 (d, J = 9.05 Hz, 1H), 7.46-7.57 (m, 1H), 7.88 (br d, J = 7.46 Hz, 1H), 8.16 (d, J = 2.32 Hz, 1H).
实施例16EExample 16E
Figure PCTCN2018091270-appb-000146
Figure PCTCN2018091270-appb-000146
氮气的保护下，实施例16D(0.15克,368.99微摩尔)的甲醇(5毫升)溶液中加入钯碳(0.03克，10％纯度)，把悬浮液抽真空用氢气置换多次然后在氢气(15psi)氛围下25℃搅拌1小时。对反应液进行过滤，对滤液进行减压浓缩得到实施例16E，产物直接用于下一步，不需要进一步纯化。Palladium on carbon (0.03 g, 10% purity) was added to a solution of EXAMPLE 16D (0.15 g, 368.99 micromoles) in MeOH (5 mL), and the suspension was vacuumed and replaced with hydrogen and then hydrogen ( Stir at 25 ° C for 1 hour in an atmosphere of 15 psi). The reaction solution was filtered, and the filtrate was concentrated under reduced vacuo.
实施例16FExample 16F
Figure PCTCN2018091270-appb-000147
Figure PCTCN2018091270-appb-000147
在25℃下，实施例16E(138毫克，366.50微摩尔)的四氢呋喃(5.00毫升)溶液中加入1-异硫氰基-4-(三氟甲氧基)苯(88.36毫克，403.15微摩尔，65.46微升),搅拌1小时，然后再加入EDCI(140.52毫克，733.01微摩尔)，使反应液升温到70℃搅拌1小时，对反应液进行减压浓缩去除四氢呋喃，残余物用水(50毫升) 稀释，然后用乙酸乙酯(20毫升×2)萃取，合并的有机层用盐水(30毫升×1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到的残余物通过板分离纯化得到实施例16F。Add 1-isothiocyanato-4-(trifluoromethoxy)benzene (88.36 mg, 403.15 micromolar) to a solution of EXAMPLE 16E (138 mg, 366.50 <RTIgt; 65.46 μl), stirred for 1 hour, then EDCI (140.52 mg, 733.01 μmol) was added, and the reaction mixture was heated to 70 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. Diluted, and then extracted with ethyl acetate (20 ml × 2). The combined organic layer was washed with brine (30 ml × 1), dried over anhydrous sodium sulfate, filtered and evaporated. Example 16F.
实施例16Example 16
Figure PCTCN2018091270-appb-000148
Figure PCTCN2018091270-appb-000148
实施例16F(134毫克,238.59微摩尔)的四氢呋喃(1.00毫升)和水(1.00毫升)溶液中加入一水合氢氧化锂(30.04毫克，715.77微摩尔)，反应液在60℃搅拌2小时。反应混合物用盐酸(1N)酸化调节PH值为3然后通过过滤收集沉淀物即为实施例16。 1H NMR(400MHz,METHANOL-d4)δ＝1.30-1.45(m,11H),1.49(s,6H),1.99(dd,J＝12.86,3.83Hz,2H),2.37(br t,J＝12.80Hz,2H),2.69(s,2H),4.96(br d,J＝3.89Hz,1H),7.34-7.55(m,1H),7.34-7.55(m,6H),7.64(d,J＝8.66Hz,1H). To a solution of Example 16F (134 mg, 238.59 <RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; The reaction mixture was acidified with hydrochloric acid (1N) to adjust pH to 3 and then the precipitate was collected by filtration. 1 H NMR (400MHz, METHANOL- d4) δ = 1.30-1.45 (m, 11H), 1.49 (s, 6H), 1.99 (dd, J = 12.86,3.83Hz, 2H), 2.37 (br t, J = 12.80 Hz, 2H), 2.69 (s, 2H), 4.96 (br d, J = 3.89 Hz, 1H), 7.34 - 7.55 (m, 1H), 7.34 - 7.55 (m, 6H), 7.64 (d, J = 8.66) Hz, 1H).
实验例1：IDH1体外酶活性测试Experimental Example 1: IDH1 in vitro enzyme activity test
IDH1突变体催化NADPH依赖的α-KG还原为2-HG，消耗的NADPH可以用荧光读出。The IDH1 mutant catalyzes the reduction of NADPH-dependent α-KG to 2-HG, and the consumed NADPH can be read by fluorescence.
试剂：Reagents:
基础反应缓冲液：50mM KH2PO4,pH 7.5,10mM MgCl2,10％glycerol,150mM NaCl,0.05％BSA,2mM b-ME,0.003％Brij35Basic reaction buffer: 50 mM KH2PO4, pH 7.5, 10 mM MgCl2, 10% glycerol, 150 mM NaCl, 0.05% BSA, 2 mM b-ME, 0.003% Brij35
底物和辅助因子：Substrate and cofactors:
IDH1 wt(野生型):65μM异柠檬酸+50μM NADPIDH1 wt (wild type): 65 μM isocitric acid + 50 μM NADP
IDH1(R132H):1500μM α-KG+15μM NADPHIDH1 (R132H): 1500μM α-KG+15μM NADPH
IDH1(R132C):500μM α-KG+15μM NADPHIDH1 (R132C): 500μM α-KG+15μM NADPH
反应过程：reaction process:
反应板的孔中加入1.33X的酶(对照孔中不加)、缓冲液和NADP或NADPH(对照孔)，待测化合物溶于100％DMSO后加入酶混合物中(Echo550，纳升级别)，简单离心后孵化60分钟，加入4X底物和辅助因子的混合物开始反应，简单离心后摇振，室温下孵化45分钟。制备3X硫辛酰胺脱氢酶和忍天青的混合物，加入至反应液中测试生成或剩余的NADPH量，简单离心后室温下孵化10分钟，使用多功能的酶标仪Envision测量(Ex/Em＝535/590nm)。1.33X enzyme (not added in the control well), buffer and NADP or NADPH (control well) were added to the wells of the reaction plate, and the test compound was dissolved in 100% DMSO and added to the enzyme mixture (Echo550, Nanoscale). After simple centrifugation, the cells were incubated for 60 minutes, and a mixture of 4X substrate and cofactor was added to start the reaction. After simple centrifugation, the mixture was shaken and incubated at room temperature for 45 minutes. Prepare a mixture of 3X lipoamide dehydrogenase and renin, add to the reaction solution to test the amount of NADPH produced or remaining, incubate for 10 minutes at room temperature after simple centrifugation, and measure with a multi-purpose microplate reader Envision (Ex/Em =535/590nm).
实验结果见表1：The experimental results are shown in Table 1:
表1 IDH1体外酶(IDH1 R132H)活性IC 50测试结果 Table 1 IDH1 in vitro enzyme (IDH1 R132H) activity IC 50 test results
Figure PCTCN2018091270-appb-000149
Figure PCTCN2018091270-appb-000149
Figure PCTCN2018091270-appb-000150
Figure PCTCN2018091270-appb-000150
表2 IDH1体外酶(IDH1 R132C、WT)活性IC 50测试结果 Table 2 IDH1 in vitro enzyme (IDH1 R132C, WT) activity IC 50 test results
Figure PCTCN2018091270-appb-000151
Figure PCTCN2018091270-appb-000151
Figure PCTCN2018091270-appb-000152
Figure PCTCN2018091270-appb-000152
实验例2：IDH1细胞学活性测试Experimental Example 2: IDH1 Cytological Activity Test
本研究将化合物与IDH1突变体细胞系共同孵育后，通过LC-MS检测细胞培养上清中的2HG含量来判断化合物对IDH1突变体的抑制活性。IDH1会催化生物体内异柠檬酸还原为α-酮戊二酸(α-KG)，而IDH1突变体则会进一步催化α-KG还原为2-羟戊二酸(2HG)。In this study, the compound was incubated with the IDH1 mutant cell line, and the 2HG content in the cell culture supernatant was determined by LC-MS to determine the inhibitory activity of the compound on the IDH1 mutant. IDH1 catalyzes the reduction of isocitrate to alpha-ketoglutarate (α-KG) in vivo, while the IDH1 mutant further catalyzes the reduction of α-KG to 2-hydroxyglutarate (2HG).
U87MG-IDH1-R132H细胞株是通过用IDH1-R132H转染U87MG细胞后筛选得到的可以稳定表达IDH1-R132H突变体的稳转细胞株，HT1080细胞株则含有内源性的IDH1-R132C突变体。The U87MG-IDH1-R132H cell line is a stable cell line stably expressing the IDH1-R132H mutant by transfecting U87MG cells with IDH1-R132H, and the HT1080 cell line contains an endogenous IDH1-R132C mutant.
实验流程如下：The experimental process is as follows:
1)化合物用DMSO作3倍梯度稀释后加入到细胞培养板中，共10个浓度，每个浓度双复孔。阴性对照孔只含DMSO，阳性对照孔含终浓度为5μM的AGI-5198。所有孔的DMSO终浓度为0.5％。1) The compound was diluted with DMSO in a 3-fold gradient and added to the cell culture plate for a total of 10 concentrations, each with double duplicate wells. The negative control wells contained only DMSO and the positive control wells contained AGI-5198 at a final concentration of 5 [mu]M. The final concentration of DMSO in all wells was 0.5%.
2)将IDH1突变体细胞株以40000个细胞/孔的密度种入已含化合物的细胞培养板中。将细胞与化合物在37℃、5％CO 2培养箱中共孵育3天。 2) The IDH1 mutant cell strain was seeded at a density of 40,000 cells/well into a cell culture plate containing the compound. The cells were incubated with the compounds for 3 days at 37 ° C in a 5% CO 2 incubator.
3)3天后，取10μl细胞培养上清，用ddH 2O水稀释20倍至200μl并混匀，从中取出50μl稀释液加入200μl沉淀剂(含0.4μg/mlD-α-Hydroxyglutaric acid-13C5的乙腈)。4000rpm离心10分钟后，取100μl上清用LC-MS检测2HG的含量。 3) After 3 days, take 10 μl of the cell culture supernatant, dilute 20-fold to 200 μl with ddH 2 O water and mix well, and take 50 μl of the dilution solution and add 200 μl of the precipitant (acetonitrile containing 0.4 μg/ml D-α-Hydroxyglutaric acid-13C5). ). After centrifugation at 4000 rpm for 10 minutes, 100 μl of the supernatant was taken to detect the content of 2HG by LC-MS.
4)同时平行用ATPlite 1Step试剂盒按说明书方法检测化合物对IDH1突变体细胞株细胞活力的影响。4) Simultaneously, the effects of the compounds on the cell viability of the IDH1 mutant cell line were examined by the ATPlite 1Step kit in parallel according to the instructions.
5)用2HG含量数据及时各浓度化合物对IDH1突变体的抑制率百分比(抑制率％)，计算公式为：抑制率％＝(CPD-ZPE)/(HPE-ZPE)×100％*5) Using 2HG content data, the percentage inhibition rate of IDH1 mutants (% inhibition rate) of each compound in time, the formula is: inhibition rate%=(CPD-ZPE)/(HPE-ZPE)×100%*
用细胞活力数据计算化合物对IDH1突变体细胞株的细胞毒性百分比(细胞毒性％)，计算公式为：细胞毒性％＝(1-CPD/ZPE)×100％*The cell viability data was used to calculate the percentage of cytotoxicity (% cytotoxicity) of the compound against the IDH1 mutant cell line, and the formula was: cytotoxicity % = (1-CPD/ZPE) × 100% *
CPD：化合物孔的信号值CPD: signal value of compound pore
ZPE：阳性对照孔信号平均值，用0.5％DMSO代替化合物ZPE: average value of positive control well signals, replacing compounds with 0.5% DMSO
HPE：阳性对照孔信号平均值，含有5uM AGI-5198HPE: Mean value of positive control well signal, containing 5uM AGI-5198
6)将抑制率％和细胞毒性％用GraphPad Prism软件拟合剂量效应曲线，并得出测试化合物的IC 50值。 6) The% inhibition and% cytotoxicity using GraphPad Prism software fitting the dose-response curves, IC 50 values obtained and the test compound.
实验结果见表3、表4：The experimental results are shown in Table 3 and Table 4:
表3 IDH1体外细胞(U87MG)活性IC 50测试结果 Table 3 IDH1 in vitro cell (U87MG) activity IC 50 test results
Figure PCTCN2018091270-appb-000153
Figure PCTCN2018091270-appb-000153
Figure PCTCN2018091270-appb-000154
Figure PCTCN2018091270-appb-000154
Figure PCTCN2018091270-appb-000155
Figure PCTCN2018091270-appb-000155
表4 IDH1体外细胞(HT1080)活性IC 50测试结果 Table 4 IDH1 in vitro cell (HT1080) activity IC 50 test results
Figure PCTCN2018091270-appb-000156
Figure PCTCN2018091270-appb-000156
Figure PCTCN2018091270-appb-000157
Figure PCTCN2018091270-appb-000157
实验例3：IDH1抑制剂体内药效动力学：对Balb/c小鼠肿瘤及血浆2-HG水平的削减作用Experimental Example 3: In vivo pharmacodynamics of IDH1 inhibitors: reduction of tumor and plasma 2-HG levels in Balb/c mice
建立IDH1R132H外源表达的U87稳定细胞株，并构建该细胞株的脑原位肿瘤模型，用以检测IDH1抑制剂对致癌代谢产物2-HG水平的削减作用。并与BAY1436032(BAY032)作对比。A U87 stable cell line expressing exogenous expression of IDH1R132H was established, and a brain orthotopic tumor model of the cell line was constructed to detect the reduction effect of IDH1 inhibitor on the level of carcinogenic metabolite 2-HG. And compared with BAY1436032 (BAY032).
将荷有U87-IDH1R132H脑原位肿瘤的小鼠分为三组，分别给于100mg/kg BAY032或者实施例1处理，每日给药两次，共给药3次，另一组小鼠不做任何处理作为阴性对照。给药0.25小时、2小时和8小时后，分别取3只小鼠的脑瘤、癌旁脑组织和血浆检测2-HG的含量，以阴性对照组小鼠的相应组织作为对照。Mice bearing U87-IDH1R132H brain orthotopic tumors were divided into three groups and administered to 100 mg/kg BAY032 or Example 1, administered twice daily for 3 times, and the other group was not. Do any treatment as a negative control. After 0.25 hours, 2 hours, and 8 hours of administration, the brain tumor, paracancerous brain tissue, and plasma of 3 mice were separately measured for 2-HG content, and the corresponding tissues of the negative control mice were used as controls.
实验结果如图1所示。给药0.25小时即可大大降低肿瘤及血浆中致癌代谢产物2-HG的含量，其效果与BAY032相当。这一效果能至少持续到8小时。在癌旁脑组织中，实施例1对2-HG含量的减低效果不明显且低于BAY032。The experimental results are shown in Figure 1. When administered for 0.25 hours, the content of the oncogenic metabolite 2-HG in tumors and plasma was greatly reduced, and the effect was comparable to that of BAY032. This effect lasts for at least 8 hours. In the paracancerous brain tissue, the effect of the reduction of the 2-HG content of Example 1 was not significant and was lower than BAY032.
实施例1在脑瘤和脑旁组织中的总暴露量(AUC)分别为540777nM·hr，58872nM·hr，而BAY032在脑瘤和脑旁组织中的总暴露量(AUC)分别为219710nM·hr，102336nM·hr。The total exposure (AUC) of Example 1 in brain tumors and paracranial tissues was 540777 nM·hr, 58872 nM·hr, respectively, while the total exposure (AUC) of BAY032 in brain tumors and paracranial tissues was 219710 nM·hr, respectively. , 102336nM·hr.
结论：本发明化合物具有显著的IDH1突变体抑制作用和良好的选择性，同时在脑瘤和脑旁组织中的具有更好的分布比例，可降低对正常脑组织的潜在副作用。Conclusion: The compounds of the present invention have significant IDH1 mutant inhibition and good selectivity, and have a better distribution ratio in brain tumors and paracranial tissues, which can reduce potential side effects on normal brain tissues.
实验例4：动力学溶解度的测定Experimental Example 4: Determination of kinetic solubility
将受试化合物溶解在DMSO中，以制备10mmol/L的储备液。用磷酸盐缓冲液稀释至理论浓度200μM(含2％DMSO)。室温震摇平衡24小时，抽滤，取上清液，采用HPLC-UV分析检测。用移液管(Eppendorf Research公司)将980μL溶出介质加入到2mL的螺旋盖的玻璃管形瓶中。将20μL各受试化合物的原液以及QC样品添加到相当于pH 6.5的动力学检测溶液的缓冲溶液中。受试化合物和DMSO溶液的终浓度分别是为200μM和2％。药瓶压盖。最大浓度的理论值为200μM。室温下以每分钟880转的速度旋转摇动该混合物24小时。将小瓶离心30分钟，每分钟13000转。用数字移液管将200μL上清液加入到96-孔板中。用高效液相色谱法光谱测定的受试化合物的溶解度。The test compound was dissolved in DMSO to prepare a 10 mmol/L stock solution. Dilute to a theoretical concentration of 200 μM (containing 2% DMSO) with phosphate buffer. The mixture was shaken at room temperature for 24 hours, suction filtered, and the supernatant was taken and detected by HPLC-UV analysis. 980 μL of dissolution medium was pipetted into a 2 mL screw-capped glass vial using a pipette (Eppendorf Research). 20 μL of the stock solution of each test compound and the QC sample were added to a buffer solution corresponding to a kinetic detection solution of pH 6.5. The final concentrations of test compound and DMSO solution were 200 μM and 2%, respectively. Pill cover. The theoretical maximum concentration is 200 μM. The mixture was shaken at 880 rpm for 24 hours at room temperature. The vial was centrifuged for 30 minutes at 13,000 rpm. 200 μL of the supernatant was added to a 96-well plate using a digital pipette. The solubility of the test compound was determined by high performance liquid chromatography.
表5 动力学溶解度的测试结果Table 5 Test results of kinetic solubility
化合物Compound 溶解度(μM)pH 2.0Solubility (μM) pH 2.0 溶解度(μM)pH 6.5Solubility (μM) pH 6.5 溶解度(μM)pH 7.4Solubility (μM) pH 7.4
BAY032BAY032 9.099.09 <1.0<1.0 20.4820.48
实施例1Example 1 185.85185.85 4.964.96 62.0762.07
如表5中所示，与BAY032相比，本发明实施1表现出优异的水溶解度(在三个不同pH值条件下)。因此，本发明的化合物比现有技术显然更易溶于水。As shown in Table 5, Example 1 of the present invention exhibited excellent water solubility (at three different pH conditions) compared to BAY032. Thus, the compounds of the invention are clearly more soluble in water than the prior art.
实验例5：体内药代动力学性质研究Experimental Example 5: In vivo pharmacokinetic properties
实验方法：该研究的目的是为了测定该化合物药代动力学参数，并计算其在雄性CD-1小鼠中的口服生物利用度。该项目使用六只雄性CD-1小鼠，三只小鼠进行静脉注射给药，给药剂量为1mg/kg，收集给药后0.0833，0.25，0.5，1，2，4，6，8，24h的血浆样品，另外三只小鼠口服灌胃给药，给药剂量为20mg/kg，收集0h(给药前)和给药后0.0833，0.25，0.5，1，2，4，6，8，24h的血浆样品，然后对收集的样品进行LC/MS/MS分析并采集数据，采集的分析数据用Phoenix WinNonlin 6.3软件计算相关药代动力学参数。Experimental Methods: The purpose of this study was to determine the pharmacokinetic parameters of the compound and calculate its oral bioavailability in male CD-1 mice. The project used six male CD-1 mice, three mice were administered intravenously at a dose of 1 mg/kg, and 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8 were collected after administration. 24h plasma samples, three other mice were orally administered by intragastric administration at a dose of 20 mg/kg, collected for 0 h (before administration) and 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8 after administration. , 24h plasma samples, then LC/MS/MS analysis and data collection of the collected samples, and the collected analytical data were calculated using Phoenix WinNonlin 6.3 software.
实验结果见表6。The experimental results are shown in Table 6.
表6 体内药代动力学实验结果Table 6 Results of in vivo pharmacokinetic experiments
Figure PCTCN2018091270-appb-000158
Figure PCTCN2018091270-appb-000158
结论：与BAY032相比，本发明化合物具有更好的生物利用度和暴露量。Conclusion: The compounds of the invention have better bioavailability and exposure compared to BAY032.

Claims (21)

  1. 式(Ⅰ)所示化合物或其药学上可接受的盐，a compound of formula (I) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2018091270-appb-100001
    Figure PCTCN2018091270-appb-100001
    其中，among them,
    T 1、T 2分别独立地选自：N或CH； T 1 and T 2 are each independently selected from: N or CH;
    R 1选自H、F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6杂烷基、C 3-6环烷基； R 1 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, or selected from C 1 1-6 alkyl, C 1-6 heteroalkane optionally substituted by 1, 2 or 3 R Base, C 3-6 cycloalkyl;
    R 2分别独立地选自H、F、Cl、Br、I、OH、NH 2，或分别独立地选自任选被1、2或3个R取代的：C 1-6烷基； R 2 are each independently selected from H, F, Cl, Br, I, OH, NH 2 or independently selected from: C 1-6 alkyl optionally substituted by 1, 2 or 3 R;
    R 3选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6杂烷基； R 3 is selected from C 1 1-6 alkyl, C 1-6 heteroalkyl optionally substituted by 1, 2 or 3 R;
    L 1选自任选被1、2或3个R取代的：-C 1-6烷基-、-C 1-6杂烷基-、-3～6元杂环烷基-、-C 3-6环烷基-C 1-6烷基-； L 1 is selected from the group consisting of: 1, 2 or 3 R substituted: -C 1-6 alkyl-, -C 1-6 heteroalkyl-, -3 to 6-membered heterocycloalkyl-, -C 3 -6 cycloalkyl-C 1-6 alkyl-;
    R选自：H、F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：C 1-6烷基、C 1-6杂烷基； R is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, or selected from the group consisting of 1, 2 or 3 R's substituted: C 1-6 alkyl, C 1-6 hetero alkyl;
    R’选自：F、Cl、Br、I、OH、NH 2、CN、Me； R' is selected from the group consisting of: F, Cl, Br, I, OH, NH 2 , CN, Me;
    所述C 1-6杂烷基、3～6元杂环烷基之“杂”选自N、-O-、-S-、-NH-； The "hetero" of the C 1-6 heteroalkyl group and the 3-6 membered heterocycloalkyl group is selected from the group consisting of N, -O-, -S-, -NH-;
    上述杂原子或杂原子团的数目分别独立地选自1、2、3或4。The number of the above heteroatoms or heteroatoms is independently selected from 1, 2, 3 or 4.
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R选自H、F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：C 1-3烷基、C 1-3烷氧基。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is selected from H, F, Cl, Br, I, OH, NH 2 , CN, or selected from 1, 2 or 3 R' substituted: C 1-3 alkyl, C 1-3 alkoxy.
  3. 根据权利要求2所述化合物或其药学上可接受的盐，其中，R选自H、F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：Me、Et、
    Figure PCTCN2018091270-appb-100002
    The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R is selected from H, F, Cl, Br, I, OH, NH 2 , CN, or selected from 1, 2 or 3 Replaced by R': Me, Et,
    Figure PCTCN2018091270-appb-100002
  4. 根据权利要求3所述化合物或其药学上可接受的盐，其中，R选自：H、F、Cl、Br、I、OH、NH 2、CN、Me、CF 3、Et、
    Figure PCTCN2018091270-appb-100003
    The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Et,
    Figure PCTCN2018091270-appb-100003
  5. 根据权利要求1～4任意一项所述化合物或其药学上可接受的盐，其中，R 1选自H、F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基、环丙基。 The compound according to any one of claims 1 to 4, wherein R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or optionally selected from the group consisting of the compound or a pharmaceutically acceptable salt thereof. 1, 2 or 3 R substituted: C 1-3 alkyl, C 1-3 alkoxy, cyclopropyl.
  6. 根据权利要求5所述化合物或其药学上可接受的盐，其中，R 1选自：H、F、Cl、Br、I、OH、NH 2、CN、 Me、CF 3、Et、
    Figure PCTCN2018091270-appb-100004
    The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Et,
    Figure PCTCN2018091270-appb-100004
  7. 根据权利要求1～4任意一项所述化合物或其药学上可接受的盐，其中，R 2分别独立地选自H、F、Cl、Br、I、OH、NH 2，或分别独立地选自任选被1、2或3个R取代的：C 1-3烷基。 The compound according to any one of claims 1 to 4, wherein R 2 is independently selected from H, F, Cl, Br, I, OH, NH 2 or independently, respectively, or a pharmaceutically acceptable salt thereof Substituted by 1, 2 or 3 R: C 1-3 alkyl.
  8. 根据权利要求7所述化合物或其药学上可接受的盐，其中，R 2分别独立地选自H、F、Cl、Br、I、OH、NH 2、Me。 The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein R 2 is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , Me.
  9. 根据权利要求1～4任意一项所述化合物或其药学上可接受的盐，其中，R 3选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基。 The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of: 1 , 2 or 3, R: C 1-3 alkyl, C 1- 3 alkoxy.
  10. 根据权利要求9所述化合物或其药学上可接受的盐，其中，R 3选自任选被1、2或3个R取代的：Me、Et、
    Figure PCTCN2018091270-appb-100005
    The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of 1, 2 or 3 R: Me, Et,
    Figure PCTCN2018091270-appb-100005
  11. 根据权利要求10所述化合物或其药学上可接受的盐，其中，R 3选自：Me、CF 3、Et、
    Figure PCTCN2018091270-appb-100006
    CH(CH 3) 2、
    Figure PCTCN2018091270-appb-100007
    The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of Me, CF 3 , Et,
    Figure PCTCN2018091270-appb-100006
    CH(CH 3 ) 2 ,
    Figure PCTCN2018091270-appb-100007
  12. 根据权利要求1～4任意一项所述化合物或其药学上可接受的盐，其中，L 1选自任选被1、2或3个R取代的：-C 1-3烷基-、-C 1-3烷基-O-、-4元杂环烷基-、-环丙基-C 1-3烷基-。 The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from the group consisting of: 1 , C or 3 R substituted: -C 1-3 alkyl-, - C 1-3 alkyl-O-, 4-membered heterocycloalkyl-, -cyclopropyl-C 1-3 alkyl-.
  13. 根据权利要求12所述化合物或其药学上可接受的盐，其中，L 1选自任选被1、2或3个R取代的：-(CH 2) 2-、-CH 2-O-、-吖丁啶基-、-环丙基-CH 2-。 The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from the group consisting of: -(CH 2 ) 2 -, -CH 2 -O-, optionally substituted by 1, 2 or 3 R; - azetidinyl-, -cyclopropyl-CH 2 -.
  14. 根据权利要求13所述化合物或其药学上可接受的盐，其中，L 1选自：-(CH 2) 2-、-CH 2C(CH 3) 2-、-CH 2-O-、
    Figure PCTCN2018091270-appb-100008
    The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from the group consisting of: -(CH 2 ) 2 -, -CH 2 C(CH 3 ) 2 -, -CH 2 -O-,
    Figure PCTCN2018091270-appb-100008
  15. 根据权利要求1或11所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018091270-appb-100009
    选自：
    Figure PCTCN2018091270-appb-100010
    Figure PCTCN2018091270-appb-100011
    The compound according to claim 1 or 11, or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2018091270-appb-100009
    From:
    Figure PCTCN2018091270-appb-100010
    Figure PCTCN2018091270-appb-100011
  16. 根据权利要求1～4任意一项所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018091270-appb-100012
    选自：     The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2018091270-appb-100012
    From:
    Figure PCTCN2018091270-appb-100013
    Figure PCTCN2018091270-appb-100013
  17. 根据权利要求1～11任意一项所述化合物或其药学上可接受的盐，其选自：A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:
    Figure PCTCN2018091270-appb-100014
    Figure PCTCN2018091270-appb-100014
    其中，among them,
    n选自：0、1或2；n is selected from: 0, 1 or 2;
    m选自：1、2或3；m is selected from: 1, 2 or 3;
    T 1、T 2、T 3分别独立地选自：N或CH； T 1 , T 2 , T 3 are each independently selected from: N or CH;
    L 2选自任选被1、2或3个R取代的：-C 1-3烷基-、-C 1-3烷氧基-； L 2 is selected from the group consisting of: 1, 2 or 3, R: -C 1-3 alkyl-, -C 1-3 alkoxy-;
    R、R 1、R 2、R 3如权利要求1～11所定义。 R, R 1 , R 2 and R 3 are as defined in claims 1 to 11.
  18. 根据权利要求17所述化合物或其药学上可接受的盐，其选自：A compound according to claim 17 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:
    Figure PCTCN2018091270-appb-100015
    Figure PCTCN2018091270-appb-100015
    其中，among them,
    n选自：0、1或2；n is selected from: 0, 1 or 2;
    m选自：1、2或3；m is selected from: 1, 2 or 3;
    T 1、T 2、T 3分别独立地选自：N或CH； T 1 , T 2 , T 3 are each independently selected from: N or CH;
    L 2选自：-(CH 2) 2-、-CH 2C(CH 3) 2-、-CH 2-O-； L 2 is selected from the group consisting of: -(CH 2 ) 2 -, -CH 2 C(CH 3 ) 2 -, -CH 2 -O-;
    R、R 1、R 2、R 3如权利要求17所定义。 R, R 1 , R 2 and R 3 are as defined in claim 17.
  19. 下式化合物：Compound of the formula:
    Figure PCTCN2018091270-appb-100016
    Figure PCTCN2018091270-appb-100016
    Figure PCTCN2018091270-appb-100017
    Figure PCTCN2018091270-appb-100017
  20. 一种药物组合物，包括治疗有效量的根据权利要求1～19任意一项所述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, as an active ingredient, and a pharmaceutically acceptable carrier.
  21. 根据权利要求1～19任意一项所述的化合物或其药学上可接受的盐或者权利要求20的组合物在制备IDH突变体抑制剂相关药物上的应用。Use of a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or a composition according to claim 20 for the preparation of a medicament for IDH mutant inhibitor.
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Publication number Priority date Publication date Assignee Title
US20160145240A1 (en) * 2014-11-26 2016-05-26 Korea Institute Of Science And Technology Heteroarylamine derivatives as protein kinase inhibitors
WO2017005674A1 (en) * 2015-07-07 2017-01-12 Bayer Pharma Aktiengesellschaft 2-aryl- and 2-arylalkyl-benzimidazoles as midh1 inhibitors
WO2017009325A1 (en) * 2015-07-16 2017-01-19 Bayer Pharma Aktiengesellschaft 5-hydroxyalkylbenzimidazoles as midh1 inhibitors
WO2017012967A1 (en) * 2015-07-21 2017-01-26 Bayer Pharma Aktiengesellschaft Fused imidazoles as midh1 inhibitors

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160145240A1 (en) * 2014-11-26 2016-05-26 Korea Institute Of Science And Technology Heteroarylamine derivatives as protein kinase inhibitors
WO2017005674A1 (en) * 2015-07-07 2017-01-12 Bayer Pharma Aktiengesellschaft 2-aryl- and 2-arylalkyl-benzimidazoles as midh1 inhibitors
WO2017009325A1 (en) * 2015-07-16 2017-01-19 Bayer Pharma Aktiengesellschaft 5-hydroxyalkylbenzimidazoles as midh1 inhibitors
WO2017012967A1 (en) * 2015-07-21 2017-01-26 Bayer Pharma Aktiengesellschaft Fused imidazoles as midh1 inhibitors

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