Pyrazole compounds

Abstract

The compound represented by formula (A) or its pharmaceutically acceptable salt, pharmaceutical composition, and effective treatment of TGF-β-mediated diseases or conditions, including but not limited to cancer, inflammatory diseases, etc.

Description

Technical Field

[0001] The present invention relates to a novel pyrazole compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same and use thereof as a TGF-β inhibitor. Background Art

[0002] 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.

[0003] 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.

[0004] 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.).

[0005] 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, autoimmune diseases, etc. Summary of the invention

[0006] The present invention provides a compound represented by general formula (A) or a pharmaceutically acceptable salt thereof:

[0007]

[0008] wherein ring Q is selected from phenyl or 5-6 membered heteroaryl;

[0009] R 1 , R 2 independently selected from hydrogen, F, Cl, Br, I, CN, OH, NO2 or optionally replaced by R a Substituted with the following groups: NH2, SH, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C1-C 10 Alkoxy, C3-C 10 Cycloalkyloxy, 3-10 membered heterocyclyloxy, C1-C 10 Alkylsulfonyl, C3-C 10 Cycloalkylsulfonyl, 3-10 membered heterocyclic sulfonyl, aminosulfonyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C6-C 10 Aryloxy, 5-10 membered heteroaryloxy, C6-C 10 Arylsulfonyl, 5-10 membered heteroarylsulfonyl;

[0010] Every R a independently selected from F, Cl, Br, I, OH, CN, =O, NO2 or optionally R b Substituted with the following groups: NH2, SH, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C1-C 10Alkoxy, C3-C 10 Cycloalkyloxy, 3-10 membered heterocyclyloxy, C1-C 10 Alkylsulfonyl, C3-C 10 Cycloalkylsulfonyl, 3-10 membered heterocyclic sulfonyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C2-C 10 Alkenyloxy, C2-C 10 Alkynyloxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C6-C 10 Aryloxy, 5-10 membered heteroaryloxy, C6-C 10 Arylsulfonyl, 5-10 membered heteroarylsulfonyl;

[0011] Every R b Independently selected from F, Cl, Br, I, OH, CN, =O, NO2, NH2, SH, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C1-C 10 Alkoxy, C3-C 10 Cycloalkyloxy, 3-10 membered heterocyclyloxy, C1-C 10 Alkylsulfonyl, C3-C 10 Cycloalkylsulfonyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C6-C 10 Aryloxy or 5-10 membered heteroaryloxy, the C1-C 10 The alkyl group is optionally substituted by F, Cl, Br, I, CN.

[0012] In some embodiments, each R b Independently selected from F, Cl, Br, I, OH, CN, =O, NO2, NH2, SH, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C1-C 10 Alkoxy, C3-C 10 Cycloalkyloxy, 3-10 membered heterocyclyloxy, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C6-C 10 aryloxy or 5-10 membered heteroaryloxy.

[0013] In some embodiments, Ring Q is phenyl or a 5-membered heteroaryl.

[0014] In some embodiments, Ring Q is phenyl, thienyl, or furanyl.

[0015] In some embodiments, Ring Q is phenyl or thienyl.

[0016] In some embodiments, R 1 , R 2 independently selected from H, C1-C6 alkoxy, 3-10 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, the C1-C6 alkoxy, 3-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace.

[0017] In some embodiments, Ring Q is phenyl.

[0018] In some embodiments, Ring Q is thienyl.

[0019] In some embodiments, Ring Q is furanyl.

[0020] In some embodiments, R 1 , R 2 independently selected from H or optionally R a Substituted C1-C6 alkoxy.

[0021] In some embodiments, R 1 , R 2 independently selected from H or optionally R a Substituted with the following groups: 3-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl.

[0022] In some embodiments, each R a independently selected from optionally R b Substituted groups: C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-8 membered heterocyclic group, C1-C 10 Alkylsulfonyl, phenyl or 5-6 membered heteroaryl.

[0023] In some embodiments, each R a independently selected from optionally R b Substituted groups: C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-8 membered heterocyclic group, C1-C 10 Alkylsulfonyl or phenyl.

[0024] In some embodiments, each R a independently selected from optionally R bSubstituted groups: C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclic group, C1-C 10 Alkylsulfonyl, phenyl or 5-6 membered heteroaryl.

[0025] In some embodiments, each R b Independently selected from F, Cl, Br, I, OH, =O, NH2, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C1-C6 alkylsulfonyl, C3-C8 cycloalkylsulfonyl, phenyl or 5-6 membered heteroaryl, the C1-C6 alkyl is optionally substituted by F, Cl, Br, I, CN.

[0026] In some embodiments, each R b Independently selected from F, Cl, Br, I, OH, =O, C1-C6 alkyl, C1-C6 alkylsulfonyl or C3-C8 cycloalkylsulfonyl, the C1-C6 alkyl is optionally substituted by F, Cl, Br, I, CN.

[0027] In some embodiments, each R b Independently selected from F, Cl, Br, I, OH, =O, NH2, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.

[0028] In some embodiments, the ring Q is phenyl, the R 1 , R 2 independently selected from H or optionally R a Substituted C1-C6 alkoxy.

[0029] In some embodiments, the ring Q is phenyl, the R 1 , R 2 independently selected from H or optionally R a Substituted C1-C6 alkoxy, wherein R a is selected from 3-10 membered heterocyclic groups.

[0030] In some embodiments, the ring Q is phenyl, the R 1 , R 2 independently selected from H or optionally R a Substituted C1-C6 alkoxy, wherein R a is selected from a 6-membered heterocyclic group.

[0031] In some embodiments, the ring Q is phenyl, the R 1 , R 2 independently selected from H or optionally R a Substituted C1-C3 alkoxy, wherein R a Selected from morpholinyl.

[0032] In some embodiments, the ring Q is thienyl, the R 1 , R 2 independently selected from H or optionally R a Substituted with the following groups: 3-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl.

[0033] In some embodiments, the ring Q is thienyl, the R 1 , R 2 independently selected from H or optionally R a Substituted with the following groups: phenyl, pyridyl, pyrazolyl, tetrahydropyridyl, Azetidinyl, benzopyrazolyl, benzimidazolyl.

[0034] In some embodiments, each R a independently selected from optionally R b Substituted from the following groups: C1-C3 alkylsulfonyl, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C3 alkoxy or phenyl.

[0035] In some embodiments, each R b Independently selected from F, Cl, Br, I, OH, =O, C1-C6 alkyl, C1-C3 alkylsulfonyl or C3-C6 cycloalkylsulfonyl, wherein the C1-C6 alkyl is optionally substituted by F, Cl, Br, I or CN.

[0036] In some embodiments, the ring Q is thienyl, the R 1 , R 2 independently selected from H, phenyl, pyridyl, pyrazolyl or tetrahydropyridyl, wherein the phenyl, pyridyl, pyrazolyl or tetrahydropyridyl is optionally replaced by R a replace.

[0037] In some embodiments, the ring Q is thienyl, the R 1 , R 2 independently selected from H, phenyl, pyridyl, pyrazolyl or tetrahydropyridyl, wherein the phenyl, pyridyl, pyrazolyl or tetrahydropyridyl is optionally replaced by R a Substitution, the R a Optional R b Substituted from the following groups: C1-C6 alkylsulfonyl, C1-C6 alkyl or 3-6 membered heterocyclic group.

[0038] In some embodiments, the ring Q is thienyl, the R 1 , R 2independently selected from H, phenyl, pyridyl, pyrazolyl or tetrahydropyridyl, wherein the phenyl, pyridyl, pyrazolyl or tetrahydropyridyl is optionally replaced by R a Substitution, the R a Optional R b The following groups substituted: C1-C6 alkylsulfonyl, C1-C6 alkyl or 3-6 membered heterocyclic group, wherein R b Selected from hydroxy, C1-C6 alkyl or =O.

[0039] In some embodiments, the ring Q is furanyl, the R 1 , R 2 Independently selected from H or a 5-6 membered heteroaryl optionally substituted by C1-C6 alkyl.

[0040] In some embodiments, the ring Q is furanyl, the R 1 , R 2 Independently selected from H or pyrazolyl optionally substituted with C1-C3 alkyl.

[0041] In some embodiments, the ring Q is furanyl, the R 1 , R 2 Independently selected from H or

[0042] In some embodiments, the R 1 , R 2 independently selected from hydrogen atoms, methoxy groups,

[0043]

[0044] In some embodiments, the R 1 , R 2 independently selected from hydrogen atoms, methoxy groups,

[0045] 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:

[0046]

[0047]

[0048]

[0049] The present invention also provides a pharmaceutical composition, which comprises a compound represented by formula (A) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0050] Furthermore, the present invention relates to the use of the 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.

[0051] Furthermore, the present invention relates to the use of the 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.

[0052] Furthermore, 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.

[0053] In a preferred embodiment of the present invention, the TGF-β mediated disease is selected from cancer, fibrotic disease or inflammatory disease.

[0054] The present invention also relates to a method for preventing or treating TGF-β-mediated diseases, which comprises administering to a patient a therapeutically effective dose of a pharmaceutical preparation comprising the compound of general formula (A) or a pharmaceutically acceptable salt thereof.

[0055] 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.

[0056] Definitions and explanations of terms

[0057] 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.

[0058] 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.

[0059] 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.

[0060] The compounds of the present invention may have asymmetric carbon atoms (optical centers) or asymmetric double bonds. Racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all within the scope of the present invention.

[0061] The graphic representations of racemates or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, wedge-shaped and dashed bonds are used. The absolute configuration of a stereocenter is represented. 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.

[0062] 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 mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present invention. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus 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. The compounds containing asymmetric atoms of the present application can be isolated in optically pure form or in racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral raw materials or chiral reagents.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. For example, if a group is substituted with 2 R's, each R has an independent option.

[0068] When a substituent is cross-bonded to a ring, the substituent may be bonded to any atom on the ring. Represents R 1 , R 2 Substitution may occur at any position on ring Q.

[0069] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0070] The term "C1-C 10 The term “alkyl” is understood to mean a straight-chain or branched, saturated, monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkyl radical is, for example, 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, the “C1-C 10 "Alkyl" may include "C1-C6 alkyl" and "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.

[0071] The term "C1-C 10 "Alkoxy" is understood to mean "C1-C10 Alkyloxy" or "C1-C 10 Alkyl-O", preferably, "C1-C 10 The "alkoxy group" may include a "C1-C6 alkoxy group" and a "C1-C3 alkoxy group".

[0072] The term "C2-C 10 "Alkenyl" is understood to mean preferably a linear or branched monovalent hydrocarbon radical, which contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkenyl radicals can be divided into "cis" and "trans" orientations (or "E" and "Z" orientations). "C2-C6 alkenyl" is understood to mean a linear or branched monovalent hydrocarbon radical, which contains one or more double bonds and has 2, 3, 4, 5 or 6 carbon atoms. "C2-C6 alkenyl" is understood to mean a linear or branched monovalent hydrocarbon radical, which contains one or more double bonds and has 2, 3, 4, 5 or 6 carbon atoms. 10 Examples of "alkenyl" include, but are not limited to, vinyl (-CH=CH2), prop-1-enyl (-CH=CHCH3), prop-2-enyl (-CH2CH=CH2), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methyl-1,3-butadienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, or hex-4-enyl.

[0073] The term "C2-C 10 "Alkynyl" is understood as preferably meaning a linear or branched, monovalent hydrocarbon radical which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. "C2-C 10 Examples of "alkynyl" include, but are not limited to, ethynyl (-C≡CH), prop-1-ynyl (1-propynyl, -C≡CCH3), prop-2-ynyl (propargyl), but-1-ynyl, but-2-ynyl or but-3-ynyl. Examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), prop-1-ynyl (1-propynyl, -C≡CCH3), prop-2-ynyl (propargyl).

[0074] The term "C3-C 10 "Cycloalkyl" refers to a fully saturated carbon ring that can exist as a monocyclic, bridged or spirocyclic ring, and the ring atoms of the carbon ring are 3 to 10 carbon atoms. Non-limiting examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decane, etc. "C3-C 10"Cycloalkyl" preferably includes "C3-C8 cycloalkyl", "C3-C6 cycloalkyl" and the like. Non-limiting examples of "C3-C8 cycloalkyl" include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl; non-limiting examples of "C3-C6 cycloalkyl" include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0075] The term "cycloalkyloxy" may be understood as "cycloalkyl-O-".

[0076] The term "3-10 membered heterocyclyl" means a saturated or partially saturated monovalent monocyclic, fused, spiro or bridged ring containing 1-5, preferably 1-3 heteroatoms selected from N, O and S. In particular, "3-10 membered heterocyclyl" includes "3-8 membered heterocyclyl", "3-6 membered heterocyclyl" and the like. The "3-10 membered heterocyclyl" may include, but is not limited to: a 4-membered ring, such as azetidinyl, oxetanyl; 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 may be benzo-fused, in particular, the heterocyclic group may also be a benzo-fused ring group of the above-mentioned 4-membered heterocyclic group, 5-membered heterocyclic group or 6-membered heterocyclic group. The heterocyclic group may be bicyclic, for example but not limited to a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring. The nitrogen-containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, for example but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, and optionally, the heterocyclic group may be a benzo-fused ring group of the above-mentioned partially unsaturated nitrogen-containing heterocyclic group, for example but not limited to According to the present invention, the heterocyclic group is non-aromatic (when the heterocyclic ring is a benzo-condensed ring, the heterocyclic group part condensed with the benzene ring is non-aromatic).

[0077] The term "heterocyclyloxy" may be read as "heterocyclyl-O-".

[0078] The term "C6-C 10 "Aryl" means a monovalent aromatic or partially aromatic hydrocarbon ring having 6 to 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), for example phenyl; "C6-C 10"Aryl" also includes bicyclic groups in which an aromatic ring is fused to a non-aromatic ring or a partially saturated ring, and the group is attached to an atom on the aromatic ring. Non-limiting examples include, but are not limited to, phenyl, naphthyl, anthracenyl, indenyl, indanyl, 1,2-dihydronaphthyl and 1,2,3,4-tetrahydronaphthyl.

[0079] The term "heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems which typically have 5 to 20 ring atoms and contain 1-5 heteroatoms independently selected from N, O and S, unless otherwise indicated.

[0080] The term "5-10 membered heteroaryl" is to be understood as including monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and which contain 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S. and which additionally in each case may be benzo-fused. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl and the like; or azinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like. 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. Optionally, "5-10 membered heteroaryl" also includes the above aromatic ring system fused with a non-aromatic ring system, in particular, "5-10 membered heteroaryl" includes a polycyclic group formed by condensing the above 5-6 membered heteroaryl with a saturated or partially saturated heterocycle, and the atoms of the above 5-6 membered heteroaryl are used as the group connection sites, non-limiting examples include but are not limited to 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl, 2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl, and the like.

[0081] 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:

[0082] (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;

[0083] (ii) inhibiting a disease or disease state, i.e., arresting its development;

[0084] (iii) ameliorating a disease or condition, even if causing regression of the disease or condition.

[0085] 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.

[0086] 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.

[0087] 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”.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0098] In all administration methods described herein, the daily dosage of the compound of formula I 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.

[0099] 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

[0100] 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.

[0101] 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.

[0102] Example 1 Preparation of Compound 001

[0103] Synthesis of 4-(3-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-6-methoxyquinolin-7-yl)oxy)propyl)morpholine (Compound 001)

[0104]

[0105] The synthetic route of compound 001 is as follows:

[0106]

[0107] Step 1: Preparation of 2-oxo-2-(tetrahydro-2H-pyran-4-yl)ethyl benzoate

[0108]

[0109] Take benzoic acid (185g, 1.52mol) and dissolve it in 2L DMF. Add potassium carbonate (383g, 2.75mol) and stir for 10 minutes. Then add compound 2-bromo-1-(tetrahydro-2H-pyran-4-yl)ethanone (285g, 1.38mol) to the system. Stir and react at room temperature for 3h. TLC monitors the reaction to be complete. Add saturated brine, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title compound. LC-MS m / z: 249.2[M+H]+.

[0110] Step 2: Preparation of 1-(dimethylamino)-3-oxo-3-(tetrahydro-2H-pyran-4-yl)prop-1-en-2-ylbenzoate

[0111]

[0112] Place 2-oxo-2-(tetrahydro-2H-pyran-4-yl)ethyl benzoate (90.9 g, 0.3 mol) and DMF-DMA (160 mL, 1.2 mol) in a reaction bottle, stir at 100°C for 3 h, and monitor the reaction by TLC until it is complete. After the reaction is complete, concentrate under reduced pressure to obtain the title compound as a brown oil. LC-MS m / z: 304.3 [M+H] + .

[0113] Step 3: Preparation of methyl 3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ylbenzoate

[0114]

[0115] Dissolve the 1-(dimethylamino)-3-oxo-3-(tetrahydro-2H-pyran-4-yl)prop-1-en-2-ylbenzoate synthesized in step 2 in a reaction bottle containing 1L of acetic acid, slowly drop 150mL of 80% hydrazine hydrate under ice bath conditions, and after the addition is complete, warm to room temperature and monitor the reaction by TLC until it is complete. After the reaction is complete, add ethyl acetate and saturated sodium bicarbonate solution, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title compound. LC-MS m / z: 273.2[M+H] + .

[0116] Step 4: Preparation of 1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ylbenzoate

[0117]

[0118] 2,2'-bipyridine (51.5g, 0.33mol), copper acetate (59.9g, 0.33mol) and 1L 1,2-dichloroethane were placed in a reaction bottle, stirred at 75°C for 25 minutes and then cooled to room temperature. Cyclopropylboric acid (51.5g, 0.6mol), sodium carbonate (63.6g, 0.6mol) and the compound 3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ylbenzoic acid methyl ester synthesized in step 3 were added to the above reaction system, stirred at 75°C for 2h under oxygen atmosphere, and monitored by TLC until the reaction was complete. Cool to room temperature, add water and extract with dichloromethane, wash the organic layer with 0.5M dilute hydrochloric acid and saturated sodium chloride aqueous solution respectively, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain the title compound. LC-MS m / z: 313.0[M+H] + .

[0119] Step 5: Preparation of 1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ol

[0120]

[0121] The compound 1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ylbenzoate synthesized in step 4 and 750 mL of methanol were placed in a reaction bottle, 900 mL of 1M NaOH solution was added and reacted at room temperature for 2 h, and TLC was monitored until the reaction was complete. After the reaction was concentrated, the pH value was adjusted to 5-6 with 1M HCl, extracted with dichloromethane, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound. LC-MS m / z: 209.1 [M+H] + .

[0122] Step 6: Preparation of 7-(benzyloxy)-4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-6-methoxyquinoline

[0123]

[0124] Take 1-cyclopropyl-3 (-tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-ol (229mg, 1.1mmol), 7-benzyloxy-4-chloro-6-methoxyquinoline (299mg, 1mmol) and cesium carbonate (625mg, 2mmol) in a single-mouth bottle, add 10mL acetonitrile, stir and reflux for 12h, and monitor the reaction by TLC until the reaction is complete. After the reaction solution is concentrated, add ice-water mixture, a large amount of solid precipitates, and the title compound is obtained after filtration and drying. LC-MS m / z: 472.2 [M + H] + .

[0125] Step 7: Preparation of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-6-methoxyquinolin-7-ol

[0126]

[0127] Place the compound prepared in step 6 in a single-mouth bottle, add 10 mL of methanol and 50 mg of 10% palladium on carbon, evacuate, and then stir at room temperature for 2 h under a hydrogen atmosphere. Monitor by TLC until the reaction is complete. Remove the palladium on carbon by suction filtration, and concentrate the filtrate to obtain the title compound. LC-MS m / z: 382.2 [M+H] + .

[0128] Step 8: Preparation of 4-(3-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-6-methoxyquinolin-7-yl)oxy)propyl)morpholine

[0129]

[0130] The compound prepared in step 7 was placed in a single-mouth bottle, and 4-(3-chloropropyl)morpholine (164 mg, 1 mmol), cesium carbonate (625 mg, 2 mmol) and a catalytic amount of NaI were added to the single-mouth bottle in sequence, and then 10 mL of acetonitrile was added. The mixture was stirred and refluxed for 12 h, and the reaction was monitored by TLC until the reaction was complete. The reaction solution was filtered and concentrated, and the title compound was separated by column chromatography. LC-MS m / z: 509.3 [M+H] + .

[0131] 1H NMR(400MHz,DMSO-d6)δ8.50-8.48(d,J=5.2Hz,1H),7.95(s,1H),7.48(s,1H),7.38 (s,1H),6.63-6.61(d,J=5.2Hz,1H),4.21-4.18(m,2H),3.93(s,3H),3.80-3.77(m,2 H),3.72-3.68(m,1H),3.60-3.58(m,4H),3.29-3.23(m,2H),2.78-2.71(m,1H),2.4 9-2.45(m,2H),2.39(s,4H),2.00-1.94(m,2H),1.70-1.66(m,4H),1.08-0.93(m,4H)

[0132] Example 2 Preparation of Compound 002

[0133] Synthesis of 4-(3-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)quinolin-7-yl)oxy)propyl)morpholine (Compound 002)

[0134]

[0135] The preparation method is the same as that of Example 1, except that the commercially available raw material 7-benzyloxy-4-chloroquinoline (CAS: 178984-56-0) is used instead of 7-benzyloxy-4-chloro-6-methoxyquinoline to obtain the title compound. LC-MS m / z: 479.3 [M+H] + .

[0136] 1 H NMR (400MHz, DMSO-d6) δ8.62-8.61(d,J=5.2Hz,1H),8.18-8.16(d,J=9.1Hz,1H),7.95(s ,1H),7.39-7.38(m,1H),7.30-7.27(m,1H),6.62-6.61(m,1H),4.21-4.18(m,2H),3.79- 3.76(m,2H),3.72-3.66(m,1H),3.60-3.58(m,4H),3.28-3.22(m,2H),2.78-2.70(m,1H) ,2.49-2.45(m,2H),2.39(s,4H),1.99-1.93(m,2H),1.67-1.63(m,4H),1.09-0.93(m,4H)

[0137] Example 3 Preparation of Compound 003

[0138] Synthesis of 7-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-2-(4-(methylsulfonyl)phenyl)thieno[3,2-b]pyridine (Compound 003)

[0139]

[0140] Synthesis route:

[0141]

[0142] Step 1: Preparation of 2-bromo-7-(((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)thieno[3,2-b]pyridine

[0143]

[0144] Weigh 1-cyclopropyl-3 (-tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-ol (2.29 g, 11 mmol) prepared in step 5 of Example 1, commercially available 2-bromo-7-chlorothieno [3,2-b] pyridine (2.49 g, 10 mmol), and cesium carbonate (6.25 g, 20 mmol) in a single-mouth bottle, add 50 mL of acetonitrile, stir and reflux for 12 h, and monitor the reaction by TLC until the reaction is complete. Filter the reaction solution, concentrate the filtrate, and separate it by column chromatography to obtain the title compound. LC-MS m / z: 420.2, 422.2 [M+H] + .

[0145] Step 2: Preparation of 7-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-2-(4-(methylsulfonyl)phenyl)thieno[3,2-b]pyridine

[0146]

[0147] The compound 2-bromo-7-(((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)thieno[3,2-b]pyridine (420 mg, 1 mmol), 4-methanesulfonylphenylboronic acid (240 mg, 1.2 mmol), potassium carbonate (417 mg, 3 mmol) and 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (37 mg, 0.05 mmol) synthesized in step 1 were weighed and placed in a reaction bottle, dioxane (20 mL) and water (5 mL) were added, the system was evacuated and replaced with argon, and the reaction was stirred at 100°C under an argon atmosphere for 1.5 h, and the reaction was monitored by TLC until the reaction was complete. Water and ethyl acetate were added for extraction, the organic phase was washed with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the title compound. LC-MS m / z: 496.1 [M+H] + .

[0148] 1 H NMR (400MHz, DMSO-d6) δ8.58-8.57(d,J=5.4Hz,1H),8.28(s,1H),8.19-8.17(d,2H),8.06-8.02(m,3H),6.83-6.82(d,J=5. 4Hz,1H),3.82-3.79(m,2H),3.74-3.68(m,1H),3.29-3.26(m,5H),2.82-2.74(m,1H),1.70-1.64(m,4H),1.09-0.94(m,4H).

[0149] Example 4 Preparation of Compound 004

[0150] Synthesis of 2-(4-(7-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)thiophene[3,2-b]pyridin-2-yl)pyridin-2-yl)propanol (Compound 004)

[0151]

[0152] Synthesis route (one-pot method):

[0153]

[0154] 2-(4-bromopyridin-2-yl)-2-propanol (260 mg, 1.2 mmol), bipyridinyl borate (380 mg, 1.5 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (80 mg, 0.12 mmol) and potassium acetate (537 mg, 3.6 mmol) were placed in a three-necked reaction bottle, 10 mL of dioxane was added, and the reaction was stirred at 100 ° C for 12 h under argon atmosphere, and monitored by TLC until the reaction was complete. The mixture was cooled to room temperature, and 5 mL of a dioxane solution of 2-bromo-7-(((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)thieno[3,2-b]pyridine (420 mg, 1 mmol) and 5 mL of an aqueous solution of potassium carbonate (417 mg, 3 mmol) were added by syringe, respectively. The mixture was stirred at 100°C for 2 h under an argon atmosphere and monitored by TLC until the reaction was complete. After the reaction was completed, water and ethyl acetate were added for extraction, and the organic phase was washed with water and a saturated sodium chloride aqueous solution in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the title compound. LC-MS m / z: 477.2 [M+H] + .

[0155] 1 H NMR(400MHz, DMSO-d6)δ8.63-8.58(dd,J=5.1Hz,J=5.4Hz,2H),8.30(s,1H),8.03(s,2H),7.79-7.77(m,1H),6.85-6.84(d,J=5.4Hz,1H),5 .40(s,1H),3.81-3.79(m,2H),3.74-3.68(m,1H),3.30-3.26(m,2H), 2.82-2.74(m,1H),1.69–1.64(m,4H),1.50(s,6H),1.10-0.94(m,4H)

[0156] Example 5 Preparation of Compound 005

[0157] Synthesis of 1-(4-(7-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)thiophen[3,2-b]pyridin-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one

[0158]

[0159] The preparation method is the same as that of Example 3, except that the commercially available raw material 1-acetyl-5,6-dihydro-2H-pyridine-4-boronic acid pinacol ester (CAS: 1227068-67-8) is used instead of 4-methanesulfonylphenylboronic acid to obtain the title compound. LC-MS m / z: 465.2 [M+H]+ .

[0160] 1 H NMR (400MHz, DMSO-d6) δ8.48-8.47(d,J=5.4Hz,1H),7.99(s,1H),7.55-7.53(d,1H),6.74-6.72(m,1H),6.42-6.40(m,1H),4.21-4.15(d,2H),3. 80-3.78(m,2H),3.71-3.65(m,3H),3.31-3.24(m,2H),2.78-2.69(m,2H ),2.58(s,1H),2.09-2.05(m,3H),1.67-1.62(m,4H),1.08-0.93(m,4H).

[0161] Example 6 Preparation of Compound 006

[0162] Synthesis of 7-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-2-(1H-pyrazol-4-yl)thienyl[3,2-b]pyridine

[0163]

[0164] The preparation method is the same as that of Example 3, except that commercially available raw material 4-pyrazoleboronic acid pinacol ester (CAS: 269410-08-4) is used instead of 4-methanesulfonylphenylboronic acid to prepare the title compound.

[0165] LC-MS m / z:408.1[M+H] + .

[0166] 1 H NMR(400MHz,DMSO-d6)δ13.30(bs,1H),8.50-8.49(d,J=5.4Hz,1H),8.42(s,1H),8.07(s,1H),8.03(s,1H),7.74(s,1H),6.72-6.71 (d,J=5.4Hz,1H),3.85-3.82(m,2H),3.76-3.71(m,1H),3.34-3.29(m,2H),2.83-2.76(m,1H),1.72-1.67(m,4H),1.12-0.97(m,4H)

[0167] Example 7 Preparation of Compound 007

[0168] Synthesis of 7-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-2-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)thieno[3,2-b]pyridine

[0169]

[0170] The preparation method is the same as that of Example 3, except that commercially available 1-(oxetane-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS: 1339890-99-1) is used instead of 4-methanesulfonylphenylboronic acid to prepare the title compound. LC-MS m / z: 464.2 [M+H] + .

[0171] 1 H NMR (400MHz, DMSO-d6) δ8.53(s,1H),8.47-8.46(d,J=5.4Hz,1H),8.16(s,1H),7.99(s,1H),7.73(s,1H),6.71-6.70(d,J=5.4Hz,1H),5.65-5. 61(m,1H),4.96-4.93(m,4H),3.81-3.78(m,2H),3.72-3.66(m,1H),3.3 1-3.25(m,2H),2.79-2.72(m,1H),1.68-1.63(m,4H),1.08-0.93(m,4H)

[0172] Example 8 Preparation of Compound 008

[0173] Synthesis of 7-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-2-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)thieno[3,2-b]pyridine

[0174]

[0175] The preparation method is the same as that of Example 3, except that commercially available 1-(tetrahydropyran-4-yl)-1H-pyrazole-4-boronic acid pinacol ester (CAS: 1040377-03-4) is used instead of 4-methanesulfonylphenylboronic acid to obtain the title compound.

[0176] LC-MS m / z:492.2[M+H] + .

[0177] 1H NMR(400MHz,DMSO-d6)δ8.52-8.50(m,2H),8.08-8.05(d,2H),7.75(s,1H ),6.76-6.75(d,J=5.4Hz,1H),4.55-4.49(m,1H),4.06-4.03(m,2H),3.87 -3.84(m,2H),3.78-3.73(m,1H),3.57-3.51(m,2H),3.37-3.31(m,2H),2 .85-2.78(m,1H),2.08-1.97(m,4H),1.74-1.69(m,4H),1.14-0.99(m,4H)

[0178] Example 9 Preparation of Compound 009

[0179] Synthesis of 1-(4-(7-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy]thieno[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

[0180]

[0181] The preparation method is the same as that of Example 3, except that commercially available 2-methyl-1-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-2-ol (CAS: 1082503-77-2) is used instead of 4-methanesulfonylphenylboronic acid to prepare the title compound. LC-MS m / z: 480.2 [M+H] + .

[0182] 1 H NMR (400MHz, DMSO-d6) δ8.46-8.45(d,J=5.4Hz,1H),8.23(s,1H),8.00(s,2H),7.70(s,1H),6.70-6.69(d,J=5.4Hz,1H),4.79(s,1 H),4.07(s,2H),3.81-3.78(m,2H),3.72-3.67(m,1H),3.31-3.25(m,2H),2.79-2.72(m,1H),1.68-1.63(m,4H),1.11-0.93(m,10H)

[0183] Example 10 Preparation of Compound 010

[0184] Synthesis of 7-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-2-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-b]pyridine

[0185]

[0186] The preparation method is the same as that of Example 3, except that commercially available 1-methylpyrazole-4-boronic acid pinacol ester (CAS: 761446-44-0) is used instead of 4-methanesulfonylphenylboronic acid to prepare the title compound.

[0187] LC-MS m / z:422.2[M+H] + .

[0188] 1 H NMR (400MHz, DMSO-d6) δ8.46-8.45(d,J=5.4Hz,1H),8.31(s,1H),7.99(s,2H),7.67(s,1H),6.70-6.69(d,J=5.4Hz,1H),3.9 0(s,3H),3.81-3.78(m,2H),3.72-3.68(m,1H),3.29-3.25(m,2H),2.77-2.74(m,1H),1.68-1.66(m,4H),1.06-0.95(m,4H).

[0189] Example 12 Preparation of Compound 012

[0190] Synthesis of 7-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-2-(1-(3-fluoropropyl)-1H-pyrazol-4-yl)thieno[3,2-b]pyridine

[0191]

[0192] Compound 006 (204 mg, 0.50 mmol) was added to 5 mL of N,N-dimethylformamide, cesium carbonate (325 mg, 1.00 mmol) and 3-fluoro-1-iodopropane (95.0 mg, 0.50 mml) were added, and the mixture was heated to 80°C and stirred until the reaction was complete as monitored by TLC. 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the title compound was separated by column chromatography.

[0193] 1H NMR(400MHz,DMSO-d6)δ8.48-8.46(m,1H),8.41(s,1H),8.04(s,1H),8.00(s ,1H),7.70(s,1H),6.72-6.70(m,1H),4.57-4.55(m,1H),4.46-4.43(m,1H), 4.31-4.28(m,2H),3.82-3.79(m,2H),3.72-3.70(m,1H),3.29-3.26(m,2H), 2.78-2.74(m,1H),2.28-2.18(m,2H),1.68-1.67(m,4H),1.07-0.96(m,4H).

[0194] LC-MS m / z:468.2[M+H] + .

[0195] Example 13 Preparation of Compound 013

[0196]

[0197] The preparation method is the same as Example 12, except that commercially available iodocyclobutane (CAS: 38557-29-8) is used instead of 3-fluoro-1-iodopropane (CAS: 462-40-8) to prepare the title compound.

[0198] LC-MS m / z:462.2[M+H] + .

[0199] 1 H NMR(400MHz, DMSO-d6)δ8.48-8.47(m,2H),8.05-8.01(m,2H),7.71(s,1H),6.72-6.71(m,1H),4.93-4.89(m,1H),3.83-3.80(m,2H), 3.72-3.70(m,1H),3.28-3.24(m,4H),2.78-2.76(m,1H),2.45-2.43(m,2H),1.86-1.84(m,2H),1.70-1.66(m,4H),1.08-0.97(m,4H).

[0200] Example 14 Preparation of Compound 014

[0201]

[0202] The preparation method is the same as Example 12, except that commercially available 1,1-difluoro-2-iodoethane (CAS: 598-39-0) is used instead of 3-fluoro-1-iodopropane (CAS: 462-40-8) to obtain the title compound.

[0203] LC-MS m / z:472.2[M+H] + .

[0204] 1 H NMR(400MHz,DMSO-d6)δ8.49-8.47(m,1H),8.41(s,1H),8.13(s,1H),8.00(s,1H),7.75(s,1H),6.73-6.72(m,1H),6.57-6.3 0(m,1H),4.75-4.66(m,2H),3.82-3.70(m,3H),3.30-3.28(m,2H),2.76-2.74(m,1H),1.67-1.66(m,4H),1.07-0.96(m,4H).

[0205] Example 15 Preparation of Compound 015

[0206]

[0207] The preparation method is the same as Example 12, except that commercially available 2,2,2-trifluoroethyl trifluoromethanesulfonate (CAS: 6226-25-1) is used instead of 3-fluoro-1-iodopropane (CAS: 462-40-8) to obtain the title compound.

[0208] LC-MS m / z:490.2[M+H] + .

[0209] 1 H NMR(400MHz,DMSO-d6)δ8.50-8.47(m,2H),8.19(s,1H),8.00(s,1H),7.79(s,1H),6.74-6.73(m,1H),5.24- 5.21(m,2H),3.82-3.69(m,3H),3.29-3.27(m,2H),2.78-2.74(m,1H),1.69-1.66(m,4H),1.07-0.96(m,4H).

[0210] Example 16 Preparation of Compound 016

[0211]

[0212] Step 1: tert-Butyl 3-(4-(7-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)thieno[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylic acid

[0213]

[0214] Compound 006 (408 mg, 1.00 mmol) was added to 5 mL of N,N-dimethylformamide, cesium carbonate (325 mg, 1.00 mmol) and 1-Boc-3-iodoazetidine (285 mg, 1.00 mml) were added, and the mixture was heated to 80°C and stirred until the reaction was complete as monitored by TLC. 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the title compound was separated by column chromatography.

[0215] LC-MS m / z:563.2[M+H] + .

[0216] Step 2: 2-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-7-(((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-(yl)oxy)thieno[3,2-b]pyridine

[0217]

[0218] The product obtained in step 1 (284 mg, 0.50 mmol) was added to 5 mL of hydrogen chloride dioxane solution and stirred at room temperature until the reaction was complete as monitored by TLC. The crude product was obtained by concentration under reduced pressure and directly used in the next step.

[0219] LC-MS m / z:463.2[M+H] + .

[0220] Step 3: Preparation of Compound 016

[0221]

[0222] The crude product (232 mg, 0.50 mmol) obtained in the previous step was added to 5 mL of N,N-dimethylformamide, and cesium carbonate (325 mg, 1.00 mmol) and 3-fluoro-1-iodopropane (95.0 mg, 0.50 mml) were added, stirred at room temperature, and monitored by TLC until the reaction was complete. 50 mL of water was added to the reaction solution, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and concentrated, and the title compound was separated by column chromatography.

[0223] LC-MS m / z:523.2[M+H]+ .

[0224] 1 H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.47-8.45(m,1H),8.08(s,1H),7.98(s,1H),7.71(s,1H),6.71-6.69(m,1H),5.05-5.01(m,1H),4.57-4.5 4(m,1H),4.45-4.42(m,1H),3.78-3.71(m,5H),3.36-3.28(m,4H),2.77 -2.73(m,1H),2.61-2.58(m,2H),1.75-1.65(m,6H),1.06-0.97(m,4H).

[0225] Example 17 Preparation of Compound 017

[0226]

[0227] The preparation method is the same as Example 12, except that commercially available 1,3,2-dioxosulfane, 5,5-difluoro, 2,2-dioxide (CAS: 1215071-15-0) is used instead of 3-fluoro-1-iodopropane (CAS: 462-40-8) to obtain the title compound.

[0228] LC-MS m / z:502.2[M+H] + .

[0229] 1 H NMR(400MHz,DMSO-d6)δ8.48-8.46(m,1H),8.38(s,1H),8.10(s,1H),7.99(s,1H),7.75(s,1H),6.72-6.71(m,1H),5.80(b r,1H),4.78-4.70(m,2H),3.81-3.67(m,5H),3.29-3.28(m,2H),2.77-2.73(m,1H),1.68-1.65(m,4H),1.06-0.95(m,4H).

[0230] Example 18 Preparation of Compound 018

[0231]

[0232] The preparation method is the same as Example 12, except that commercially available 2,2-difluoropropyl trifluoromethanesulfonate (CAS: 784193-15-3) is used instead of 3-fluoro-1-iodopropane (CAS: 462-40-8) to prepare the title compound.

[0233] LC-MS m / z:486.2[M+H] + .

[0234] 1 H NMR(400MHz,DMSO-d6)δ8.48-8.46(m,1H),8.38(s,1H),8.11(s,1H),7.99(s,1H),7.75(s,1H),6.72-6.71(m,1H), 4.71-4.68(m,2H),3.81-3.69(m,3H),3.28-3.26(m,2H),2.76-2.74(m,1H),1.71-1.62(m,7H),1.06-0.95(m,4H).

[0235] Example 19 Preparation of Compound 019

[0236]

[0237] The preparation method is the same as that of Example 3, except that commercially available 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS: 1206640-82-5) is used instead of 4-methanesulfonylphenylboronic acid to obtain the title compound.

[0238] LC-MS m / z:458.2[M+H] + .

[0239] 1 H NMR(400MHz,DMSO-d6)δ8.90(s,1H),8.52-8.50(m,1H),8.41(s,1H),7.99(s,1H),7.90(s,1H),8.02-7.73(m,1H), 6.76-6.74(m,1H),3.81-3.69(m,3H),3.32-3.25(m,2H),2.76-2.74(m,1H),1.69-1.66(m,4H),1.06-0.96(m,4H).

[0240] Example 20 Preparation of Compound 020

[0241]

[0242] The preparation method is the same as that of Example 3, except that commercially available 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (CAS: 847818-74-0) is used instead of 4-methanesulfonylphenylboronic acid to obtain the title compound.

[0243] LC-MS m / z:422.2[M+H] + .

[0244] 1 H NMR (400MHz, DMSO-d6) δ8.47-8.45(m,1H),7.54(s,1H),7.47(s,1H),7.33(s,1H),6.61-6.60(m,1H),6.49(s,1H),4.04( s,3H),3.89-3.86(m,2H),3.54-3.50(m,1H),3.35-3.29(m,2H),2.77-2.74(m,1H),1.84-1.68(m,4H),1.07-0.95(m,4H).

[0245] Example 21 Preparation of Compound 021

[0246]

[0247] The preparation method is the same as Example 3, except that commercially available phenylboronic acid (CAS: 98-80-6) is used instead of 4-methanesulfonylphenylboronic acid to prepare the title compound.

[0248] LC-MS m / z:418.2[M+H] + .

[0249] 1 H NMR(400MHz,DMSO-d6)δ8.50-8.48(m,1H),7.77-7.75(m,3H),7.49-7.41(m,4H),6.63-6.62(m,1H),3.97-3 .93(m,2H),3.60-3.58(m,1H),3.43-3.36(m,2H),2.86-2.83(m,1H),1.92-1.76(m,4H),1.13-1.04(m,4H).

[0250] Example 22 Preparation of Compound 022

[0251]

[0252] The preparation method is the same as that of Example 3, except that commercially available 4-trifluoromethoxyphenylboronic acid (CAS: 139301-27-2) is used instead of 4-methanesulfonylphenylboronic acid to prepare the title compound.

[0253] LC-MS m / z:502.2[M+H] + .

[0254] 1H NMR(400MHz,DMSO-d6)δ8.51-8.50(m,1H),7.78-7.73(m,3H),7.41(s,1H),7.33-7.31(m,2H),6.65-6.64(m,1H), 3.97-3.94(m,2H),3.60-3.59(m,1H),3.43-3.36(m,2H),2.86-2.82(m,1H),1.92-1.76(m,4H),1.14-1.04(m,4H).

[0255] Example 23 Preparation of Compound 023

[0256]

[0257] The preparation method is the same as that of Example 3, except that commercially available 2-methylindazole-5-boronic acid pinacol ester (CAS: 1189746-27-7) is used instead of 4-methanesulfonylphenylboronic acid to prepare the title compound.

[0258] LC-MS m / z:472.2[M+H] + .

[0259] 1 H NMR(400MHz,DMSO-d6)δ8.41-8.40(m,1H),7.97(s,1H),7.92(s,1H),7.72-7.61(m,3H),7.34(s,1H),6.55-6.54(m,1H),4.1 8(s,3H),3.90-3.87(m,2H),3.52-3.51(m,1H),3.36-3.30(m,2H),2.80-2.76(m,1H),1.86-1.70(m,4H),1.08-0.96(m,4H).

[0260] Example 24 Preparation of Compound 024

[0261]

[0262] The preparation method is the same as that of Example 3, except that commercially available 1-methyl-1H-benzimidazole-5-boronic acid naphthalene ester (CA S: 1107627-02-0) is used instead of 4-methanesulfonylphenylboronic acid to obtain the title compound.

[0263] LC-MS m / z:472.2[M+H] + .

[0264] 1H NMR (400MHz, CDCl3) δ8.51-8.49(m,1H),7.94(s,1H),7.89-7.86(m,1H),7.78( s,1H),7.76(s,1H),7.73-7.71(m,1H),7.42(s,1H),6.64-6.62(m,1H),4.0-3. 97(m,1H),3.94(s,3H),3.63-3.58(m,1H),3.44-3.38(m,2H),2.89-2.82(m,2H ),1.97-1.87(m,2H),1.80-1.77(m,2H),1.17-1.12(m,2H),1.08-1.03(m,2H).

[0265] Example 25 Preparation of Compound 025

[0266]

[0267] The preparation method is the same as Example 3, except that commercially available 6-(2-hydroxypropane-2-yl)pyridine-3-boronic acid (CAS: 1088496-42-7) is used instead of 4-methanesulfonylphenylboronic acid to prepare the title compound.

[0268] LC-MS m / z:477.2[M+H] + .

[0269] 1 H NMR(400MHz,DMSO-d6)δ9.04-9.04(m,1H),8.57-8.56(m,1H),8.29-8.26(m,1 H),8.16(s,1H),8.03(s,1H),7.82-7.80(m,1H),6.81-6.79(m,1H),5.39(s,1 H),3.83-3.80(m,2H),3.75-3.70(m,1H),3.32-3.30(m,2H),2.83-2.75(m,1H ),1.72-1.67(m,4H),1.51-1.49(m,6H),1.11-1.08(m,2H),1.01-0.96(m,2H).

[0270] Example 26 Preparation of Compound 026

[0271]

[0272] The preparation method is the same as that of Example 16, except that 3-fluoro-1-iodopropane in step 3 is replaced by methanesulfonic anhydride (CAS: 7143-01-3) to obtain the title compound.

[0273] LC-MS m / z:541.2[M+H] + .

[0274] 1 H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.50-8.48(m,1H),8.21(s,1H),8.00 (s,1H),7.76(s,1H),6.73-6.72(m,1H),5.39-5.32(m,1H),4.35-4.33(m,4 H),3.82-3.80(m,2H),3.72-3.70(m,1H),3.32-3.30(m,2H),3.16(s,3H),2 .81-2.73(m,1H),1.68-1.67(m,4H),1.07-1.06(m,2H),0.98-0.96(m,2H).

[0275] Example 27 Preparation of Compound 027

[0276]

[0277] The preparation method is the same as that of Example 16, except that 1-Boc-3-iodoazetidine in step 1 is replaced by N-Boc-4-iodopiperidine, and 3-fluoro-1-iodopropane in step 3 is replaced by cyclopropanesulfonyl chloride (CAS: 139631-62-2) to obtain the title compound.

[0278] LC-MS m / z:595.2[M+H] + .

[0279] 1 H NMR (400MHz, CDCl3) δ8.40-8.38(s,1H),7.77(s,1H),7.71(s,1H),7.41(s,1H),7.33(s,1H),6.54-6.53(m ,1H),4.30-4.22(m,1H),3.93-3.86(m,4H),3.55-3.50(m,1H),3.35-3.29(m,2H),3.03-2.97(m,2H),2.79 -2.72(m,1H),2.29 -2.22(m,3H),2.17 -2.07(m,2H),1.87-1.77(m,2H),1.72-1.70(m,2H),1.17-1.13(m,2H),1.09-1.04(m,2H),1.00-0.95(m,4H).

[0280] Example 28 Preparation of Compound 028

[0281]

[0282] The preparation method is the same as that of Example 16, except that 3-fluoro-1-iodopropane in step 3 is replaced by 2,2,2-trifluoroethyl trifluoromethanesulfonate (CAS: 6226-25-1) to obtain the title compound.

[0283] LC-MS m / z:545.2[M+H] + .

[0284] 1 H NMR (400MHz, CDCl3) δ8.40-8.38(s,1H),7.81-7.80(m,2H),7.42(s,1H),7.33(s,1H) ),6.54-6.53(m,1H),5.00-4.97(m,1H),3.99-3.95(m,2H),3.89-3.86(m,2H),3.78 -3.74(m,2H),3.55-3.49(m,1H),3.35-3.29(m,2H),3.16-3.09(m,2H),2.80-2.72( m,1H),1.87-1.80(m,2H),1.70-1.68(m,2H),1.08-1.03(m,2H),1.00-0.95(m,2H).

[0285] Example 29 Preparation of Compound 029

[0286]

[0287] The preparation method is the same as that of Example 3, except that commercially available p-methoxyphenylboronic acid (CAS: 5720-07-0) is used instead of 4-methanesulfonylphenylboronic acid to prepare the title compound.

[0288] LC-MS m / z:545.2[M+H] + .

[0289] 1H NMR (400MHz, DMSO-d6) δ8.51-8.50(m,1H),8.00(s,1H),7.91(s,1H),7.85-7.83(m,2H),7.10-7.08(m,2H),6.75-6.73(m,1H),3.85(s,3 H),3.84-3.79(m,2H),3.74-3.69(m,1H),3.34-3.28(m,2H),2.82-2.74(m,1H),1.71-1.66(m,4H),1.10-1.06(m,2H),1.00-0.95(m,2H).

[0290] Example 30 Preparation of Compound 030

[0291]

[0292] The preparation method is the same as that of Example 3, except that commercially available 4-trifluoromethylphenylboronic acid (CAS: 128796-39-4) is used instead of 4-methanesulfonylphenylboronic acid to prepare the title compound.

[0293] LC-MS m / z:486.2[M+H] + .

[0294] 1 H NMR(400MHz,DMSO-d6)δ8.57-8.56(m,1H),8.24(s,1H),8.14-8.12(m,2H),8.02(s,1H),7.89-7.87(m,2H),6.82-6.81(m,1H),3.8 2-3.78(m,2H),3.73-3.68(m,1H),3.29-3.26(m,2H),2.81-2.74(m,1H),1.70-1.64(m,4H),1.09-1.05(m,2H),0.99-0.94(m,2H).

[0295] Example 31 Preparation of Compound 031

[0296]

[0297] The preparation method is the same as that of Example 3, except that the 2-bromo-7-chlorothieno[3,2-b]pyridine in step 1 is replaced by 7-chloro-2-iodofuro[3,2-b]pyridine (CAS: 1071540-54-9), and the 4-methanesulfonylphenylboronic acid in step 2 is replaced by 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS: 761446-44-0) to obtain the title compound.

[0298] LC-MS m / z:406.2[M+H] + .

[0299] 1 H NMR (400MHz, DMSO-d6) δ8.35(s,1H),8.28-8.27(m,1H),7.99(s,1H),7.94(s,1H),7.18(s,1H),6.66-6.61(m,1H),3.92(s,3H),3. 82-3.78(m,2H),3.72-3.66(m,1H),3.34-3.26(m,2H),2.82-2.74(m,1H),1.71-1.66(m,4H),1.07-1.03(m,2H),0.97-0.92(m,2H).

[0300] Example 32 Preparation of Compound 032

[0301]

[0302] The preparation method is the same as that of Example 3, except that commercially available (1-(4-fluorophenyl)-1H-pyrazol-4-yl)boronic acid (CAS: 1072945-89-1) is used instead of 4-methanesulfonylphenylboronic acid to obtain the title compound.

[0303] LC-MS m / z:502.2[M+H] + .

[0304] 1 H NMR(400MHz,DMSO-d6)δ9.13(s,1H),8.50-8.49(m,1H),8.35(s,1H),8.00(s,1H),7.98-7.94(m,2H),7.84(s,1H),7.44-7.39(m,2H),6.74-6.7 2(m,1H),3.82-3.78(m,2H),3.73-3.67(m,1H),3.30-3.26(m,2H),2.81 -2.73(m,1H),1.70-1.64(m,4H),1.09-1.05(m,2H),0.98-0.93(m,2H).

[0305] Example 33 Preparation of Compound 033

[0306]

[0307] The preparation method is similar to that of Example 16, except that 1-Boc-3-iodoazetidine in step 1 is replaced by N-Boc-4-iodopiperidine, and 3-fluoro-1-iodopropane in step 3 is replaced by 2,2,2-trifluoroethyl trifluoromethanesulfonate (CAS: 6226-25-1) to obtain the title compound.

[0308] LC-MS m / z:573.2[M+H] + .

[0309] 1 H NMR (400MHz, CDCl3) δ8.46-8.44(m,1H),7.83(s,1H),7.78(s,1H),7.46(s,1H),7.40(s,1 H),6.60-6.59(m,1H),4.23-4.16(m,1H),3.97-3.93(m,2H),3.62-3.57(m,1H),3.43-3.36 (m,2H),3.15-3.12(m,2H),3.10-3.03(m,2H),2.87-2.79(m,1H),2.64-2.58(m,2H),2.21 -2.11(m,4H),1.95-1.84(m,2H),1.79-1.78(m,2H),1.16-1.11(m,2H),1.08-1.02(m,2H).

[0310] Example 34 Preparation of Compound 034

[0311]

[0312] The preparation method is similar to that of Example 12, except that 3-fluoro-1-iodopropane is replaced with 2-[1-(ethylsulfonyl)-3-azetidinylidene]acetonitrile (CAS: 1187595-85-2) to give the title compound.

[0313] LC-MS m / z:594.2[M+H] + .

[0314] 1H NMR (400MHz, CDCl3) δ8.49-8.48(m,1H),7.96(s,1H),7.94(s,1H),7.54(s,1H),7.41 (s,1H),6.64-6.62(m,1H),4.61-4.59(m,2H),4.24-4.22(m,2H),3.97-3.94(m,2H),3 .61-3.57(m,1H),3.43-3.37(m,4H),3.12-3.07(m,2H),2.87-2.80(m,1H),1.95-1.8 4(m,2H),1.79-1.76(m,2H),1.44-1.41(m,3H),1.16-1.11(m,2H),1.07-1.02(m,2H).

[0315] Example 35 Preparation of Compound 035

[0316]

[0317] The preparation method is the same as that of Example 3, except that 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (CAS: 2057507-40-9) is used instead of 4-methanesulfonylphenylboronic acid to obtain the title compound. LC-MS m / z: 477.2 [M+H] + .

[0318] 1 H NMR (400MHz, DMSO-d6) δ8.50-8.48 (m, 1H), 8.00 (m, 2H), 7.53 (s, 1H), 6.72-6.70 (m, 1H), 4.20-4.18 (m, 2H), 3.89 (s, 2H), 3.84-3.79 (m, 2H), 3.74-3.68 (m, 1H), 3.50-3.27 (m, 5H), 2.94-2.92 (m, 2H), 2.81-2.73 (m, 1H), 1.70-1.65 (m, 4H), 1.10-1.06 (m, 2H), 1.00-0.95 (m, 2H). Test examples of biological activity and related properties

[0319] Test Example 1: Determination of the inhibitory effect of the compounds of the present invention on TGFβRI kinase activity

[0320] The inhibitory effect of the compounds of the present invention on the activity of TGFβRI kinase ALK5 was tested using the following method.

[0321] Enzyme activity was detected using the ADP-Glo ​​kinase assay kit (V9102 / 3, Promega). 50 nl of a 3-fold serial dilution of a compound dissolved in 100% DMSO (the initial concentration of the test was 10 μM), 2.5 μl of ALK5 (Cat. 09-141, Carna) enzyme solution (final concentration 12.5 nM) 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 then incubated at room temperature for 10 minutes after adding 2.5 μl of reaction buffer. Add 2.5 μl of a mixed solution of ATP and TGFβRI substrate peptide (peptide: Cat.T36-58, SignalChem, peptide final concentration 0.1 mg / ml, ATP at Km concentration), react at 28°C for 2 hours, add 5 μl of the ADP-Glo ​​solution in the kit to each well, and place at 28°C for 30 minutes. Use Envision multifunctional microplate reader to detect the chemiluminescent signal value. Calculate the IC value of the compound's inhibitory effect on the enzyme based on the concentration of each compound and the corresponding signal value. 50 value.

[0322] 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.

[0323] Table 1 IC of the compounds of the present invention for inhibiting the activity of TGFβRI kinase ALK5 50

[0324]

[0325]

[0326] Test Example 2: Determination of the inhibitory effect of the compounds of the present invention on p38α kinase activity

[0327] The following experimental method was used to determine the inhibitory effect of the compounds of the present invention on p38α kinase activity:

[0328] The enzyme activity was detected using a p38α kinase assay kit (V9591, Promega). 5 μl of a 3-fold serial dilution of the compound dissolved in 100% DMSO (the initial test concentration was 10 μM) and 10 μl of a p38α enzyme (Cat. 04-152, Carna) solution (final concentration 6 nM) prepared with reaction buffer (50 mM HEPES, pH 7.5; 0.0015% Brij-35) were added to a 384-well plate (Cat. No. 4512, Corning) in sequence and incubated at room temperature for 10 minutes. Add 10 μl of a mixed solution of ATP and p38 substrate peptide 5-FAM-IPTSPITTTYFFFKKK-COOH (Cat. 112396, GL) (final peptide concentration 3 μM, ATP at Km concentration), react at 28°C for 60 min, and add 25 μl of stop solution (100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% Coating Reagent #3; 50 mM EDTA) to each well to terminate the reaction. Use Envision multifunctional microplate reader to detect the chemical generation signal value. Calculate the IC value of the compound's inhibitory effect on the enzyme based on the concentration of each compound and the corresponding signal value. 50 value.

[0329] 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 2 below.

[0330] Table 2 IC values ​​of the inhibitory effect of the compounds of the present invention on p38α kinase activity 50

[0331] Test compound <![CDATA[IC 50 (nM)]]> 004 >10000 005 >10000 007 >10000 009 >10000 010 >10000

[0332] Test Example 3: Determination of the inhibitory activity of the compounds of the present invention on the Smad signaling pathway of TGFβRI

[0333] The following experimental method is used to determine the inhibitory activity of the compounds of the present invention on the Smad signaling pathway of TGFβRI:

[0334] This embodiment uses TGFβ / SMAD reporter gene cell line (BPS Bioscience, Cat.60653) to detect the inhibitory effect of molecules on the TGF-β1 protein signaling pathway. TGF-β1 protein binds to receptors on the cell surface, initiates a signal cascade reaction, causes SMAD2 and SMAD3 phosphorylation and activation, and forms a complex with SMAD4. Then, the SMAD complex is transferred to the nucleus and binds to the SMAD binding element in the nucleus, thereby causing the transcription and expression of TGFβ / SMAD response genes. The TGFβ / SAMD reporter gene cell line includes a firefly luciferase gene, which is stably integrated into HEK293 cells and is controlled by SMAD response elements. When cells are stimulated by human TGF-β1, the cells express firefly luciferase, and after adding substrate, luciferase catalyzes the substrate to emit light, and the light intensity value can be read on a microplate reader. After adding the molecule to be tested, if it can inhibit the signaling pathway of TGF-β1, a decrease in the reading value can be detected.

[0335] The cells were plated at 0.35 × 10 6 The density of cells / mL was set, and 100 μl was added to each well of a 96-well white-opaque plate (Corning, Cat.3917), and cultured in a 37°C, 5% CO2 incubator for 24 hours. The molecule to be detected was diluted 4-fold at a starting concentration of 5 μM, for a total of 7 gradients. The diluted molecule was then mixed with 2 μg / ml TGF-β1 protein (Perpotech, Cat.100-21) in a 1:1 ratio, and 100 μl was added to each well of the cells cultured overnight, with 3 replicates for each gradient. After continuing to culture in a 37°C, 5% CO2 incubator for 18 hours, 100 μl of luciferase substrate (Promega, G7940) was added to each well and detected on a microplate reader. The readings were fitted with a 4-parameter equation to obtain the IC 50 value.

[0336] 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 3 below.

[0337] Table 3 IC values ​​of the inhibitory effects of the compounds of the present invention on the Smad signaling pathway 50

[0338] Test compound <![CDATA[IC 50 (nM)]]> 001 18.31 002 32.90 003 13.06 004 64.28 005 56.80 006 48.66 007 51.52 008 26.77 009 64.24 010 37.13

[0339] Test Example 4: Pharmacokinetics of the compounds of the present invention

[0340] Mice were used as test animals, and the drug concentration in plasma at different time points after oral administration and intravenous administration of the compound of the present invention were determined by LC / MS / MS method. The pharmacokinetic behavior of the compound of the present invention in rats was studied, and its pharmacokinetic characteristics were evaluated.

[0341] Trial plan

[0342] 2.1 Trial Drugs

[0343] Positive control group compounds, compounds 001, 004, 005, 007, 009, and 010.

[0344] 2.2 Experimental animals

[0345] Forty-two healthy adult BALB / c male mice were equally divided into 7 groups, with 6 mice in each group, 3 mice were gavaged and 3 mice were intravenously injected. The mice were purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd., with animal production license number: SCXK (Zhejiang) 2019-0001.

[0346] 2.3 Drug preparation

[0347] Weigh a certain amount of drug, dissolve it in 20% PG 5% ethanol 75% water, prepare it to 1 mg / ml for oral administration. Weigh a certain amount of drug, dissolve it in 4% PG 1% ethanol 95% water, prepare it to 0.2 mg / ml for intravenous injection.

[0348] 2.4 Administration

[0349] Oral gavage group: BALB / c mice were fasted overnight and then given the drug by oral gavage. The dosage was 10 mg / kg and the administration volume was 10 mL / kg.

[0350] Intravenous group: BALB / c mice were fasted overnight and intravenously administered. The dosage was 1 mg / kg and the administration volume was 5 mL / kg.

[0351] operate

[0352] After oral or intravenous administration to mice, 40 μL of blood was collected from the eye socket at 5 min, 15 min, 30 min, 1 h, 2 h, 6 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.

[0353] Determine the content of the test compound in mouse plasma after oral or intravenous administration of different concentrations of drugs: take the sample and melt at room temperature, vortex for 1 minute; quantitatively transfer 15μL to a 2ml 96-well plate, add 150μL internal standard precipitant, oscillate (1200rpm*3min); centrifuge (4000rpm*15min), transfer 100μL of the supernatant to a 1ml 96-well plate; blow dry with nitrogen, add 100μL of re-solution (acetonitrile and water 1:9), oscillate and shake (900rpm*3min), and inject 20μL for analysis. LC / MS / MS conditions: mobile phase A: 0.1% formic acid aqueous solution, mobile phase B: 0.1% formic acid acetonitrile, chromatographic column: ACE C18 5μm (3.0mm*50mm), column temperature: 35℃, flow rate 0.5ml / min.

[0354] The pharmacokinetic parameters of the compounds of the present invention are as follows:

[0355] Table 4 Pharmacokinetic parameters of the compounds after a single intravenous injection in mice

[0356]

[0357] Table 5 Pharmacokinetic parameters of the compounds after single oral administration in mice

[0358]

[0359] Test Example 5: Antitumor efficacy test of the compounds of the present invention on CT26 tumor-bearing mice

[0360] 1. Purpose of the experiment

[0361] The effects of Compound 001, Compound 002, Compound 005, Compound 007, Compound 009 and Compound 010 on inhibiting the growth of mouse colon cancer cell CT26 xenografts in BALB / c mice were evaluated.

[0362] 2. Experimental drugs

[0363] Compounds 001, 004, 005, 007, 009 and 010 were prepared into a 3 mg / ml aqueous solution with 20% PG + 5% ethanol + 10% solutol + 65% water. The dosage was 30 mg / kg and the oral gavage volume was 10 ml / kg.

[0364] The positive control drug mPD-1-RMP1-14 (purchased from bioxcell, Catalog Number: BE0188) was injected intraperitoneally.

[0365] 3. Experimental methods and materials

[0366] 3.1 Experimental animals and housing conditions

[0367] The BALB / c mice used in the experiment were female and purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd. They weighed 16-18g when purchased. After the animals were purchased, they were fed for 3 days for adaptive feeding before the experiment began. Feeding conditions: SPF grade. Animal feeding method: 12 / 12 hours light / dark cycle adjustment, temperature 20-26℃, humidity 40-70%, animals were given standard sterilized mouse feed, and free access to food and water.

[0368] 3.2 Model Purchase and Construction

[0369] The right rib of the mouse was prepared one day in advance, and CT26 cells (1*10^5 / mouse, purchased from ATCC) were inoculated subcutaneously. When the tumor volume grew to 60-80 mm 3 The medication was divided into groups at about 2 hours.

[0370] 3.3 Animal grouping

[0371] After the tumor volume reached the grouping condition, the mice were randomly divided into groups according to the tumor volume, with 6 mice in each group.

[0372] Table 6 Animal grouping and dosing regimen

[0373] Test substance Dosage (mg / kg) Dosage Dosing frequency Blank control group NA IG Bid mPD-1-RMP1-14 10 IP Biw 001 30 IG Bid 004 30 IG Bid 005 30 IG Bid 007 30 IG Bid 009 30 IG Bid 010 30 IG Bid

[0374] Note: Bid means twice a day; Biw means twice a week; IG means oral administration, IP means intraperitoneal injection

[0375] 3.4 Experimental methods

[0376] The day after the animals were grouped, the drug administration began. Each mouse was administered the drug according to the dosing frequency in the table above. The blank group was gavaged with 20% PG + 5% ethanol + 10% solutol + 65% water to prepare a 3 mg / ml aqueous solution. The tumor volume was measured 3 times a week and the animal body weight was weighed 3 times. The drug administration lasted for 2 weeks in total.

[0377] 3.5 Statistics

[0378] The formula for calculating tumor volume (V) is: V = 1 / 2 × L 长 ×L 短 2

[0379] Relative tumor volume (RTV) = V T / V0

[0380] Where V0, V T The tumor volumes are at the beginning and end of the experiment, respectively.

[0381] Relative tumor proliferation rate T / C (%) = T RTV / C RTV

[0382] C RTV , T RTV These are the relative tumor volumes of the blank control group and the experimental group at the end of the experiment.

[0383] 4. Results

[0384] The data on the efficacy of the compounds on CT26 tumor-bearing mice are shown in Table 7.

[0385] Table 7 The efficacy of the compounds of the present invention on CT26 tumor-bearing mice transplanted tumors

[0386] Example No. RTV T / C(%) Blank control 4.01 - mPD-1-RMP1-14 2.16 53.80 001 0.86 21.49 004 0.92 22.93 005 1.42 35.42 007 1.84 46.13 009 0.98 24.53 010 1.52 37.98 .

Claims

1. A compound represented by formula (A) or a pharmaceutically acceptable salt thereof: wherein ring Q is phenyl; R 1 Selected from H or C1-C6 alkoxy; R 2 Selected from R a Substituted C1-C6 alkoxy, and R a The heterocyclic group is selected from 5-6 membered heterocyclic groups, wherein the heterocyclic group is a saturated monovalent monocyclic ring containing 1-3 heteroatoms selected from N, O and S.

2. The compound of formula (A) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The R 1 is selected from a hydrogen atom or a methoxy group, R 2 Selected from 3. A compound represented by formula (A) or a pharmaceutically acceptable salt thereof: wherein ring Q is thienyl; R 1 Selected from H; R 2 Selected from 5-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the 5-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace; Every R a Independently selected from optionally R b Substituted groups: C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-8 membered heterocyclic group, C1-C 10 Alkylsulfonyl or phenyl; Every R b Independently selected from F, Cl, Br, I, OH, =O, C1-C6 alkyl, C1-C6 alkylsulfonyl or C3-C8 cycloalkylsulfonyl, wherein the C1-C6 alkyl is optionally substituted by F, Cl, Br, I, CN; The heterocyclic group or heteroaryl group contains 1 to 3 heteroatoms selected from N, O and S. The heterocyclic group is a saturated or partially saturated monovalent monocyclic, fused, spiro or bridged ring.

4. The compound of formula (A) or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that: The ring Q is a thienyl group, the R 1 Selected from H, R 2 Selected from R a Substituted with the following groups: phenyl, pyridyl, pyrazolyl, tetrahydropyridyl, Benzopyrazolyl, benzimidazolyl.

5. The compound of formula (A) or a pharmaceutically acceptable salt thereof according to claim 4, characterized in that: The R 1 Selected from hydrogen atoms, R 2 Selected from 6. The following compound or a pharmaceutically acceptable salt thereof:

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

8. Use of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7, in the preparation of a medicament for preventing or treating a TGF-β-mediated disease.

Images