WO2024149366A1 - Procédé de préparation d'un intermédiaire d'inhibiteur de rock - Google Patents

Procédé de préparation d'un intermédiaire d'inhibiteur de rock Download PDF

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WO2024149366A1
WO2024149366A1 PCT/CN2024/071961 CN2024071961W WO2024149366A1 WO 2024149366 A1 WO2024149366 A1 WO 2024149366A1 CN 2024071961 W CN2024071961 W CN 2024071961W WO 2024149366 A1 WO2024149366 A1 WO 2024149366A1
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formula
compound
compound represented
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alkyl
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胡钦铨
娄军
王亮
张轶涵
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Wuhan Createrna Science and Technology Co Ltd
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Wuhan Createrna Science and Technology Co Ltd
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    • 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

Definitions

  • the invention belongs to the field of preparation methods of pharmaceutical compounds, and particularly relates to a preparation method of a ROCK inhibitor intermediate.
  • ROCK Rho-associated protein kinase
  • Rho kinase is a serine/threonine protein kinase and is the most detailed Rho downstream target effector molecule with the most detailed functional studies.
  • ROCK is distributed in tissues throughout the body, including ROCK1 (ROK ⁇ , p160-ROCK) and ROCK2 (ROK ⁇ ) subtypes, which regulate actin filament assembly and activin contraction, regulate the damage response of various cells, especially epithelial cells, endothelial cells and fibroblasts, and mediate the fibrosis process in the pathogenesis of IPF; ROCK also plays a role in many signaling pathways involved in autoimmunity and inflammation.
  • ROCK signaling can interfere with a variety of fibrosis initiation conditions, reduce fibroblast activation and collagen deposition, and improve organ function.
  • Preclinical studies have shown that both ROCK1 and ROCK2 play a role in pulmonary fibrosis.
  • ROCK kinase is activated in the lungs of IPF patients and disease-related animal models, and ROCK kinase inhibitors can prevent tissue fibrosis in the model and induce regression of established fibrosis.
  • ROCK inhibitors may dilate blood vessels but may not necessarily induce systemic hypotension. Therefore, ROCK kinase inhibitors have great potential for the treatment of idiopathic pulmonary fibrosis.
  • ROCK inhibitors that have been marketed worldwide are mainly fasudil, rosudil and natridil, and their indications are mainly cerebral vasospasm, glaucoma and high intraocular pressure.
  • ROCK inhibitor for IPF indication there is no ROCK inhibitor for IPF indication on the market.
  • Patent application CN113929678A discloses a ROCK inhibitor that has a good selective inhibitory effect on ROCK2.
  • the patent application also discloses a preparation method for this type of compound, but there are problems such as a long synthetic route, cumbersome preparation and purification operations, low yield and purity of intermediates and final products, obvious amplification effect, difficult quality control, high cost, and unsuitability for industrial production, which cannot meet the needs of industrial-scale production.
  • the present invention provides a method for preparing a compound represented by the following formula A, comprising the following steps (1) or (2):
  • the compound represented by formula A is prepared by formula A1 through step (1) or step (2);
  • X is a halogen, for example, Cl, Br or I;
  • Re is H, C 1-6 alkyl, basic group or basic radical. a molecule such as Na + , K + , methyl, ethyl, n-propyl or isopropyl;
  • Re1 , Re2 and Re3 are the same or different and are independently Cl, Br or I;
  • Step (1) Compound A1 is first subjected to a reduction reaction to obtain Compound A2, and Compound A2 is then subjected to a carboxylation reaction to obtain a compound represented by Formula A;
  • Step (2) Compound A1 is first subjected to a carboxylation reaction to obtain Compound A3, and Compound A3 is then subjected to a reduction reaction to obtain a compound represented by Formula A;
  • step (1) or (2) compound A1 or A2 wherein E is H is first subjected to a substitution reaction with X 1 -C( ⁇ O)C(R e1 )(R e2 )(R e3 ) to obtain compound A1 or A2 wherein E is -C( ⁇ O)C(R e1 )(R e2 )(R e3 ), and then the compound represented by formula A is prepared according to the route of step (1) and/or (2);
  • X 1 is a halogen, such as Cl, Br or I.
  • a method for preparing a compound represented by formula A comprises the following steps: Compound A1 is first subjected to a reduction reaction to obtain Compound A2, and Compound A2 is then subjected to a carboxylation reaction to obtain a compound represented by formula A;
  • E, X, and PG are defined as described in any one of the items;
  • the reduction reaction can be carried out under the action of a reducing agent, and the reducing agent is sodium borohydride, sodium cyanoborohydride, sodium acetate borohydride, potassium borohydride, borane or lithium aluminum hydride.
  • the reducing agent is sodium borohydride, sodium cyanoborohydride, sodium acetate borohydride, potassium borohydride, borane or lithium aluminum hydride.
  • the reduction reaction can be carried out in the presence of a solvent
  • the solvent can be an organic solvent, water or a mixed solvent thereof, for example, at least one of methanol, ethanol, isopropanol, n-propanol, tetrahydrofuran or water, preferably methanol, ethanol, a mixed solvent of water and methanol, or a mixed solvent of water and ethanol.
  • the temperature of the reduction reaction may be -20-50°C, for example, 10-30°C.
  • the reduction reaction time may be 0.1-24 h, for example 0.5-14 h.
  • the hydrolysis reaction may be carried out under the action of a base, and the base may be an inorganic base, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate or potassium phosphate.
  • a base may be an inorganic base, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate or potassium phosphate.
  • the hydrolysis reaction can be carried out in the presence of a solvent
  • the solvent can be an organic solvent, water or a mixed solvent thereof, for example, at least one of water, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, n-propanol, isopropanol, tert-butanol, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, toluene or acetone, preferably water, a mixed solvent of water and methanol, or a mixed solvent of water and ethanol.
  • the temperature of the hydrolysis reaction may be 0-120°C, preferably 10-80°C, for example 20-60°C.
  • the hydrolysis reaction time may be 1-48 hours, for example, 1-14 hours.
  • the preparation method of compound A1 comprises the following steps:
  • the reaction solution after the reaction in step (a) can be directly used in the reaction in step (b) without post-treatment.
  • the methylating agent may be methyl iodide, dimethyl sulfate, or trimethyl phosphate.
  • step (a) and step (b) may be carried out in the presence of a solvent, and the solvent is at least one of acetonitrile, tetrahydrofuran, 1,4-dioxane, and 2-methyltetrahydrofuran.
  • the reaction temperature of step (a) may be 0-80°C, preferably 20-50°C, more preferably 25-40°C, for example 25°C, 35°C or 40°C.
  • the reaction time of step (a) is 2-24 h, preferably 3-15 h, for example 3 h, 5 h, 6 h or 14 h.
  • step (a) compound PG-X can be reacted with compound A1-1 in batches.
  • step (a) the molar ratio of compound PG-X to compound A1-1 is (0.9-1.2):1, preferably 0.9:1 or 1:1.
  • the temperature of step (b) may be 0-60°C, preferably 20-50°C, more preferably 25-45°C, such as 25, 35°C or 45°C.
  • the reaction time of step (b) is 2-48 h, preferably 10-40 h, for example 12 h, 14 h or 40 h.
  • the present invention also provides the use of the preparation method of the compound of formula A in the preparation of the compound represented by formula (I).
  • R is H or C 1-6 alkyl
  • W and V are the same or different, and are independently selected from CH or N, and W and V are not N at the same time;
  • Y is selected from a chemical bond, -NH- or -N(C 1-6 alkyl)-; the C 1-6 alkyl in the -N(C 1-6 alkyl)- is unsubstituted or optionally substituted by one, two or more Rs ;
  • ring C is selected from the following groups which are unsubstituted or optionally substituted by one, two or more Ra : 3-6 membered heterocyclyl or 5-12 membered heteroaryl; said Ra is selected from F, Cl, CN, OH or C1-6 alkyl which is optionally substituted by one, two or more halogens;
  • ring C is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R b : C 3- 6 cycloalkyl, C 1-6 alkyl, 3-6 membered heterocyclyl or 5-12 membered heteroaryl; said R b is selected from 5-12 membered heteroaryl substituted by F, Cl, CN, OH, F or Cl;
  • the ring G does not exist or is a C 6-12 aryl group
  • the ring J is a 5-12 membered heteroaryl group, preferably a pyrazolyl group or an indazolyl group;
  • the R e is selected from halogen, CN, OH, unsubstituted or optionally substituted by one, two or more R s : C 1-6 alkyl, C 3- 6 cycloalkyl, C 1-6 alkoxy, C 6-12 aryl, 3-6 membered heterocyclyl or 5-12 membered heteroaryl;
  • the Rs is selected from halogen, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 6-12 aryl or 5-12 membered heteroaryl;
  • R g and R f are each independently selected from halogen, preferably F or Cl;
  • p 0, 1, 2, 3 or 4;
  • q 0, 1, 2, 3, or 4;
  • n 0, 1 or 2.
  • the ring C is selected from the following groups which are unsubstituted or optionally substituted with one, two or more Ra : azetidinyl, oxetanyl, azopentyl.
  • ring C is selected from azetidinyl which is unsubstituted or substituted with one, two or more F; azetidinyl which is unsubstituted or substituted with one, two or more CN; azetidinyl which is unsubstituted or substituted with one, two or more CF2 ; azetidinyl which is unsubstituted or substituted with one, two or more CF3 ; azetidinyl which is unsubstituted or substituted with F and/or OH; preferably:
  • ring C is selected from the following groups which are unsubstituted or optionally substituted with one, two or more Rb : cyclobutane, cyclopentane, cyclohexane, methyl, ethyl, n-propyl, isopropyl, pyridazinyl, azetidinyl, azocyclopentanyl, piperidinyl, pyridinyl.
  • ring C is selected from cyclobutane which is unsubstituted or substituted with one, two or more F; isopropyl; pyridazinyl; azetidinyl which is unsubstituted or substituted with one, two or more CN; azocyclopentane which is substituted with F and/or OH; ethyl which is unsubstituted or substituted with one, two or more F; -N-chloropyridine-piperidinyl; unsubstituted, or pyridinyl substituted by one, two or more F; preferably
  • Ring G is absent or is phenyl.
  • the present invention also provides a preparation method of formula (I), comprising: reacting a compound represented by formula (I-1) or a salt thereof with a compound represented by formula (I-2) to obtain a compound represented by formula (I);
  • L is a leaving group, for example, a halogen
  • the reaction of the compound represented by formula (I-1) or its salt with the compound represented by formula (I-2) is carried out in a reaction solvent;
  • the reaction solvent may be an organic solvent, water or a mixed solvent thereof;
  • the organic solvent is, for example, one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-diisopropylethylamine, dichloromethane, n-hexane, ethyl acetate, diethyl ether, methyl tert-butyl ether, toluene, chloroform, cyclohexane, 1,4-dioxane or acetone; more preferably, methanol, ethanol, One or more of n-butanol, N,N-dimethyl
  • the volume mass ratio of the reaction solvent to the compound represented by formula (I-1) or its salt is 4-5 mL/g, for example, 4 mL/g.
  • the method for preparing the compound represented by formula (I-1) or a salt thereof comprises the following steps:
  • Step A reacting the compound represented by formula (I-1a) with the compound represented by formula (I-1b) to obtain the compound represented by formula (I-1c);
  • Step B removing the protecting group Q in the compound represented by formula (I-1c) to obtain the compound represented by formula (I-1) or a salt thereof;
  • step A when R in step A is C 1-6 alkyl, the compound of formula (I-1a) wherein R is H is first subjected to a substitution reaction with X 1 -R to obtain the compound of formula (I-1a) wherein R is C 1-6 alkyl, and then the compound of formula (I-1c) is prepared according to the route of step A;
  • m is 0 or 1; when m is 1, Q is a protecting group on ring J, preferably tetrahydropyranyl (THP); when m is 0, the compound represented by formula (I-1a) and the compound represented by formula (I-1b) can directly react to obtain the compound represented by formula (I-1);
  • step B the protecting group Q in the compound represented by formula (I-1c) is removed in the presence of an acid to obtain a compound represented by formula (I-1) or a salt thereof; preferably, the salt is a hydrochloride salt, and the acid is a hydrogen chloride solution, for example, a solution of hydrogen chloride in ethyl acetate.
  • the salt is a hydrochloride salt
  • the acid is a hydrogen chloride solution, for example, a solution of hydrogen chloride in ethyl acetate.
  • the preparation method of the compound represented by formula (I-2) comprises the following steps:
  • Step I reacting the compound represented by formula A with the compound represented by formula (I-2a) or its hydrochloride to obtain the compound represented by formula (I-2b);
  • Step II removing the leaving group PG from the compound represented by formula (I-2b) to obtain the compound represented by formula (I-2);
  • R' is H, -OH or -NH 2 ;
  • the compound represented by formula (I-1) is compound IN-10 having the following structure:
  • the compound represented by formula (I-2) is compound IN-07 having the following structure:
  • the compound represented by formula (I) is compound L027 having the following structure:
  • the salt of the compound represented by formula (I-1) is compound IN-10 hydrochloride having the following structure:
  • the present invention protects a method for preparing a ROCK inhibitor intermediate, which reduces the number of steps in the overall route through a reasonable route sequence, can achieve multi-step continuous casting, and is simple to post-process; at the same time, each step and the overall yield are high, there are few by-products, the reaction conditions are mild, and the product purity is high.
  • the intermediate preparation method of the present invention is low in cost, has no obvious amplification effect, is suitable for large-scale production, and has good application prospects.
  • the present invention also provides an application of the ROCK inhibitor intermediate preparation method in the ROCK inhibitor, and provides a new ROCK inhibitor preparation method with a short reaction route, simple operation, controllable product quality, good safety, and suitability for industrialized scale-up production.
  • FIG. 2 1 H NMR of IN-04 in Preparation Example 2.
  • FIG. 4 1 H NMR of IN-03′ in Comparative Example 1.
  • room temperature described in the specification of this application should be understood as the ambient temperature when the experiment is performed, for example, 10-35°C, preferably 25°C ⁇ 5°C.
  • halogen refers to F, Cl, Br, and I. In other words, F, Cl, Br, and I may be described as “halogen" in the present specification.
  • C 1-6 alkyl is understood to preferably mean a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms.
  • the alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, n-butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,
  • C 1-6 alkoxy means "-OC 1-6 alkyl", wherein C 1-6 alkyl has the above definition.
  • C 3-6 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, or 6 carbon atoms.
  • the C 3-6 cycloalkyl may be a monocyclic hydrocarbon group, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane.
  • 3-6 membered heterocyclyl means a saturated monovalent monocyclic or bicyclic system containing 1-5, preferably 1-3 heteroatoms selected from N, O and S.
  • the heterocyclyl may be connected to the rest of the molecule by any one of its ring carbon atoms or nitrogen atoms (if present).
  • the heterocyclyl may include, but is not limited to, 4-membered rings such as azetidinyl, oxetanyl, 5-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl (tetrahydropyrrolyl or azocyclopentyl), imidazolidinyl, pyrazolidinyl, pyrrolinyl, or 6-membered rings such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.
  • the heterocyclyl is non-aromatic.
  • C6-12aryl is to be understood as preferably meaning a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12 carbon atoms, in particular a ring having 6 carbon atoms (" C6 aryl”), for example phenyl; or biphenyl, or a ring having 9 carbon atoms (“ C9 aryl”), for example indanyl or indenyl, or a ring having 10 carbon atoms (“ C10 aryl”), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl.
  • 5-12 membered heteroaryl is to be understood as including monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S, and in each case may be benzo-fused.
  • heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and benzo derivatives thereof, for example benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridin ...
  • heterocyclyl, heteroaryl or heteroarylene includes all possible isomeric forms thereof, such as positional isomers thereof.
  • pyridyl or pyridylene includes pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl and pyridin-4-yl;
  • thienyl or thienylene includes thien-2-yl, thien-2-yl, thien-3-yl and thien-3-yl.
  • the term "leaving group” as used herein shall mean a charged or uncharged atom or group that leaves during a substitution or displacement reaction. Suitable examples include, but are not limited to, H, F, Br, Cl, I, mesylate, tosylate, benzyl, p-methoxy benzyl, p-methylbenzyl or 2,4-dimethoxybenzyl, etc.
  • basic group as used herein shall mean an electron-deficient or positively charged organic group capable of forming a carboxylate with a carboxylic acid group, suitable examples include but are not limited to methyl, ethyl, n-propyl or isopropyl.
  • alkali ion shall mean an alkali metal ion or an alkaline earth metal ion, suitable examples include but are not limited to Na + , K + , Ca 2+ , Mg 2+ .
  • any method for preparing the compounds of the invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved. This may be accomplished by conventional protecting groups, such as those described in textbooks or reference books in the art.
  • the protecting groups may be removed at a convenient subsequent stage using methods known in the art.
  • other reagents may be used for the deprotection step, including but not limited to Pd/C, Pd(OH) 2 , PdCl 2 , Pd(OAc) 2 /Et 3 SiH, Raney nickel, appropriately selected acids, appropriately selected bases, fluorides, and the like.
  • the target compound can be isolated according to a known method, for example, by extraction, filtration or silica gel column chromatography.
  • 3-bromopyridine-4-aldehyde (20g, 107.5mmol), glycine ethyl ester hydrochloride (18g, 1.2eq), sodium carbonate (28.49g, 2.5eq), Cu2O (1.54g, 0.1eq) and solvent dimethyl sulfoxide (200mL, 10V) were added to the reaction bottle.
  • the reaction was carried out at 80°C for 20h.
  • the reaction system was cooled to room temperature, and ammonia water (50mL, 2.5V) and water (300mL, 15V) were added to the reaction system, extracted with ethyl acetate, and the organic phases were combined after separation.
  • the 1 H NMR of IN-01 is shown in FIG1 .
  • Filter to remove inorganic salts wash the filter cake with acetonitrile (5 mL), combine the filtrate and concentrate to dryness by rotary evaporation to obtain 2.7 g of yellow solid, which is directly used for the next step without purification.
  • the obtained off-white solid was slurried with ethanol/water (10 mL/5 mL) at room temperature for 14-16 h, filtered, and the obtained filter cake was dried with a diaphragm pump to obtain 1.06 g of compound IN-04 as a white solid.
  • the yield from IN-01 to IN-04 was 67.5%, and the HPLC purity of the obtained IN-04 was 94.74%.
  • the 1 H NMR of IN-04 is shown in FIG2 .
  • the filter cake was rinsed with ethyl acetate/n-heptane (volume ratio: 1/4), and the obtained filter cake was dried to obtain 11.4 kg of yellow solid (IN-02), with a yield of 90% and a HPLC purity of 94%.
  • step (3) Add NaOH (1.63 kg, 2.0 eq) and H 2 O (22 L, 3 V) to the solution obtained in step (2), raise the temperature to 50° C., and react for 1 h. Concentrate the reaction solution, remove acetonitrile, and add 30 L of ethanol to obtain an ethanol/water solution of IN-04'.
  • Tetrahydrofuran (4 L), IN-06 (400 g) and Pd/C (40 g, 10% w/w) were added to the reaction kettle, and the reaction was carried out at 50°C for 4 h under a hydrogen pressure of 20-25 atm.
  • the reaction solution was cooled and filtered, and the filtrate was concentrated under reduced pressure to obtain 282 g of IN-07 as an off-white solid with an HPLC purity of 99.2% and a yield of 94%.

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Abstract

La présente invention concerne un procédé de préparation d'un intermédiaire d'un inhibiteur de ROCK tel que représenté par la formule (A) et un procédé l'utilisant pour préparer l'inhibiteur de ROCK. Une séquence de voies rationnelles permet de réduire le nombre d'étapes de l'ensemble des voies, permet une alimentation en continu à plusieurs étapes, et permet de simplifier le post-traitement. De plus, le rendement de chaque étape et le rendement total sont supérieurs, et le procédé présente peu de sous-produits, une pureté de produit élevée, une voie de réaction courte, un fonctionnement simple, une qualité de produit contrôlable et une bonne sécurité, et est approprié pour une production à l'échelle industrielle.
PCT/CN2024/071961 2023-01-13 2024-01-12 Procédé de préparation d'un intermédiaire d'inhibiteur de rock Ceased WO2024149366A1 (fr)

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WO2018108156A1 (fr) * 2016-12-16 2018-06-21 成都先导药物开发有限公司 Inhibiteur de rock son application
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WO2021093795A1 (fr) * 2019-11-15 2021-05-20 武汉朗来科技发展有限公司 Inhibiteur de rock, son procédé de préparation et son utilisation
CN113929678A (zh) * 2020-07-14 2022-01-14 武汉朗来科技发展有限公司 一种rock抑制剂及其制备方法和用途
WO2022111222A1 (fr) * 2020-11-26 2022-06-02 安润医药科技（苏州）有限公司 Dérivé d'amine servant d'antagoniste du récepteur ep4 de la prostaglandine et son utilisation
CN115340529A (zh) * 2021-05-14 2022-11-15 武汉朗来科技发展有限公司 一种rock抑制剂的酸加成盐及盐的晶型、组合物和药物用途

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Publication number Priority date Publication date Assignee Title
WO2009037001A2 (fr) * 2007-09-19 2009-03-26 4Sc Ag Nouvelles pyridines tétrahydrocondensées
CN102216300A (zh) * 2009-09-30 2011-10-12 浙江贝达药业有限公司 作为蛋白激酶抑制剂的化合物和组合物
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WO2018108156A1 (fr) * 2016-12-16 2018-06-21 成都先导药物开发有限公司 Inhibiteur de rock son application
CN108203433A (zh) * 2016-12-16 2018-06-26 成都先导药物开发有限公司 一种rock抑制剂及其应用
CN111825675A (zh) * 2019-04-15 2020-10-27 武汉朗来科技发展有限公司 Rock抑制剂及其制备方法和用途
WO2021093795A1 (fr) * 2019-11-15 2021-05-20 武汉朗来科技发展有限公司 Inhibiteur de rock, son procédé de préparation et son utilisation
CN113929678A (zh) * 2020-07-14 2022-01-14 武汉朗来科技发展有限公司 一种rock抑制剂及其制备方法和用途
WO2022111222A1 (fr) * 2020-11-26 2022-06-02 安润医药科技（苏州）有限公司 Dérivé d'amine servant d'antagoniste du récepteur ep4 de la prostaglandine et son utilisation
CN115340529A (zh) * 2021-05-14 2022-11-15 武汉朗来科技发展有限公司 一种rock抑制剂的酸加成盐及盐的晶型、组合物和药物用途

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