Quinoline compounds

Abstract

The present invention provides a compound represented by general formula (A) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition, which are used to treat TGF-β-mediated related diseases and conditions, including but not limited to cancer, fibrotic diseases or inflammatory diseases.

Description

[0001] The present invention claims priority to a prior application with patent number 202011228021.0 filed with the State Intellectual Property Office of China on November 6, 2020, entitled “Quinoline Compounds”. The entire text of the above-mentioned prior application is incorporated herein by reference. Technical Field

[0002] The present invention relates to a novel quinoline compound or a pharmaceutically acceptable salt, a pharmaceutical composition containing the same and use thereof as a TGF-β inhibitor. Background Art

[0003] Transforming growth factor-β (TGF-β) is a multifunctional cytokine that regulates cell proliferation, differentiation and apoptosis through complex receptor signaling pathways on the cell surface in autocrine, paracrine and endocrine ways. In mammals, TGF-β mainly exists in three forms: TGF-β1, TGF-β2 and TGF-β3, which are located on different chromosomes, among which TGF-β1 has the highest proportion in somatic cells. TGF-β has three main cell receptors, namely type I (ALK5), type II and type III receptors. Type I (ALK5) and type II receptors are transmembrane serine / threonine kinases.

[0004] TGF-β1 transduces signals through two highly conserved single-transmembrane serine / threonine kinases, namely type I (ALK5) and type II TGF-β receptors. The latter phosphorylates serine / threonine residues in the ALK5GS region, creates binding sites for Smad proteins, and causes ALK5 activation, ultimately exerting biological functions through signaling pathways such as Smad.

[0005] TGF-β is a multifunctional growth factor superfamily with a wide range of biological activities. Studies have shown that TGF-β is involved in early embryonic development, cartilage and bone formation, extracellular matrix synthesis, inflammation, fibrosis, tumor formation and development, etc. Therefore, abnormal TGF-β signaling is related to the occurrence of various diseases, including cancer (such as colon cancer, melanoma, hepatocellular carcinoma, renal cancer, glioblastoma, pancreatic cancer, lung cancer and gastric cancer, etc.), fibrotic diseases (such as renal fibrosis, liver fibrosis, pulmonary fibrosis, etc.), inflammatory diseases (such as arthritis, chronic nephritis, acute nephritis, etc.).

[0006] Although some progress has been made in the treatment of malignant tumors, fibrotic diseases, inflammatory diseases and other related diseases, and some TGF-β small molecule inhibitors have been reported in existing literature for the treatment of cancer and / or fibrotic diseases (such as patent document WO2016057278A1), there are still a large number of patients who cannot get satisfactory clinical treatment effects, so there is still a need for better and more effective clinical treatments and solutions. In view of this, the present invention creatively designs a series of compounds based on the prior art, provides a series of TGF-β inhibitors with novel structures, excellent efficacy, high bioavailability, and good drugability, and is used to effectively treat TGF-β related diseases and conditions, including but not limited to tumors, fibrotic diseases, inflammatory diseases, etc. Summary of the invention

[0007] The present invention provides a compound represented by general formula (A) or a pharmaceutically acceptable salt thereof:

[0008]

[0009] in,

[0010] R 1 Selected from C1-C 10 Alkyl, the C1-C 10 The alkyl group is optionally substituted with halogen, CN, =O, OH, O(C1-C3 alkyl), NH2, NH(C1-C3 alkyl), or N(C1-C3 alkyl);

[0011] X is selected from O, NH, S or a chemical bond;

[0012] R 2 is selected from a 4- to 14-membered heterocyclic group containing at least one N atom as a ring atom, the 4- to 14-membered heterocyclic group being optionally substituted by R a replace;

[0013] R a is selected from halogen, CN, =O, OH, O(C1-C3 alkyl), NH2, NH(C1-C3 alkyl), N(C1-C3 alkyl)2, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R b replace;

[0014] R b Selected from F, Cl, Br, I, CN, OH, =O, NH2 or C1-C6 alkyl.

[0015] In some embodiments, R 1 is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by halogen, CN, =O or OH.

[0016] In some embodiments, R 1 is selected from C1-C3 alkyl, wherein the C1-C3 alkyl is optionally substituted by halogen, CN, =O or OH.

[0017] In some embodiments, R 1 Selected from methyl, ethyl, propyl or isopropyl.

[0018] In some embodiments, R 1 Selected from methyl.

[0019] In some embodiments, X is selected from O, NH, or a chemical bond. In some embodiments, X is selected from O or a chemical bond.

[0020] In some embodiments, X is selected from O.

[0021] In some embodiments, X is selected from a chemical bond.

[0022] In some embodiments, R 2 is selected from a 5-10 membered heterocyclic group containing at least one N atom as a ring atom, the 5-10 membered heterocyclic group is optionally replaced by R a replace.

[0023] In some embodiments, R 2 is selected from a 5-10 membered heterocyclic group containing one, two, three or four N atoms as ring atoms, the 5-10 membered heterocyclic group is optionally replaced by R a replace.

[0024] In some embodiments, R 2 is selected from 5-6 membered heteroaryl containing one or two N atoms as ring atoms, the 5-6 membered heteroaryl is optionally substituted by R a replace.

[0025] In some embodiments, R 2 is selected from a 9-10 membered heterocyclic group containing three or four N atoms as ring atoms, the 9-10 membered heterocyclic group is optionally replaced by R a replace.

[0026] In some embodiments, R 2 Selected from pyrazolyl or The pyrazolyl or Optional R a replace.

[0027] In some embodiments, R 2 Selected from or Said Optional R a replace.

[0028] In some embodiments, R a is selected from halogen, CN, OH, O(C1-C3 alkyl) or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally replaced by R b replace.

[0029] In some embodiments, R a is selected from C1-C3 alkyl, wherein the C1-C3 alkyl is optionally replaced by R b replace.

[0030] In some embodiments, R b is selected from F, Cl, Br, I or CN.

[0031] In some embodiments, R b Selected from F.

[0032] In some embodiments, R a Selected from methyl or trifluoromethyl.

[0033] In some embodiments, R 2 Selected from

[0034] In some embodiments, the compound or pharmaceutically acceptable salt represented by the general formula (A) is selected from the following compounds or pharmaceutically acceptable salts:

[0035]

[0036] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof of the present invention. In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient.

[0037] In another aspect, the present invention relates to a method for treating a disease mediated by TGF-β in a mammal, comprising administering a therapeutically effective amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0038] On the other hand, the present invention relates to the use of a compound represented by general formula (A) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a drug for preventing or treating a TGF-β-mediated disease.

[0039] On the other hand, the present invention relates to the use of a compound represented by general formula (A) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating TGF-β-mediated diseases.

[0040] In another aspect, the present invention relates to a compound of formula (A) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating a TGF-β-mediated disease.

[0041] In some embodiments, the TGF-β mediated disease is selected from cancer, a fibrotic disease, or an inflammatory disease.

[0042] The compound of the present invention has a novel structure, excellent pharmacokinetic properties, significant drug efficacy, can effectively treat TGF-β-mediated related diseases and symptoms, and has strong drugability.

[0043] Definitions and explanations of terms

[0044] Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The group definitions and compound structures after such combination and combination shall fall within the scope recorded in the specification of this application.

[0045] The term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable non-toxic acids or bases, including salts of inorganic acids and bases, and organic acids and bases.

[0046] The compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all within the scope of the present invention.

[0047] The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, wedge-shaped bonds and dashed bonds are used to represent the absolute configuration of a stereocenter. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the present invention.

[0048] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

[0049] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0050] The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0051] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, such as physiologically / pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.

[0052] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo will not occur on an aromatic group.

[0053] The term "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be appreciated by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and / or cannot be synthesized will be introduced.

[0054] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0055] The term "C1-C 10The term “alkyl” is understood to mean a straight or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkyl radical includes, but is not limited to, methyl, ethyl, propyl, 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, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. Preferably, “C1-C 10 "Alkyl" may include "C1-C6 alkyl" or "C1-C3 alkyl", "C1-C6 alkyl" is understood to mean a straight chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, and "C1-C3 alkyl" is understood to mean a straight chain or branched saturated monovalent hydrocarbon group having 1, 2, or 3 carbon atoms.

[0056] The term "C3-C6 cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0057] The term "4-14 membered heterocyclyl" means a monovalent monocyclic, bicyclic or tricyclic ring containing 1 to 7, preferably 1 to 5 heteroatoms independently selected from N, O and S as ring atoms, and the number of ring atoms is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, respectively. The term "5-12 membered heterocyclyl" means a monovalent monocyclic, bicyclic or tricyclic ring containing 1 to 7, preferably 1 to 5 heteroatoms independently selected from N, O and S as ring atoms, and the number of ring atoms is 5, 6, 7, 8, 9, 10, 11 or 12, respectively. The term "5-10 membered heterocyclyl" means a monovalent monocyclic, bicyclic or tricyclic ring containing 1 to 5 heteroatoms independently selected from N, O and S as ring atoms, and the number of ring atoms is 5, 6, 7, 8, 9 or 10, respectively. The term "9-10 membered heterocyclic group" means a monovalent monocyclic, bicyclic or tricyclic ring containing 1 to 5, preferably 1 to 4 heteroatoms independently selected from N, O and S as ring atoms, and the number of ring atoms is 9 or 10, respectively.

[0058] The heterocyclic group described in the "4-14 membered heterocyclic group", "5-12 membered heterocyclic group", "5-10 membered heterocyclic group" or "9-10 membered heterocyclic group" of the present invention may be saturated or partially saturated, or aromatic.

[0059] The "4-14 membered heterocyclic group" of the present invention can be a saturated or partially saturated monovalent monocyclic, bicyclic or tricyclic ring, including but not limited to: a 4-membered ring, such as azetidinyl and oxetanyl; or a 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a partially saturated 6-membered ring such as tetrahydropyridinyl; or a 7-membered ring, such as diazepanyl; optionally, the heterocyclic group can also be fused with an aryl or heteroaryl group. The heterocyclic group can also be bicyclic, including but not limited to: a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered ring, such as a hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring, a 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl ring.

[0060] The "4-14 membered heterocyclyl" of the present invention may also be a heteroaromatic ring system, including but not limited to "5-10 membered heteroaryl" or "5-6 membered heteroaryl", etc. The term "5-10 membered heteroaryl" is understood to include such monovalent monocyclic or bicyclic aromatic ring systems: it has 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and it contains 1-5, preferably 1-3 heteroatoms independently selected from N, O and S; and, in each case, may be benzo-fused. In particular, the "5-10 membered heteroaryl" is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc. and their benzo derivatives, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolyl, quinazolinyl, isoquinolyl, etc. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and it contains 1-3, preferably 1-2 heteroatoms independently selected from N, O and S. In particular, "5-6 membered heteroaryl" includes but is not limited to thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, etc.

[0061] The term "treatment" means administering the compound or formulation described herein to prevent, improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0062] (i) preventing a disease or disease state from occurring in a mammal, particularly where such mammal is susceptible to such disease state but has not yet been diagnosed as having such disease state;

[0063] (ii) inhibiting a disease or disease state, i.e., arresting its development;

[0064] (iii) ameliorating a disease or condition, even if causing regression of the disease or condition.

[0065] The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0066] The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients can enhance the handling characteristics of a pharmaceutical preparation, i.e., make the preparation more suitable for direct compression by increasing fluidity and / or adhesion. Examples of typical "pharmaceutically acceptable carriers" suitable for the above-mentioned preparations are: sugars, starches, cellulose and its derivatives, etc., which are commonly used excipients in pharmaceutical preparations.

[0067] The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0068] The words “comprise”, “comprise” or “comprises” and their English variations such as comprises or comprising should be construed in an open, non-exclusive sense, ie, “including but not limited to”.

[0069] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention.

[0070] The present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0071] Certain isotope-labeled compounds of the present application (e.g. 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0072] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.

[0073] The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0074] Typical routes of administration of the compounds of the present application or their pharmaceutically acceptable salts or their pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0075] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0076] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be prepared by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

[0077] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

[0078] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0079] In all administration methods of the compounds of general formula (A) described herein, the daily dosage is 0.01 to 100 mg / kg body weight, preferably 0.05 to 50 mg / kg body weight, more preferably 0.1 to 30 mg / kg body weight, in the form of single or divided doses.

[0080] The chemical reactions of the specific embodiments of the present invention are carried out in a suitable solvent, which must be suitable for the chemical changes of the present invention and the reagents and materials required. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments. DETAILED DESCRIPTION

[0081] The following examples illustrate the technical solutions of the invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0082] Unless otherwise specified, the ratios expressed for mixed solvents are volume mixing ratios.

[0083] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The units of NMR shifts are 10 -6 (ppm). The solvents for NMR determination are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 ” refers to the half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0084] The eluent mentioned below may be a mixed eluent formed by two or more solvents, the ratio of which is the volume ratio of each solvent.

[0085] Example 1: 7-(1-methyl-1H-pyrazol-4-yl)-4-((2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)oxy)quinoline

[0086]

[0087] Step 1: Synthesis of 7-bromo-4-((2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)oxy)quinoline

[0088]

[0089] 2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-ol (2.15 g, 10.0 mmol) was added to 20 mL of N,N-dimethylformamide, and 7-bromo-4-chloroquinoline (2.42 g, 10.0 mmol) and cesium carbonate (3.25 g, 10.0 mmol) were added. The mixture was heated to 100°C and stirred for 6 hours until the reaction was complete. The reaction solution was poured into 200 mL of ice water, and the solid was filtered and dried to obtain the title compound.

[0090] Step 2: Synthesis of 7-(1-methyl-1H-pyrazol-4-yl)-4-((2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)oxy)quinoline

[0091]

[0092] 7-Bromo-4-((2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)oxy)quinoline (4.20 g, 10.0 mmol), 1-methyl-4-pyrazoleboronic acid pinacol ester (2.08 g, 10.0 mmol), tris(dibenzylideneacetone)dipalladium (45.0 mg, 0.50 mmol), 2-dicyclohexylphospho-2,4,6-triisopropylbiphenyl (47.6 mg, 0.10 mmol) and potassium phosphate (4.24 g, 20.0 mmol) were added to 20 mL of 1,4-dioxane, and the reaction was completed after heating to 100°C under argon protection and stirring for 6 hours.

[0093] The reaction solution was purified by column chromatography (SiO2, dichloromethane / methanol = 40 / 1) to obtain the title compound.

[0094] 1 H NMR (400 Hz, DMSO-d6) δ H 8.89-8.88(m,1H),8.56-8.53(m,2H),8.22-8.18(m,3H),7.67-7.65(m,2H),7.17-7.16(m,1H),6.9 7-6.96(m,1H),4.30-4.26(m,2H),3.95(s,3H),3.00-2.97(m,2H),2.67-2.66(m,2H),1.57(s,3H).

[0095] LC / MS (m / z, MH + ):423.2.

[0096] Example 2 7-(1-methyl-1H-pyrazol-4-yl)-4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoline

[0097]

[0098] Step 1: Synthesis of 4-chloro-7-(1-methyl-1H-pyrazol-4-yl)quinoline

[0099]

[0100] 7-Bromo-4-chloroquinoline (500 mg, 2.10 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (520 mg, 2.50 mmol), potassium carbonate (573 mg, 4.20 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (240 mg, 0.21 mmol) were added to 4 ml of a mixed solution (dioxane: water = 3:1), and the mixture was heated to 100°C under argon protection and stirred for 6 hours before the reaction was completed. The reaction solution was subjected to column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound.

[0101] Step 2: Synthesis of 7-(1-methyl-1H-pyrazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

[0102]

[0103] 4-Chloro-7-(1-methyl-1H-pyrazol-4-yl)quinoline (200 mg, 0.82 mmol), bis-pinacol borate (418 mg, 1.64 mmol), potassium acetate (242 mg, 2.46 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (60.0 mg, 0.08 mmol) were added to 3 ml of dioxane, and the reaction was completed after heating to 100°C under argon protection and stirring for 6 hours. The reaction solution was subjected to column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound.

[0104] Step 3: Synthesis of 2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl trifluoromethanesulfonate

[0105]

[0106] 2-(6-Methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-ol (50.0 mg, 0.23 mmol) was added to 2 mL of anhydrous dichloromethane, and pyridine (37.0 mg, 0.46 mmol) was added. Trifluoromethanesulfonic anhydride (98.0 mg, 0.35 mmol) was added in an ice bath under argon protection. The reaction was stirred for 30 min. The reaction solution was concentrated and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound.

[0107] Step 4: Synthesis of 7-(1-methyl-1H-pyrazol-4-yl)-4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoline

[0108]

[0109] 7-(1-methyl-1H-pyrazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (50.0 mg, 0.14 mmol), 2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl trifluoromethanesulfonate (96.0 mg, 0.21 mmol), potassium carbonate (40.0 mg, 0.28 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (11.0 mg, 0.014 mmol) were added to 4 ml of a mixed solution (dioxane: water = 3:1). The mixture was heated to 100°C under argon protection and stirred for 8 hours. The reaction was completed. The reaction solution was concentrated and then subjected to column chromatography (SiO2, dichloromethane / methanol = 40 / 1) to obtain the title compound.

[0110] 1 H NMR (400 Hz, DMSO-d6) δ H 8.82-8.81(m,1H),8.33(s,1H),8.17(s,1H),8.04(s,1H),7.63-7.56(m,4H),7.35-7.34(m,1H),6. 75-6.74(m,1H),4.31-4.28(m,2H),3.89(s,3H),2.89-2.83(m,2H),2.65-2.64(m,2H),1.82(s,3H).

[0111] LC / MS (m / z, MH + ):407.2

[0112] Example 3: 4-((2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline

[0113]

[0114] Step 1: Synthesis of 4-((2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline

[0115]

[0116] 7-Bromo-4-((2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)oxy)quinoline (50.0 mg, 0.12 mmol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (33.0 mg, 0.14 mmol), tris(dibenzylideneacetone)dipalladium (11.0 mg, 0.01 mmol), 2-dicyclohexylphospho-2,4,6-triisopropylbiphenyl (5.00 mg, 0.01 mmol) and cesium carbonate (116 mg, 0.36 mmol) were added to 20 mL of 1,4-dioxane, and the reaction was completed after heating to 100°C under argon protection and stirring for 6 hours. The reaction solution was purified by column chromatography (SiO2, dichloromethane / methanol = 40 / 1) to obtain the title compound.

[0117] 1 H NMR (400 Hz, DMSO-d6) δ H 8.55-8.54(m,1H),8.32-8.30(m,1H),7.74-7.70(m,1H),7.60-7.58(m,2H),7.42-7.41(m,1H),6.95-6.93(m,1H),6.66-6.65(m ,1H),4.95(s,2H),4.37-4.34(m,2H),4.26-4.24(m,2H),4.08-4.05(m,2H),2.93-2.90(m,2H),2.64-2.61(m,2H),1.74(s,3H).

[0118] LC / MS (m / z, MH + ):533.2.

[0119] Biological activity and related properties test examples

[0120] Test Example 1: Determination of the inhibitory effect of the compounds of the present invention on TGFβRI kinase activity

[0121] The inhibitory effect of the compounds of the present invention on the activity of TGFβRI kinase ALK5 was tested using the following method.

[0122] Enzyme activity was detected using the ADP-Glo ​​Kinase Assay Kit (V9102 / 3, Promega). 50 nl of a 3-fold gradient dilution of a compound dissolved in 100% DMSO, 2.5 μl of ALK5 (Cat. 09-141, Carna) enzyme solution (2x) prepared with reaction buffer (40 mM Tris, pH 7.5; 20 mM MgCl2; 0.10% BSA; 1 mM DTT) were added to a 384-well plate (Cat. No. 4512, Corning) in sequence, and 2.5 μl of reaction buffer was added and incubated at room temperature for 10 minutes. After adding 2.5 μl of a mixed solution of ATP and TGFβRI substrate polypeptide (2x), react at 28°C for 2 hours, 5 μl of the ADP-Glo ​​solution in the kit was added to each well and placed at 28°C for 30 minutes. The chemiluminescent signal value was detected using an Envision multi-function microplate reader. The IC value of the compound's inhibitory effect on the enzyme was calculated based on the concentrations of the compound and the corresponding signal values. 50 value.

[0123] The biological activity of the compounds of the present invention was determined by the above test, and the IC 50 The values ​​are shown in Table 1 below.

[0124] Table 1 IC of the compounds of the present invention for inhibiting the activity of TGFβRI kinase ALK5 50

[0125] Test compound <![CDATA[IC 50 (nM)]]> Example 1 8.3 Example 2 3.8 Example 3 11

[0126] Test Example 2: Pharmacokinetics test of the compounds of the present invention

[0127] Mice were used as test animals, and the drug concentration in plasma at different time points after oral administration of the compound of the present invention was determined by LC / MS / MS method, so as to study the pharmacokinetic behavior of the compound of the present invention in mice and evaluate its pharmacokinetic characteristics.

[0128] Trial plan

[0129] 2.1 Trial Drugs

[0130] Compound Example 1, Example 2.

[0131] 2.2 Experimental animals

[0132] Six healthy adult BALB / c male mice were equally divided into two groups, with 3 mice in each group. The mice were purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd., with animal production license number: SCXK (Zhejiang) 2019-0001.

[0133] 2.3 Drug preparation

[0134] Weigh a certain amount of drug, dissolve it in 20% PG, 5% ethanol, 75% water, and prepare it into 5 mg / ml for oral administration.

[0135] 2.4 Administration

[0136] BALB / c mice were fasted overnight and then gavage-administered. The dosage was 10 mg / kg and the administration volume was 2 mL / kg.

[0137] After oral administration to mice, 40 μL of blood was collected from the eye socket at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, and 24 h after administration, anticoagulated with 5 μL EDTA-K2, and centrifuged at 12000 rpm, 4 °C, for 5 min to separate plasma, which was then stored at -20 °C.

[0138] Determine the content of the test compound in mouse plasma after oral administration of different concentrations of the drug: take the sample to melt at room temperature, vortex for 1 min; quantitatively transfer 15 μL to a 2ml 96-well plate, add 150 μL of internal standard precipitant, and oscillate (1200rpm*3min); centrifuge (4000rpm*15min), transfer 100 μL of the supernatant to a 1ml 96-well plate; blow dry with nitrogen, add 100 μL of re-solution (acetonitrile and water 1:9), oscillate and shake (900rpm*3min), and inject 20 μL for analysis. LC / MS / MS conditions: mobile phase A: 0.1% formic acid aqueous solution (the volume of formic acid accounts for 0.1% of the total volume of formic acid and water), mobile phase B: 0.1% formic acid acetonitrile (the volume of formic acid accounts for 0.1% of the total volume of formic acid and acetonitrile), chromatographic column: ACE C18 5μm (3.0mm*50mm), column temperature: 35°C, flow rate 0.5ml / min.

[0139] The pharmacokinetic parameters of the compounds of the present invention are as follows:

[0140] Table 2 Pharmacokinetic parameters of the compounds after single oral administration in mice

[0141]

Claims

1. A compound represented by general formula (A) or a pharmaceutically acceptable salt thereof: in, R 1 Selected from C1-C 10 Alkyl, the C1-C 10 The alkyl group is optionally substituted with halogen, CN, =O, OH, O(C1-C3 alkyl), NH2, NH(C1-C3 alkyl), or N(C1-C3 alkyl); X is selected from O or S; R 2 is selected from a 4- to 14-membered heterocyclic group containing at least one N atom as a ring atom, the 4- to 14-membered heterocyclic group being optionally substituted by R a replace; R a is selected from halogen, CN, OH, O(C1-C3 alkyl), NH2, NH(C1-C3 alkyl), N(C1-C3 alkyl)2, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R b replace; R b Selected from F, Cl, Br, I, CN, OH, =O, NH2 or C1-C6 alkyl.

2. The compound represented by general formula (A) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The R 1 is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by halogen, CN, =O or OH.

3. The compound represented by general formula (A) or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that: R 1 is selected from C1-C3 alkyl, wherein the C1-C3 alkyl is optionally substituted by halogen, CN, =O or OH.

4. The compound represented by general formula (A) or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that: R 1 Selected from methyl, ethyl, propyl or isopropyl.

5. The compound represented by general formula (A) or a pharmaceutically acceptable salt thereof according to claim 4, characterized in that: R 1 Selected from methyl.

6. The compound represented by general formula (A) or a pharmaceutically acceptable salt thereof according to claim 5, characterized in that: The X is selected from O.

7. The compound represented by general formula (A) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The R 2 is selected from a 5-10 membered heterocyclic group containing one, two, three or four N atoms as ring atoms, the 5-10 membered heterocyclic group is optionally replaced by R a replace.

8. The compound represented by general formula (A) or a pharmaceutically acceptable salt thereof according to claim 7, characterized in that: The R 2 Selected from pyrazolyl or The pyrazolyl or Optional R a replace.

9. The compound represented by general formula (A) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The R a is selected from halogen, CN, OH, O(C1-C3 alkyl) or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally replaced by R b replace.

10. The compound represented by general formula (A) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The R b is selected from F, Cl, Br, I or CN.

11. The compound of formula (A) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the following structures:

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

13. Use of the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 12, in the preparation of a medicament for preventing or treating a TGF-β-mediated disease.

14. The use according to claim 13, wherein the TGF-β mediated disease is selected from cancer, fibrotic disease or inflammatory disease.

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