WO2021136333A1 - 一种制备3-位被酰胺基烷基取代的香豆素类化合物的方法及其产物和相关中间体 - Google Patents

一种制备3-位被酰胺基烷基取代的香豆素类化合物的方法及其产物和相关中间体 Download PDF

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WO2021136333A1
WO2021136333A1 PCT/CN2020/141203 CN2020141203W WO2021136333A1 WO 2021136333 A1 WO2021136333 A1 WO 2021136333A1 CN 2020141203 W CN2020141203 W CN 2020141203W WO 2021136333 A1 WO2021136333 A1 WO 2021136333A1
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alkyl
compound
group
formula
tumors
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PCT/CN2020/141203
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French (fr)
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曾庆平
王瑞平
段洁
魏旭东
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复星弘创(苏州)医药科技有限公司
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Priority to JP2022540994A priority Critical patent/JP2023509180A/ja
Priority to MX2022008241A priority patent/MX2022008241A/es
Priority to EP20910574.1A priority patent/EP4089090A4/en
Priority to CN202080091526.9A priority patent/CN114929692A/zh
Priority to CA3163528A priority patent/CA3163528A1/en
Priority to US17/758,267 priority patent/US20230067666A1/en
Publication of WO2021136333A1 publication Critical patent/WO2021136333A1/zh

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Definitions

  • the invention relates to the field of medicinal chemistry, and in particular to a method for preparing coumarin compounds whose 3-position is substituted by an amidoalkyl group, and products and related intermediates thereof.
  • Inositol enzyme 1 ⁇ is an endonuclease, which is mainly located in the endoplasmic reticulum connected to the nucleus. It regulates gene expression by exerting the catalytic function of endonuclease, thereby affecting the endoplasmic reticulum. Processing and modification of unfolded proteins.
  • IRE-1 ⁇ an important part of the signaling pathway of this mechanism, will be activated and removed
  • UTR unfolded protein response
  • a specific base sequence on the target mRNA regulates the expression of related genes, thereby enhancing protein folding and modification, alleviating the stress of the endoplasmic reticulum, repairing the imbalance of the internal environment of the cell, and promoting cell survival. Therefore, the function of IRE-1 ⁇ is closely related to diseases in many fields such as tumor, metabolism, immunity, viral infection, and cardiovascular.
  • tumor cells for cancer, the rapid proliferation of malignant tumor cells has caused tumor cells to be generally in an out-of-control state due to the interaction of various factors such as hypoxia, insufficient nutrient supply, metabolic disorders, and carcinogenic pressure.
  • various factors such as hypoxia, insufficient nutrient supply, metabolic disorders, and carcinogenic pressure.
  • Such tumor microenvironment continues to affect the internal Plasma reticulum folding; in addition, chemotherapy, biological therapy, and radiation therapy can also cause endoplasmic reticulum stress response and fight apoptosis through UPR. Therefore, IRE-1 ⁇ in tumor cells is continuously and extensively activated under long-term stress, making it It becomes an ideal tumor target that can be acted by drugs (such as IRE-1 ⁇ inhibitors).
  • CN103079558 A discloses a class of small molecule compounds that use a coumarin structure as the core and can inhibit IRE-1 ⁇ , in which compounds with the following specific structures are provided. This is a potent, low-toxic, highly selective IRE-1 ⁇ inhibitor
  • CN107973784 A discloses the following synthetic route of an ethyl acetoacetate compound (2-(N,N-dimethylaminocarbonylmethyl)ethyl acetoacetate) substituted by an amidoalkyl group at the ⁇ -position:
  • the 1,3-dicarbonyl group in the ethyl acetoacetate structure of this compound undergoes condensation reaction with iminoamide derivatives under alkaline conditions and is used to synthesize pyrimidine compounds
  • the first aspect of the present invention provides a method for preparing a compound of formula (VII), comprising
  • R 1 and R 2 are each independently selected from hydrogen, halogen and -O (C 1-8 alkyl), wherein the alkyl is optionally substituted with 1 or 2 groups selected from the group consisting of halogen, C 1-8 alkyl group substituted by 1-2 hydroxy groups, -O (C 1-8 alkyl group);
  • R 3 is -LC(O)NR 5 R 6 , and L is C 1-3 alkylene;
  • R 4 is -O(C 1-6 alkyl
  • R 5 and R 6 are each independently selected from hydrogen, -O (C 1-8 alkyl), C 3-10 cyclic hydrocarbon group, wherein the alkyl group and cyclic hydrocarbon group are optionally 1 or 2 selected from the following Group substitution: halogen, -O (C 1-8 alkyl), -NH 2 , -NH (C 1-8 alkyl), -N (C 1-8 alkyl) 2 , five- to seven-membered hetero Cyclic group, wherein the heterocyclic group contains 1-2 heteroatoms selected from N, O, S, and the heterocyclic group is optionally composed of 1-2 groups selected from C 1-8 alkyl Replace; or
  • R 5 and R 6 together with the N atom to which they are connected form a five- to seven-membered heterocyclic group, which optionally contains an additional heteroatom selected from N, O, S, and optionally Substituted by 1 or 2 groups selected from: halogen, C 1-8 alkyl, -O (C 1-8 alkyl) , -NH 2 , -NH (C 1-8 alkyl), -N (C 1-8 alkyl) 2 .
  • the second aspect of the present invention provides a method for preparing a compound of formula (I), which includes the step (A) described in the first aspect of the present invention and the following step (B):
  • R 1 , R 2 and R 3 are as defined in the first aspect of the present invention.
  • the third aspect of the present invention provides an intermediate compound, the structure of which is shown in the following formula (V):
  • R 3 and R 4 are as defined in the first aspect of the present invention.
  • the crystal form I of compound Orin1001 is provided, wherein the X-ray powder diffraction pattern of the crystal form I is about 8.44 ⁇ 0.2°, 13.11 ⁇ 0.2°, 15.70 ⁇ 0.2°, 19.73 ⁇ 0.2°, There are characteristic peaks at the diffraction angles (2 ⁇ ) of 21.00 ⁇ 0.2° and 22.91 ⁇ 0.2°,
  • the present invention provides a pharmaceutical composition comprising the crystal form I of the present invention and one or more pharmaceutically acceptable carriers.
  • the present invention also provides the crystalline form I of the present invention or the pharmaceutical composition of the present invention when preparing to treat or prevent diseases, disorders or conditions related to unfolded protein response (UPR), or when preparing to treat or prevent
  • URR unfolded protein response
  • RIDD IRE1-dependent decay
  • Figure 1 shows the X-ray powder diffraction (XRPD) pattern of Form I.
  • FIG. 1 shows the thermogravimetric analysis (TGA) spectrum of Form I.
  • FIG. 3 shows the differential scanning calorimetry (DSC) spectrum of Form I.
  • Figure 4 shows the dynamic moisture adsorption (DVS) spectrum of Form I.
  • Fig. 5 shows the XRPD comparison chart of Form I before and after DVS detection.
  • Fig. 6 shows the result of stability test of Form I (XRPD)-Day 7, where "-1" and "-2" at the end of the annotation of the curve represent “Sample-1” and “Sample-2", respectively.
  • Fig. 7 shows the result of stability test of crystal form I (XRPD)-day 14, where "-1" and “-2" at the end of the annotation of the curve represent “Sample-1” and “Sample-2", respectively.
  • Fig. 8 shows the particle size distribution test chart of crystal form I.
  • Figure 9 shows the test results (XRPD) of Form I after mechanical treatment.
  • substituted and “substituted” mean that one or more (for example, one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that it does not exceed the specified amount.
  • the specified atom has the normal valence in the current situation and the substitution forms a stable compound. Combinations of substituents and/or variables are only permissible when such combinations form stable compounds.
  • the position of the substituent may be one or more hydrogen atoms, provided that the structure formed can make the compound reach a stable state.
  • the point of attachment of a substituent can be from any suitable position of the substituent.
  • one or more or “at least one” can mean one, two, three, four, five, six, seven, eight, nine or more (A).
  • mn used herein refers to the range of m to n and the sub-range composed of each point value therein and each point value.
  • C 1-8 covers the range of 1-8 carbon atoms, and should be understood to also cover any sub-range therein and each point value, such as C 2-5 , C 3-4 , C 1- 2.
  • C 3-10 should also be understood in a similar manner, for example, it can cover any sub-range and point value contained therein, such as C 3-9 , C 6-9 , C 6-8 , C 6- 7. C 7-10 , C 7-9 , C 7-8 , C 8-9, etc. and C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 and so on.
  • the expression "three yuan to ten yuan” should be understood as covering any sub-range and each point value, such as 3-5 yuan, 3-6 yuan, 3-7 yuan, 3-8 yuan, 4-5 Yuan, 4-6 yuan, 4-7 yuan, 4-8 yuan, 5-7 yuan, 5-8 yuan, 6-7 yuan, 7-8 yuan, 9-10 yuan, etc., and 3, 4, 5, 6, 7, 8, 9, 10 yuan, etc.
  • Other similar expressions in this article should also be understood in a similar way.
  • halogen or halogen or “halo” should be understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine or bromine atom.
  • alkyl refers to a saturated linear, branched or cyclic hydrocarbon group.
  • C 1-8 alkyl refers to a saturated linear, branched or saturated chain having 1-8 (for example, 1, 2, 3, 4, 5, 6, 7 or 8) carbon atoms Cyclic hydrocarbon group.
  • C 1-6 alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, new Pentyl, 3-methylpentan-3-yl, hexyl (e.g., n-hexyl, cyclohexyl, etc.).
  • the "C 1-8 alkyl group” covers the sub-range therein, such as “C 1-3 alkyl group", “C 2-3 alkyl group", “C 4-6 alkyl group” and the like.
  • alkylene when used alone or in combination with other groups herein, refers to a saturated linear or branched divalent hydrocarbon group.
  • C 1-8 alkylene refers to an alkylene group having 1-8 carbon atoms, such as methylene, ethylene, propylene, butylene, 1-methylethylene, 2 -Methyl ethylene or methyl propylene, etc.
  • alkoxy refers to an alkyl group as defined above connected to an oxygen atom by a single bond. The alkoxy group is connected to the rest of the molecule through an oxygen atom.
  • the alkoxy group can be represented as -O (alkyl).
  • C 1-8 alkoxy or “-O (C 1-8 alkyl)” refers to an alkoxy group containing 1-8 carbon atoms, in which the alkyl part can be linear, branched or cyclic ⁇ Like structure.
  • Alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n-pentoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • cyclic hydrocarbon group refers to a saturated or unsaturated non-aromatic cyclic hydrocarbon group composed of carbon atoms and hydrogen atoms, and preferably contains 1 or 2 rings.
  • the cyclic hydrocarbon group may be a monocyclic ring, a fused polycyclic ring, a bridged ring or a spiro ring structure.
  • the cyclic hydrocarbon group may have 3-10 carbon atoms, that is, "C 3-10 cyclic hydrocarbon group", such as C 3-8 cyclic hydrocarbon group, C 5 cyclic hydrocarbon group, C 6 cyclic hydrocarbon group, C 7 cyclic hydrocarbon group.
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, spiro[3.3]heptyl, and the like.
  • heterocyclic group or “heterocyclic hydrocarbon group” means having, for example, 3-10 (suitably 3-8, more suitably 3-7, 5-7, especially 4-6)
  • a monocyclic or bicyclic non-aromatic ring system of ring atoms three-membered to ten-membered, three-membered to eight-membered, three-membered to six-membered), wherein at least one ring atom (for example, 1, 2, or 3) is selected from N , O and S heteroatoms, and the remaining ring atoms are C.
  • the ring system can be saturated (also can be understood as the corresponding "heterocycloalkyl”) or unsaturated (that is, having one or more double bonds and/or triple bonds in the ring).
  • the heterocyclic group may be, for example, a 4-membered ring, such as azetidinyl, oxetanyl, or a 5-membered ring, such as tetrahydrofuranyl, dioxanyl, pyrrolidinyl, imidazolidinyl, pyridine Oxazolidinyl, pyrrolinyl, oxopyrrolidinyl, 2-oxoimidazolidine-1-yl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl , Thiomorpholinyl, piperazinyl, 1,1-dioxo-1,2-thiazin-2-yl or trithiazyl; or 7-membered ring, such as diazayl ring.
  • a 4-membered ring such as azetidinyl, oxetanyl, or a 5-membere
  • the heterocyclic group may be benzo-fused.
  • the heterocyclic group can be bicyclic without limitation, for example a 5,5-membered ring, such as hexahydrocyclopentane[c]pyrrole-2(1H)-yl) ring; or a 5,6-membered bicyclic ring, such as Hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring.
  • the ring containing the nitrogen atom may be partially unsaturated, that is, it may contain one or more double bonds without limitation, such as 2,5-dihydro-1H-pyrrolyl, 4H- [1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl ring, or it may be benzo-fused without limitation, for example Dihydroisoquinolinyl ring.
  • hydrocarbon solvent refers to a solvent of linear, branched or cyclic hydrocarbon having 1-10 carbon atoms.
  • the hydrocarbon can be saturated or unsaturated.
  • hydrocarbon solvents include, for example, alkane solvents, including but not limited to n-pentane, n-hexane, cyclohexane, n-heptane, octane or a combination thereof, preferably hexane or heptane.
  • hydrocarbon solvents also include aromatic hydrocarbon solvents, which contain at least one aromatic ring and are optionally substituted with linear, branched, or cyclic hydrocarbon groups.
  • Aromatic solvents include but are not limited to benzene, toluene, xylene or a combination thereof, preferably toluene, xylene or a combination thereof.
  • halogenated alkanes solvent refers to the alkane solvents mentioned above, of which one or more (e.g. 1-6, 1-5, 1-4, 1-3, or 1-2 A) The hydrogen atom is replaced by a halogen.
  • the halogens may be the same or different, and may be located on the same or different C atoms.
  • Halogenated alkane solvents include, but are not limited to, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, hexachloroethane and 1,2,3-trichloropropane or a combination thereof, preferably two Chloroform, trichloromethane, 1,2-dichloroethane or a combination thereof, especially dichloromethane.
  • ester solvent refers to solvents of esters having 3-10 carbon atoms. Ester solvents include, but are not limited to, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, pentyl acetate or a combination thereof, preferably ethyl acetate, isopropyl acetate, butyl acetate or a combination thereof.
  • ether-based solvent refers to an ether solvent having 2-10 carbon atoms.
  • ether solvents include, but are not limited to, diethyl ether, isopropyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether or a combination thereof, preferably tetrahydrofuran, methyltetrahydrofuran, Dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, or a combination thereof.
  • nitrile solvent refers to a solvent of nitriles having 2-10 carbon atoms.
  • nitrile solvents include, but are not limited to, acetonitrile, propionitrile, butyronitrile, benzonitrile, benzylacetonitrile or a combination thereof, preferably acetonitrile, benzonitrile, benzylacetonitrile or a combination thereof, especially acetonitrile.
  • disubstituted amide solvent refers to an amide solvent: an amide formed by linking a C 1-3 alkyl acyl group with an amine compound, in which two amide N atoms are independently selected from the C 1-3 alkyl group. Alkyl substitution, or the two substituents on the amide N atom together with the amide N atom to which it is connected form a five- to seven-membered heterocyclic ring containing one N atom.
  • disubstituted amide solvents include, but are not limited to, N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, N-methylpyrrolidone or a combination thereof.
  • room temperature refers to about 20-30°C, preferably about 25°C.
  • the percentages, parts, etc. herein are all by weight. Unless otherwise stated, the concentration is calculated by weight, the liquid ratio in the mixed solution is calculated by volume, and the ratio (including percentage) of the reaction reagent to the compound and the reaction yield are calculated by mole.
  • crystalline form or "crystalline” refers to any solid substance exhibiting a three-dimensional order, as opposed to an amorphous solid substance, which produces a characteristic X-ray powder diffraction pattern with well-defined peaks.
  • X-ray powder diffraction (XRPD) pattern refers to an experimentally observed diffraction pattern or a parameter, data or value derived therefrom.
  • the XRPD pattern is usually characterized by peak position (abscissa) and/or peak intensity (ordinate).
  • the XRPD pattern can be measured on an instrument of Bruker D8advance X, for example.
  • the term "2 ⁇ " refers to the peak position expressed in degrees (°) based on the setting in the X-ray diffraction experiment, and is usually the unit of abscissa in the diffraction pattern. If the incident beam forms an angle ⁇ with a certain lattice plane, the reflection is diffracted, and the experimental setup needs to record the reflected beam at an angle of 2 ⁇ . It should be understood that the specific 2 ⁇ value of the specific crystal form mentioned herein is intended to mean the 2 ⁇ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein.
  • the term "substantially" for X-ray diffraction peaks means that the representative peak position and intensity change are taken into account. There may be differences in the XRPD patterns between the results obtained by measuring the same polymorphs for a variety of reasons.
  • the sources of errors include differences in sample preparation (such as sample height), instrument errors, scale errors, and operational errors (including errors in determining peak positions).
  • Preferential orientation that is, the lack of random orientation in the crystals of XRPD samples, may result in significant differences in relative peak heights. Scale errors and sample height errors usually cause all peaks in the diffraction pattern to be shifted by the same amount in the same direction.
  • the same method can be used to make up for the differences between the diffractometers, so that the XRPD peak positions obtained by the two different instruments are consistent.
  • the peak positions of a particular polymorph usually differ by about ⁇ 0.2° (2 ⁇ ).
  • the relative peak intensity will also vary due to differences between instruments and the degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be considered. This is only a qualitative measurement.
  • DSC Differential scanning calorimetry
  • TGA Thermogravimetric analysis
  • Dynamic moisture adsorption is a common method to investigate the moisture adsorption of drugs, excipients or packaging materials through a dynamically accelerated moisture adsorption process.
  • the moisture adsorption isotherm is usually used to describe the correlation between sample moisture content and relative humidity in the process of sample moisture adsorption.
  • the DVS profile can be measured, for example, on an instrument of model IGASorp.
  • particle size distribution refers to the range of particle size distribution, which can be expressed by the particle size corresponding to the cumulative particle size distribution ratio (expressed as a fraction, decimal, or percentage) reaching a specific value, such as D(0.5) Or D50 represents the median particle size.
  • the particle size distribution can be measured by a laser light diffraction method, for example, can be measured by a Mastersizer laser particle size analyzer manufactured by Malvern, USA.
  • atomic economy means that in the chemical synthesis process, the synthesis method and process are designed to convert as many atoms of the raw material used in the reaction process as possible into the product molecule.
  • a reaction or synthesis route with high atom economy can increase efficiency and reduce the generation of by-products or waste.
  • pharmaceutically acceptable means that it is compatible with other components in the formulation and has no unacceptable toxicity to the subject and the user.
  • “Pharmaceutically acceptable carrier” refers to those carrier materials that have no obvious stimulating effect on organisms and do not impair the biological activity and performance of the active compound. “Pharmaceutically acceptable carriers” include but are not limited to glidants, sweeteners, diluents, preservatives, dyes/colorants, flavors, surfactants, wetting agents, dispersants, disintegrants, Stabilizer, solvent or emulsifier.
  • administration refers to a method that enables the compound or composition to be delivered to a desired site of biological action. These methods include, but are not limited to, parenteral (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration and the like.
  • the term "effective amount” refers to the amount of the active ingredient that will achieve the desired effect to a certain extent after administration, such as one that relieves the condition being treated Species or multiple symptoms or to prevent the occurrence of a disease or its symptoms.
  • “Individual” as used herein includes human or non-human animals, especially humans.
  • the first aspect of the present invention provides a method for preparing a compound of formula (VII), comprising
  • R 1 and R 2 are each independently selected from hydrogen, halogen and -O (C 1-8 alkyl), wherein the alkyl is optionally substituted with 1 or 2 groups selected from the group consisting of halogen, C 1-8 alkyl group substituted by 1-2 hydroxy groups, -O (C 1-8 alkyl group);
  • R 3 is -LC(O)NR 5 R 6 , and L is C 1-3 alkylene;
  • R 4 is -O(C 1-6 alkyl
  • R 5 and R 6 are each independently selected from hydrogen, -O (C 1-8 alkyl), C 3-10 cyclic hydrocarbon group, wherein the alkyl group and cyclic hydrocarbon group are optionally 1 or 2 selected from the following Group substitution: halogen, -O (C 1-8 alkyl), -NH 2 , -NH (C 1-8 alkyl), -N (C 1-8 alkyl) 2 , five- to seven-membered hetero Cyclic group, wherein the heterocyclic group contains 1-2 heteroatoms selected from N, O, S, and the heterocyclic group is optionally composed of 1-2 groups selected from C 1-8 alkyl Replace; or
  • R 5 and R 6 together with the N atom to which they are connected form a five- to seven-membered heterocyclic group, which optionally contains an additional heteroatom selected from N, O, S, and optionally Substituted by 1 or 2 groups selected from: halogen, C 1-8 alkyl, -O (C 1-8 alkyl) , -NH 2 , -NH (C 1-8 alkyl), -N (C 1-8 alkyl) 2 .
  • R 1 and R 2 are each independently selected from hydrogen, halogen, and -O (C 1-4 alkyl), wherein the alkyl group is optionally substituted by 1 or 2 groups selected from Substitution: halogen, -O (C 1-4 alkyl).
  • R 1 and R 2 are each independently selected from hydrogen, halogen, and -O(C 1-2 alkyl), wherein the alkyl group is optionally substituted by halogen or methoxy.
  • R 1 and R 2 are each independently hydrogen, methoxy or
  • R 4 is -O (C 1-4 alkyl), preferably -O (C 1-3 alkyl). In a more preferred embodiment, R 4 is -O(C 1-2 alkyl). In a particular embodiment, R 4 is ethoxy.
  • L is methylene or ethylene. In a preferred embodiment, L is methylene.
  • R 5 and R 6 are each independently selected from hydrogen, C 1-6 alkyl, wherein the alkyl is optionally substituted with 1-2 groups selected from the group consisting of halogen, -O (C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2 , five- to seven-membered heterocyclic group, wherein the heterocyclic ring
  • the group contains 1-2 heteroatoms selected from N, O, S, and the heterocyclic group is optionally substituted with 1-2 groups selected from C 1-6 alkyl; or
  • R 5 and R 6 together with the N atom to which they are connected form a five- to seven-membered heterocyclic group, which optionally contains an additional heteroatom selected from N, O, S, and optionally Substituted by 1-2 groups selected from: halogen, C 1-6 alkyl, -O (C 1-6 alkyl) , -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2 .
  • R 5 and R 6 are each independently selected from hydrogen, C 1-4 alkyl, wherein said alkyl is optionally substituted with 1-2 groups selected from the group consisting of halogen, -O (C 1-2 alkyl), -NH (C 1-2 alkyl), -N (C 1-2 alkyl) 2 , five- to seven-membered heterocyclic group, wherein the heterocyclic group contains 1-2 heteroatoms selected from N, O, S, and at least one of the heteroatoms is N, and the heterocyclic group is optionally substituted with 1-2 heteroatoms selected from C 1-4 alkyl Group substitution; or
  • R 5 and R 6 together with the N atom to which they are connected form a five- to seven-membered heterocyclic group, which optionally contains an additional heteroatom selected from N, O, S, and optionally Substituted by 1-2 groups selected from the group consisting of halogen, C 1-4 alkyl, -O (C 1-2 alkyl), -NH (C 1-2 alkyl), -N (C 1- 2 alkyl) 2.
  • R 5 and R 6 are each independently selected from hydrogen, C 1-2 alkyl, wherein said alkyl is optionally substituted with 1-2 groups selected from the following: methyl Oxy, dimethylamino, morpholinyl, piperidinyl or piperazinyl, said morpholinyl, piperidinyl or piperazinyl is optionally substituted by methyl; or
  • R 5 and R 6 together with the N atom to which they are attached form a morpholinyl, piperidinyl or piperazinyl group, which is optionally substituted by methyl.
  • R 5 and R 6 are each independently selected from hydrogen, C 1-2 alkyl, wherein said alkyl is substituted by morpholino; or
  • R 5 and R 6 together with the N atom to which they are attached form a morpholinyl group.
  • the compound of formula (VII) has the structure of compound 5A2, and step (A) is as follows: react compound 1 with compound B1 to prepare compound 5A2
  • step (A) is carried out under acidic conditions.
  • the reaction temperature is -20°C to 70°C.
  • the reaction temperature is -5°C to 60°C.
  • the reaction temperature is 20°C to 50°C.
  • the second aspect of the present invention provides a method for preparing a compound of formula (I), which includes the step (A) described in the first aspect of the present invention and the following step (B):
  • R 1 , R 2 and R 3 are as defined in the first aspect of the present invention.
  • the formylation reagent is selected from hexamethylenetetramine and paraformaldehyde.
  • step (B) is carried out in the presence of an acid.
  • the reaction temperature is 50°C to 120°C, preferably 60°C to 100°C, more preferably 80°C to 90°C.
  • the compound of formula (I), the reaction product of step (A), is purified as follows:
  • Step i mixing the crude compound of formula (I) with a halogenated alkane solvent and water to obtain a mixture.
  • Step ii Separate the organic phase of the mixture obtained in Step i, concentrate to obtain a solid, and wash the solid with a suitable solvent to obtain a crystalline compound of formula (I).
  • a step of washing the mixture is further included between step i and step ii.
  • an alkaline aqueous solution is used to wash the mixture.
  • step i and step ii a step of adjusting the pH value of the mixture is further included, wherein the pH value of the mixture is adjusted to be close to neutral.
  • the pH is adjusted to about 6 to 8, preferably about 7.
  • step ii after separating the organic phase in step ii and before concentrating, it further includes a step of filtration or centrifugation, and the solution obtained by filtration or centrifugation is concentrated to obtain a solid.
  • the step of filtering or centrifuging is filtering.
  • a drying step is further included to substantially remove or partially remove the moisture in the organic phase.
  • the suitable solvent described in step ii is an organic solvent.
  • the organic solvent is selected from nitrile solvents, ester solvents, and combinations thereof, preferably nitrile solvents or ester solvents.
  • the nitrile solvent is selected from acetonitrile, benzonitrile, benzylacetonitrile or a combination thereof, preferably acetonitrile.
  • the ester solvent is selected from ethyl acetate, isopropyl acetate, butyl acetate or a combination thereof, preferably ethyl acetate.
  • the crude compound of formula (I) in step i refers to the residue obtained by concentrating the reaction mixture under reduced pressure to remove the solvent therein after the reaction in step (A) is completed.
  • the crude compound of formula (I) in step i means that after the reaction in step (A) is completed, the residue obtained by concentrating the reaction mixture under reduced pressure is dissolved in a solvent, and a short pad of silica gel ) After filtration, the residue obtained by concentrating the filtrate.
  • step (B) intermediate compound of formula (VII) reacts with formylation reagent to obtain compound of formula (I), it is purified according to a method including the following steps:
  • Step i Concentrate the reaction solution, add water and a seed crystal of the compound of formula (I) to induce crystallization;
  • Step ii Separate the crude product obtained in Step i, stir with a suitable solvent under heating, and then lower the temperature to obtain a crystalline compound of formula (I).
  • step ii after separating the crude product in step ii and before stirring with a suitable solvent under heating, the step of rinsing the crude product with a suitable solvent is further included.
  • step ii is separated to obtain the crystalline compound of formula (I), it further includes the steps of rinsing with a suitable solvent and drying.
  • the suitable solvent in step ii is selected from a nitrile solvent or a mixed solvent of a nitrile solvent and water.
  • the nitrile solvent is selected from acetonitrile, benzonitrile, benzylacetonitrile or a combination thereof, preferably acetonitrile.
  • the heating temperature in step ii is preferably 40-80°C, more preferably 50-70°C.
  • the heating time of step ii is at least 2 hours, preferably at least 4 hours, and more preferably at least 8 hours.
  • the compound of formula (I) has the structure of compound Orin1001, and step (A) is as follows: react compound 5A2 with a formylation reagent to prepare compound Orin1001
  • the method of the present invention further includes the following steps (a) and (b) before step (A).
  • X is halogen; L, R 3 , R 5 and R 6 are as defined above.
  • the reaction is carried out in an organic solvent.
  • the organic solvent is a neutral aprotic solvent.
  • the organic solvent is selected from hydrocarbon solvents, halogenated hydrocarbon solvents, ether solvents, disubstituted amide solvents, ester solvents, and combinations thereof.
  • the hydrocarbon solvent is selected from toluene, xylene, and combinations thereof.
  • the halogenated hydrocarbon solvent is dichloromethane.
  • the ether solvent is selected from tetrahydrofuran, methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, and combinations thereof.
  • the disubstituted amide solvent is selected from N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, N,N- Diethylacetamide, N-methylpyrrolidone and combinations thereof.
  • the ester solvent is selected from ethyl acetate, isopropyl acetate, butyl acetate, and combinations thereof.
  • the reaction temperature is -10°C to 60°C, preferably 0°C to room temperature, more preferably 0°C to 10°C.
  • X is halogen; R 3 and R 4 are as defined above.
  • the reaction is carried out in the presence of a base, which is an organic base or an inorganic base.
  • the organic base is selected from NaNH 2 , sodium alkoxide, K-HMDS, Li-HMDS.
  • the inorganic base is selected from carbonates and metal hydrides.
  • the carbonate is selected from sodium carbonate, potassium carbonate, lithium carbonate; preferably sodium carbonate or potassium carbonate.
  • the carbonate is potassium carbonate.
  • the metal hydride is selected from NaH, KH, LiH, CaH 2 . In a particular embodiment, the metal hydride is NaH.
  • the reaction is carried out in an organic solvent.
  • the organic solvent is a neutral aprotic solvent.
  • the organic solvent is selected from hydrocarbon solvents, halogenated hydrocarbon solvents, ether solvents, disubstituted amide solvents, and combinations thereof.
  • the hydrocarbon solvent is selected from toluene, xylene, and combinations thereof.
  • the halogenated hydrocarbon solvent is dichloromethane.
  • the ether solvent is selected from tetrahydrofuran, methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, and combinations thereof.
  • the disubstituted amide solvent is selected from N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, N,N- Diethylacetamide, N-methylpyrrolidone and combinations thereof.
  • the reaction temperature is -20 to 100°C, preferably -20 to 80°C, more preferably -10 to 60°C.
  • step (a) is as follows:
  • the compound of formula (III) has the structure of compound C1
  • the compound of formula (IV) is ethyl acetoacetate
  • the compound of formula (V) has the structure of compound B1 as follows
  • Step (b) is as follows:
  • X in step (a) or step (b) is selected from Cl and Br. In a preferred embodiment, X is Br.
  • the method of the first aspect of the invention is implemented through the following route:
  • step (a), step (b) and step (A) are as defined above.
  • the method of the second aspect of the invention is implemented through the following route:
  • step (a), step (b), step (A) and step (B) are as described above definition.
  • the third aspect of the present invention provides an intermediate compound, the structure of which is shown in the following formula (V):
  • R 3 and R 4 are as defined in the first aspect of the present invention.
  • R 3 is -LC(O)NR 5 R 6 , and L is methylene or ethylene;
  • R 4 is -O(C 1-6 alkyl
  • R 5 and R 6 are each independently selected from hydrogen, C 1-6 alkyl, wherein the alkyl is optionally substituted with 1-2 groups selected from the group consisting of halogen, -O(C 1-6 alkane Group), -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2 , five- to seven-membered heterocyclic group, wherein the heterocyclic group contains 1-2 Heteroatoms selected from N, O, S, and the heterocyclic group is optionally substituted with 1-2 groups selected from C 1-6 alkyl; or
  • R 5 and R 6 together with the N atom to which they are connected form a five- to seven-membered heterocyclic ring, which optionally contains 1 additional heteroatom selected from N, O, S, and is optionally substituted by 1 -2 substitutions selected from the following groups: halogen, C 1-6 alkyl, -O (C 1-6 alkyl) , -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2 .
  • R 3 is -LC(O)NR 5 R 6 , and L is methylene;
  • R 4 is -O(C 1-6 alkyl
  • R 5 and R 6 are each independently selected from hydrogen, C 1-4 alkyl, wherein the alkyl is optionally substituted with 1-2 groups selected from the group consisting of halogen, -O(C 1-2 alkane Group), -NH(C 1-2 alkyl), -N(C 1-2 alkyl) 2 , five- to seven-membered heterocyclic group, wherein the heterocyclic group contains 1-2 selected from N, O, S heteroatoms, and at least one of the heteroatoms is N, and the heterocyclic group is optionally substituted with 1-2 groups selected from C 1-4 alkyl groups; or
  • R 5 and R 6 together with the N atom to which they are connected form a five- to seven-membered heterocyclic ring, which optionally contains 1 additional heteroatom selected from N, O, S, and is optionally substituted by 1 -2 substitutions selected from the following groups: halogen, C 1-4 alkyl, -O (C 1-2 alkyl), -NH (C 1-2 alkyl), -N (C 1-2 alkane) Base) 2 .
  • R 3 is -LC(O)NR 5 R 6 , and L is methylene;
  • R 4 is -O(C 1-6 alkyl
  • R 5 and R 6 together with the N atom to which they are connected form a morpholine ring.
  • the intermediate compound of formula (V) is compound B1:
  • the crystal form I of compound Orin1001 is provided, wherein the X-ray powder diffraction pattern of the crystal form I is about 8.44 ⁇ 0.2°, 13.11 ⁇ 0.2°, 15.70 ⁇ 0.2°, 19.73 ⁇ 0.2°, There are characteristic peaks at the diffraction angles (2 ⁇ ) of 21.00 ⁇ 0.2° and 22.91 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form I is about 8.44 ⁇ 0.2°, 10.91 ⁇ 0.2°, 10.68 ⁇ 0.2°, 13.11 ⁇ 0.2°, 15.70 ⁇ 0.2°, 17.54 ⁇ 0.2°, 19.73 ⁇ 0.2
  • the X-ray powder diffraction pattern of Form I is about 8.44 ⁇ 0.2°, 10.91 ⁇ 0.2°, 10.68 ⁇ 0.2°, 13.11 ⁇ 0.2°, 15.70 ⁇ 0.2°, 16.90 ⁇ 0.2°, 17.54
  • the X-ray powder diffraction pattern of the crystal form I has a characteristic peak at the diffraction angle (2 ⁇ ) as shown in Table 1. In another embodiment, the X-ray powder diffraction pattern of Form I is substantially as shown in FIG. 1.
  • the crystal form I satisfies at least one of the following (1) to (3):
  • thermogravimetric analysis chart is basically shown in Figure 2;
  • the starting temperature of the crystalline form I is about 239°C ⁇ 5°C, and the peak temperature is about 242°C ⁇ 5°C.
  • the crystal form I is an anhydrate crystal form.
  • the X-ray powder diffraction pattern of crystal form I is measured by the following method: X-ray powder diffractometer: Bruker D8 advance X; radiation source: Cu-K ⁇ ; scanning range: 3°(2 ⁇ ) ⁇ 40 °(2 ⁇ ); scanning step: 0.02°(2 ⁇ ); scanning speed: 0.3sec/step.
  • thermogravimetric analysis pattern of crystal form I is determined by the following method: TGA thermogravimetric analyzer: TA TGA Q500; temperature range: room temperature to 350°C; scanning rate: 10°C/min; protective gas: nitrogen ; Flow rate: 40mL/min (balance) or 60mL/min (sample).
  • the differential scanning calorimetry profile of Form I is determined by the following method: DSC differential scanning calorimetry analyzer: TA DSC Q200; temperature range: 25°C ⁇ 300°C; scanning rate: 10°C /min; Shielding gas: nitrogen; flow rate: 50mL/min.
  • the dynamic moisture adsorption profile of crystal form I is determined by the following method: DVS dynamic moisture adsorber: IGASORP; temperature: 25°C; temperature stability: 0.1°C/min; carrier gas: nitrogen; flow rate: 250mL /min; scan: 2; minimum time: 30min; maximum time: 2 hours; waiting limit: 98%; humidity change gradient: adsorption: 0,10,20,30,40,50,60,70,80,90; Desorption: 80,70,60,50,40,30,20,10,0.
  • the particle size distribution (PSD) of the crystal form I is measured using Malvern Mastersizer 2000.
  • the parameters used can be: pump speed: 2500 rpm; dispersant volume: 800 mL; dispersant: water; dispersion medium: 1% Tween 80.
  • the mechanical treatment stability of the crystal form I is determined by the following method: place the crystal form I in a mortar, grind for 2 min and 5 min, respectively, perform XRPD detection, and analyze the ground solid.
  • the particle size distribution (PSD) of Form I is shown in Table 2.
  • the bulk density of crystal form I is 0.72 g/ml
  • the tap density is 0.90 g/ml
  • the Carr index is 20%
  • the angle of repose is 30.6°.
  • the crystal form I of the present invention has excellent stability. For example, after mechanical treatment, the diffraction pattern remains basically unchanged.
  • the present invention provides a pharmaceutical composition comprising the crystal form I of the present invention and one or more pharmaceutically acceptable carriers.
  • the present invention also provides the crystalline form I of the present invention or the pharmaceutical composition of the present invention when preparing to treat or prevent diseases, disorders or conditions related to unfolded protein response (UPR), or when preparing to treat or prevent
  • URR unfolded protein response
  • RIDD IRE1-dependent decay
  • Another aspect of the present invention also relates to the crystalline form I of the present invention or the pharmaceutical composition of the present invention, for the treatment or prevention of diseases, disorders or conditions associated with unfolded protein responses, or for the treatment or prevention and regulation of IRE1- A disease, disorder, or condition associated with a target of dependent decay.
  • Yet another aspect of the present invention also provides methods for treating or preventing diseases, disorders, or conditions associated with unfolded protein responses, or methods for treating or preventing diseases, disorders, or conditions associated with targets that modulate IRE1-dependent decay,
  • the method includes administering an effective amount of the crystalline form I of the present invention or the pharmaceutical composition of the present invention to an individual in need, or making a therapeutically effective amount of the crystalline form I of the present invention for the disease, disorder, or condition.
  • the pharmaceutical composition of the present invention appears in an individual's body.
  • the disease, disorder or condition associated with the unfolded protein response is selected from tumors, diseases related to metabolism, diseases related to immunity, viral infections and cardiovascular diseases.
  • the disease, disorder or condition associated with the unfolded protein response is selected from B cell autoimmune diseases, cancer, and viral infections.
  • the treatable B-cell autoimmune disease is selected from: Addision's disease, antiphospholipid syndrome, aplastic anemia, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune Hypophysitis, Autoimmune Lymphocytic Proliferative Disease, Autoimmune Myocarditis, Yau Shier Syndrome, Acquired Epidermolysis Bullosa, Giant Cell Arteritis, Goodpasture Syndrome, Grave S disease, Guerlain-Barr syndrome, Hashimoto's thyroiditis, idiopathic thrombocytopenic purpura, IgA nephropathy, myasthenia gravis, pemphigus foliaceous, pemphigus vulgaris, nodular Arteritis, polymyositis/dermatomyositis, rheumatoid arthritis,
  • the treatable cancer is a solid tumor.
  • the solid tumor is selected from breast tumors, bone tumors, prostate tumors, lung tumors, adrenal tumors (such as adrenocortical tumors), bile duct tumors, bladder tumors, bronchial tumors, nerve tissue tumors (including neurons and Gliomas), gallbladder tumors, stomach tumors, salivary gland tumors, esophageal tumors, small intestine tumors, cervical tumors, colon tumors, rectal tumors, liver tumors, ovarian tumors, pancreatic tumors, pituitary adenomas and secretory adenomas.
  • the treatable cancer is a drug-resistant or radiation-resistant solid tumor. In one embodiment, the treatable cancer is a hematological tumor. In a further embodiment, the hematological tumor is lymphoma or leukemia. In another embodiment, the hematological tumor is indeterminate monoclonal gammopathy (MGUS), a precursor of myeloma.
  • MGUS monoclonal gammopathy
  • the lymphoma is selected from multiple myeloma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma (e.g., cutaneous T-cell lymphoma, such as Sezari syndrome and mycosis fungoides, diffuse Large cell lymphoma, HTLV-1-related T cell lymphoma, nodal peripheral T cell lymphoma, extranodal peripheral T cell lymphoma, central nervous system lymphoma, and AIDS-related lymphoma tumor).
  • Hodgkin’s lymphoma e.g., Hodgkin’s lymphoma
  • non-Hodgkin’s lymphoma e.g., cutaneous T-cell lymphoma, such as Sezari syndrome and mycosis fungoides
  • diffuse Large cell lymphoma HTLV-1-related T cell lymphoma
  • nodal peripheral T cell lymphoma nodal peripheral T cell lymphoma
  • the leukemia is selected from acute and chronic lymphocytic and myeloid leukemia (e.g., acute lymphocytic or lymphoblastic leukemia, acute myeloid leukemia, acute myeloid leukemia, chronic myeloid leukemia Leukemia, chronic lymphocytic leukemia, T-cell prelymphocytic leukemia, adult T-cell leukemia and hairy cell leukemia).
  • a treatable viral infection is an enveloped viral infection that utilizes an unfolded protein response pathway when replicating and forming infectious offspring.
  • the treatable viral infection is selected from measles virus, pox virus, Ebola virus (Ebola).
  • the treatable viral infection is an infection selected from Epstein Barr virus (EBV), cytomegalovirus (CMV), viruses of the flavivirus genus (for example, Japanese encephalitis virus and West Nile virus) and C Those infections caused by hepatitis B virus (HCV).
  • EBV Epstein Barr virus
  • CMV cytomegalovirus
  • HCV hepatitis B virus
  • the disease, disorder, or condition related to the target that modulates IRE1-dependent decay is selected from neurological disorders, disorders involving insulin overproduction, and disorders involving inflammation.
  • the neurological disorder is schizophrenia.
  • the condition involving insulin overproduction is type II diabetes.
  • the condition involving inflammation is selected from the group consisting of glomerulonephritis, various forms of arthritis, multiple sclerosis and inflammatory bowel disease.
  • the method of the present invention Compared with the method in the prior art (such as CN103079558 A), the method of the present invention has the advantages of simplicity and efficiency, high atom utilization, and high yield.
  • the intermediate 5A2 was prepared according to the method of CN103079558 A, the route is as follows:
  • the route includes:
  • Step (1) Prepare ethyl acetoacetate compound (compound 2) whose ⁇ -position is substituted by ester alkyl group (compound 2) from ethyl acetoacetate (SM1) and ethyl bromoacetate (SM2), the yield is 80%; 2): Preparation of coumarin compounds (compound 3) whose 3-position is substituted by ester group alkyl, yield 60%; step (3): preparation of compound 4, yield 67%; step (4): pass acid Amine condensation reaction introduces an amide group to prepare compound 5A2.
  • step (4) was performed according to the method of CN103079558 A in Example 62, and the crude compound 5A2 was obtained, and the yield was 43%.
  • the total yield of the above steps (1) to (4) is about 13.8%, and the total yield of the above steps (2) to (4) is about 17.3%.
  • Steps (2) to (4) are three-step continuous linear reactions carried out in a linear synthesis mode.
  • Step (2) constructs coumarin with compound 1 through a ring-closure reaction.
  • step (3) and step (4) further introduce an amide group on the 3-position substituent to obtain compound 5A2.
  • the ester group needs to be introduced into compound 3 first, and then removed and converted into an amide group.
  • the steps are cumbersome, the atom economy is not good, and the yield is low.
  • the acetyl whose ⁇ -position is substituted by amidoalkyl is first prepared through two steps. Alkyl acetate (for example, see the method for preparing the compound of formula (V) or the preparation of intermediate compound B1, or for example the method shown in Example 1), and then directly construct the coumarin core through a ring closure step with compound 1 .
  • the total number of the above steps is 3.
  • the preparation method of the present invention realizes a convergence synthesis (convergent synthesis), reduces the steps of continuous reaction, and is beneficial to further improving production efficiency.
  • the inventors unexpectedly discovered that the present invention utilizes a ring-closure reaction between an acetoacetate alkyl ester compound substituted by an amidoalkyl group at the ⁇ -position and a substituted phenol compound to construct a coumarin core, which is to achieve convergent synthesis, reduce reaction steps, The key to improving the total reaction yield, atomic economy and production efficiency.
  • the amide group is introduced by the acyl halide compound of formula (II) (or compound D1) having a bifunctional group, and the ester group is introduced into CN103079558 A and then hydrolyzed, and then the acid amine condensation is carried out. Compared with, obviously have higher atomic utilization rate.
  • the preparation method of the present invention also realizes a higher total yield, which is beneficial to industrialized production.
  • the total yield of Example 1 to Example 2 is about 46.6%.
  • the method for preparing coumarin compounds whose 3-position is substituted by an amidoalkyl group of the present invention has the following advantages: optimizing the introduction time of the amide group, first preparing the 1,3-dicarbonyl compound containing the amide substitution, It is then used for ring closure to efficiently construct the coumarin core structure and side chains containing amide groups in a simple route, with high atom utilization and high yield, which is conducive to industrial production.
  • a convergent synthesis route is constructed, which shortens the steps of continuous reaction, which is beneficial to further improve production efficiency.
  • the crystal form I of Orin1001 of the present invention has high purity, high stability, good operability, simple preparation process, and can be applied to large-scale production.
  • X-ray powder diffractometer Bruker D8 advance X
  • the radiation source is Cu-K ⁇
  • the test scan range is 3°(2 ⁇ ) ⁇ 40°(2 ⁇ )
  • the scan step size is 0.02°(2 ⁇ )
  • the scan speed is 0.3 sec/step.
  • TGA thermogravimetric analyzer TA TGA Q500, the temperature range is from room temperature to 350°C, the scanning rate is 10°C/min, the protective gas is nitrogen, and the flow rate is 40mL/min (balance) or 60mL/min (sample).
  • DSC Differential Scanning Calorimetry Analyzer TA DSC Q200, the temperature range is 25°C ⁇ 300°C, the scanning rate is 10°C/min, the protective gas is nitrogen, and the flow rate is 50mL/min.
  • DVS dynamic moisture adsorber IGASORP, temperature is 25°C, temperature stability: 0.1°C/min, carrier gas is nitrogen, flow rate is 250mL/min, scan: 2, minimum time is 30min, maximum time is 2 hours, waiting for the upper limit 98%, humidity gradient: adsorption: 0,10,20,30,40,50,60,70,80,90; desorption: 80,70,60,50,40,30,20,10,0 .
  • HPLC Reaction monitoring: Waters Acquity Arc liquid chromatography system or equivalent equipment; Column: ZORBA ⁇ Eclipse ⁇ DB C18, 4.6 ⁇ 150mm, 3.5 ⁇ m, or the same type of chromatographic column; Mobile phase A: 0.05% trifluoroacetic acid Aqueous solution; mobile phase B: 0.05% trifluoroacetic acid acetonitrile solution; concentration gradient running time: 20 minutes.
  • HPLC Purity determination: Waters Acquity Arc liquid chromatography system or equivalent equipment; Chromatographic column: Eclipse ⁇ DB C18, 4.6 ⁇ 150mm, 3.5 ⁇ m, or the same type of chromatographic column; Column temperature: 30°C; Detection wavelength: 210nm; Mobile phase A: 0.05% trifluoroacetic acid aqueous solution; mobile phase B: 0.05% trifluoroacetic acid acetonitrile solution; concentration gradient running time: 20 minutes.
  • LC-MS use Shimadzu LCMS 2010 (chromatographic column: sepax ODS 50 ⁇ 2.0mm, 5 ⁇ m), or Agilent 1200 HPLC, 1956 MSD (chromatographic column: Shim-pack XR-ODS 30 ⁇ 3.0mm, 2.2 ⁇ m), or NB -PDM-LCMS-004 (Column: Agilent SB-C18 4.6x50mm 1.8 ⁇ m, or poroshell SB-C 18 2.7um 3.0*50mm, SN: USCFE02201), ionization method ES(+).
  • halogenated acetyl halide (compound D1) is reacted with amine (morpholine) to prepare ⁇ -halogenated amide (compound C1), and then it is reacted with ethyl acetoacetate to prepare ⁇ -position amide alkane Group-substituted ethyl acetoacetate compound (Intermediate B1).
  • the intermediate B1 undergoes a condensation reaction with a substituted phenol compound (compound 1), and the ring is closed to obtain the coumarin compound 5A2 whose 3-position is substituted by an amidoalkyl group, which introduces the aldehyde by reacting with hexamethylenetetramine (HMTA) Base to obtain the target compound Orin1001.
  • HMTA hexamethylenetetramine
  • Method A uses bromoacetyl bromide to prepare intermediate B1:
  • Intermediate C1-1 can be prepared by referring to the method disclosed in Example A9 Step 1 of International Patent Application WO1999032436, or prepared according to Method 1 or Method 2 below.
  • bromoacetyl bromide (D1-1, 250g, 1.00eq.) and dichloromethane (3.75L) were added to a 5L four-neck flask, and the temperature was reduced to 5°C with a brine bath.
  • Add morpholine (216g, 2.00eq.) dropwise and control the temperature to 0-10°C. After the addition is completed, control the reaction temperature to be ⁇ 10°C, and stir for 30 minutes. Remove the salt water bath and react at room temperature for 2 hours. TLC detection showed that the bromoacetyl bromide reaction was complete. The temperature of the system was reduced to ⁇ 10°C, and saturated aqueous NH 4 Cl (1.25L) was added dropwise.
  • THF (4.45kg, 5.0L) was added to intermediate C1-1 (4.93kg, 1.00eq.), stirred to obtain a clear THF solution of intermediate C1-1, and cooled to 0-5°C for use.
  • THF 17.8kg, 20.0L
  • NaH 60%, 0.845kg, 1.10eq.
  • ethyl acetoacetate 2.50kg, 1.00eq.
  • 0 ⁇ 5°C in advance into the kettle, stir at 0 ⁇ 5°C for at least 0.5 hours, and then add the above prepared intermediate at 0 ⁇ 5°C THF solution of C1-1.
  • reaction was continued to stir at 0-5°C for at least 2 hours. Sampling was sent to HPLC to monitor the reaction until the peak area of intermediate C1-1 was ⁇ 5.0%.
  • a saturated aqueous NH 4 Cl solution (35.0 L) was added at 0-5°C, and the mixture was allowed to stand to separate layers.
  • the aqueous phase was extracted with ethyl acetate (25.0L), the organic layers were combined, and concentrated under reduced pressure at about 45°C to 5.0 ⁇ 1.0V, then water (6.5L) was added, and the mixture was stirred for 15 minutes. The mixture was allowed to stand and separate into layers, and the organic layer was concentrated under reduced pressure at 45° C. until no obvious fraction was dripped out.
  • Method B uses chloroacetyl chloride to prepare intermediate B1:
  • Intermediate C1-2 can be prepared by referring to the method disclosed in US Pat. No. 5,753,660 A, Part A, or according to the following method.
  • the mixture was centrifuged, and the solid obtained by centrifugation was rinsed with water (8.0 L) and acetonitrile (5.5 L x 2) respectively to obtain a wet solid.
  • the reactor was replaced with nitrogen 3 times.
  • the XRPD pattern of crystal form I is basically shown in Figure 1.
  • the 2 ⁇ data table is shown in Table 1.
  • thermogravimetric analysis when heated to 200°C, there is a weight loss gradient of about 0.017%, and the thermogravimetric analysis chart is basically shown in Figure 2. It can be seen from Figure 2 that Orin1001 crystal form I is anhydrous.
  • the crystal form I gained 0.34% in weight after equilibrium at 90% relative humidity, which only slightly induced moisture, and the crystal form did not change after the DVS measurement.
  • the DVS detection result is basically shown in Figure 4, and the XRPD comparison chart before and after the DVS detection is basically shown in Figure 5. It can be seen from Figures 4 and 5 that the Orin1001 crystal form I is slightly hygroscopic.
  • Trifluoroacetic acid (230.40kg, 150.0L, 20.0V) was added to the reaction kettle, and the temperature was lowered to 0-10°C. Control the temperature below 10°C, add hexamethylenetetramine (HMTA, 23.44kg, 7.50eq.) and intermediate 5A2 (7.44kg, 1.00eq.). Adjust the temperature to 80 ⁇ 5°C and stir for at least 40 hours. Sampling was sent to HPLC to monitor the reaction until the peak area of intermediate 5A2 was ⁇ 5.0%. The reaction solution was concentrated under reduced pressure to about 120L at a temperature below 70°C. The temperature was lowered to 0-10°C, and purified water (200.0L) and Orin1001 seed crystals (1.00wt%) were added.
  • the crystal form I was tested for particle size distribution (PSD) and mechanical treatment stability. The results are as follows.
  • Form I is a granular crystal, and its particle size is 50-100 ⁇ m when observed under a microscope (Nikon Eclipse LV100POL).
  • PSD particle size distribution
  • the bulk density of crystal form I is 0.72g/ml, the tap density is 0.90g/ml, the Carr index is 20%, the angle of repose is 30.6°, and the fluidity is very good.
  • the powder with good fluidity is not easy to fly, the adsorption is small, the viscosity is also small, and it has the convenience of industrial application.

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Abstract

涉及一种制备3-位被酰胺基烷基取代的香豆素类化合物的方法及其相关中间体。所述方法包括：步骤(A)：使式(VI)的化合物与式(V)的化合物反应，以制备式(VII)化合物。其中R 1和R 2各自独立地选自氢、卤素和-O(C 1-8烷基)，其中所述烷基任选地被1或2个选自以下的基团取代：卤素、被1-2个羟基取代的C 1-8烷基、-O(C 1-8烷基)； R 3为-L-C(O)NR 5R 6，L为C 1-3亚烷基。

Description

一种制备3-位被酰胺基烷基取代的香豆素类化合物的方法及其产物和相关中间体
本申请要求2019年12月31日提交的题为“一种制备3-位被酰胺基烷基取代的香豆素类化合物的方法及其产物和相关中间体”的第201911422365.2号中国申请的优先权，该中国申请的全文整体援引加入本文。
技术领域
本发明涉及药物化学领域，并且具体地涉及一种制备3-位被酰胺基烷基取代的香豆素类化合物的方法及其产物和相关中间体。
背景技术
癌症或肿瘤是发达国家的第二大死亡原因，尽管先进的早期检测技术、新的治疗手段和改善的治疗结果不断出现，仍然需要新的药物和治疗方法来改善患者的生活质量。需肌醇酶1α(IRE-1α)是一种核酸内切酶，主要位于与细胞核相连的内质网内，通过发挥核酸内切酶的催化功能来调控基因的表达，进而影响内质网中未折叠蛋白的加工和修饰。当细胞受到缺氧、饥饿、炎症、病毒感染、致癌等负面因素刺激而处于内环境失衡状态时，会发生内质网应激反应，引起蛋白质的合成与折叠障碍并可最终导致细胞凋亡。此时一种称为“未折叠蛋白质应答”(UPR)的细胞自我保护机制将被启动并用于对抗内质网应激：作为该机制信号通路重要组成部分的IRE-1α将被激活并通过切除目标mRNA上的一段特定碱基序列来调控相关基因的表达，进而增强蛋白质的折叠和修饰，缓解内质网应激压力，修复细胞内环境失衡状态，促使细胞存活。因此，IRE-1α的功能与肿瘤、代谢、免疫、病毒感染、心血管等多个领域的疾病均有密切关联。特别地，对于癌症而言，恶性肿瘤细胞的大量快速增殖造成肿瘤细胞普遍处于缺氧、营养供应不足、代谢紊乱、致癌压力等多种因素交互作用的失控状态，这样的肿瘤微环境持续影响内质网折叠；此外，化疗、生物治疗和辐射治疗亦可导致内质网应激反应并通过UPR对抗凋亡，因此肿瘤细胞中的IRE-1α在长期的应激下被持续广泛激活，使其成为可被药物(例如IRE-1α抑制剂)作用的理想肿瘤靶点。
CN103079558 A公开了一类以香豆素(coumarin)结构为母核、可抑制IRE-1α的小分子化合物，其中提供了具有如下具体结构的化合物。这是一种强效、低毒、高选择性的IRE-1α抑制剂
Figure PCTCN2020141203-appb-000001
CN107973784 A公开了一种α-位被酰胺基烷基取代的乙酰乙酸乙酯化合物(2-(N,N- 二甲基氨基羰基甲基)乙酰乙酸乙酯)的如下合成路线：
Figure PCTCN2020141203-appb-000002
该化合物中乙酰乙酸乙酯结构中的1,3-二羰基在碱性条件下与亚氨酰胺衍生物发生缩合反应，用于合成嘧啶化合物
Figure PCTCN2020141203-appb-000003
发明内容
本发明的第一方面提供一种制备式(VII)的化合物的方法，包括
步骤(A)：使式(VI)的化合物与式(V)的化合物反应，以制备式(VII)化合物
Figure PCTCN2020141203-appb-000004
其中R 1和R 2各自独立地选自氢、卤素和-O(C 1-8烷基)，其中所述烷基任选地被1或2个选自以下的基团取代：卤素、被1-2个羟基取代的C 1-8烷基、-O(C 1-8烷基)；
R 3为-L-C(O)NR 5R 6，L为C 1-3亚烷基；
R 4为-O(C 1-6烷基)；
R 5和R 6各自独立地选自氢、-O(C 1-8烷基)、C 3-10环烃基，其中所述烷基、环烃基任选地被1或2个选自以下的基团取代：卤素、-O(C 1-8烷基)、-NH 2、-NH(C 1-8烷基)、-N(C 1-8烷基) 2、五元至七元杂环基，其中所述杂环基含有1-2个选自N、O、S的杂原子，并且所述杂环基任选地被1-2个选自C 1-8烷基的基团取代；或者
R 5和R 6连同与其相连的N原子一起形成五元至七元杂环基，所述杂环基任选地含有1个选自N、O、S的额外的杂原子，并且任选地被1或2个选自以下的基团取代：卤素、C 1-8烷基、-O(C 1-8烷基)、-NH 2、-NH(C 1-8烷基)、-N(C 1-8烷基) 2。
本发明的第二方面提供一种制备式(I)化合物的方法，包括本发明第一方面所述的步骤(A)和以下步骤(B)：
步骤(B)：由式(VII)化合物制备式(I)化合物
Figure PCTCN2020141203-appb-000005
其中，R 1、R 2和R 3如本发明的第一方面所定义。
本发明的第三方面提供一种中间体化合物，其结构如下式(V)所示：
Figure PCTCN2020141203-appb-000006
其中R 3和R 4如本发明的第一方面所定义。
在本发明的第四方面，提供化合物Orin1001的晶型I，其中所述晶型I的X射线粉末衍射图谱在约8.44±0.2°、13.11±0.2°、15.70±0.2°、19.73±0.2°、21.00±0.2°、22.91±0.2°的衍射角(2θ)处有特征峰，
Figure PCTCN2020141203-appb-000007
在又一方面，本发明提供一种药物组合物，其包含本发明的晶型I以及一种或多种药学上可接受的载体。
在又一方面，本发明还提供本发明的晶型I或者本发明的药物组合物在制备治疗或预防与未折叠蛋白质应答(UPR)相关的疾病、病症或病况，或者在制备治疗或预防与调节IRE1-依赖性衰解(RIDD)的靶标相关的疾病、病症或病况的药物中的应用。
附图说明
图1示出晶型I的X射线粉末衍射(XRPD)图谱。
图2示出晶型I的热重分析(TGA)图谱。
图3示出晶型I的差示扫描量热分析(DSC)图谱。
图4示出晶型I的动态水分吸附(DVS)图谱。
图5示出晶型I的DVS检测前后的XRPD对比图。
图6示出晶型I稳定性测试结果(XRPD)-第7天，其中曲线的标注末尾的“-1”和“-2”分别表示“样品-1”和“样品-2”。
图7示出晶型I稳定性测试结果(XRPD)-第14天，其中曲线的标注末尾的“-1”和“-2” 分别表示“样品-1”和“样品-2”。
图8示出晶型I的粒度分布测试图。
图9示出晶型I机械处理后测试结果(XRPD)。
具体实施方式
一般术语和定义
除非另有定义，本文所用所有技术和科学术语与本发明所属领域的普通技术人员通常理解的含义相同。若存在矛盾，则以本申请提供的定义为准。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。本文引用的所有专利、已经公开的专利申请和出版物均通过引用并入到本文中。
术语“约”、“大约”当与数值变量并用时，通常指该变量的数值和该变量的所有数值在实验误差内(例如对于平均值95％的置信区间内)或在指定数值的±10％内，或更宽范围内。
术语“任选”或“任选存在”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。
术语“取代”和“取代的”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。当描述某取代基不存在时，应当理解该取代基的位置可以为一个或多个氢原子，前提是形成的结构能使化合物达到稳定的状态。
如果取代基被描述为“任选地…被取代”，则取代基可以是未被取代的，或者可以是被取代的。如果某个原子或基团被描述为任选地被取代基列表中的一个或多个取代，则该原子或基团上的一个或多个氢可被独立地选择的、任选的取代基替代。当取代基为氧代(即＝O)时，意味着两个氢原子被取代。
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。
表述“包含”或与其同义的类似表述“包括”、“含有”和“具有”等是开放性的，不排除额外的未列举的元素、步骤或成分。表述“由…组成”排除未指明的任何元素、步骤或成分。表述“基本上由…组成”指范围限制在指定的元素、步骤或成分，加上任选存在的不会实质上影响所要求保护的主题的基本和新的特征的元素、步骤或成分。应当理解，表述“包含”涵盖表述“基本上由…组成”和“由…组成”。
术语“一种(个)或多种(个)”或者“至少一种(个)”可以表示一、二、三、四、五、六、七、八、九种(个)或更多种(个)。
当公开了数值范围的下限和上限时，落入该范围中的任何数值和任何包括的范围都被具体公开。特别地，本文公开的值的每个取值范围应理解为表示涵盖于较宽范围中的每个数值和范围。
本文所用的表述m-n指m至n的范围以及由其中的各个点值组成的亚范围以及各个点值。例如，表述“C 1-8”涵盖1-8个碳原子的范围，并应理解为还涵盖其中的任意亚 范围以及每个点值，例如C 2-5、C 3-4、C 1-2、C 1-3、C 1-4、C 1-5、C 1-6、C 1-7等，以及C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8等。例如，表述“C 3-10”也应当以类似的方式理解，例如可以涵盖包含于其中的任意亚范围和点值，例如C 3-9、C 6-9、C 6-8、C 6-7、C 7-10、C 7-9、C 7-8、C 8-9等以及C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10等。又例如，表述“三元至十元”应理解为涵盖其中的任意亚范围以及每个点值，例如3-5元、3-6元、3-7元、3-8元、4-5元、4-6元、4-7元、4-8元、5-7元、5-8元、6-7元、7-8元、9-10元等，以及3、4、5、6、7、8、9、10元等。本文中其他类似的表述也应当以类似的方式理解。
除非文中另有说明，单数形式指代如“一”、“一个”、“该”，包含复数指代。
术语“卤”或“卤素”或“卤代”应理解为表示氟(F)、氯(Cl)、溴(Br)或碘(I)原子，优选氟、氯或溴原子。
术语“烷基”，如本文中单独或与其他基团组合使用时，指饱和的直链、支链或环状烃基。如本文中所使用，术语“C 1-8烷基”指具有1-8个(例如1、2、3、4、5、6、7或8个)碳原子的饱和直链、支链或环状烃基。例如“C 1-6烷基”可以是甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、3-甲基戊烷-3-基、己基(例如正己基、环己基，等)。“C 1-8烷基”涵盖其中的亚范围，例如“C 1-3烷基”、“C 2-3烷基”、“C 4-6烷基”等。
术语“亚烷基”，在本文中单独或与其他基团组合使用时，指饱和的直链或支链的二价烃基。例如，术语“C 1-8亚烷基”指具有1-8个碳原子的亚烷基，例如亚甲基、亚乙基、亚丙基、亚丁基、1-甲基亚乙基、2-甲基亚乙基或甲基亚丙基等。
术语“烷氧基”，是指与氧原子以单键相连的如上定义的烷基。烷氧基与分子的其他部分通过氧原子相连。烷氧基可以表示为-O(烷基)。“C 1-8烷氧基”或“-O(C 1-8烷基)”是指含有1-8个碳原子的烷氧基，其中的烷基部分可为直链、支链或环状结构。烷氧基包括但不仅限于，甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、正戊氧基、环戊基氧基、环己基氧基等。
术语“环烃基”是指由碳原子和氢原子组成的饱和或不饱和的非芳香性的环状烃基，优选包含1或2个环。所述环烃基可以是单环、稠合多环、桥环或螺环结构。环烃基可以具有3-10个碳原子，即“C 3-10环烃基”，例如C 3-8环烃基、C 5环烃基、C 6环烃基、C 7环烃基。环烃基的非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、双环[2.2.1]庚基和螺[3.3]庚基等。
术语“杂环基”或“杂环烃基”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-7个，5-7个，特别是4-6个)环原子的单环或双环的非芳香环体系(三元至十元、三元至八元、三元至六元)，其中至少一个环原子(例如1、2或3个)是选自N、O和S的杂原子，且其余环原子是C。该环体系可以是饱和(也可以理解为相应的“杂环烷基”)或不饱和的(即在环内具有一个或多个双键和/或三键)。该术语还涵盖这样的情况，其中的C原子可以被氧代(＝O)取代和/或环上的S原子可以被1个或2个氧代(＝O)取代。杂环基可以是例如4-元环，如氮杂环丁烷基、氧杂环丁烷基；或者5-元环，如四氢呋喃基、二噁烷基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基、氧代吡咯烷基、2-氧代咪唑烷 -1-基；或者6-元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基、1,1-二氧代-1,2-噻嗪烷-2-基或三噻烷基；或者7-元环，如二氮杂基环。任选地，杂环基可以是苯并稠和的。杂环基可以是双环的，不受其限制，例如5,5-元环，如六氢环戊烷[c]吡咯-2(1H)-基)环；或者5,6-元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。如上文所提到的，包含氮原子的环可以是部分不饱和的，即其可以包含一个或多个双键，不受其限制，例如2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基环，或者其可以是苯并稠合的，不受其限制，例如二氢异喹啉基环。
术语“烃类”溶剂指具有1-10个碳原子的直链、支链或环状烃的溶剂。所述烃可以是饱和或不饱和的。烃类溶剂的实例例如有烷烃类溶剂，包括但不限于正戊烷、正己烷、环己烷、正庚烷、辛烷或其组合，优选己烷或庚烷。烃类溶剂的实例还例如有芳烃类溶剂，其含有至少一个芳香环，并任选地被直链、支链或环状烃基取代。芳烃类溶剂包括但不限于苯、甲苯、二甲苯或其组合，优选甲苯、二甲苯或其组合。
术语“卤代烷烃类”溶剂，是指上文所述的烷烃类溶剂，其中一个或多个(例如1-6个、1-5个、1-4个、1-3个，或者1-2个)氢原子被卤素代替。本领域技术人员应当理解，当卤素取代基多于一个时，卤素可以相同也可以不同，并且可以位于相同或不同的C原子上。卤代烷烃类溶剂包括但不限于二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷、六氯乙烷和1,2,3-三氯丙烷或其组合，优选二氯甲烷、三氯甲烷、1,2-二氯乙烷或其组合，特别是二氯甲烷。
术语“酯类”溶剂是指具有3-10个碳原子的酯的溶剂。酯类溶剂包括但不限于乙酸乙酯、乙酸丙酯、乙酸异丙酯、乙酸丁酯、乙酸戊酯或其组合，优选乙酸乙酯、乙酸异丙酯、乙酸丁酯或其组合。
术语“醚类”溶剂是指具有2-10个碳原子的醚的溶剂。醚类溶剂的实例包括但不限于乙醚、异丙醚、四氢呋喃、甲基四氢呋喃、二氧六环、乙二醇二甲醚、甲基叔丁基醚或其组合，优选四氢呋喃、甲基四氢呋喃、二氧六环、乙二醇二甲醚、甲基叔丁基醚或其组合。
术语“腈类”溶剂是指具有2-10个碳原子的腈的溶剂。腈类溶剂的实例包括但不限于乙腈、丙腈、丁腈、苯腈、苯乙腈或其组合，优选乙腈、苯腈、苯乙腈或其组合，特别是乙腈。
术语“二取代酰胺类溶剂”溶剂是指这样的酰胺类溶剂：C 1-3烷基酰基与胺化合物连接形成的酰胺，其中酰胺N原子被二个各自独立地选自C 1-3烷基的烷基取代，或者酰胺N原子上的二个取代基连同与其相连的酰胺N原子一起形成含有一个N原子的五至七元杂环。二取代酰胺类溶剂实例包括但不限于N,N-二甲基甲酰胺、N,N-二乙基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基乙酰胺、N-甲基吡咯烷酮或其组合。
如本文中所使用的，术语“室温”指约20-30℃，优选约25℃。
除非另有说明，本文的百分比、份数等都按重量计。除非另有声明，浓度以重量计，混合溶液中的液体比例以体积计算，反应试剂与化合物的比例(包括百分比)、反应收率以摩尔量计。
术语“晶型”或“晶体”是指呈现三维排序的任意固体物质，与无定形固体物质相反，其产生具有边界清楚的峰的特征性X-射线粉末衍射图谱。
术语“X-射线粉末衍射(XRPD)图谱”是指实验观察的衍射图或源于其的参数、数据或值。XRPD图谱通常由峰位(横坐标)和/或峰强度(纵坐标)表征。XRPD图谱可例如在型号为Bruker D8advance X的仪器上测量。
如本文中所使用，术语“2θ”是指基于X射线衍射实验中设置的以度数(°)表示的峰位，并且通常是在衍射图谱中的横坐标单位。如果入射束与某晶格面形成θ角时反射被衍射，则实验设置需要以2θ角记录反射束。应当理解，在本文中提到的特定晶型的特定2θ值意图表示使用本文所述的X射线衍射实验条件所测量的2θ值(以度数表示)。
如本文中所使用的，对于X-射线衍射峰的术语“基本上”意指将代表性峰位和强度变化考虑在内。在分别测量同一多晶型所得到的结果之间可能由于多种原因导致XRPD图样存在差异。误差的来源包括样本制备的差异(例如样本高度)、仪器误差、标度误差和操作误差(包括在确定峰位置时的误差)。优先取向，也就是在XRPD样本的结晶中缺乏随机取向，可能导致相对峰高存在显著性差异。标度误差和样本高度误差通常导致衍射图中的所有峰沿着相同方向位移相同的数量。通常，可以使用同一方法弥补衍射仪之间存在的差异，从而使得由两种不同仪器获得的XRPD峰位具有一致性。当这些方法被应用于来自相同或不同衍射仪的XRPD测量结果时，某特定多晶型的峰位通常相差大约±0.2°(2θ)。此外，本领域技术人员会理解，相对峰强度也会因仪器间的差异以及结晶性程度、优先取向、制备的样品表面以及本领域技术人员已知的其它因素而出现变化，并应将其看作仅为定性测量。
差示扫描量热分析(DSC)测定当晶体由于其晶体结构发生变化或晶体熔化而吸收或释放热时的转变温度。对于同种化合物的同种晶型，在连续的分析中，热转变温度和熔点误差典型的在约5℃之内。当描述某个化合物具有某一给定的DSC峰或熔点时，指的是该DSC峰或熔点±5℃。“基本上”也将这种温度的变化考虑在内。DSC提供了一种辨别不同晶型的辅助方法。不同的晶体形态可根据其不同的转变温度特征而加以识别。需要指出的是对于混合物而言，其DSC峰或熔点可能会在更大的范围内变动。此外，由于在物质熔化的过程中伴有分解，因此熔化温度与升温速率相关。DSC图谱可例如在型号为TA DSC Q200的仪器上测量。
热重分析(TGA)是测定化合物的热稳定性的常见方法。在本文中，TGA还用来测定化合物的水合状态。测试过程中升温速率会对图谱产生一定的影响。例如过高的升温速率不利于中间产物的测出。TGA图谱可例如在型号为TA TGA Q500的仪器上测量。
动态水分吸附(DVS)是通过动态加速的水分吸附过程来考察药物、辅料或包装材料对水分吸附情况的常见方法。通常使用水分等温吸附线描述样品水分吸附过程中样品水分含量与相对湿度的关联程度。DVS图谱可例如在型号为IGAsorp的仪器上测量。
本文所用的“粒度分布(PSD)”表示粒径分布范围，其可以用累计粒度分布比例(例如表示为分数、小数或百分数)达到特定值时所对应的粒径来表示，例如D(0.5)或D50表示中值粒径。粒度分布可以通过激光光衍射法测得，例如可以通过美国Malvern公司 的Mastersizer激光粒度分析仪测得。
术语“原子经济性”是指在化学合成过程中，合成方法和工艺被设计成能把反应过程中所用原料的原子尽可能多地转化到产物分子中。原子经济性高的反应或合成路线可以提高效率，减少副产物或废物的产生。
术语“药学上可接受”是指与制剂中的其它组分相容，并且对施用对象服用者无不可接受的毒害。
“药学上可接受的载体”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些载体物质。“药学上可接受的载体”包括但不限于助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、崩解剂、稳定剂、溶剂或乳化剂。
术语“给药”或“给予”等指可以使化合物或组合物能够递送至期望的生物作用位点的方法。这些方法包括但不限于肠胃外(包括静脉内、皮下、腹膜内、肌内、血管内注射或输注)、局部、直肠给药等。
如本文中所使用的术语“有效量”(例如“治疗有效量”或“预防有效量”)指给药后会在一定程度上实现预期效果的活性成分的量，例如缓解所治疗病症的一种或多种症状或预防病症或其症状的出现。
如本文所使用的“个体”包括人或非人动物，特别是人。
下述发明详述旨在举例说明非限制性实施方案，使本领域其它技术人员更充分地理解本发明的技术方案、其原理及其实际应用，以便本领域其它技术人员可以以许多形式修改和实施本发明，使其可最佳地适应特定用途的要求。
本发明的制备方法
本发明的第一方面提供一种制备式(VII)的化合物的方法，包括
步骤(A)：使式(VI)的化合物与式(V)的化合物反应，以制备式(VII)化合物
Figure PCTCN2020141203-appb-000008
其中R 1和R 2各自独立地选自氢、卤素和-O(C 1-8烷基)，其中所述烷基任选地被1或2个选自以下的基团取代：卤素、被1-2个羟基取代的C 1-8烷基、-O(C 1-8烷基)；
R 3为-L-C(O)NR 5R 6，L为C 1-3亚烷基；
R 4为-O(C 1-6烷基)；
R 5和R 6各自独立地选自氢、-O(C 1-8烷基)、C 3-10环烃基，其中所述烷基、环烃基任选地被1或2个选自以下的基团取代：卤素、-O(C 1-8烷基)、-NH 2、-NH(C 1-8烷基)、-N(C 1-8烷基) 2、五元至七元杂环基，其中所述杂环基含有1-2个选自N、O、S的杂原子，并且所述杂环基任选地被1-2个选自C 1-8烷基的基团取代；或者
R 5和R 6连同与其相连的N原子一起形成五元至七元杂环基，所述杂环基任选地含有1个选自N、O、S的额外的杂原子，并且任选地被1或2个选自以下的基团取代：卤素、C 1-8烷基、-O(C 1-8烷基)、-NH 2、-NH(C 1-8烷基)、-N(C 1-8烷基) 2。
在一实施方案中，R 1和R 2各自独立地选自氢、卤素和-O(C 1-4烷基)，其中所述烷基任选地被1或2个选自以下的基团取代：卤素、-O(C 1-4烷基)。在一优选的实施方案中，R 1和R 2各自独立地选自氢、卤素和-O(C 1-2烷基)，其中烷基任选地被卤素或甲氧基取代。在一更优选的实施方案中，R 1和R 2各自独立地为氢、甲氧基或
Figure PCTCN2020141203-appb-000009
在一实施方案中，R 4为-O(C 1-4烷基)，优选-O(C 1-3烷基)。在一更优选的实施方案中，R 4为-O(C 1-2烷基)。在一特别的实施方案中，R 4为乙氧基。
在一实施方案中，L为亚甲基或亚乙基。在一优选的实施方案中，L为亚甲基。
在一实施方案中，R 5和R 6各自独立地选自氢、C 1-6烷基，其中所述烷基任选地被1-2个选自以下的基团取代：卤素、-O(C 1-6烷基)、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、五元至七元杂环基，其中所述杂环基含有1-2个选自N、O、S的杂原子，并且所述杂环基任选地被1-2个选自C 1-6烷基的基团取代；或者
R 5和R 6连同与其相连的N原子一起形成五元至七元杂环基，所述杂环基任选地含有1个选自N、O、S的额外的杂原子，并且任选地被1-2个选自以下的基团取代：卤素、C 1-6烷基、-O(C 1-6烷基)、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2。
在一优选的实施方案中，R 5和R 6各自独立地选自氢、C 1-4烷基，其中所述烷基任选地被1-2个选自以下的基团取代：卤素、-O(C 1-2烷基)、-NH(C 1-2烷基)、-N(C 1-2烷基) 2、五元至七元杂环基，其中所述杂环基含有1-2个选自N、O、S的杂原子，并且所述杂原子中的至少一个为N，并且所述杂环基任选地被1-2个选自C 1-4烷基的基团取代；或者
R 5和R 6连同与其相连的N原子一起形成五元至七元杂环基，所述杂环基任选地含有1个选自N、O、S的额外的杂原子，并且任选地被1-2个选自以下的基团取代：卤素、C 1-4烷基、-O(C 1-2烷基)、-NH(C 1-2烷基)、-N(C 1-2烷基) 2。
在一更优选的实施方案中，R 5和R 6各自独立地选自氢、C 1-2烷基，其中所述烷基任选地被1-2个选自以下的基团取代：甲氧基、二甲氨基、吗啉基、哌啶基或哌嗪基，所述吗啉基、哌啶基或哌嗪基任选地被甲基取代；或者
R 5和R 6连同与其相连的N原子一起形成吗啉基、哌啶基或哌嗪基，所述吗啉基、哌啶基或哌嗪基任选地被甲基取代。
在一进一步优选的实施方案中，R 5和R 6各自独立地选自氢、C 1-2烷基，其中所述烷基被吗啉基取代；或者
R 5和R 6连同与其相连的N原子一起形成吗啉基。
在一实施方案中，所述式(VII)的化合物具有如下化合物5A2的结构，步骤(A)如下：使化合物1与化合物B1反应，以制备化合物5A2
Figure PCTCN2020141203-appb-000010
在一实施方案中，步骤(A)在酸性条件下进行。在另一实施方案中，反应温度为-20℃至70℃。在一优选的实施方案中，反应温度为-5℃至60℃。在一更优选的实施方案中，反应温度为20℃至50℃。
本发明的第二方面提供一种制备式(I)化合物的方法，包括本发明第一方面所述的步骤(A)和以下步骤(B)：
步骤(B)：由式(VII)化合物制备式(I)化合物
Figure PCTCN2020141203-appb-000011
其中，R 1、R 2和R 3如本发明的第一方面所定义。
在一实施方案中，甲酰化试剂选自六亚甲基四胺、多聚甲醛。在一优选的实施方案中，步骤(B)在酸存在下进行。在另一优选的实施方案中，反应温度为50℃至120℃，优选60℃至100℃，更优选80℃至90℃。
在一实施方案中，步骤(A)反应完成后，按如下方法纯化步骤(A)的反应产物式(I)化合物：
步骤i：将式(I)化合物粗品与卤代烷烃类溶剂和水混合，得到混合物。
步骤ii：分出步骤i得到混合物的有机相，浓缩得到固体，将固体用合适的溶剂洗涤，得到结晶态的式(I)化合物。
在另一实施方案中，步骤i与步骤ii之间还包括洗涤混合物的步骤。在另一实施方案中，使用碱性的水溶液来洗涤混合物。
在又一实施方案中，步骤i与步骤ii之间还包括调节混合物pH值的步骤，其中调节混合物pH值至接近中性。在另一实施方案中，调节pH值至约6至8，优选约7。
在另一实施方案中，步骤ii分出有机相后、浓缩之前，还包括过滤或离心的步骤，过滤或离心得到的溶液浓缩得到固体。优选地，所述过滤或离心的步骤为过滤。在又一实施方案中，步骤ii分出有机相后，还包括干燥步骤，以基本除去或部分地除去有机相中的水分。
在另一实施方案中，步骤ii所述合适的溶剂为有机溶剂。在一实施方案中，有机溶剂选自腈类溶剂、酯类溶剂及其组合，优选为腈类溶剂或酯类溶剂。在一实施方案中，腈类溶剂选自乙腈、苯腈、苯乙腈或其组合，优选为乙腈。在另一实施方案中，酯类溶 剂选自乙酸乙酯、乙酸异丙酯、乙酸丁酯或其组合，优选为乙酸乙酯。
在另一实施方案中，步骤i所述式(I)化合物粗品是指在步骤(A)反应完成后，减压浓缩反应混合物以除去其中的溶剂，从而得到的残余物。在又一实施方案中，步骤i所述式(I)化合物粗品是指在步骤(A)反应完成后，减压浓缩反应混合物得到的残余物经过溶剂溶解、短硅胶层(short pad of silica gel)过滤之后，浓缩滤液得到的残余物。
在一实施方案中，步骤(B)中间体式(VII)化合物与甲酰化试剂反应得到式(I)化合物后，按照包括下述步骤的方法纯化：
步骤i：浓缩反应液，加入水和式(I)化合物晶种诱导析晶；
步骤ii：分离步骤i得到的粗产品，与合适的溶剂在加热条件下搅拌，然后降温，分离得到结晶态的式(I)化合物。
在一实施方案中，步骤ii分离粗产品之后、与合适的溶剂在加热条件下搅拌之前，还包括用合适的溶剂淋洗粗产品的步骤。
在又一实施方案中，步骤ii分离得到结晶态的式(I)化合物之后，还包括用合适的溶剂淋洗、干燥的步骤。
在另一实施方案中，步骤ii所述合适的溶剂选自腈类溶剂或腈类溶剂与水的混合溶剂。在另一实施方案中，腈类溶剂选自乙腈、苯腈、苯乙腈或其组合，优选乙腈。
在另一实施方案中，步骤ii所述加热温度优选40-80℃，更优选50-70℃。
在另一实施方案中，步骤ii的加热时间至少2h，优选至少4h，更优选至少8小时。
在一实施方案中，所述式(I)的化合物具有如下化合物Orin1001的结构，步骤(A)如下：使化合物5A2与甲酰化试剂反应，以制备化合物Orin1001
Figure PCTCN2020141203-appb-000012
在一实施方案中，本发明的方法在步骤(A)之前还包括以下步骤(a)和步骤(b)。
步骤(a)：使式(II)化合物与胺化合物HNR 5R 6发生缩合反应，以制备式(III)化合物
Figure PCTCN2020141203-appb-000013
其中X为卤素；L、R 3、R 5和R 6如上文所定义。在一实施方案中，反应在有机溶剂中进行。在一优选的实施方案中，有机溶剂为中性非质子性溶剂。在一进一步优选的实施方案中，有机溶剂选自烃类溶剂、卤代烃类溶剂、醚类溶剂、二取代酰胺类溶剂、酯类溶剂及其组合。在一实施方案中，烃类溶剂选自甲苯、二甲苯及其组合。在一实施方案中，卤代烃类溶剂为二氯甲烷。在另一实施方案中，醚类溶剂选自四氢呋喃、甲基 四氢呋喃、二氧六环、乙二醇二甲醚，甲基叔丁基醚及其组合。在又一实施方案中，所述二取代酰胺类溶剂选自N,N-二甲基甲酰胺、N,N-二乙基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基乙酰胺、N-甲基吡咯烷酮及其组合。在另一实施方案中，所述酯类溶剂选自乙酸乙酯、乙酸异丙酯、乙酸丁酯及其组合。在一实施方案中，反应温度为-10℃至60℃，优选0℃至室温，更优选0℃至10℃。
步骤(b)：使式(III)化合物与式(IV)化合物反应以制备式(V)化合物
Figure PCTCN2020141203-appb-000014
其中X为卤素；R 3和R 4如上文所定义。在又一实施方案中，反应在碱的存在下进行，所述碱为有机碱或无机碱。在一实施方案中，有机碱选自NaNH 2、醇钠、K-HMDS、Li-HMDS。在另一实施方案中，无机碱选自碳酸盐和金属氢化物。在一实施方案中，碳酸盐选自碳酸钠、碳酸钾、碳酸锂；优选碳酸钠或碳酸钾。在一特别的实施方案中，碳酸盐为碳酸钾。在另一实施方案中，金属氢化物选自NaH、KH、LiH、CaH 2。在一特别的实施方案中，金属氢化物为NaH。在一实施方案中，反应在有机溶剂中进行。在一优选的实施方案中，所述有机溶剂为中性非质子性溶剂。在一进一步优选的实施方案中，有机溶剂选自烃类溶剂、卤代烃类溶剂、醚类溶剂、二取代酰胺类溶剂及其组合。在一实施方案中，所述烃类溶剂选自甲苯、二甲苯及其组合。在一实施方案中，卤代烃类溶剂为二氯甲烷。在另一实施方案中，所述醚类溶剂选自四氢呋喃、甲基四氢呋喃、二氧六环、乙二醇二甲醚，甲基叔丁基醚及其组合。在又一实施方案中，所述二取代酰胺类溶剂选自N,N-二甲基甲酰胺、N,N-二乙基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基乙酰胺、N-甲基吡咯烷酮及其组合。在一实施方案中，反应温度为-20至100℃，优选-20至80℃，更优选-10至60℃。
在一实施方案中，所述式(II)的化合物具有如下化合物D1的结构，所述式(III)的化合物具有如下化合物C1的结构，步骤(a)如下：
步骤(a)：使化合物D1与吗啉发生缩合反应，以制备化合物C1
其中X为卤素。
Figure PCTCN2020141203-appb-000015
在另一实施方案中，所述式(III)的化合物具有如下化合物C1的结构，所述式(IV)的化合物为乙酰乙酸乙酯，所述式(V)的化合物具有如下化合物B1的结构，步骤(b)如下：
步骤(b)：使化合物C1与乙酰乙酸乙酯反应，以制备化合物B1
Figure PCTCN2020141203-appb-000016
其中X为卤素。
在一实施方案中，步骤(a)或步骤(b)中的X选自Cl和Br。在一优选的实施方案中，X为Br。
在一实施方案中，本发明第一方面的方法通过以下路线实施：
Figure PCTCN2020141203-appb-000017
其中X、L、R 1、R 2、R 3、R 4、R 5、R 6、步骤(a)、步骤(b)和步骤(A)如上文所定义。
在一实施方案中，本发明第二方面的方法通过以下路线实施：
Figure PCTCN2020141203-appb-000018
其中X、L、R 1、R 2、R 3、R 4、R 5、R 6、甲酰化试剂、步骤(a)、步骤(b)、步骤(A)和步骤(B)如上文所定义。
本发明的第三方面提供一种中间体化合物，其结构如下式(V)所示：
Figure PCTCN2020141203-appb-000019
其中R 3和R 4如本发明的第一方面所定义。
在一实施方案中，
R 3为-L-C(O)NR 5R 6，L为亚甲基或亚乙基；
R 4为-O(C 1-6烷基)；
R 5和R 6各自独立地选自氢、C 1-6烷基，其中所述烷基任选地被1-2个选自以下的基团取代：卤素、-O(C 1-6烷基)、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、五元至七元杂环基，其中所述杂环基含有1-2个选自N、O、S的杂原子，并且所述杂环基任选地被1-2个选自C 1-6烷基的基团取代；或者
R 5和R 6连同与其相连的N原子一起形成五元至七元杂环，所述杂环任选地含有1个选自N、O、S的额外的杂原子，并且任选地被1-2个选自以下的基团取代：卤素、C 1-6烷基、-O(C 1-6烷基)、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2。
在另一实施方案中，
R 3为-L-C(O)NR 5R 6，L为亚甲基；
R 4为-O(C 1-6烷基)；
R 5和R 6各自独立地选自氢、C 1-4烷基，其中所述烷基任选地被1-2个选自以下的基团取代：卤素、-O(C 1-2烷基)、-NH(C 1-2烷基)、-N(C 1-2烷基) 2、五元至七元杂环基，其中所述杂环基含有1-2个选自N、O、S的杂原子，并且所述杂原子中的至少一个为N，并且所述杂环基任选地被1-2个选自C 1-4烷基的基团取代；或者
R 5和R 6连同与其相连的N原子一起形成五元至七元杂环，所述杂环任选地含有1个选自N、O、S的额外的杂原子，并且任选地被1-2个选自以下的基团取代：卤素、C 1-4烷基、-O(C 1-2烷基)、-NH(C 1-2烷基)、-N(C 1-2烷基) 2。
在又一实施方案中，
R 3为-L-C(O)NR 5R 6，L为亚甲基；
R 4为-O(C 1-6烷基)；
R 5和R 6连同与其相连的N原子一起形成吗啉环。
在一特别的实施方案中，式(V)的中间体化合物为化合物B1：
Figure PCTCN2020141203-appb-000020
本发明的晶型I
在本发明的第四方面，提供化合物Orin1001的晶型I，其中所述晶型I的X射线粉末衍射图谱在约8.44±0.2°、13.11±0.2°、15.70±0.2°、19.73±0.2°、21.00±0.2°、22.91±0.2°的衍射角(2θ)处有特征峰。
在一实施方案中，晶型I的X射线粉末衍射图谱在约8.44±0.2°、10.91±0.2°、 10.68±0.2°、13.11±0.2°、15.70±0.2°、17.54±0.2°、19.73±0.2°、21.00±0.2°、22.91±0.2°、26.27±0.2°的衍射角(2θ)处有特征峰。在一优选的实施方案中，晶型I的X射线粉末衍射图谱在约8.44±0.2°、10.91±0.2°、10.68±0.2°、13.11±0.2°、15.70±0.2°、16.90±0.2°、17.54±0.2°、19.73±0.2°、21.00±0.2°、22.91±0.2°、26.27±0.2°、28.64±0.2°的衍射角(2θ)处有特征峰。
在一实施方案中，晶型I的X射线粉末衍射图谱在如表1所示的衍射角(2θ)处有特征峰。在另一实施方案中，晶型I的X射线粉末衍射图谱基本上如图1所示。
表1 Orin1001 XRPD 2θ角数据表
2θ角(°) 强度％ 2θ角(°) 强度％
8.44 27.6 26.27 81
10.68 15.1 27.28 13.2
10.91 17.2 28.06 7.1
13.11 23.1 28.64 30.6
15.12 13.4 29.50 8.8
15.70 87.7 29.79 8
16.19 12.3 30.58 17.9
16.9 36.6 31.32 9.3
17.30 19.8 31.67 17.9
17.54 46 32.23 9.5
18.15 7.5 32.70 6.3
19.73 87.1 33.20 6.9
20.14 30.8 33.62 7
21.00 76.5 34.05 10.1
21.34 31.7 36.21 4.3
22.91 100 36.73 6.2
23.49 9.6 37.58 8.3
23.86 7.3 37.98 8.1
24.61 8.3 38.63 8.5
25.33 17.1 39.67 6.1
25.96 25.8 - -
在一实施方案中，所述晶型I满足以下(1)至(3)中的至少一个：
(1)热重分析图谱基本上如图2所示；
(2)差示扫描量热分析图谱基本上如图3所示；
(3)动态水分吸附图谱基本上如图4所示。
在一实施方案中，当用DSC进行表征时，所述晶型I的起始温度约为239℃±5℃，峰值温度约为242℃±5℃。
在一实施方案中，晶型I为无水物晶型。
在一实施方案中，晶型I的X射线粉末衍射图谱采用下述方法测定：X-射线粉末衍射仪：Bruker D8 advance X；辐射源：Cu-Kα；扫描范围：3°(2θ)～40°(2θ)；扫描步长：0.02°(2θ)；扫描速度：0.3sec/step。
在一实施方案中，晶型I的热重分析图谱采用下述方法测定：TGA热重分析仪：TA TGA Q500；温度范围：室温～350℃；扫描速率：10℃/min；保护气体：氮气；流速：40mL/min(天平)或60mL/min(样品)。
在一实施方案中，晶型I的差示扫描量热分析图谱采用下述方法测定：DSC差示扫描量热分析仪：TA DSC Q200；温度范围：25℃～300℃；扫描速率：10℃/min；保护气体：氮气；流速：50mL/min。
在一实施方案中，晶型I的动态水分吸附图谱采用下述方法测定：DVS动态水分吸附仪：IGAsorp；温度：25℃；温度稳定性：0.1℃/min；载气：氮气；流速：250mL/min；扫描：2；最小时间：30min；最大时间：2小时；等待上限：98％；湿度变化梯度：吸附：0,10,20,30,40,50,60,70,80,90；脱吸附：80,70,60,50,40,30,20,10,0。
在一实施方案中，晶型I的粒度分布(PSD)采用Malvern Mastersizer 2000测定。所用的参数可以为：泵速度：2500rpm；分散剂体积：800mL；分散剂：水；分散介质：1％吐温80。
在一实施方案中，晶型I的机械处理稳定性采用以下方法测定：将晶型I置于研钵中，分别研磨2min、5min，进行XRPD检测，分析研磨后的固体。
在一实施方案中，晶型I的粒度分布(PSD)如表2所示。
表2晶型I的粒度分布(PSD)数据
D(0.1) D(0.5) D(0.9)
67.1μm 115.5μm 206.4μm
在一实施方案中，晶型I的堆积密度为0.72g/ml，振实密度为0.90g/ml,卡尔指数为20％，休止角为30.6°。
在一实施方案中，晶型I的机械处理稳定性结果如图9所示。
本发明的晶型I具有优异的稳定性。例如通过机械处理后，衍射图谱保持基本不变。
药物组合物和用途
在一方面，本发明提供一种药物组合物，其包含本发明的晶型I以及一种或多种药学上可接受的载体。
在又一方面，本发明还提供本发明的晶型I或者本发明的药物组合物在制备治疗或预防与未折叠蛋白质应答(UPR)相关的疾病、病症或病况，或者在制备治疗或预防与调节IRE1-依赖性衰解(RIDD)的靶标相关的疾病、病症或病况的药物中的应用。
本发明的又一方面还涉及本发明的晶型I或者本发明的药物组合物，用于治疗或预防与未折叠蛋白质应答相关的疾病、病症或病况，或者用于治疗或预防与调节IRE1-依 赖性衰解的靶标相关的疾病、病症或病况。
本发明的又一方面还提供治疗或预防与未折叠蛋白质应答相关的疾病、病症或病况的方法，或者治疗或预防与调节IRE1-依赖性衰解的靶标相关的疾病、病症或病况的方法，所述方法包括向有需要的个体给药有效量的本发明的晶型I或者本发明的药物组合物，或者，使针对所述疾病、病症或病况的治疗有效量的本发明的晶型I或者本发明的药物组合物出现在个体体内。
在一实施方案中，所述与未折叠蛋白质应答相关的疾病、病症或病况选自肿瘤、与代谢相关的疾病、与免疫相关的疾病、病毒感染和心血管疾病。
在一实施方案中，所述与未折叠蛋白质应答相关的疾病、病症或病况选自B细胞自身免疫疾病、癌症和病毒感染。在一实施方案中，可治疗的B-细胞自身免疫疾病选自：艾迪生病(Addision’s disease)、抗磷脂综合征、再生障碍性贫血、自体免疫溶血性贫血、自身免疫性肝炎、自身免疫性垂体炎、自身免疫性淋巴细胞增生性疾病、自身免疫性心肌炎、丘-施二氏综合征、后天性大疱性表皮松解、巨细胞性动脉炎、古德帕斯彻综合征、格雷夫斯病、格-巴二氏综合征、桥本甲状腺炎、特发性血小板减少性紫癜、IgA肾病、重症肌无力、落叶型天疱疮(pemphigus foliaceous)、寻常天疱疮、结节性多动脉炎、多发性肌炎/皮肌炎、类风湿性关节炎、硬皮病、斯耶格仑综合征、全身性红斑狼疮、高安氏动脉炎(Takayasu’s arteritis)和韦格纳肉芽肿病(Wegener’s granulomatosis)。在一实施方案中，可治疗的癌症为实体瘤。在一进一步的实施方案中，实体瘤选自乳腺肿瘤、骨肿瘤、前列腺肿瘤、肺肿瘤、肾上腺肿瘤(如肾上腺皮质瘤)、胆管肿瘤、膀胱肿瘤、支气管肿瘤、神经组织肿瘤(包括神经元和神经胶质瘤)、胆囊肿瘤、胃肿瘤、唾液腺肿瘤、食道肿瘤、小肠肿瘤、子宫颈肿瘤、结肠肿瘤、直肠肿瘤、肝肿瘤、卵巢肿瘤、胰腺肿瘤、垂体腺瘤和分泌腺瘤。在一实施方案中，可治疗的癌症为药物-耐受性或辐射-耐受性实体瘤。在一实施方案中，可治疗的癌症为血液肿瘤。在一进一步的实施方案中，血液肿瘤为淋巴瘤或白血病。在另一实施方案中，血液肿瘤为未定性单克隆丙种球蛋白病(MGUS)，一种骨髓瘤的前体。在一实施方案中，淋巴瘤选自多发性骨髓瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤(例如，皮肤T细胞淋巴瘤，如塞扎里综合征和蕈样霉菌病、弥漫性大细胞淋巴瘤、HTLV-1相关T细胞淋巴瘤、结节外周性T细胞淋巴瘤、结节外外周性T细胞淋巴瘤(extranodal peripheral T cell lymphoma)、中枢神经系统淋巴瘤和AIDS-相关淋巴瘤)。在又一实施方案中，白血病选自急性和慢性的淋巴细胞性和髓细胞性白血病(例如，急性淋巴细胞性或淋巴母细胞性白血病、急性髓细胞性白血病、急性骨髓性白血病、慢性髓细胞性白血病、慢性淋巴细胞性白血病、T细胞前淋巴细胞性白血病、成人T细胞性白血病和毛细胞性白血病)。在一实施方案中，可治疗的病毒感染为在复制和形成感染性后代时利用未折叠蛋白质应答途径的被膜病毒感染。在一进一步的实施方案中，可治疗的病毒感染选自麻疹病毒、痘病毒、埃博拉病毒(Ebola)。在又一实施方案中，可治疗的病毒感染为感染选自Epstein Barr病毒(EBV)、巨细胞病毒(CMV)、黄病毒属的病毒(例如，日本脑炎病毒和西尼罗病毒)和丙型肝炎病毒(HCV)所致的那些感染。
在一实施方案中，所述与调节IRE1-依赖性衰解的靶标相关的疾病、病症或病况选自神经病症、涉及胰岛素超量产生的病症和涉及炎症的病症。在一优选的实施方案中，神经病症为精神分裂症。在另一优选的实施方案中，涉及胰岛素超量产生的病症为II型糖尿病。在又一优选的实施方案中，涉及炎症的病症选自肾小球性肾炎、各种形式的关节炎、多发性硬化和炎性肠病。
有益效果
与现有技术(如CN103079558 A)中的方法相比，本发明的方法具有简洁高效、原子利用率高、收率高的优点。
按照CN103079558 A的方法制备中间体5A2，路线如下：
Figure PCTCN2020141203-appb-000021
该路线包括：
步骤(1)：由乙酰乙酸乙酯(SM1)和溴代乙酸乙酯(SM2)制备α-位被酯基烷基取代的乙酰乙酸乙酯化合物(化合物2)，收率80％；步骤(2)：制备3-位被酯基烷基取代的香豆素类化合物(化合物3)，收率60％；步骤(3)：制备化合物4，收率67％；步骤(4)：通过酸胺缩合反应引入酰胺基团，制备化合物5A2。其中，按照CN103079558 A实施例62的方法进行步骤(4)，得到的为粗品化合物5A2，收率为43％。上述步骤(1)至步骤(4)的总收率为约13.8％，其中上述步骤(2)至步骤(4)的总收率为约17.3％。
以上一共包括4个步骤，步骤(2)至步骤(4)是以直线合成(linear synthesis)方式进行的三步连续的直线反应，其中步骤(2)通过关环反应与化合物1构建香豆素母核，步骤(3)和步骤(4)进一步在3-位取代基上引入酰胺基团，以获得化合物5A2。在此过程中，需要先在化合物3中引入酯基，再将其去除和转换成酰胺基，步骤繁琐，原子经济性不佳，并且产率较低。
与之相比，本发明的制备3-位被酰胺基烷基取代的香豆素类化合物(例如化合物5A2)的方法中，首先通过两个步骤制备α-位被酰胺基烷基取代的乙酰乙酸烷基酯(例如参见制备式(V)化合物或制备中间体化合物B1的方法，或例如实施例1所示的方法)，然后通过一个与化合物1的关环步骤直接构建香豆素母核。上述步骤的总数为3。通过上述“先构建模块，再进行汇聚”的思路，本发明的制备方法实现了汇聚式合成(convergent synthesis)，减少了连续反应的步骤，有利于进一步提高生产效率。发明人出人意料地发现，本发明利用α-位被酰胺基烷基取代的乙酰乙酸烷基酯化合物与取代苯酚 化合物进行关环反应构建香豆素母核，是实现汇聚式合成、减少反应步骤、提高反应总收率、原子经济性和生产效率的关键。
此外，本发明的制备方法中，通过具有双官能团的式(II)的酰卤化合物(或化合物D1)来引入酰胺基团，与CN103079558 A引入酯基再水解、然后进行酸胺缩合的方法相比，明显具备更高的原子利用率。
本发明的制备方法还实现了更高的总收率，有利于工业化生产。例如，作为本发明的代表性实例，实施例1至实施例2的总收率约为46.6％。
因此，本发明的制备3-位被酰胺基烷基取代的香豆素类化合物的方法具有以下优点：优化了酰胺基团的引入时机，先制备包含酰胺取代的1,3-二羰基化合物，再将其用于关环，以简洁的路线高效构建了香豆素母核结构及包含酰胺基团的侧链，原子利用率高、收率高，有利于工业化生产。并且构建了汇聚式合成路线，缩短了连续反应的步骤，有利于进一步提高生产效率。
本发明的Orin1001的晶型I纯度高，稳定性高，可操作性好，制备工艺简单，可应用于大规模生产。
实施例
下述实施例中所使用的仪器设备及检测条件如下：
X-射线粉末衍射仪：Bruker D8 advance X，辐射源为Cu-Kα，测试的扫描范围为3°(2θ)～40°(2θ)，扫描步长为0.02°(2θ)，扫描速度为0.3sec/step。
TGA热重分析仪：TA TGA Q500，温度范围为室温～350℃，扫描速率为10℃/min，保护气体为氮气，流速为40mL/min(天平)或60mL/min(样品)。
DSC差示扫描量热分析仪：TA DSC Q200，温度范围为25℃～300℃，扫描速率为10℃/min，保护气体为氮气，流速为50mL/min。
DVS动态水分吸附仪：IGAsorp，温度为25℃，温度稳定性：0.1℃/min，载气为氮气，流速为250mL/min，扫描：2，最小时间为30min，最大时间为2小时，等待上限为98％，湿度变化梯度：吸附：0,10,20,30,40,50,60,70,80,90；脱吸附：80,70,60,50,40,30,20,10,0。
HPLC(反应监控)：采用Waters Acquity Arc液相色谱系统或等同仪器；色谱柱：ZORBA×Eclipse×DB C18，4.6×150mm，3.5μm，或同类型色谱柱；流动相A：0.05％三氟乙酸水溶液；流动相B：0.05％三氟乙酸乙腈溶液；浓度梯度运行时间：20分钟。
HPLC(纯度测定)：采用Waters Acquity Arc液相色谱系统或等同仪器；色谱柱：Eclipse×DB C18，4.6×150mm，3.5μm，或同类型色谱柱；柱温：30℃；检测波长：210nm；流动相A：0.05％三氟乙酸水溶液；流动相B：0.05％三氟乙酸乙腈溶液；浓度梯度运行时间：20分钟。
LC-MS：采用Shimadzu LCMS 2010(色谱柱：sepax ODS 50×2.0mm,5μm)，或Agilent 1200 HPLC,1956 MSD(色谱柱：Shim-pack XR-ODS 30×3.0mm,2.2μm)，或NB-PDM-LCMS-004(色谱柱：Agilen SB-C18 4.6x50mm 1.8μm，或poroshell SB-C 18  2.7um 3.0*50mm,SN:USCFE02201)，电离方式ES(+)。
合成方案
Figure PCTCN2020141203-appb-000022
首先将卤代乙酰卤(化合物D1)与胺(吗啉)反应，制备α-位卤代的酰胺(化合物C1)，然后将其与乙酰乙酸乙酯反应，制备得到α-位被酰胺基烷基取代的乙酰乙酸乙酯化合物(中间体B1)。中间体B1与取代苯酚化合物(化合物1)进行缩合反应，关环得到3-位被酰胺基烷基取代的香豆素类化合物5A2，其通过与六亚甲基四胺(HMTA)反应引入醛基，得到目标化合物Orin1001。
实施例1：中间体B1的制备
方法A用溴乙酰溴制备中间体B1：
步骤1：中间体C1-1的制备
Figure PCTCN2020141203-appb-000023
中间体C1-1可以参照国际专利申请WO1999032436的实施例A9 Step 1中公开的方法制备，或者按照以下方法1或方法2制备。
方法1(低温反应)：
向反应釜中加入二氯甲烷(75.0L)和溴乙酰溴(D1-1，5.0kg，1.00eq.)，降温至0℃～5℃，加入事先预冷至0℃～5℃的吗啡啉(4.32kg，2.00eq.)，于0～5℃下至少搅拌0.5小时，TLC监控反应直到Rf＝0的原料消失。在0～5℃下用饱和NH 4Cl水溶液(25.0L)淬灭反应，继续搅拌至少20分钟。将反应液静置分层后，分出有机相并用饱和NH 4Cl水溶液(25.0L)洗涤。在≤45℃下减压浓缩有机相直至无明显馏分滴出。以同样规模制备另一批。两个批次合并，共得到中间体2-溴-1-吗啡啉乙烷-1-酮(C1-1)9.25kg，收率90.0％，HPLC检测纯度为99.6％。H 1NMR(300MHz,DMSO-d 6)δ3.44-3.49(m,4H), 3.55-3.69(m,4H)4.13(S,2H).LC-MS:[M+1] +＝208.1
方法2(室温反应)：
氮气保护下，向5L四口瓶内加入溴乙酰溴(D1-1，250g，1.00eq.)和二氯甲烷(3.75L)，用盐水浴降温至5℃。滴加吗啡啉(216g，2.00eq.)并控制温度0～10℃。滴加完毕后，控制反应温度≤10℃，搅拌30分钟。撤去盐水浴，室温反应2小时。TLC检测，溴乙酰溴反应完全。将体系温度降至≤10℃，滴加饱和NH 4Cl水溶液(1.25L)。将混合物分液，有机相用饱和NH 4Cl水溶液(1.25L)再洗涤一次。在≤45℃下减压浓缩有机相直至无明显馏分滴出，得到中间体2-溴-1-吗啡啉乙烷-1-酮(C1-1)234.8g，收率：90.0％，KF＝0.27％，HPLC检测纯度为99.2％。H-NMR(DMSO-d6)δ3.40-3.50(m,4H),3.50-3.60(m,4H),4.11(s,2H).
步骤2：中间体B1的制备
Figure PCTCN2020141203-appb-000024
方法1(以NaH为碱)：
向中间体C1-1(4.93kg，1.00eq.)中加入THF(4.45kg，5.0L)，搅拌得到中间体C1-1的THF澄清溶液，并冷至0～5℃，备用。向反应釜中加入THF(17.8kg，20.0L)，再加入NaH(60％，0.845kg，1.10eq.)，并降温至0～5℃。向釜内加入事先冷至0～5℃的乙酰乙酸乙酯(2.50kg，1.00eq.)，于0～5℃下搅拌至少0.5小时后，再加入上述配制好的0～5℃的中间体C1-1的THF溶液。反应继续在0～5℃下搅拌至少2小时。取样送HPLC检测以监控反应，直至中间体C1-1的峰面积≤5.0％。于0～5℃下加入饱和NH 4Cl水溶液(35.0L)，将混合物静置分层。用乙酸乙酯(25.0L)萃取水相，合并有机层，并在约45℃下减压浓缩至5.0±1.0V后加入水(6.5L)，搅拌15分钟。将混合物静置分层，将有机层在45℃下减压浓缩至无明显馏分滴出。向残余物中加入正庚烷(5.0L)，搅拌至少0.5小时后，将混合物静置分层，收集下层液体至瓶中，得到中间体2-乙酰基-4-吗啡啉基-4-氧代丁酸乙酯(B1)4.45kg，收率90.0％(粗品)，中间体B1纯度经HPLC检测为84.7％，直接用于下一步反应。 1H NMR:(300MHz,DMSO-d 6)δ1.17-1.24(m,3H),2.27(s,3H),2.77-2.94(m,2H),3.38-3.60(m,8H),3.98-4.05(m,1H),4.07-4.16(m,2H).LC-MS:[M+1] +＝258.2
方法2(以碳酸钾为碱)：
2-1：向反应釜中加入THF(8.90kg，10.0L)、中间体C1-1(1.89kg，1.05eq.)和碳酸钾(3.19kg，3.00eq.)，在40±5℃下搅拌至少15小时，取样送HPLC检测以监控反应，直到中间体C1-1的峰面积≤5.0％。将反应混合物冷却至室温，过滤，滤饼用THF(2.0L x 2)淋洗。合并滤液，用氯化钠水溶液洗涤。有机层合并后于约45℃下减压浓缩至无明 显馏分滴出，得到中间体2-乙酰基-4-吗啡啉基-4-氧代丁酸乙酯(B1)1.99kg，收率为101％(粗品)，中间体B1纯度经HPLC检测为86.2％，直接用于下一步反应。B1表征结果与上文一致。
2-2：向反应釜中加入THF(20.55kg，10V)、中间体C1-1(4.37kg，1.05eq.)、乙酰乙酸乙酯(2.32kg，1.00eq.)和碳酸钾(7.40kg，3.00eq.)，在40±5℃下搅拌至少16小时，取样送HPLC检测以监控反应，直到中间体C1-1的峰面积≤5.0％。如果16h后反应没有完成，则向反应混合物中加入少量的水，40±5℃下搅拌4h，如有必要则重复一次，直到中间体C1-1的峰面积≤5.0％。将反应混合物冷却至25±5℃，过滤，滤饼用THF(2.0V x 2)淋洗。合并滤液，用氯化钠水溶液洗涤。有机层合并后于45℃以下减压浓缩至无明显馏分滴出，得到中间体2-乙酰基-4-吗啡啉基-4-氧代丁酸乙酯(B1)4.87kg，收率为106％，中间体B1纯度经HPLC检测为86.2％。B1表征结果与上文一致。
方法B用氯乙酰氯制备中间体B1：
Figure PCTCN2020141203-appb-000025
步骤1：中间体C1-2的制备：
中间体C1-2可以参照美国专利US5753660 A实施例57 Part A中公开的方法来制备，或者按照以下方法来制备。
氮气保护下，将二氯甲烷(1.54L)和氯乙酰氯(D1-2，300g，1.05eq.)加入到5L的四口瓶中，用冰水浴降温至≤10℃。将K 2CO 3(523g，1.5eq.)分批加入，并控制温度≤20℃。滴加吗啡啉(220g，1.0eq.)，同时控制温度≤20℃，有白雾生成，放热。滴加完毕后，自然升温至20℃。搅拌3小时，TLC检测，氯乙酰氯消失。用冰水浴控制温度≤10℃，滴加水(1.54L)，观察到放热。将混合物静置分离水相和有机相，水相用二氯甲烷(1.5L x 2)萃取。合并有机相，水洗(1.0L x 2)。有机相用硫酸钠干燥。将有机相减压浓缩至无明显馏分，得到中间体2-氯-1-吗啡啉乙烷-1-酮(C1-2，290g)，为黄色油状液体，收率70％，纯度经HPLC检测为97％。 1H-NMR(300MHz,CDCl 3):δ3.51-3.54(m,2H),3.61-3.64(m,2H),3.68-3.74(m,4H),4.06(s,2H).LC-MS:[M+1] +＝164
步骤2：中间体B1的制备：
向500mL三口瓶加入乙酰乙酸乙酯(23.86g，1.5eq.)和甲基叔丁基醚(160mL)，降温至0℃，加入碳酸钾(25.34g，1.5eq.)。控制反应温度0～5℃，搅拌30分钟。加入中间体C1-2(20.00g，1.0eq.)的甲基叔丁基醚溶液，加热至50℃，反应过夜。取样送HPLC检测，显示C1-2含量为2.2％。过滤，滤饼用二氯甲烷淋洗，滤液减压浓缩，得油状物。将油状物溶于二氯甲烷中，水洗。水相用二氯甲烷萃取一次。合并有机相，用饱和氯化 钠溶液洗涤。将有机相减压浓缩至干，得到中间体2-乙酰基-4-吗啡啉基-4-氧代丁酸乙酯(B1)39g，为浅黄色油状物，收率124.1％(粗品)。中间体B1纯度经HPLC检测为88.6％，直接用于下一步反应。
实施例2：中间体5A2的制备
Figure PCTCN2020141203-appb-000026
1：向反应釜中加入甲磺酸(19.98kg，13.5L)，控制温度≤40℃，加入4-甲氧基-1,3-苯二酚(1，2.7kg，1.00eq.)。再加入中间体B1(5.5kg，1.10eq.)。反应于40±5℃下搅拌至少18小时，取样送HPLC检测以监控反应，直至原料1的峰面积≤5.0％。将反应液冷至0～5℃，控制温度≤40℃，加入水(27.0L)，再冷至0～5℃搅拌16小时。将混合物离心，离心得到的固体用水(8.0L)和乙腈(5.5L x 2)分别淋洗，得到湿固体。将反应釜用氮气置换3次。加入乙腈(13.5L)和上述湿固体，加热至70±5℃并搅拌至少1小时。降温至25±5℃，将混合物离心，离心得到的固体用乙腈(4.0L x 2)淋洗，然后转移至真空烘箱中，控温40～45℃(箱体温度)真空干燥至少8小时，冷却至室温，得到5g的中间体7-羟基-6-甲氧基-4-甲基-3-(2-吗啡啉基-2-氧代乙基)-2H-苯并吡喃-2-酮(5A2)，收率60％，纯度99.5％。 1H-NMR:(300MHz/DMSO-d 6)δ2.31(s,3H),3.44-3.45(m,2H)3.55-3.65(m,8H),3.87(s,3H),6.78(s,1H),7.16(s,1H),10.19(s,1H).LC-MS:[M+1] +＝334.2
2：向反应釜A中加入甲磺酸(50mL，5.0V)，控制温度≤40℃，加入中间体B1(25.06g，0.95eq.)，再加入4-甲氧基-1,3-苯二酚(1，10.0g，1.00eq.)，反应于40±5℃下搅拌至少24小时。取样送HPLC检测以监控反应，直至原料1的峰面积≤5.0％。如果24h后反应没有完成并且残留的中间体B1＜4％，则于40±5℃下滴加中间体B1(0.05eq.)，搅拌至少5小时，如有必要重复该操作直到原料1的峰面积≤5.0％。向反应釜B中加入水(100mL，10.0V)，然后向反应釜B中滴加反应釜A的反应混合物，2.5±2.5℃下搅拌至少16小时。将混合物离心，离心得到的固体用水(30mL，3.0V)和乙腈(20mL×2，2.0V x 2)分别淋洗，得到湿固体。将反应釜A用氮气置换3次。加入乙腈(50mL，5.0V)和上述湿固体，加热至70±5℃并搅拌至少8小时。降温至25-30℃，将混合物离心，离心得到的固体用乙腈(15mL×2，1.5V×2)淋洗，然后转移至真空烘箱中，控温40～45℃(箱体温度)真空干燥至少8小时，冷却至室温，得到8.5g中间体7-羟基-6-甲氧基-4-甲基-3-(2-吗啡啉基-2-氧代乙基)-2H-苯并吡喃-2-酮(5A2)，收率36％，纯度99.7％。表征结果与上文一致。
实施例3：化合物Orin1001的制备
Figure PCTCN2020141203-appb-000027
方法1：
向反应瓶内加入中间体5A2(10g，1.00eq.)、六亚甲基四胺(HMTA，16.8g，4.00eq.)和三氟乙酸(500mL)，在氮气氛下于90℃加热1.5小时。LC-MS检测反应完全。将反应液冷却至室温，减压浓缩除去溶剂，得到残余物。向获得的残余物中加入水(30mL)，并用10％碳酸氢钠水溶液中和。二氯甲烷萃取(1000mL x 3)，合并有机相，硫酸钠干燥，浓缩，再分别用乙腈和乙酸乙酯洗涤，得到化合物Orin1001(黄色固体，5g)。收率46％。 1H NMR(TH03493-010-2M CDCl 3,400MHz):δ12.45(s,1H,OH),10.59(s,1H,CHO),7.24(s,1H,ArH),3.95(s,3H,CH 3),3.78-3.62(m,10H,CH 2),2.46(s,3H,CH 3).LC-MS[M+H] +＝362.2。
对最终获得的化合物Orin1001进行X射线粉末衍射(XRPD)检测，证实其为结晶态，命名为晶型I。
对该晶型I进行了TGA、DSC、DVS及稳定性测试。结果如下。
1)XRPD检测
晶型I的XRPD图谱基本如图1所示。2θ数据表如表1所示。
2)TGA测试
根据热重分析(TGA)结果，在加热至200℃时，具有约0.017％的重量损失梯度，其热重分析图基本如图2所示。由图2可知Orin1001晶型I为无水物。
3)DSC测试
根据差示扫描量热分析(DSC)结果，在加热至239.4℃附近开始出现吸热峰，其差示扫描量热分析图基本如图3所示。由图3可知Orin1001晶型I的起始温度(Tonset)约为239℃±5℃，例如为239℃；峰值温度(Tpeak)约为242℃±5℃，例如为242℃。
4)DVS测试
根据动态水分吸附(DVS)结果，晶型I在90％相对湿度下平衡后增重0.34％，仅为略引湿，并且晶型在DVS测量后未改变。其DVS检测结果基本如图4所示，DVS检测前后的XRPD对比图基本如图5所示。由图4和图5可知所述Orin1001晶型I为轻微吸湿。
5)稳定性测试
取晶型I的两份样品分别放置于40℃/75％相对湿度(RH)条件下，以及烘箱内温60℃(未控制湿度)条件下14天，分别在第0、7和14天取样进行HPLC纯度检测和XRPD检测，结果显示晶型I具有很好的化学和物理稳定性(表3、表4、图6、图7)。
表3晶型I稳定性测试结果(HPLC纯度：峰面积％)-第7天
Figure PCTCN2020141203-appb-000028
表4晶型I稳定性测试结果(HPLC纯度：峰面积％)-第14天
Figure PCTCN2020141203-appb-000029
由表3、表4、图6、图7可知，Orin1001晶型I具有优异的稳定性。
方法2：
向反应釜中加入三氟乙酸(230.40kg，150.0L，20.0V)，降温至0～10℃。控温10℃以下，加入六亚甲基四胺(HMTA，23.44kg，7.50eq.)与中间体5A2(7.44kg，1.00eq.)。调节温度至80±5℃，搅拌至少40小时。取样送HPLC检测以监控反应，直至中间体5A2的峰面积≤5.0％。将反应液在70℃以下减压浓缩至120L左右。降温至0～10℃，加入纯化水(200.0L)与Orin1001晶种(1.00wt％)。保持0～10℃继续搅拌至少16小时。离心，滤饼用纯化水(5.0L)淋洗，乙腈(5.0L x 2)淋洗。将反应釜用氮气置换三次。向反应釜中加入乙腈(27.0L)、纯化水(13.5L)与上述得到的湿滤饼。加热至60±5℃并搅拌至少8小时。降温至25～30℃，离心，滤饼用乙腈(7.5L x 2)淋洗。将滤饼转移至真空烘箱，控温40～45℃(箱体温度)真空干燥至少4小时。停止烘料，烘箱内温降至30℃以下，得到Orin1001(黄色固体，4.61kg)，收率57％，HPLC检测纯度为99.9％。表征结果与上文一致。
对该晶型I进行了粒度分布(PSD)及机械处理稳定性测试。结果如下。
1)晶型I的粒度分布(PSD)测试
晶型I为颗粒状晶体，显微镜(Nikon Eclipse LV100POL)下观察其粒径为50-100μm。
使用Malvern Mastersizer 2000测定晶型I的粒度分布(PSD)。泵速度：2500rpm；分散剂体积：800mL；遮蔽度：10％-20％；分散剂：水；分散介质：1％吐温80；背景测量时间：12s；样品测量时间：12s；测量循环：3。结果如下表所示：
D(0.1) D(0.5) D(0.9)
67.1μm 115.5μm 206.4μm
晶型I的堆积密度为0.72g/ml，振实密度为0.90g/ml,卡尔指数为20％，休止角为30.6°，流动性非常好。流动性好的粉末不易飞扬、吸附性小、粘性也小，具有工业上应用的便利性。
2)机械处理稳定性测试
将晶型I置于研钵中，分别研磨2min、5min，进行XRPD检测，分析研磨后的固 体。结果如图8所示，结果显示研磨2min、5min后，晶型不发生改变，表明晶型I具有良好的机械处理稳定性，有利于大规模工业化生产。
虽然本发明已阐述并描述了典型的实施方案，但本发明并不限于所述细节。由于各种可能的修改和替换没有背离本发明的精神，本领域技术人员可使用常规试验能够想到的本发明的变型和等同物，因此所有这些变型和等同物都落入由以下权利要求书所定义的本发明的精神和范围内。

Claims (25)

  1. 一种制备式(VII)的化合物的方法，包括
    步骤(A)：使式(VI)的化合物与式(V)的化合物反应，以制备式(VII)化合物
    Figure PCTCN2020141203-appb-100001
    其中R 1和R 2各自独立地选自氢、卤素和-O(C 1-8烷基)，其中所述烷基任选地被1-2个-选自以下的基团取代：卤素、被1-2个羟基取代的C 1-8烷基、-O(C 1-8烷基)；
    R 3为-L-C(O)NR 5R 6，L为C 1-3亚烷基；
    R 4为-O(C 1-6烷基)；
    R 5和R 6各自独立地选自氢、C 1-8烷基、C 3-10环烃基，其中所述烷基、环烃基任选地被1-2个选自以下的基团取代：卤素、-O(C 1-8烷基)、-NH 2、-NH(C 1-8烷基)、-N(C 1-8烷基) 2、五元至七元杂环基，其中所述杂环基含有1-2个选自N、O、S的杂原子，并且所述杂环基任选地被1-2个选自C 1-8烷基的基团取代；或者
    R 5和R 6连同与其相连的N原子一起形成五元至七元杂环基，所述杂环基任选地含有1个选自N、O、S的额外的杂原子，并且任选地被1-2个选自以下的基团取代：卤素、C 1-8烷基、-O(C 1-8烷基)、-NH 2、-NH(C 1-8烷基)、-N(C 1-8烷基) 2。
  2. 权利要求1的方法，其中R 1和R 2各自独立地选自氢、卤素和-O(C 1-4烷基)，其中所述烷基任选地被1-2个选自以下的基团取代：卤素、-O(C 1-4烷基)；优选地，R 1和R 2各自独立地选自氢、卤素和-O(C 1-2烷基)，其中所述烷基任选地被卤素或甲氧基取代；更优选地，R 1和R 2各自独立地为氢、甲氧基或
    Figure PCTCN2020141203-appb-100002
  3. 权利要求1的方法，其中R 4为-O(C 1-4烷基)；优选-O(C 1-2烷基)；更优选乙氧基。
  4. 权利要求1的方法，其中L为亚甲基或亚乙基，优选亚甲基。
  5. 权利要求1的方法，其中R 5和R 6各自独立地选自氢、C 1-6烷基，其中所述烷基任选地被1-2个选自以下的基团取代：卤素、-O(C 1-6烷基)、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、五元至七元杂环基，其中所述杂环基含有1-2个选自N、O、S的杂原子，并且 所述杂环基任选地被1-2个选自C 1-6烷基的基团取代；或者
    R 5和R 6连同与其相连的N原子一起形成五元至七元杂环基，所述杂环基任选地含有1个选自N、O、S的额外的杂原子，并且任选地被1-2个选自以下的基团取代：卤素、C 1-6烷基、-O(C 1-6烷基)、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2；
    优选地，R 5和R 6各自独立地选自氢、C 1-4烷基，其中所述烷基任选地被1-2个选自以下的基团取代：卤素、-O(C 1-2烷基)、-NH(C 1-2烷基)、-N(C 1-2烷基) 2、五元至七元杂环基，其中所述杂环基含有1-2个选自N、O、S的杂原子，并且所述杂原子中的至少一个为N，并且所述杂环基任选地被1-2个选自C 1-4烷基的基团取代；或者
    R 5和R 6连同与其相连的N原子一起形成五元至七元杂环基，所述杂环基任选地含有1个选自N、O、S的额外的杂原子，并且任选地被1-2个选自以下的基团取代：卤素、C 1-4烷基、-O(C 1-2烷基)、-NH(C 1-2烷基)、-N(C 1-2烷基) 2；
    更优选地，R 5和R 6各自独立地选自氢、C 1-2烷基，其中所述烷基任选地被1-2个选自以下的基团取代：甲氧基、二甲氨基、吗啉基、哌啶基或哌嗪基，所述吗啉基、哌啶基或哌嗪基任选地被甲基取代；或者
    R 5和R 6连同与其相连的N原子一起形成吗啉基、哌啶基或哌嗪基，所述吗啉基、哌啶基或哌嗪基任选地被甲基取代；
    进一步优选地，R 5和R 6各自独立地选自氢、C 1-2烷基，其中所述烷基被吗啉基取代；或者
    R 5和R 6连同与其相连的N原子一起形成吗啉基。
  6. 权利要求1的方法，其中所述式(VII)的化合物具有如下化合物5A2的结构，所述制备式(VII)的化合物的方法包括
    步骤(A)：使化合物1与化合物B1反应，以制备化合物5A2
    Figure PCTCN2020141203-appb-100003
  7. 权利要求1-6中任一项的方法，其中步骤(A)在酸性条件下进行，和/或反应温度为-20℃至70℃，优选-5℃至60℃，更优选20℃至50℃。
  8. 一种制备式(I)化合物的方法，包括
    步骤(A)：使式(VI)化合物与式(V)化合物反应，以制备式(VII)化合物
    Figure PCTCN2020141203-appb-100004
    步骤(B)：由式(VII)化合物制备式(I)化合物
    Figure PCTCN2020141203-appb-100005
    其中，R 1、R 2、R 3和R 4如权利要求1所定义。
  9. 一种中间体化合物，其结构如下式(V)所示：
    Figure PCTCN2020141203-appb-100006
    其中R 3和R 4如权利要求1-5任一项所定义。
  10. 权利要求9的中间体化合物，其为化合物B1：
    Figure PCTCN2020141203-appb-100007
  11. 权利要求1的方法，在步骤(A)之前还包括：
    步骤(a)：使式(II)化合物与胺化合物HNR 5R 6发生缩合反应，以制备式(III)化合物
    Figure PCTCN2020141203-appb-100008
    其中X为卤素，优选Cl或Br，更优选Br；L、R 3、R 5和R 6如权利要求1所定义；
    优选地，反应在有机溶剂中进行；更优选地，有机溶剂为中性非质子性溶剂；进一步优选地，有机溶剂选自烃类溶剂、醚类溶剂、二取代酰胺类溶剂、酯类溶剂及其组合；
    更优选地，
    所述烃类溶剂选自二氯甲烷、甲苯、二甲苯及其组合；和/或
    所述醚类溶剂选自四氢呋喃、甲基四氢呋喃、二氧六环、乙二醇二甲醚，甲基叔丁基醚及其组合；和/或
    所述二取代酰胺类溶剂选自N,N-二甲基甲酰胺、N,N-二乙基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基乙酰胺、N-甲基吡咯烷酮及其组合；和/或
    所述酯类溶剂选自乙酸乙酯、乙酸异丙酯、乙酸丁酯及其组合；和/或
    反应温度为-10℃至60℃，优选0℃至室温，更优选0℃至10℃；
    步骤(b)：使式(III)化合物与式(IV)化合物反应以制备式(V)化合物
    Figure PCTCN2020141203-appb-100009
    其中X为卤素，优选Cl或Br，更优选Br；R 4如权利要求1所定义；
    优选地，反应在碱的存在下进行，所述碱为有机碱或无机碱；
    更优选地，
    所述有机碱选自NaNH 2、醇钠、K-HMDS、Li-HMDS；和/或
    所述无机碱选自碳酸盐和金属氢化物；优选地，所述碳酸盐选自碳酸钠、碳酸钾、碳酸锂；更优选碳酸钠或碳酸钾，特别优选碳酸钾；和/或所述金属氢化物选自NaH、KH、LiH、CaH 2，特别优选NaH；
    优选地，反应在有机溶剂中进行；优选地，所述有机溶剂为中性非质子性溶剂；进一步优选地，有机溶剂选自烃类溶剂、醚类溶剂、二取代酰胺类溶剂及其组合；
    更优选地，
    所述烃类溶剂选自二氯甲烷、甲苯、二甲苯及其组合；和/或
    所述醚类溶剂选自四氢呋喃、甲基四氢呋喃、二氧六环、乙二醇二甲醚，甲基叔丁基醚及其组合；和/或
    所述二取代酰胺类溶剂选自N,N-二甲基甲酰胺、N,N-二乙基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基乙酰胺、N-甲基吡咯烷酮及其组合；
    和/或
    反应温度为-20至100℃，优选-20至80℃，更优选-10至60℃。
  12. 权利要求6的方法，在步骤(A)之前还包括：
    步骤(a)：使化合物D1与吗啉发生缩合反应，以制备化合物C1
    Figure PCTCN2020141203-appb-100010
    步骤(b)：使化合物C1与乙酰乙酸乙酯反应，以制备化合物B1
    Figure PCTCN2020141203-appb-100011
    其中X为卤素，优选Cl或Br，更优选Br。
  13. 下式化合物的晶型I，其中所述晶型I的X射线粉末衍射图谱在约8.44±0.2°、13.11±0.2°、15.70±0.2°、19.73±0.2°、21.00±0.2°、22.91±0.2°的衍射角(2θ)处有特征峰，
    Figure PCTCN2020141203-appb-100012
  14. 权利要求13的晶型I，其中所述晶型I的X射线粉末衍射图谱在约8.44±0.2°、10.91±0.2°、10.68±0.2°、13.11±0.2°、15.70±0.2°、17.54±0.2°、19.73±0.2°、21.00±0.2°、22.91±0.2°、26.27±0.2°的衍射角(2θ)处有特征峰，
    优选地在约8.44±0.2°、10.91±0.2°、10.68±0.2°、13.11±0.2°、15.70±0.2°、16.90±0.2°、17.54±0.2°、19.73±0.2°、21.00±0.2°、22.91±0.2°、26.27±0.2°、28.64±0.2°的衍射角(2θ)处有特征峰。
  15. 权利要求13或14的晶型I，其中所述晶型I的X射线粉末衍射图谱在如表1所示的衍射角(2θ)处有特征峰。
  16. 权利要求13-15中任一项的晶型I，其中所述晶型I的X射线粉末衍射图谱基本上如图1所示。
  17. 权利要求13-16中任一项的晶型I，其中所述晶型I满足以下(1)至(3)中的至少一个：
    (1)热重分析图谱基本上如图2所示；
    (2)差示扫描量热分析图谱基本上如图3所示；
    (3)动态水分吸附图谱基本上如图4所示。
  18. 权利要求13-17中任一项的晶型I，其中当用DSC进行表征时，所述晶型I的起始温度约为239℃±5℃，峰值温度约为242℃±5℃。
  19. 权利要求13-18中任一项的晶型I，其为无水物晶型。
  20. 一种制备权利要求13-19中任一项的晶型I的方法，包括：
    步骤i：在步骤(B)反应结束后，浓缩反应液，加入水和式(I)化合物晶种诱导析晶；
    步骤ii：分离步骤i得到的粗产品，与合适的溶剂在加热条件下搅拌，然后降温，分离得到结晶态的式(I)化合物。
  21. 权利要求20的方法，其中
    步骤ii分离粗产品之后、与合适的溶剂在加热条件下搅拌之前，还包括用合适的溶剂淋洗粗产品的步骤；和/或
    步骤ii分离得到结晶态的式(I)化合物之后，还包括用合适的溶剂淋洗、干燥的步骤；和/或
    步骤ii所述合适的溶剂选自腈类溶剂或腈类溶剂与水的混合溶剂；优选地，腈类溶剂选自乙腈、苯腈、苯乙腈或其组合，优选乙腈；和/或
    步骤ii所述加热温度优选40-80℃，更优选50-70℃；和/或
    步骤ii的加热时间至少2h，优选至少4h，更优选至少8小时。
  22. 一种药物组合物，其包含权利要求13-19中任一项的晶型I以及一种或多种药学上可接受的载体。
  23. 权利要求13-19中任一项的晶型I或者权利要求22的药物组合物在制备治疗或预防与未折叠蛋白质应答相关或者与调节IRE1-依赖性衰解的靶标相关的疾病、病症或病况的药物中的应用。
  24. 权利要求23的应用，其中所述与未折叠蛋白质应答相关的疾病、病症或病况选自B细胞自身免疫疾病、癌症和病毒感染；优选地，
    所述B-细胞自身免疫疾病选自：艾迪生病(Addision’s disease)、抗磷脂综合征、再生障碍性贫血、自体免疫溶血性贫血、自身免疫性肝炎、自身免疫性垂体炎、自身免疫性淋巴细胞增生性疾病、自身免疫性心肌炎、丘-施二氏综合征、后天性大疱性表皮松解、巨细胞性动脉炎、古德帕斯彻综合征、格雷夫斯病、格-巴二氏综合征、桥本甲状腺炎、特发性血小板减少性紫癜、IgA肾病、重症肌无力、落叶型天疱疮、寻常天疱疮、结节性多动脉炎、多发性肌炎/皮肌炎、类风湿性关节炎、硬皮病、斯耶格仑综合征、全身性红斑狼疮、高安氏动脉炎和韦格纳肉芽肿病；和/或
    所述癌症为选自以下的实体瘤：乳腺肿瘤、骨肿瘤、前列腺肿瘤、肺肿瘤、肾上腺肿瘤、胆管肿瘤、膀胱肿瘤、支气管肿瘤、神经组织肿瘤、胆囊肿瘤、胃肿瘤、唾液腺肿瘤、食道肿瘤、小肠肿瘤、子宫颈肿瘤、结肠肿瘤、直肠肿瘤、肝肿瘤、卵巢肿瘤、胰腺肿瘤、垂体腺瘤和分泌腺瘤；和/或
    所述癌症为药物-耐受性或辐射-耐受性实体瘤；和/或
    所述癌症为选自以下的血液肿瘤：淋巴瘤、白血病和未定性单克隆丙种球蛋白病(MGUS)；优选地，所述淋巴瘤选自多发性骨髓瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤，和/或白血病选自急性和慢性的淋巴细胞性和髓细胞性白血病；和/或
    所述病毒感染为被膜病毒感染；优选地，病毒感染为在复制和形成感染性后代时利用未折叠蛋白质应答途径的被膜病毒感染；更优选地，病毒感染选自麻疹病毒、痘病毒、埃博拉病毒(Ebola)、Epstein Barr病毒(EBV)、巨细胞病毒(CMV)、黄病毒属的病毒、和 丙型肝炎病毒(HCV)所致的感染；其中所述黄病毒属的病毒优选为日本脑炎病毒或西尼罗病毒。
  25. 权利要求23的应用，其中
    所述与调节IRE1-依赖性衰解的靶标相关的疾病、病症或病况选自神经病症、涉及胰岛素超量产生的病症和涉及炎症的病症；
    优选地，所述神经病症为精神分裂症，所述涉及胰岛素超量产生的病症为II型糖尿病，所述涉及炎症的病症选自肾小球性肾炎、各种形式的关节炎、多发性硬化和炎性肠病。
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