WO2024032598A1 - TGF-β抑制剂化合物及其用途 - Google Patents

TGF-β抑制剂化合物及其用途 Download PDF

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WO2024032598A1
WO2024032598A1 PCT/CN2023/111704 CN2023111704W WO2024032598A1 WO 2024032598 A1 WO2024032598 A1 WO 2024032598A1 CN 2023111704 W CN2023111704 W CN 2023111704W WO 2024032598 A1 WO2024032598 A1 WO 2024032598A1
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group
alkyl
membered
heteroalicyclic
haloalkyl
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PCT/CN2023/111704
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English (en)
French (fr)
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路良
赵赛赛
张龙争
黄海
张霁旋
朱俊杰
王晓龙
陈佳昕
凌杉村
廖新伟
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河南迈英诺医药科技有限公司
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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Definitions

  • the present application provides a class of novel compounds with pharmaceutical activity that can be used to inhibit fibroblast growth factor receptor (TGF).
  • TGF fibroblast growth factor receptor
  • the present application also relates to compositions comprising said compounds, and the use of said compounds and said compositions in the preparation of medicaments for the treatment of diseases or conditions associated with TGF.
  • TGF- ⁇ Transforming Growth Factor ⁇
  • TGF- ⁇ Transforming Growth Factor ⁇
  • TGF- ⁇ superfamily TGF- ⁇ superfamily
  • TGF- ⁇ has three main cellular receptors: type I receptor (TGF ⁇ R1), type II receptor (TGF ⁇ R2) and type III receptor (TGF ⁇ R3).
  • Type I and type II receptors are transmembrane serine/threonine kinases. Both transmit information at the same time.
  • Type III receptors do not transmit information. Their main function is to transmit TGF- ⁇ to type II receptors through receptor II. Providing ligands indirectly affects signaling.
  • TGF- ⁇ 1, TGF- ⁇ 2 and TGF- ⁇ 3 There are three subtypes of TGF- ⁇ (TGF- ⁇ 1, TGF- ⁇ 2 and TGF- ⁇ 3), which are present in most cells together with receptors. Each isoform is expressed in a tissue-specific and developmentally regulated manner.
  • TGF- ⁇ and activin regulate a large number of cellular processes, such as cell cycle arrest of epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, inflammatory cell recruitment, immunosuppression, wound healing, and the extracellular matrix of production.
  • TGF- ⁇ signaling is associated with many diseases, such as cancer, renal fibrosis, liver fibrosis, pulmonary fibrosis, viral infection, chronic nephritis, acute nephritis, diabetic nephropathy, osteoporosis, arthritis, Wound healing, ulcers, corneal trauma, heart valve stenosis, congestive cardiac necrosis, neurological damage, Alzheimer's syndrome, peritoneal or subcutaneous adhesions, arteriosclerosis and tumor metastasis growth, etc.
  • diseases such as cancer, renal fibrosis, liver fibrosis, pulmonary fibrosis, viral infection, chronic nephritis, acute nephritis, diabetic nephropathy, osteoporosis, arthritis, Wound healing, ulcers, corneal trauma, heart valve stenosis, congestive cardiac necrosis, neurological damage, Alzheimer's syndrome, peritoneal or subcutaneous adhesions, arteriosclerosis and tumor metastasis growth
  • n 1, 2 or 3;
  • R 1 is selected from H, halogen, -OH, -NO 2 , -CN, -SF 5 , -SH, -SC 1-4 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6 alkoxy group, C 1-6 haloalkoxy group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 3-7 alicyclic group, 3-10 membered heteroalicyclic group, C 6-12 bicyclic aliphatic group Ring group, 6-12 membered bicyclic heteroalicyclic group, C 8-15 membered tricyclic alicyclic group, 8-15 membered tricyclic heteroalicyclic group, C 5-8 aryl group, 5-10 membered heteroaryl group, C 7-11 bicyclic aryl group, 7-11 membered bicyclic heteroaryl group, -C 1-4 alkyl group-(C 3-7 alicyclic group), -C 1-4 alkyl group-(3-10 membered
  • R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 at each occurrence is independently selected from: H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 ester Cyclic group, 3-10 membered heteroalicyclic group, C 5-8 aryl group, 5-7 membered heteroaryl group, C 7-11 bicyclic aryl group, 7-11 membered bicyclic heteroaryl group, -C 1-4 alkyl Base-(C 3-7 alicyclic group), -C 1-4 alkyl-(3-10 membered heteroalicyclic group), -C 1-4 alkyl-(C 6-12 bicyclic alicyclic group) , -C 1-4 alkyl-(6-12 membered bicyclic heteroalicyclic group), -C 1-4 alkyl-(C 8-15 membered tricyclic alicyclic group), -C 1-4 alkyl-( 8-15 membered tricyclic heteroalicyclic group), -
  • R 2 is 1, 2, 3 or 4, and each R 2 is independently selected from H, halogen, -CN, -OH, -NO 2 , -NR 7 R 8 , C 1-4 alkane base, C 1-4 haloalkyl group, C 1-4 alkoxy group, C 3-6 alicyclic group and 4-6 membered heteroalicyclic group;
  • R 3 is 1, 2 or 3, and each R 3 is independently selected from H, halogen, -CN, -OH, -NO 2 , -NR 7 R 8 , C 1-4 alkyl group, C 1-4 haloalkyl group, C 1-4 alkoxy group, C 3-6 alicyclic group and 4-6 membered heteroalicyclic group base;
  • R 7 and R 8 at each occurrence is independently selected from: H, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or R 7 , R 8 and the combination thereof The N atoms together form a 3-6 membered ring;
  • optical isomer means that when a compound has one or more chiral centers, each chiral center can exist in R configuration or S configuration, and the various isomers formed thereby are optical isomers. conformation. Optical isomers include all diastereoisomers, enantiomers, meso, racemates or mixtures thereof. Optical isomers can be separated, for example, by chiral chromatography columns or by chiral synthesis.
  • geometric isomer means that when a double bond is present in a compound, the compound may exist as cis isomer, trans isomer, E isomer and Z isomer. Geometric isomers include cis isomers, trans isomers, E isomers, Z isomers or mixtures thereof.
  • tautomer refers to an isomer resulting from the rapid movement of an atom between two positions in a molecule. Those skilled in the art can understand that tautomers can transform into each other and may reach an equilibrium state and coexist in a certain state.
  • isotopes suitable for inclusion in the compounds of the present application include isotopes of hydrogen, such as 2 H(D) and 3 H(T); isotopes of carbon, such as 11 C, 13 C, and 14 C; and chlorine isotopes, such as and _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
  • the isotopically labeled compounds can be used in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes deuterium (ie D) and carbon-14 (ie 14 C) are particularly useful for this purpose given their ease of introduction and convenience of detection means.
  • the compounds of the present application are isotopically labeled compounds, wherein H is optionally substituted with D at each occurrence.
  • positron emitting isotopes such as 11 C, 18 F, 15 O, and 13 N
  • PET Positron Emission Topography
  • the isotopically labeled compounds may generally be prepared by conventional techniques known to those skilled in the art or by using a suitable isotopically labeled reagent in place of a previously used non-labeled reagent.
  • the compounds of the present application may exist in the form of their pharmaceutically acceptable salts.
  • pharmaceutically acceptable means that the corresponding compound, carrier or molecule is suitable for administration to humans.
  • the term refers to a product certified for use in mammals (preferably humans) by any national regulatory agency such as CFDA (China), EMEA (Europe), FDA (USA), etc.
  • the pharmaceutically acceptable salts include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids that form nontoxic salts. Examples include, but are not limited to: acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate , camphor sulfonate, citrate, cyclohexylamine sulfonate, ethylene disulfonate, formate, fumarate, grape heptonate, gluconate, glucuronate, hexanate Fluorophosphate, 2-(4-hydroxybenzyl)benzoate, hydrochloride/chloride, hydrobromide/bromide, Hydroiodide/iodide, 2-Isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2 -Na
  • Suitable base addition salts are formed from bases that form nontoxic salts. Examples include, but are not limited to: aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts. Half-salts of acids and bases may also be formed, such as hemisulfate and hemicalcium salts.
  • suitable salts see Handbook of Pharmaceutical Salts: Properties, Selection and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.
  • the compounds of the present application may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • Compounds can also exist in one or more crystalline states, known as polymorphs, or they can exist as amorphous solids. All these forms are included within the scope of this application.
  • the present application also includes prodrugs of the compounds of the present application.
  • prodrug refers to a derivative that is converted into a compound of the present application through reactions with enzymes, gastric acid, etc. under physiological conditions in vivo, such as through oxidation, reduction, hydrolysis, etc., respectively catalyzed by enzymes. Therefore, certain derivatives of the compounds of the present invention may themselves have little or no pharmacological activity and, when administered to or on the body, can be converted into compounds of the present invention with the desired activity.
  • the present application also includes metabolites of the compounds of the present application.
  • the term "metabolite” refers to all molecules in a cell or organism, preferably a human, derived from any compound of the present application.
  • substituted means that one or more (preferably 1 to 5, more preferably 1 to 3, most preferably 1 or 2) hydrogen atoms in a group are independently substituted by a corresponding number replaced by substituents.
  • the term “optionally” or “optionally” means that the event it describes may or may not occur.
  • a group that is “optionally substituted” means that the group may be unsubstituted or substituted.
  • halogen refers to -F, -Cl, -Br, or -I.
  • alkyl refers to saturated aliphatic hydrocarbons, including straight and branched chains. In some embodiments, an alkyl group has 1-8, or 1-6, or 1-4, or 1-3 carbon atoms.
  • C 1-8 alkyl refers to a straight or branched chain radical of atoms having 1 to 8 carbon atoms.
  • C 1-8 alkyl includes in its definition the terms “C 1-6 alkyl”, “C 1-3 alkyl", “C 1-4 alkyl” and the like.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, iso Pentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, 2,3- Dimethylbutyl, hexyl, etc.
  • Alkyl groups may be optionally substituted with one or more (eg, 1 to 5) suitable substituents.
  • alkenyl refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight and branched chains having at least one carbon-carbon double bond.
  • alkenyl groups have 2-8 carbon atoms, 2-6 carbon atoms, 3-6 carbon atoms, or 2-4 carbon atoms.
  • C 2-8 alkenyl refers to a straight or branched chain unsaturated radical of 2 to 8 carbon atoms (having at least one carbon-carbon double bond). The double bond may or may not be the point of attachment to another group.
  • Alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, butenyl, pentenyl, 3-hexenyl, and the like. Alkenyl groups may be optionally substituted with one or more (eg, 1 to 5) suitable substituents. When a compound of formula (I) contains an alkenyl group, the alkenyl group may be present in pure E form, pure Z form, or any mixture thereof.
  • alkynyl refers to an aliphatic hydrocarbon having at least one carbon-carbon triple bond, including straight and branched chains having at least one carbon-carbon triple bond.
  • an alkynyl group has 2-8 carbon atoms, 2-6 carbon atoms, 3-6 carbon atoms, or 2-4 carbon atoms.
  • C 2-8 alkynyl refers to a straight or branched chain unsaturated radical of 2 to 8 carbon atoms (having at least one carbon-carbon triple bond). The triple bond may or may not be the point of attachment to another group.
  • Alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 2-methyl-2-propynyl, butynyl, pentynyl, 3-hexynyl, and the like.
  • the alkynyl group may optionally be substituted by one or more (e.g., 1 to 5) Substituted with appropriate substituents.
  • C 3-8 alicyclic group refers to an alicyclic group having 3 to 8 ring-forming carbon atoms.
  • C 3-7 alicyclic group refers to an alicyclic group having 3 to 7 ring-forming carbon atoms.
  • C 3-6 alicyclic group refers to an alicyclic group having 3 to 6 ring-forming carbon atoms.
  • the alicyclic group may be a monocyclic ring.
  • the definition of alicyclic groups also includes unsaturated non-aromatic alicyclic groups.
  • alicyclic groups are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclohexadienyl, cyclopentenyl, cycloheptenyl and cyclooctenyl.
  • Alicyclic groups may be optionally substituted with one or more suitable substituents.
  • C 6-12 bicycloalicyclic group is a two-ring-containing alicyclic group having 6 to 12 ring-forming carbon atoms.
  • the bicyclic alicyclic radicals may be fused or may include bridged bicyclic alicyclic radical systems.
  • C 8-15 membered tricyclic alicyclic group is a three-ring-containing alicyclic group having 8 to 15 ring-forming carbon atoms. Tricyclic alicyclic groups can be fused or bridged.
  • n-membered heteroalicyclic group refers to an alicyclic group having m ring-forming carbon atoms and (nm) ring-forming heteroatoms selected from the group consisting of O, S, and N.
  • the term "4-8 membered heteroalicyclic group” means that the heteroalicyclic substituent contains a total of 4 to 8 ring atoms, at least one of which is a heteroatom;
  • the term “4-6 membered heteroalicyclic group” means The heteroalicyclic substituent contains a total of 4 to 6 ring atoms, at least one of which is a heteroatom;
  • the term “3-10 membered heteroalicyclic” means that the heteroalicyclic substituent contains a total of 3 to 10 ring atoms, At least one of them is a heteroatom.
  • n-membered bicyclic heteroalicyclic group refers to a bicyclic heteroalicyclic group having m ring-forming carbon atoms and (nm) ring-forming heteroatoms, the heteroatoms being selected from O, S, and N.
  • heteroalicyclic groups include, but are not limited to, azetidinyl, thietanyl, dihydrofuryl, dihydrothienyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydrotriazinyl, Tetrahydropyrazolyl, tetrahydroxazinyl, tetrahydropyrimidinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, octahydrobenzothiazolyl, imidazolidinyl, pyrrolidinyl, piperidinyl, Piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiazinyl, tetrahydrothiodia
  • aryl refers to a 5 to 16 membered carbocyclic aromatic group having at least one ring with a conjugated pi electron system.
  • Aryl groups may have conjugated or fused rings and may be unsubstituted or substituted as indicated. Examples of aryl groups include phenyl, naphthalenyl, anthracenyl, phenanthrenyl, azulenyl, and biphenyl.
  • C 5-16 aryl refers to an aryl group having an aromatic ring containing 5 to 16 carbon atoms.
  • C 5-8 aryl refers to an aryl group having an aromatic ring containing 5, 6, 7 or 8 carbon atoms, such as phenyl.
  • heteroaryl refers to a 5 to 16 membered aromatic group having at least one ring with a conjugated pi electron system and containing 1 to 4 heteroatoms such as N, O, or S. Heteroaryl groups may have conjugated or fused rings and may be unsubstituted or substituted as indicated.
  • heteroaryl groups include thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl ( isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl ), pyridizinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, indolizinyl , benzofuranyl, benzothienyl, indazolyl, benzimidazoyl, benzothiazolyl, purinyl, quinolizinyl ( quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naph
  • n-membered heteroaryl refers to a heteroaryl group having m aromatic ring-forming carbon atoms and (n-m) aromatic ring-forming heteroatoms selected from O, S and N.
  • 5-7 membered heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, pyranyl, pyridazinyl, pyrimidinyl, pyrazinyl.
  • Heteroaryl groups may be optionally substituted with one or more suitable substituents.
  • C 7-11 bicyclic aryl refers to a bicyclic aryl group having 7-11 carbon atoms, such as naphthyl, indenyl, and the like. Bicyclic aryl groups may be optionally substituted with one or more suitable substituents.
  • n-membered bicyclic heteroaryl refers to a bicyclic heteroaryl group having m carbon atoms forming an aromatic bicyclic ring and (n-m) heteroatoms forming an aromatic bicyclic ring, the heteroatoms being selected from From O, S and N.
  • 7-11 membered bicyclic heteroaryl groups include, but are not limited to, quinolyl, isoquinolyl, indolyl, purinyl, benzothiazolyl, and the like.
  • Bicyclic heteroaryl groups may be optionally substituted with one or more suitable substituents.
  • 11-15 membered tricyclic group includes, but is not limited to, acridinyl and the like.
  • the 11-15 membered tricyclic group may be optionally substituted with one or more suitable substituents.
  • haloalkyl refers to an alkyl group having one or more halogen substituents (up to a perhaloalkyl group, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom) .
  • C 1-6 haloalkyl refers to a C 1-6 alkyl group having one or more halogen substituents (up to a perhaloalkyl group, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atoms replaced).
  • C 1-4 haloalkyl refers to a C 1-4 alkyl group having one or more halogen substituents (up to a perhaloalkyl group, i.e., each hydrogen atom of the alkyl group is substituted by a halogen atom);
  • C 1-3 haloalkyl refers to a C 1-3 alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., each of the alkyl groups hydrogen atoms are all replaced by halogen atoms);
  • C 1-2 haloalkyl refers to a C 1-2 alkyl group (i.e., methyl or ethyl) having one or more halogen substituents (up to Perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom).
  • C 1 haloalkyl refers to a methyl group having 1, 2 or 3 halogen substituents.
  • haloalkyl groups include: CF3 , C2F5 , CHF2 , CH2F , CH2CF3 , CH2Cl , and the like.
  • alkoxy refers to an alkyl group with a single bond attached to an oxygen atom. The point of attachment of the alkoxy group to the molecule is through the oxygen atom. Alkoxy groups may be described as alkyl-O-.
  • C 1-6 alkoxy refers to a straight or branched chain alkoxy group containing 1 to 6 carbon atoms.
  • C 1-6 alkoxy includes in its definition the term "C 1-3 alkoxy”.
  • Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, hexyloxy, and the like. Alkoxy groups may be optionally substituted with one or more suitable substituents.
  • 3-14 membered ring refers to a saturated or unsaturated ring system having 3-14 ring-forming atoms.
  • R 1 may be any substituent commonly used in organic chemistry, which is not particularly limited.
  • R1 is C1-6 alkyl, for example, R1 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl , 2-pentyl, 3-pentyl, isopentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2, 3-dimethylpropyl, 2,3-dimethylbutyl, hexyl.
  • R 1 is a C 3-7 alicyclic group, for example, R 1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclohexadiene base, cyclopentenyl, cycloheptenyl.
  • R 1 is a 3-10 membered heteroalicyclic group, for example, R 1 is selected from azetidinyl, thietanyl, dihydrofuranyl, dihydrothienyl, tetrahydrothiophene base, tetrahydrofuranyl, tetrahydrotriazinyl, tetrahydropyrazolyl, tetrahydroxazinyl, tetrahydropyrimidinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, octahydrobenzothiazolyl, imidazole Alkyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, t
  • R1 is H, halogen, -OH, -NO2 , -CN, -SF5 , or -SH.
  • R is selected from -SC 1-4 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2- 8 alkenyl, C 2-8 alkynyl.
  • R1 is selected from C 5-8 aryl (such as phenyl), 5-10 membered heteroaryl (such as furyl, thienyl, pyrrolyl, thiazolyl, pyrazolyl, imidazolyl, Pyridyl, pyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc.), -C 1-4 alkyl-(C 5-8 aryl), -C 1-4 alkyl-(5-10 yuan) heteroaryl).
  • C 5-8 aryl such as phenyl
  • 5-10 membered heteroaryl such as furyl, thienyl, pyrrolyl, thiazolyl, pyrazolyl, imidazolyl, Pyridyl, pyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc.
  • R 1 is selected from -SC 1-4 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2 -8 alkenyl, C 2-8 alkynyl, C 3-7 alicyclic group, 3-10 membered heteroalicyclic group, C 6-12 bicyclic alicyclic group, 6-12 membered bicyclic heteroalicyclic group, C 5 -8 aryl, 5-10 membered heteroaryl, C 7-11 bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein -SC 1-4 alkyl, C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 alicyclic group, 3-10 membered heteroalicyclic group base, C 6-12 bicyclic alicyclic group, 6-12 member
  • R1 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, and cyclobutyl groups.
  • the methyl, ethyl, propyl, isopropyl or cyclobutyl group may be optionally substituted by 0, 1 or 2 substituents each independently selected from the following group: methyl, ethyl, Cyclopentyl, cyclopropyl, -CN, -OH, morpholinyl, piperidinyl, the substituent may be optionally substituted by 0, 1 or 2 substituents each independently selected from the following groups : Methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH.
  • R1 is selected from (1-hydroxycyclopropyl)ethyl, 3-hydroxycyclobutyl, 2-cyanoethyl, 2-hydroxyethyl, 2-cyano- 1-cyclopentylethyl, 1-cyanopropane, 2-morpholinoethyl, ethyl and (1-methylpiperidin-4-yl)methyl.
  • R1 is selected from halogen, such as F.
  • R1 is selected from the group consisting of piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, and azetidinyl.
  • Aldinyl and azetidinyl may be optionally substituted by 0, 1 or 2 substituents each independently selected from the following group: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH.
  • R1 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclobutyl, said methyl, ethyl, propyl, isopropyl or cyclobutyl
  • the group may be optionally substituted by 0, 1 or 2 substituents each independently selected from the following group: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH, morpholinyl, pipera Aldyl, the substituent may be optionally substituted by 0, 1 or 2 substituents each independently selected from the following groups: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, - OH.
  • R1 is selected from piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, azetidinyl.
  • R1 is selected from 3,5-dimethylpiperazinyl, morpholinyl, 3-hydroxypyrrolidinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl base, 4-hydroxypiperidinyl, 1-methylpiperidinyl, 1-ethylpiperidin-4-yl, 1-methylazetidin-3-yl.
  • R1 is selected from H, methyl, ethyl, n-propyl, isopropyl, butyl, methoxy, ethoxy, hydroxyl, cyclopropyl, cyclobutyl, cyclobutyl, Pentyl, cyclohexyl, morpholinomethyl, hydroxycyclobutyl, hydroxycyclohexyl, cyanoethoxy, cyanomethyl, pyridin-3-yl, 1-methyl-1H-pyrazole-4- base, 1-methyl-1H-pyrazol-3-yl, 4-methylpiperazin-1-yl, 1-methylpiperidin-4-yl, morpholinyl, pyrrolidin-3-yl, 3 -Hydroxypyrrolidin-1-yl, 3-cyanopyrrolidin-1-yl.
  • R 1 is selected from H, halogen, -OH, -NO 2 , -CN, -SF 5 , -SH, -SC 1-4 alkyl, C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 alicyclic group, 4-6 membered heteroalicyclic group, C 5-8 aryl group, 5-10 membered hetero Aryl, -C 1-4 alkyl-(C 3-7 alicyclic group), -C 1-4 alkyl-(3-10 membered heteroalicyclic group), -C 1-4 alkyl-(C 5-8 aryl), -C 1-4 alkyl-(5-10 membered heteroaryl), -N(R 10 )(R 11 ), wherein -SC 1-4 alkyl, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6
  • R1 is selected from H, halogen, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy base, pentyloxy, hexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperazinyl, piperidyl, morpholinyl, pyrrolidinyl, pyrrolyl , morpholinyl, pyridyl and pyrazolyl, among which methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy , hexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohehexyl,
  • R1 is selected from H, methyl, methylpiperazinyl, pyrrolidinyl, methylpiperazinyl, hydroxycyclobutyl, methylpyrazolyl, hydroxyethyl, hydroxypropyl base, methylpiperidinyl, morpholinyl, hydroxypyrrolidinyl.
  • R 2 can be selected from H, halogen, -CN, -OH, -NO 2 , -NR 7 R 8 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy group, C 3-6 alicyclic group and 4-6 membered heteroalicyclic group.
  • R2 is H.
  • R2 is halogen, for example, R2 is selected from F, Cl, Br, I.
  • R2 is -CN.
  • R2 is -NO2 .
  • R 2 is C 1-3 alkyl or C 1-3 haloalkyl, for example, R 2 is selected from optionally substituted with one or more halogen atoms (e.g., fluorine, chlorine, bromine, iodine) Methyl, ethyl, propyl, isopropyl.
  • halogen atoms e.g., fluorine, chlorine, bromine, iodine
  • R 2 is C 1-3 alkoxy, for example, R 2 is selected from methoxy, ethoxy, propoxy, isopropoxy.
  • R 2 is a C 3-6 alicyclic group, for example, R 2 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl.
  • R 2 is a 4-6 membered heteroalicyclic group, for example, R 2 is selected from oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrofuranyl Thienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, piperazinyl.
  • R 2 is -NR 7 R 8 , wherein each of R 7 and R 8 at each occurrence is independently selected from: H, C 1-3 alkyl (e.g., methyl, ethyl, propyl , isopropyl, etc.), C 1-3 haloalkyl (such as methyl, ethyl, propyl, isopropyl substituted by one or more halogen atoms selected from fluorine, chlorine, bromine, iodine), C 1-3 alkoxy (such as methoxy, ethoxy, propoxy, isopropoxy), or R 7 , R 8 and the N atoms connected to them together form a 3-6 membered ring (such as pyrrole, Pyridine, pyrimidine, imidazole, pyrazole, pyrrolidine, hexahydropyridine, etc.).
  • C 1-3 alkyl e.g., methyl, ethyl, propyl , isopropy
  • R 3 can be selected from H, halogen, -CN, -OH, -NO 2 , -NR 7 R 8 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy group, C 3-6 alicyclic group and 4-6 membered heteroalicyclic group.
  • R3 is H.
  • R3 is halogen, for example, R3 is selected from F, Cl, Br, I.
  • R3 is -CN.
  • R 3 is -NO 2 .
  • R 3 is C 1-3 alkyl or C 1-3 haloalkyl, for example, R 3 is selected from optionally substituted with one or more halogen atoms (e.g., fluorine, chlorine, bromine, iodine) Methyl, ethyl, propyl, isopropyl.
  • halogen atoms e.g., fluorine, chlorine, bromine, iodine
  • R 3 is C 1-3 alkoxy, for example, R 3 is selected from methoxy, ethoxy, propoxy, isopropoxy.
  • R 3 is a C 3-6 alicyclic group, for example, R 3 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl.
  • R 3 is a 4-6 membered heteroalicyclic group, for example, R 3 is selected from oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrofuranyl Thienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, piperazinyl.
  • R 3 is -NR 7 R 8 , wherein each of R 7 and R 8 at each occurrence is independently selected from: H, C 1-3 alkyl (e.g., methyl, ethyl, propyl , isopropyl, etc.), C 1-3 haloalkyl (such as methyl, ethyl, propyl, isopropyl substituted by one or more halogen atoms selected from fluorine, chlorine, bromine, iodine), C 1-3 alkoxy (such as methoxy, ethoxy, propoxy, isopropoxy), or R 7 , R 8 and the N atoms connected to them together form a 3-6 membered ring (such as pyrrole, Pyridine, pyrimidine, imidazole, pyrazole, pyrrolidine, hexahydropyridine, etc.).
  • C 1-3 alkyl e.g., methyl, ethyl, propyl , isopropy
  • R3 and R2 can be the same.
  • R 3 and R 2 are both halogens, such as Cl; for another example, R 3 and R 2 are both methyl.
  • R 3 and R 2 are both Cl.
  • R 3 and R 2 are both H.
  • R3 and R2 can be different.
  • L is CH2 .
  • L is a linkage (i.e., the R 1 and N atoms are directly connected by a covalent bond).
  • n 1, 2 or 3.
  • n 1
  • n is 2.
  • n 3.
  • n may be combined in any manner with any of the embodiments of R 1 , R 2 , R 3 , L and Ring A as described above and below.
  • the compound of formula (I) in this application may have one of the following structures:
  • n, L, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above;
  • n, L, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above;
  • n, L, R 1 , R 2 , R 3 and R 4 are as defined above;
  • Ring B is a 3 to 8-membered ring containing 1 N atom, and R a is selected from H, halogen, -CN, -OH, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy.
  • the compound of formula (I) of the present application is selected from the compounds shown in the corresponding embodiments.
  • the compound of formula (I) of the present application can be synthesized by conventional organic synthesis methods according to the specific structure of the compound by those skilled in the art.
  • the compound of formula (I) of the present application can inhibit the activity of TGF- ⁇ , that is, it can be used as a TGF- ⁇ inhibitor.
  • the compound of formula (I) of the present application can especially be used to inhibit TGF- ⁇ type I receptor (TGF ⁇ R1), that is, used as a TGF- ⁇ 1 inhibitor.
  • the present application provides a pharmaceutical composition, which contains the compound of the present application as described above or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and one or more pharmaceutically acceptable carriers, adjuvants or excipients.
  • compositions of the present application can be prepared in a manner well known in the pharmaceutical art and can be administered by a variety of routes, depending on whether local or systemic treatment is desired and depending on the site to be treated. Administration may be topical (including ophthalmic and to mucosa, including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of a powder or aerosol, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral, or parenteral.
  • topical including ophthalmic and to mucosa, including intranasal, vaginal and rectal delivery
  • pulmonary e.g., by inhalation or insufflation of a powder or aerosol, including by nebulizer; intratracheal, intranasal, epidermal and transdermal
  • ocular oral, or parenteral.
  • Methods for ocular delivery may include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction via a balloon catheter or ophthalmic insert surgically placed in the conjunctival sac.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial (eg, intrathecal or intracerebroventricular) administration.
  • Parenteral administration may be in the form of a single bolus dose or may be, for example, by a continuous infusion pump.
  • Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders.
  • the preparation may be in the form of tablets, as a powder or granules in hard gel capsules, or in the form of lozenges or lozenges.
  • Solid carriers may include conventional excipients such as binders, fillers, tableting lubricants, disintegrating agents, wetting agents, and the like.
  • the tablets may be film-coated if desired by conventional techniques.
  • a liquid carrier the preparations may be in the form of a syrup, lotion, ointment, soft gel capsule, sterile vehicle for injection, aqueous or non-aqueous liquid suspension, or may be formulated with water or other appropriate Carrier-restored dry product.
  • Liquid preparations may contain conventional additives such as suspending agents, emulsifiers, wetting agents, non-aqueous vehicles (including edible oils), preservatives, and flavoring and/or coloring agents.
  • the carrier will consist at least in large part of sterile water, although saline solutions, dextrose solutions, and the like may also be used.
  • injectable suspensions may also be used, in which case conventional suspending agents may be used.
  • Conventional preservatives, buffering reagents, etc. may also be added to parenteral dosage forms.
  • Pharmaceutical compositions are prepared by conventional techniques appropriate to the desired formulation containing appropriate amounts of the active ingredient (ie, the compound of the present application).
  • compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for sterile injectable solutions or dispersions.
  • suitable aqueous and non-aqueous carriers, diluents, solvents include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectables Organic esters (eg, ethyl oleate).
  • compositions may also contain various excipients such as preservatives, wetting agents, emulsifying agents and dispersing agents. Inhibition of the action of microorganisms can be ensured by various antibacterial and antifungal agents (for example, parabens, chlorobutanol, phenol, sorbic acid, etc.). Isotonic agents such as sugar, sodium chloride, etc. may also be included. Prolonged absorption of injectable pharmaceutical dosage forms can be brought about by the use of agents that delay absorption (eg, aluminum monostearate and gels).
  • agents that delay absorption eg, aluminum monostearate and gels.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one inert excipient (or carrier) (for example, sodium citrate or dicalcium phosphate), which may also include: (a) fillers or admixtures (for example, starch, lactose, sucrose, glucose, mannitol and silicic acid); (b) binders (e.g.
  • ком ⁇ онентs e.g., glycerol
  • Disintegrants e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain synthetic silicates, sodium carbonate
  • solution retardants for example, paraffin wax
  • absorption enhancers for example, quaternary ammonium compounds
  • wetting agents for example, cetyl alcohol and glycerol monostearate
  • adsorbents e.g., kaolin and bentonite
  • lubricants e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate
  • Solid compositions of a similar type may also be used as fillers in soft-filled and hard-filled gel capsules using excipients such as lactose and high molecular weight polyethylene glycols.
  • Solid dosage forms eg, tablets, dragees, capsules, pills, and granules
  • coatings and shells eg, enteric coatings and others known in the art. They may contain opacifying agents, and they may be compositions which release the active compound or active compounds in a certain part of the intestinal tract in a delayed manner. Examples of useful embedding compositions are polymeric substances and waxes.
  • the active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, dispersions, syrups, and elixirs.
  • liquid dosage forms may contain inert diluents (e.g., water or other solvents), solubilizers, and emulsifiers commonly used in the art (e.g., ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzene Methanol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide), oil (specifically, cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame oil), propylene glycol Triol, tetrahydrofuranol, fatty acid esters of polyethylene glycol and sorbitan or mixtures of these substances, etc.
  • inert diluents e.g., water or other solvents
  • solubilizers emul
  • compositions may also include, for example, wetting agents, emulsifying and suspending agents, perfuming, flavoring and perfuming agents.
  • Suspensions may contain, in addition to the active compound, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, sorbitan esters, microcrystalline fibers, aluminum metahydroxide, bentonite, agar-agar and Gum tragacanth or mixtures of these substances, etc.
  • suspending agents for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, sorbitan esters, microcrystalline fibers, aluminum metahydroxide, bentonite, agar-agar and Gum tragacanth or mixtures of these substances, etc.
  • Dosage forms for topical administration of the compounds of the present application include ointments, powders, sprays, and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any desired preservatives, buffers or propellants.
  • Ophthalmic formulations, eye ointments, powders and solutions are also included within the scope of this application.
  • the amount of the compound of the present application in the pharmaceutical composition and dosage form can be appropriately determined by those skilled in the art as needed.
  • the compound of the present application can be present in the pharmaceutical composition or dosage form in a therapeutically effective amount.
  • the application provides the compound of formula (I) of the application or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutical Acceptable salts thereof, or prodrugs thereof, or metabolites thereof, or pharmaceutical compositions as described above are used in the preparation of medicaments for the treatment of diseases or conditions related to TGF- ⁇ (especially related to TGF- ⁇ 1) use in.
  • the present application also provides a method for treating a disease or condition associated with TGF- ⁇ (especially TGF- ⁇ 1), the method comprising administering a therapeutically effective amount of the present application to a patient in need thereof.
  • TGF- ⁇ especially TGF- ⁇ 1
  • the patient is preferably a mammal, more preferably a human patient.
  • the route of administration may be oral, topical (including but not limited to topical application, spraying, etc.), parenteral (including subcutaneous, intramuscular, cortical and intravenous) administration, bronchial administration or nasal administration, etc.
  • the amount administered is a therapeutically effective amount and can be determined by those skilled in the art according to actual needs.
  • a disease or disorder related to TGF- ⁇ may be cancer, viral infection, chronic nephritis, acute nephritis, diabetic nephropathy, osteoporosis, arthritis, wound Healing, scars, ulcers, corneal trauma, heart valve stenosis, congestive cardiac necrosis, neurological impairment, Alzheimer's syndrome, peritoneal or subcutaneous adhesions, arteriosclerosis, skin aging due to skin fibrosis and fat loss, bone disorders or chondrocyte disorders, hypophosphatemic disorders and fibrotic diseases of organs, especially hepatocellular carcinoma, breast cancer, bladder cancer, colorectal cancer, melanoma, mesothelioma, lung cancer, prostate cancer, pancreatic adenocarcinoma, testis Carcinoma, thyroid cancer, squamous cell carcinoma, glioblastoma, neuroblastoma, uterine cancer, rhabdomyos
  • the disease or disorder associated with TGF- ⁇ is cancer.
  • the compounds of the present application can be used, for example, to inhibit the proliferation and metastasis of cancer cells.
  • Exemplary cancers include bladder cancer, breast cancer, cervical cancer, colorectal cancer, small bowel cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, head and neck cancer (e.g., larynx, hypopharynx, nasopharynx, oropharynx , lip and oral cavity), kidney cancer, liver cancer (eg, hepatocellular carcinoma, cholangiocarcinoma), lung cancer (eg, adenocarcinoma, small cell lung cancer and non-small cell lung cancer, small cell carcinoma and non-small cell carcinoma, Bronchial cancer, bronchial adenoma, pleuropulmonary blastoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (such as exocrine pancreatic cancer), thyroid cancer, parathyroid cancer, skin cancer (eg, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin
  • Additional exemplary cancers include hematopoietic malignancies such as leukemia or lymphoma, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, acute myeloid leukemia, Hodgkin or non-Hodgkin lymphoma, myeloproliferative neoplasms (e.g., polycythemia vera, essential thrombocythemia, and primary myelofibrosis), Waldenstrom's macroglobulinemia, trichomoniasis Cellular lymphoma, chronic myeloid lymphoma, acute lymphoblastic lymphoma, AIDS-related lymphoma, and Burkitt lymphoma.
  • leukemia or lymphoma multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, cutaneous T-cell lymph
  • Additional exemplary cancers include eye tumors, glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, and osteosarcoma.
  • the disease or disorder associated with TGF- ⁇ is selected from the group consisting of hepatocellular carcinoma, breast cancer, bladder cancer, colorectal cancer, melanoma, mesothelioma, lung cancer, prostate cancer, pancreatic adenocarcinoma , testicular cancer, thyroid cancer, squamous cell carcinoma, glioblastoma, neuroblastoma, uterine cancer, and rhabdomyosarcoma.
  • the disease or disorder associated with TGF- ⁇ is selected from the group consisting of skeletal and chondrocyte disorders, including but not limited to achondroplasia, hypochondrogenesis, dwarfism, Lethal achondroplasia (TD) (clinical forms TD I and TD II), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beer- Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, and premature cranial suture closure syndrome.
  • achondroplasia hypochondrogenesis
  • dwarfism dwarfism
  • Lethal achondroplasia (TD) (clinical forms TD I and TD II)
  • Apert syndrome Crouzon syndrome
  • Jackson-Weiss syndrome Jackson-Weiss syndrome
  • Beer- Beare-Stevenson cutis gyrate syndrome Pfeiffer syndrome
  • premature cranial suture closure syndrome premature cranial suture closure syndrome.
  • the disease or disorder associated with TGF- ⁇ is a hypophosphatemic disorder, including, for example, X-linked hypophosphatemic rickets (X-linked hypophosphatemic rickets), autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, and tumor-induced osteomalacia (tumor-induced osteromaIacia) .
  • X-linked hypophosphatemic rickets X-linked hypophosphatemic rickets
  • autosomal recessive hypophosphatemic rickets autosomal recessive hypophosphatemic rickets
  • autosomal dominant hypophosphatemic rickets autosomal dominant hypophosphatemic rickets
  • tumor-induced osteomalacia tumor-induced osteomalacia
  • the disease or disorder associated with TGF- ⁇ is selected from fibrotic diseases.
  • fibrotic diseases include cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, and wound healing.
  • the disease or disorder related to TGF- ⁇ is a skin disease, especially skin scars, skin fibrosis, skin aging caused by fat loss, etc.
  • Example 1 1-(2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3- yl) )pyridin-2-yl)-4,6-dihydropyrro[3,4-d]imidazol-5(1H)-yl)ethane-1-one
  • Synthetic intermediate 1-d 3-bromo-2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole.
  • Intermediate 1-c 313.8 mg, 1.6 mmol
  • NBS 279.5 mg, 1.6 mmol
  • the yield is 66.4%.
  • Synthetic intermediate 1-1 tert-butyl 2-(4-bromopyridin-2-yl)-3a,4,6,6a-tetrahydropyrro[3,4-d]imidazole-5(1H)-carboxylate ester
  • Synthetic intermediate 1-2 2-(4-bromopyridin-2-yl)-4,6-dihydropyrro[3,4-d]imidazole-5(1H)-carboxylic acid tert-butyl ester
  • Synthetic intermediate 1-3 2-(4-bromopyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo [3,4-d]imidazole-5(1H)-carboxylic acid tert-butyl ester
  • Synthetic intermediate 1-4 (2-(5-(tert-butoxycarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6 -Tetrahydropyrrolo[3,4-d]imidazol-2-yl)pyridin-4-yl)boronic acid
  • Synthetic intermediate 1-5 2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl )pyridin-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H) -tert-butyl carboxylate
  • Synthetic intermediate 1-6 2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl )pyridin-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole
  • Synthetic intermediate 1-7 1-(2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole- 3-yl)pyridin-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5 (1H)-yl)ethane-1-one
  • Synthetic compound 2 2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridine- 2-yl)-1,4,5,6-tetrahydropyrro[3,4-d]imidazole
  • Synthetic compound 3 5-methyl-2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrole[1,2-a]imidazole-3- (yl)pyridin-2-yl)-1,4,5,6-tetrahydropyrrole[3,4-d]imidazole
  • Example 4 (4-methylpiperazin-1-yl)(2-(4-(2-(6-methylpyridin-2-yl))-6,7-dihydro-5H-pyrrolo [1 ,2-a]imidazol-3-yl)pyridin-2-yl)-4,6-dihydropyrro[3,4-d]imidazol-5(1H)-yl)methanone (MDI-980)
  • Synthetic compound 4 (4-methylpiperazin-1-yl)(2-(4-(2-(6-methylpyridin-2-yl))-6,7-dihydro-5H-pyrrolo[1 ,2-a]imidazol-3-yl)pyridin-2-yl)-4,6-dihydropyrro[3,4-d]imidazol-5(1H)-yl)methanone
  • Dissolve intermediate 1-6 (40.0 mg, 0.1 mmol) in 10 ml of DCM, add triphosgene (23.1 mg, 0.1 mmol) to the system, cool the system to 0°C, and add triethylamine (80.8 mg, 0.8 mmol), react for 0.5 hours, add N-methylpiperidine (8.0 mg, 0.1 mmol) to the system, and raise to room temperature for reaction. After the reaction is completed, add water to quench, extract with DCM, combine the organic phases, wash with saturated brine, and concentrate.
  • Synthetic intermediate 6-2 2-methyl-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyridine
  • Synthetic intermediate 6-3 2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-6-methylpyridine
  • Synthetic intermediate 6-4 2-(4-(4-(6-methylpyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H -imidazol-5-yl)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrro[3,4-d ] Imidazole-5(1H)-carboxylic acid tert-butyl ester
  • intermediate 1-3 (300.0mg, 0.6mmol) in 10ml of 1,4-dioxane, add potassium acetate (178.0mg, 1.8mmol) and pinacol diborate (184.0mg, 0.7mmol), Under nitrogen protection, add Pd(dppf)Cl 2 (45.0mg, 0.1mmol), react at 85°C overnight, add intermediate 6-3 (90.0mg, 0.2mmol), potassium acetate (178.0mg, 1.8mmol), 1ml H 2 O, Pd(dppf)Cl 2 (45.0 mg, 0.1 mmol), react at 100°C for 6 hours, filter, concentrate and purify to obtain 50.0 mg of intermediate 6-4, yield: 11.5%.
  • Synthetic intermediate 6-5 (2-(4-(4-(6-methylpyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-imidazol-5-yl)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrro[3,4- d]imidazole-5(1H)-yl)(pyrrolidin-1-yl)methanone
  • Synthetic intermediate 7-2 2-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyridine
  • Synthetic intermediate 7-3 2-(4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-methylpyridine
  • Synthetic intermediate 7-4 2-(4-(3-(6-methylpyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4- yl)pyridin-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H )-tert-butylcarboxylate
  • reaction solution was lowered to room temperature, intermediate 7-3 (195.1 mg, 0.6 mmol), potassium carbonate (251.1 mg, 1.8 mmol) were added to the reaction solution, and Pd(dppf)Cl 2 (45.0 mg, 0.1 mmol) was added. , add 2 ml of water, replace nitrogen, and react at 100°C for 24 hours.
  • the reaction solution was filtered, water was added to the filtrate, and extracted twice with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain a total of 203.6 mg of intermediate 7-4, with a yield of 50.8%. .
  • Synthetic intermediate 7-5 2-(4-(3-(6-methylpyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4- yl)pyridin-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole
  • Synthetic intermediate 7-6 (4-methylpiperazin-1-yl)(2-(4-(3-(6-methylpyridin-2-yl))-1-(tetrahydro-2H-pyran -2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydro Pyrrolo[3,4-d]imidazole-5(1H)-yl)methanone
  • Synthetic compound 7 (4-methylpiperazin-1-yl)(2-(4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)pyridine-2- yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)methanone
  • Example 61 (4-methylpiperazin-1-yl)(2-(4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-8H-imidazo [2 ,1-c][1,4]oxazin-3-yl)pyridin-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) methanone
  • Synthetic intermediate 61-3 2-(4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-8H-imidazo[2,1-c][1,4] Oxazin-3-yl)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrro[3,4-d ] Imidazole-5(1H)-carboxylic acid tert-butyl ester
  • intermediate 61-2 (35.0 mg, 0.1 mmol), potassium carbonate (28.4 mg, 0.2 mmol), 2 ml H 2 O and Pd-127 (7.8 mg, 0.01 mmol), and react at 100°C under nitrogen protection. 5 hours, cooled to room temperature, added water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified to obtain 42.0 mg of intermediate 61-3, yield: 65.0%.
  • Synthetic intermediate 61-4 2-(6-methylpyridin-2-yl)-3-(2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 ,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)pyridin-4-yl)-5,6-dihydro-8H-imidazo[2,1-c][ 1,4]oxazine
  • Synthetic intermediate 61-5 (4-methylpiperazin-1-yl) (2-(4-(2-(6-methylpyridin-2-yl))-5,6-dihydro-8H-imidazole And[2,1-c][1,4]oxazin-3-yl)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4 ,6-dihydropyrro[3,4-d]imidazol-5(1H)-yl)methanone
  • Example 62 (4-methylpiperazin-1-yl)(2-(4-(2-(6-methylpyridin-2-yl)) -5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazol-3-yl)pyridin-2-yl)-4,6-dihydropyrro[3,4-d]imidazol-5(1H)-yl)methanone
  • Synthetic intermediate 62-1 ethyl 3-(6-methylpyridin-2-yl)-3-oxopropionate
  • Synthetic intermediate 62-2 ethyl 3-(6-methylpyridin-2-yl)-3-((2-oxopyrrolidin-1-yl)imino)propionate
  • Synthetic intermediate 62-3 2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid
  • Synthetic intermediate 62-4 3-bromo-2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole
  • Synthetic intermediate 62-5 2-(4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3- yl)pyridin-2-yl]-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydroxypyrrolo[3,4-d]imidazole-5( 1H)-tert-butylcarboxylate
  • reaction solution was lowered to room temperature, intermediate 62-4 (60.0 mg, 0.2 mmol) was dissolved in 4 m dioxane, and potassium carbonate (89.2 mg, 0.6 mmol) was added to the reaction solution, and Pd (dppf) was added Cl 2 (16.0 mg, 0.02 mmol), add 3 ml of water, replace with nitrogen, and react at 100°C for 20 hours.
  • the reaction solution was filtered, water was added to the filtrate, and extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain a total of 70.6 mg of intermediate 62-5, yield 52.9%.
  • Synthetic intermediate 62-6 2-(4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3- yl)pyridin-2-yl]-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d] imidazole
  • Synthetic intermediate 62-7 (4-methylpiperazin-1-yl) (2-(4-(2-(6-methylpyridin-2-yl))-5,6-dihydro-4H-pyrrole And[1,2-b]pyrazol-3-yl)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydro Pyrrolo[3,4-d]imidazole-5(1H)-yl)methanone
  • Dissolve intermediate 63-1 (5.0g, 27.5mmol) in 50ml methanol, add sodium methoxide (3.0g, 55.4mmol) to the reaction solution, react at room temperature for 16 hours, concentrate the reaction solution to remove methanol, and concentrate Add water to the mixture, extract twice with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain 4.8 g of crude intermediate 63-2, with a yield of 81.4%.
  • Synthetic intermediate 63-4 tert-butyl 2-(4-bromopyridin-2-yl)-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate ester
  • Synthetic intermediate 63-5 2-(4-bromopyridin-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3,4,6,7- Tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester
  • Synthetic intermediate 63-6 (2-(5-(tert-butoxycarbonyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7 -Tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)pyridin-4-yl)boronic acid
  • Synthetic intermediate 63-7 2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl )pyridin-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3,4,6,7-tetrahydro-5H-imidazo[4,5- c]tert-butylpyridine-5-carboxylate
  • Synthetic intermediate 63-8 2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl )pyridin-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5- c]pyridine
  • Synthetic intermediate 63-9 (2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3- yl)pyridin-2-yl)-5-(methylsulfonyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro -3H-imidazo[4,5-c]pyridine
  • Synthetic compound 63 2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridine- 2-yl)-5-(methylsulfonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine
  • the principle of the activity test is that TGF ⁇ R1 phosphorylates the substrate TGF ⁇ R1tide and consumes ATP.
  • the ADP-Glo method was used to detect the kinase activity test and determine the IC50 value to evaluate the inhibitory ability of the test compound on human TGF ⁇ R1.
  • DSM was used as a negative control
  • LY364947 was used as a positive control.
  • the specific experimental steps are as follows. Compounds were diluted 4-fold with DMSO in a dilution plate with a final starting concentration of 10 ⁇ M and 10 concentration gradient points. Dilute the compound 50-fold into the kinase reaction buffer and shake on a shaker for 20 minutes.
  • Compound inhibition rate (%inh) 100%-(compound-positive control)/(negative control-positive control)*100%.
  • Positive control IC50 is within 3 times of the previous average value
  • the compound of the present application exhibits an effect of inhibiting TGF ⁇ R1 that is equivalent to or better than that of the positive control LY364947, and therefore can be used to treat TGF- ⁇ -related (especially those related to TGF- ⁇ ). TGF- ⁇ 1 related) diseases or conditions.

Abstract

本申请涉及TGF-β抑制剂化合物及其用途。具体地，本申请公开了如式(I)所示的化合物、或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物。本申请还涉及所述化合物在医学方面的应用。

Description

TGF-β抑制剂化合物及其用途 技术领域
本申请提供了一类具有药学活性的新颖化合物，所述化合物可用于抑制成纤维细胞生长因子受体(fibroblast growth factor receptor,TGF)。本申请还涉及包含所述化合物的组合物，以及所述化合物和所述组合物在制备用于治疗与TGF相关的疾病或病症的药物中的用途。
背景技术
转化生长因子-β(Transforming Growth Factor β，TGF-β)是一种多功能细胞因子，其通过细胞表面复杂的受体信号传导途径参与调节细胞的增殖、分化和凋亡。TGF-β与活化素(activins)、抑制素(inhibins)、骨形成蛋白(bone morphogenetic proteins)等多种相关蛋白共同属于转化生长因子β超家族(TGF-βsuperfamily，TGF-βs)。
TGF-β有3个主要的细胞受体：I型受体(TGFβRl)、II型受体(TGFβR2)和III型受体(TGFβR3)。I型和II型受体是跨膜丝氨酸/苏氨酸激酶，二者同时传导信息，III型受体不传递信息，功能主要是将TGF-β传递给II型受体，通过为受体II提供配体而间接地影响信号传导。TGF-β存在三种亚型(TGF-βl、TGF-β2和TGF-β3)，它们与受体一起存在于大多数细胞中。每种亚型都以组织特异性和发育调节的方式表达。
TGF-β和激活素等相关因子调节大量细胞过程，例如上皮细胞和造血细胞的细胞周期阻滞、间充质细胞增殖和分化的控制、炎性细胞募集、免疫抑制、伤口愈合和细胞外基质的产生。研究表明，异常的TGF-β信号和许多种疾病相关，比如癌症、肾纤维化、肝纤维化、肺纤维化、病毒感染、慢性肾炎、急性肾炎、糖尿病肾病、骨质疏松症、关节炎、伤口愈合、溃疡、角膜创伤、心脏瓣膜狭窄、充血性心脏坏死、神经功能损伤、阿尔兹海默综合征、腹膜或皮下粘连、动脉硬化症和肿瘤转移生长等。
因素，人们希望开发新的TGF-β抑制剂来预防和/或治疗涉及该信号通路的多种疾病。
发明内容
一、化合物
在第一个方面，本申请提供了式(I)的化合物：
或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，其中：
n＝1、2或3；
L为(C＝O)、(O＝S＝O)、((C＝O)-CH2)、CH2或连接键；
R1选自H、卤素、-OH、-NO2、-CN、-SF5、-SH、-S-C1-4烷基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-8烯基、C2-8炔基、C3- 7脂环基、3-10元杂脂环基、C6-12双环脂环基、6-12元双环杂脂环基、C8-15元三环脂环基、8-15元三环杂脂环基、C5-8芳基、5-10元杂芳基、C7-11双环芳基、7-11元双环杂芳基、-C1-4烷基-(C3-7脂环基)、-C1-4烷基-(3-10元杂脂环基)、-C1-4烷基-(C6-12双环脂环基)、-C1-4烷基-(6-12元双环杂脂环基)、-C1-4烷基-(C8-15元三环脂环基)、-C1-4烷基-(8-15元三环杂脂环基)、-C1-4烷基-(C5-8芳基)、-C1-4烷基-(5-10元杂芳基)、-N(R10)(R11)、-N(R10)(C(＝O)R11)、-N(R10)(C(＝O)-OR11)、-N(R12)(C(＝O)-N(R10)(R11))、-C(＝O)-N(R10)(R11)、-C(＝O)-R12、-C(＝O)-OR12、-OC(＝O)R12、-N(R10)(S(＝O)2R11)、-S(＝O)2-N(R10)(R11)、-SR12和-OR12，其中所述-S-C1-4烷基、C1-6烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-8烯基、C2-8炔基、C3-7脂环基、3-10元杂脂环基、C6-12双环脂环基、6-12元双环杂脂环基，C8-15元三环脂环 基、8-15元三环杂脂环基、C5-8芳基、5-7元杂芳基、C7-11双环芳基、7-11元双环杂芳基、-C1-4烷基-(C3-7脂环基)、-C1-4烷基-(3-10元杂脂环基)、-C1- 4烷基-(C6-12双环脂环基)、-C1-4烷基-(6-12元双环杂脂环基)-C1-4烷基-(C8-15元三环脂环基)、-C1-4烷基-(8-15元三环杂脂环基)、-C1-4烷基-(C5-8芳基)和-C1-4烷基-(5-10元杂芳基)各自任选地被0、1、2、3或4个R1a取代，且R1a独立选自卤素、-OH、-NO2、-CN、-SF5、-SH、-S-C1-4烷基、氧代、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C2-8烯基、C2-8炔基、C3- 7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基、-N(R13)(R14)、-N(R13)(C(＝O)R14)、-N(R13)(C(＝O)-OR14)、-N(R15)(C(＝O)-N(R13)(R14))、-C(＝O)-N(R13)(R14)、-C(＝O)-R15、-C(＝O)-OR15、-OC(＝O)R15、-N(R13)(S(＝O)2R14)、-S(＝O)2-N(R13)(R14)、-SR15和-OR15；且
R10、R11、R12、R13、R14、和R15各自在每次出现时独立地选自：H、C1-6烷基、C1-6卤代烷基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基、C7-11双环芳基、7-11元双环杂芳基、-C1-4烷基-(C3-7脂环基)、-C1- 4烷基-(3-10元杂脂环基)、-C1-4烷基-(C6-12双环脂环基)、-C1-4烷基-(6-12元双环杂脂环基)、-C1-4烷基-(C8-15元三环脂环基)、-C1-4烷基-(8-15元三环杂脂环基)、-C1-4烷基-(C5-8芳基)和-C1-4烷基-(5-10元杂芳基)，其中该群组内的各个选项任选地被0、1、2、3或4个各自独立选自以下群组的取代基所取代：卤素、-OH、-NH2、-NH(CH3)、-N(CH3)2、-CN、-NO2、-SF5、-SH、-S-C1-4烷基、氧代、C1-4烷基、C2-6烯基、C2-6炔基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基、C7-11双环芳基、7-11元双环杂芳基、C1- 4羟烷基、-S-C1-4烷基、-C(＝O)H、-C(＝O)-C1-4烷基、-C(＝O)-O-C1-4烷基、-C(＝O)-NH2、-C(＝O)-N(C1-4烷基)2、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基；或者R10、R11以及与它们相连的原子共同形成3-14元环；或者R13、R14以及与它们相连的原子共同形成3-14元环；
R2的个数为1、2、3或4个，且每个R2各自独立地选自H、卤素、-CN、-OH、-NO2、-NR7R8、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C3-6脂环基和4-6元杂脂环基；
R3的个数为1、2或3个，且每个R3各自独立地选自H、卤素、-CN、 -OH、-NO2、-NR7R8、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C3-6脂环基和4-6元杂脂环基；
R7和R8各自在每次出现时独立地选自：H、C1-6烷基、C1-4卤代烷基、C1-4烷氧基，或者R7、R8以及与它们相连的N原子共同形成3-6元环；
环A为含氮的芳香环并满足：1)G1＝NR4，G2＝CR5；或者2)G1＝CR4，G2＝NR5；或者3)G1＝CR4，G2＝O或S；其中R4和R5各自独立地选自H、卤素、-CN、-OH、-NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基；或者R4和R5以及与它们相连的原子一起形成3-8元环。
除非另有规定，在本申请中所使用的各种技术术语应该按照本领域技术人员通常所理解的含义进行解释。为了避免歧义，下面对一些术语进行定义。
除非另有指明，本文所述的“式(I)所示的化合物”或“本申请的化合物”等术语中所使用的“化合物”也涵盖其任意光学异构体、几何异构体、互变异构体或异构体的混合物。
术语“光学异构体”意指，当化合物具有一个或更多个手性中心时，每个手性中心可以存在R构型或S构型，由此构成的各种异构体为光学异构体。光学异构体包括所有的非对映异构体、对映异构体、内消旋体、外消旋体或其混合物形式。例如，通过手性色谱柱或通过手性合成可以分离光学异构体。
术语“几何异构体”意指，当化合物中存在双键时，该化合物可以存在顺式异构体、反式异构体、E型异构体和Z型异构体。几何异构体包括顺式异构体、反式异构体、E型异构体、Z型异构体或其混合物形式。
术语“互变异构体”指因分子中某一原子在两个位置迅速移动而产生的异构体。本领域技术人员可以理解：互变异构体之间可以互相转变，在在某一状态下可能会达到一种平衡状态而共存。
除非另有指明，本文所述的“式(I)所示的化合物”或“本申请的化合物”等术语也涵盖该化合物中一个或者多个原子被其同位素原子代替而得到的同位素标记化合物。
适用于包含在本申请的化合物中的同位素的实例包括氢的同位素，诸如2H(D)和3H(T)；碳的同位素，诸如11C、13C和14C；氯的同位素，诸如36Cl；氟的同位素，诸如18F；碘的同位素，诸如12 3I和12 5I；氮的同位素，诸如13N和15N；氧的同位素，诸如15O、17O和18O；以及硫的同位素，诸如35S。
所述同位素标记化合物(例如包含放射性同位素的那些)可用于药物和/或底物组织分布研究。考虑到引入的容易性和检测手段的方便性，放射性同位素氘(即D)和碳-14(即14C)对于该目的是特别有用的。
利用诸如氘(即D)的较重同位素进行取代可以提供某些治疗方面的益处并且因此在某些情况下可以是优选的，所述治疗方面的益处例如是由更大的代谢作用稳定性(例如，增长的体内半衰期或者减小的剂量要求)带来的。因此，在一些实施方式中，本申请的化合物是同位素标记化合物，其中H在每次出现时任选地被D取代。
利用正电子放射同位素(诸如11C、18F、15O和13N)进行取代可以用于正电子放射受体图像(Positron Emission Topography(PET))研究，用于检测底物受体占用状态。
所述同位素标记化合物一般可以通过本领域技术人员已知的常规技术或者通过使用合适的同位素标记试剂代替先前使用的非标记试剂来进行制备。
本申请的化合物可以以其药学上可接受的盐的形式存在。
术语“药学上可接受的”是指相应的化合物、载体或分子适于给予人。优选地，该术语是指由管理机构例如CFDA(中国)、EMEA(欧洲)、FDA(美国))等任一国家管理机构认证的可用于哺乳动物(优选人)。
所述药学上可接受的盐类包括其酸加成盐和碱加成盐。适当的酸加成盐是由形成无毒性盐的酸所形成的。其实例包括但不限于：乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己胺磺酸盐、乙二磺酸盐、甲酸盐、反丁烯二酸盐、葡萄庚糖酸盐、葡萄糖酸盐、葡萄糖醛酸盐、六氟磷酸盐、2-(4-羟苄基)苯甲酸盐、氢氯化物/氯化物、氢溴化物/溴化物、 氢碘化物/碘化物、2-羟乙磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘酸盐、2-萘磺酸盐、烟碱酸盐、硝酸盐、乳清酸盐、草酸盐、十六酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、葡萄糖二酸盐、硬脂酸盐、水杨酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。适当的碱加成盐是由形成无毒性盐的碱所形成的。其实例包括但不限于：铝、精氨酸、钙、胆碱、二乙胺、二乙醇胺、甘氨酸、赖氨酸、镁、葡甲胺、乙醇胺、钾、钠、氨丁三醇和锌盐。还可形成酸和碱的半盐，例如半硫酸盐和半钙盐。关于合适的盐的综述，参见Handbook of Pharmaceutical Salts:Properties,Selection and Use by Stahl and Wermuth(Wiley-VCH,2002)。用于制备本文中所述的化合物的药学上可接受的盐的方法是本领域技术人员已知的。
此外，本申请化合物可以以非溶剂化形式以及与药学上可接受的溶剂如水、乙醇等的溶剂化形式存在。化合物也可以以一种或多种结晶状态存在，即多晶型，或者它们可以作为无定形固体存在。所有这些形式都包含在本申请的范围内。
本申请还包括本申请的化合物的前药。术语“前药”是指通过与酶、胃酸等在生理条件下在活体内例如通过各自在酶催化下进行的氧化、还原、水解等反应转化为本申请化合物的衍生物。因此，本申请化合物的某些衍生物本身可能具有很少或没有药理学活性，当给药至体内或身体上时，可以转化成具有所需活性的本申请化合物。
本申请还包括本申请的化合物的代谢物。术语“代谢物”是指在细胞或有机体优选人中源自本申请任意化合物的所有分子。
在本文中使用时，术语“被取代”是指基团中的一个或多个(优选1至5个，更优选1至3个，最优选1个或2个)氢原子独立地被相应数目的取代基所代替。
在本文中使用时，术语“独立地”是指当化学或基团取代基的个数超过一个时，这些化学基团或取代基可以相同也可以不同。
在本文中使用时，术语“任选”或“任选地”表示其所描述的事件可以发生或不发生。例如，一个基团“任选地被取代”表示：该基团可以是未被取代的，也可以是被取代的。
术语“卤素”或“卤”是指-F,-Cl,-Br,或-I。
在本文中使用时，术语“烷基”是指饱和的脂族烃，包括直链及支链。在一些实施方式中，烷基基团具有1-8个、或1-6个、或1-4个、或1-3个碳原子。例如，术语“C1-8烷基”是指具有1-8个碳原子的直链或支链原子团。术语“C1-8烷基”在其定义中包括术语“C1-6烷基”、“C1-3烷基”和“C1-4烷基”等。烷基的实例包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、2-戊基、3-戊基、异戊基、新戊基、(R)-2-甲基丁基、(S)-2-甲基丁基、3-甲基丁基、2,3-二甲基丙基、2,3-二甲基丁基、己基等。烷基基团可任选地被一或多个(例如，1至5个)适当的取代基所取代。
在本文中使用时，术语“烯基”是指具有至少一个碳-碳双键的脂族烃，包括具有至少一个碳-碳双键的直链及支链。在一些实施方式中，烯基基团具有2-8个碳原子、2-6个碳原子、3-6个碳原子、或2-4个碳原子。例如，术语“C2-8烯基”是指具有2-8个碳原子的直链或支链的不饱和原子团(具有至少一个碳-碳双键)。所述双键可以是或者可以不是另一基团的连接点。烯基包括但不限于乙烯基、1-丙烯基、2-丙烯基、2-甲基-2-丙烯基、丁烯基、戊烯基、3-己烯基等。烯基基团可任选地被一或多个(例如，1至5个)适当的取代基所取代。当式(I)的化合物含有烯基基团时，该烯基基团可以纯E形式、纯Z形式、或其任何混合物存在。
在本文中使用时，术语“炔基”是指具有至少一个碳-碳三键的脂族烃，包括具有至少一个碳-碳三键的直链及支链。在一些实施方式中，炔基基团具有2-8个碳原子、2-6个碳原子、3-6个碳原子、或2-4个碳原子。例如，术语“C2-8炔基”是指具有2-8个碳原子的直链或支链的不饱和原子团(具有至少一个碳-碳三键)。所述三键可以是或者可以不是另一基团的连接点。炔基包括但不限于乙炔基、1-丙炔基、2-丙炔基、2-甲基-2-丙炔基、丁炔基、戊炔基、3-己炔基等。炔基基团可任选地被一或多个(例如，1至5个) 适当的取代基所取代。
在本文中使用时，术语“C3-8脂环基”是指具有3-8个形成环的碳原子的脂环基。术语“C3-7脂环基”是指具有3-7个形成环的碳原子的脂环基。术语“C3-6脂环基”是指具有3-6个形成环的碳原子的脂环基。所述脂环基可以是单环环。脂环基的定义还包括不饱和的非芳族脂环基。脂环基的实例为，例如环丙基、环丁基、环戊基、环己基、环己烯基、环庚基、环辛基、环己二烯基、环戊烯基、环庚烯基和环辛烯基。脂环基可任选地被一或多个适当的取代基所取代。
本文中使用时，术语“C6-12双环脂环基”是具有6-12个形成环的碳原子的含有两个环的脂环基。双环脂环基可稠合，也可包括桥连双环脂环基系统。
本文中使用时，术语“C8-15元三环脂环基”是具有8-15个形成环的碳原子的含有三个环的脂环基。三环脂环基可稠合，也可桥连。
在本文中使用时，术语“n元杂脂环基”是指具有m个形成环的碳原子和(n-m)个形成环的杂原子的脂环基，所述杂原子选自O、S及N。例如，术语“4-8元杂脂环基”是指杂脂环基取代基含有总共4至8个环原子，其中至少一个是杂原子；术语“4-6元杂脂环基”是指杂脂环基取代基含有总共4至6个环原子，其中至少一个是杂原子；术语“3-10元杂脂环基”是指杂脂环基取代基含有总共3至10个环原子，其中至少一个是杂原子。术语“n元双环杂脂环基”是指具有m个形成环的碳原子和(n-m)个形成环的杂原子的双环杂脂环基，所述杂原子选自O、S及N。杂脂环基的实例包括，但不限于，氮杂环丁烷基、硫杂环丁烷基、二氢呋喃基、二氢噻吩基、四氢噻吩基、四氢呋喃基、四氢三嗪基、四氢吡唑基、四氢噁嗪基、四氢嘧啶基、八氢苯并呋喃基、八氢苯并咪唑基、八氢苯并噻唑基、咪唑烷基、吡咯烷基、哌啶基、哌嗪基、噁唑烷基、噻唑烷基、吡唑烷基、硫代吗啉基、四氢吡喃基、四氢噻喃基、四氢噻嗪基、四氢噻二嗪基、四氢噁唑基、吗啉基、氧杂环丁烷基、四氢二嗪基、噁嗪基、氧杂噻嗪基、奎宁环基、苯并二氢吡喃基(chromanyl)、异苯并二氢吡喃基(isochromanyl)、二氢苯并二噁英基(dihydrobenzodioxinyl)、苯并二氧 杂环戊烯基(benzodioxolyl)、苯并噁嗪基、二氢吲哚基、二氢苯并呋喃基、四氢喹啉基、异色满基(isochromyl)、二氢-1H-异吲哚基、2-氮杂双环[2.2.1]庚酰基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氧杂环庚烷基、硫杂环庚烷基、氮杂环庚烷基等。杂脂环基可任选地被一或多个适当的取代基所取代。
在本申请中，“芳基”指具有至少一个带有共轭π电子系统的环的5至16元碳环芳族基团。芳基可具有共轭或稠合环且可未经取代或如所说明经取代。芳基的实例包括苯基(phenyl)、萘基(naphthalenyl)、蒽基(anthracenyl)、菲基(phenanthrenyl)、薁基(azulenyl)及联苯基(biphenyl)。在本文中使用时，术语“C5-16芳基”是指具有含5-16个碳原子的芳环的芳基。类似地，术语“C5-8芳基”是指具有含5、6、7或8个碳原子的芳环的芳基，例如苯基。
在本申请中，“杂芳基”指具有至少一个带有共轭π电子系统的环且含有1至4个诸如N、O或S的杂原子的5至16元芳族基团。杂芳基可具有共轭或稠合环且可未经取代或如所说明经取代。杂芳基的实例包括噻吩基(thienyl,)、呋喃基(furanyl)、吡咯基(pyrrolyl)、吡唑基(pyrazolyl)、咪唑基(imidazoyl)、恶唑基(oxazolyl)、异恶唑基(isoxazolyl)、噻唑基(thiazolyl)、异噻唑基(isothiazolyl)、三唑基(triazolyl)、恶二唑基(oxadiazolyl)、噻二唑基(thiadiazolyl)、四唑基(tetrazolyl)、吡啶基(pyridinyl)、吡啶嗪基(pyridizinyl)、嘧啶基(pyrimidinyl)、吡嗪基(pyrazinyl)、三嗪基(triazinyl)、吲哚基(indolyl)、异吲哚基(isoindolyl)、吲嗪基(indolizinyl)、苯并呋喃基(benzofuranyl)、苯并噻吩基(benzothienyl)、吲唑基(indazolyl)、苯并咪唑基(benzimidazoyl)、苯并噻唑基(benzothiazolyl)、嘌呤基(purinyl)、喹嗪基(quinolizinyl)、喹啉基(quinolinyl)、异喹啉基(isoquinolinyl)、噌啉基(cinnolinyl)、呔嗪基(phthalazinyl)、喹唑啉基(quinazolinyl)、喹喏啉基(quinoxalinyl)、萘啶基(naphthyridinyl)、喋啶基(pteridinyl)、咔唑基(carbazolyl)、吖啶基(acridinyl)、啡嗪基(phenazinyl)、啡噻嗪基(phenothiazinyl)或啡恶嗪基 (phenoxazinyl)。
在本文中使用时，术语“n元杂芳基”是指具有m个形成芳环的碳原子和(n-m)个形成芳环的杂原子的杂芳基，所述杂原子选自O、S及N。例如，5-7元杂芳基包括但不限于呋喃基、噻吩基、吡咯基、噻唑基、吡唑基、咪唑基、吡啶基、吡喃基、哒嗪基、嘧啶基、吡嗪基。杂芳基可任选地被一或多个适当的取代基所取代。
在本文中使用时，术语“C7-11双环芳基”是指具有7-11个碳原子的双环芳基，例如萘基、茚基等。双环芳基可任选地被一或多个适当的取代基所取代。
在本文中使用时，术语“n元双环杂芳基”是指具有m个形成芳族双环的碳原子和(n-m)个形成芳族双环的杂原子的双环杂芳基，所述杂原子选自O、S及N。例如，7-11元双环杂芳基包括但不限于喹啉基、异喹啉基、吲哚基、嘌呤基、苯并噻唑基等。双环杂芳基可任选地被一或多个适当的取代基所取代。
在本文中使用时，术语“11-15元三环基”包括但不限于吖啶基等。11-15元三环基可任选地被一或多个适当的取代基所取代。
在本文中使用时，术语“卤代烷基”是指具有一或多个卤素取代基的烷基基团(至多全卤代烷基，即，烷基基团的每个氢原子均被卤素原子所取代)。例如，术语“C1-6卤代烷基”是指具有一或多个卤素取代基的C1-6烷基基团(至多全卤代烷基，即，烷基基团的每个氢原子均被卤素原子所取代)。另举一例，术语“C1-4卤代烷基”是指具有一或多个卤素取代基的C1-4烷基基团(至多全卤代烷基，即，烷基基团的每个氢原子均被卤素原子所取代)；术语“C1-3卤代烷基”是指具有一或多个卤素取代基的C1-3烷基基团(至多全卤代烷基，即，烷基基团的每个氢原子均被卤素原子所取代)；且术语“C1-2卤代烷基”是指具有一或多个卤素取代基的C1-2烷基基团(即，甲基或乙基)(至多全卤代烷基，即，烷基基团的每个氢原子均被卤素原子所取代)。再另举一例，术语“C1卤代烷基”是指具有1、2或3个卤素取代基的甲基基团。卤代烷基基团的例子包括：CF3、C2F5、CHF2、CH2F、CH2CF3、CH2Cl等。
在本文中使用时，术语“烷氧基”是指单键连接至氧原子的烷基。烷氧基与分子的连接点是通过氧原子。烷氧基可被描述为烷基-O-。术语“C1-6烷氧基”是指包含1-6个碳原子的直链或支链的烷氧基。术语“C1-6烷氧基”在其定义中包括术语“C1-3烷氧基”。烷氧基包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、己氧基等。烷氧基可任选地被一或多个适当的取代基所取代。
在本文中使用时，术语“3-14元环”是指具有3-14个成环原子的饱和或不饱和环体系。
本文中，与取代基个数、碳原子个数、环原子个数相关的数目范围表示该范围内所有整数的逐个列举，而范围仅是作为一种简化的表示法。例如：“4-6元”表示4、5或6元；“5-7元”表示5、6或7元；“7-11元”表示7、8、9、10或11元；“4-8元”表示4、5、6、7或8元；“3-10元”表示3、4、5、6、7、8、9或10元；“3-14元”表示3、4、5、6、7、8、9、10、11、12、13或14元；“C1-3”表示1个(C1)、2个(C2)或3个碳原子(C3)；“C1-4”表示1个(C1)、2个(C2)、3个碳原子(C3)或4个碳原子(C4)；“C3-6”表示3个(C3)、4个(C4)、5个(C5)或6个碳原子(C6)；“C3- 8”表示3个(C3)、4个(C4)、5个(C5)、6个(C6)、7个(C7)或8个碳原子(C8)；“C5-7”表示5个(C5)、6个(C6)或7个碳原子(C7)；“C7-11”表示7个(C7)、8个(C8)、9个(C9)、10个(C10)或11个碳原子(C11)。因此，与取代基个数、碳原子个数、环原子个数相关的数目范围也涵盖其任意一个子范围，且每一个子范围也视为被本文公开。
在如上所述的式(I)中，R1可以是有机化学中常见的任何取代基，其并不特别受限。
在一些实施方式中，R1为C1-6烷基，例如R1选自甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、2-戊基、3-戊基、异戊基、新戊基、(R)-2-甲基丁基、(S)-2-甲基丁基、3-甲基丁基、2,3-二甲基丙基、2,3-二甲基丁基、己基。
在一些实施方式中，R1为C3-7脂环基，例如R1选自环丙基、环丁基、环戊基、环己基、环己烯基、环庚基、环己二烯基、环戊烯基、环庚烯基。
在一些实施方式中，R1为3-10元杂脂环基，例如R1选自氮杂环丁烷基、硫杂环丁烷基、二氢呋喃基、二氢噻吩基、四氢噻吩基、四氢呋喃基、四氢三嗪基、四氢吡唑基、四氢噁嗪基、四氢嘧啶基、八氢苯并呋喃基、八氢苯并咪唑基、八氢苯并噻唑基、咪唑烷基、吡咯烷基、哌啶基、哌嗪基、噁唑烷基、噻唑烷基、吡唑烷基、硫代吗啉基、四氢吡喃基、四氢噻喃基、四氢噻嗪基、四氢噻二嗪基、四氢噁唑基、吗啉基、氧杂环丁烷基、四氢二嗪基、噁嗪基、氧杂噻嗪基、奎宁环基、苯并二氢吡喃基、异苯并二氢吡喃基、二氢苯并二噁英基、苯并二氧杂环戊烯基、苯并噁嗪基、二氢吲哚基、二氢苯并呋喃基、四氢喹啉基、异色满基、二氢-1H-异吲哚基、氧杂环庚烷基、硫杂环庚烷基、氮杂环庚烷基。
在一些实施方式中，R1为H、卤素、-OH、-NO2、-CN、-SF5或-SH。
在一些实施方式中，R选自-S-C1-4烷基、C1-6烷基、C1-6卤代烷基、C1- 6烷氧基、C1-6卤代烷氧基、C2-8烯基、C2-8炔基。
在一些实施方式中，R1选自C5-8芳基(例如苯基)、5-10元杂芳基(例如呋喃基、噻吩基、吡咯基、噻唑基、吡唑基、咪唑基、吡啶基、吡喃基、哒嗪基、嘧啶基、吡嗪基等)、-C1-4烷基-(C5-8芳基)、-C1-4烷基-(5-10元杂芳基)。
在一些实施方式中，R1选自-N(R10)(R11)、-N(R10)(C(＝O)R11)、-N(R10)(C(＝O)-OR11)、-N(R12)(C(＝O)-N(R10)(R11))、-C(＝O)-N(R10)(R11)、-C(＝O)-R12、-C(＝O)-OR12、-OC(＝O)R12、-N(R10)(S(＝O)2R11)、-S(＝O)2-N(R10)(R11)、-SR12和-OR12，其中R10、R11、R12各自在每次出现时独立地选自：H、C1-6烷基、C1-6卤代烷基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基、C7-11双环芳基、7-11元双环杂芳基、-C1-4烷基-(C3-7脂环基)、-C1-4烷基-(3-10元杂脂环基)、-C1-4烷基-(C6-12双环脂环基)、-C1-4烷基-(6-12元双环杂脂环基)、-C1-4烷基-(C8-15元三环脂环基)、-C1-4烷基-(8-15元三环杂脂环基)、-C1-4烷基-(C5-8芳基)和-C1-4烷基-(5-10元杂芳基)，其中该群组内的各个选项任选地被0、1、2、3或4个各自独立选自以下群组的取代基所取代：卤素、-OH、-NH2、-NH(CH3)、-N(CH3)2、-CN、-NO2、-SF5、-SH、-S-C1-4烷基、氧代、C1-4烷基、C2-6烯基、C2-6炔基、C3-7脂环基、3- 10元杂脂环基、C5-8芳基、5-7元杂芳基、C7-11双环芳基、7-11元双环杂芳基、C1-4羟烷基、-S-C1-4烷基、-C(＝O)H、-C(＝O)-C1-4烷基、-C(＝O)-O-C1-4烷基、-C(＝O)-NH2、-C(＝O)-N(C1-4烷基)2、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基；或者R10、R11以及与它们相连的原子共同形成3-14元环。
在一些实施方式中，R1选自-S-C1-4烷基、C1-6烷基、C1-6卤代烷基、C1- 6烷氧基、C1-6卤代烷氧基、C2-8烯基、C2-8炔基、C3-7脂环基、3-10元杂脂环基、C6-12双环脂环基、6-12元双环杂脂环基、C5-8芳基、5-10元杂芳基、C7-11双环芳基、7-11元双环杂芳基，其中所述-S-C1-4烷基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-8烯基、C2-8炔基、C3-7脂环基、3-10元杂脂环基、C6-12双环脂环基、6-12元双环杂脂环基、C5-8芳基、5-10元杂芳基、C7-11双环芳基、7-11元双环杂芳基是未经取代的或各自任选地被1、2、3或4个R1a取代，且R1a独立选自卤素、-OH、-NH2、-NH(CH3)、-N(CH3)2、-CN、-NO2、-SF5、-SH、-S-C1-4烷基、氧代、C1-4烷基、C2-6烯基、C2-6炔基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基、C7-11双环芳基、7-11元双环杂芳基、C1-4羟烷基、-S-C1-4烷基、-C(＝O)H、-C(＝O)-C1-4烷基、-C(＝O)-O-C1-4烷基、-C(＝O)-NH2、-C(＝O)-N(C1-4烷基)2、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基。
上述对于R1列举的任意示例基团都应被理解为是任选地被取代的；即在适当的时候，上述对于R1给出的任意基团可以任选地被0、1、2、3或4个R1a取代，且R1a独立选自卤素、-OH、-NO2、-CN、-SF5、-SH、-S-C1-4烷基、氧代、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C2-8烯基、C2-8炔基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基、-N(R13)(R14)、-N(R13)(C(＝O)R14)、-N(R13)(C(＝O)-OR14)、-N(R15)(C(＝O)-N(R13)(R14))、-C(＝O)-N(R13)(R14)、-C(＝O)-R15、-C(＝O)-OR15、-OC(＝O)R15、-N(R13)(S(＝O)2R14)、-S(＝O)2-N(R13)(R14)、-SR15和-OR15，其中R13、R14、和R15各自在每次出现时独立地选自：H、C1-6烷基、C1-6卤代烷基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基、C7-11双环芳基、7-11元双环杂芳基、-C1-4烷基-(C3-7脂环基)、-C1-4烷基-(3-10元杂脂环基)、 -C1-4烷基-(C6-12双环脂环基)、-C1-4烷基-(6-12元双环杂脂环基)、-C1-4烷基-(C8-15元三环脂环基)、-C1-4烷基-(8-15元三环杂脂环基)、-C1-4烷基-(C5-8芳基)和-C1-4烷基-(5-10元杂芳基)，其中该群组内的各个选项任选地被0、1、2、3或4个各自独立选自以下群组的取代基所取代：卤素、-OH、-NH2、-NH(CH3)、-N(CH3)2、-CN、-NO2、-SF5、-SH、-S-C1-4烷基、氧代、C1-4烷基、C2-6烯基、C2-6炔基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基、C7-11双环芳基、7-11元双环杂芳基、C1-4羟烷基、-S-C1-4烷基、-C(＝O)H、-C(＝O)-C1-4烷基、-C(＝O)-O-C1-4烷基、-C(＝O)-NH2、-C(＝O)-N(C1-4烷基)2、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基；或者R13、R14以及与它们相连的原子共同形成3-14元环。
在一些优选的实施方式中，R1选自甲基、乙基、丙基、异丙基、环丁基基团。所述甲基、乙基、丙基、异丙基或环丁基基团可以任选地被0、1或2个各自独立选自以下群组的取代基所取代：甲基、乙基、环戊基、环丙基、-CN、-OH、吗啉基、哌啶基，所述取代基又可以任选地被0、1或2个各自独立选自以下群组的取代基所取代：甲基、乙基、环戊基、环丙基、-CN、-OH。例如，在一些优选的实施方式中，R1选自(1-羟基环丙基)乙基、3-羟基环丁基、2-氰基乙基、2-羟乙基、2-氰基-1-环戊基乙基、1-氰基丙烷、2-吗啉代乙基、乙基和(1-甲基哌啶-4-基)甲基。
在一些优选的实施方式中，R1选自卤素，例如F。
在一些优选的实施方式中，R1选自哌嗪基、吗啉基、吡咯烷基、哌啶基和氮杂环丁烷基，所述哌嗪基、吗啉基、吡咯烷基、哌啶基和氮杂环丁烷基可以任选地被0、1或2个各自独立选自以下群组的取代基所取代：甲基、乙基、环戊基、环丙基、-CN、-OH。在一些优选的实施方式中，R1选自甲基、乙基、丙基、异丙基、环丁基基团，所述甲基、乙基、丙基、异丙基或环丁基基团可以任选地被0、1或2个各自独立选自以下群组的取代基所取代：甲基、乙基、环戊基、环丙基、-CN、-OH、吗啉基、哌啶基，所述取代基又可以任选地被0、1或2个各自独立选自以下群组的取代基所取代：甲基、乙基、环戊基、环丙基、-CN、-OH。
在一些优选的实施方式中，R1选自哌嗪基、吗啉基、吡咯烷基、哌啶基、氮杂环丁烷基。例如，在一些优选的实施方式中，R1选自3,5-二甲基哌嗪基、吗啉基、3-羟基吡咯烷基、4-甲基哌嗪基、4-乙基哌嗪基、4-羟基哌啶基、1-甲基哌啶基、1-乙基哌啶-4-基、1-甲基氮杂环丁烷-3-基。
在一些优选的实施方式中，R1选自H、甲基、乙基、正丙基、异丙基、丁基、甲氧基、乙氧基、羟基、环丙基、环丁基、环戊基、环己基、吗啉代甲基、羟基环丁基、羟基环己基、氰基乙氧基、氰基甲基、吡啶-3-基、1-甲基-1H-吡唑-4-基、1-甲基-1H-吡唑-3-基、4-甲基哌嗪-1-基、1-甲基哌啶-4-基、吗啉基、吡咯烷-3-基、3-羟基吡咯烷-1-基、3-氰基吡咯烷-1-基。
在一些优选的实施方式中，R1选自H、卤素、-OH、-NO2、-CN、-SF5、-SH、-S-C1-4烷基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-6脂环基、4-6元杂脂环基、C5-8芳基、5-10元杂芳基、-C1-4烷基-(C3-7脂环基)、-C1-4烷基-(3-10元杂脂环基)、-C1-4烷基-(C5-8芳基)、-C1-4烷基-(5-10元杂芳基)、-N(R10)(R11)，其中所述-S-C1-4烷基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-6脂环基、4-6元杂脂环基、C5-8芳基、5-10元杂芳基、-C1-4烷基-(C3-7脂环基)、-C1-4烷基-(3-10元杂脂环基)、-C1- 4烷基-(C5-8芳基)、-C1-4烷基-(5-10元杂芳基)各自任选地被0、1、2、3或4个R1a取代，且R1a独立选自卤素、-OH、-NO2、-CN、氧代、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基；且R10、R11和R12各自在每次出现时独立地选自：H、C1-6烷基、C1-6卤代烷基、C3-7脂环基、3-10元杂脂环基，其中该群组内的各个选项任选地被0、1、2、3或4个各自独立选自以下群组的取代基所取代：卤素、-OH、-NH2、氧代、C1-4烷基、C1-4羟烷基、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基；或者R10、R11以及与它们相连的原子共同形成3-8元环R1选自H、卤素、-OH、-NO2、-CN、-SF5、-SH、-S-C1-4烷基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-6脂环基、4-6元杂脂环基、C5-8芳基、5-10元杂芳基、-C1-4烷基-(C3-7脂环基)、-C1-4烷基-(3-10元杂脂环基)、-C1-4烷基-(C5-8芳基)、-C1-4烷基-(5-10元杂芳基)、-N(R10)(R11)，其中所述-S-C1-4烷基、C1-6烷基、C1-6卤代烷基、 C1-6烷氧基、C1-6卤代烷氧基、C3-6脂环基、4-6元杂脂环基、C5-8芳基、5-10元杂芳基、-C1-4烷基-(C3-7脂环基)、-C1-4烷基-(3-10元杂脂环基)、-C1-4烷基-(C5-8芳基)、-C1-4烷基-(5-10元杂芳基)各自任选地被0、1、2、3或4个R1a取代，且R1a独立选自卤素、-OH、-NO2、-CN、氧代、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基；且R10、R11和R12各自在每次出现时独立地选自：H、C1-6烷基、C1-6卤代烷基、C3-7脂环基、3-10元杂脂环基，其中该群组内的各个选项任选地被0、1、2、3或4个各自独立选自以下群组的取代基所取代：卤素、-OH、-NH2、氧代、C1-4烷基、C1-4羟烷基、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基；或者R10、R11以及与它们相连的原子共同形成3-8元环。
在一些优选的实施方式中，R1选自H、卤素、-OH、甲基、乙基、丙基、丁基、戊基、己基、甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基、环丙基、环丁基、环戊基、环己基、环庚基、苯基、哌嗪基、哌啶基、吗啉基、吡咯烷基、吡咯基、吗啉基、吡啶基和吡唑基，其中的甲基、乙基、丙基、丁基、戊基、己基、甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基、环丙基、环丁基、环戊基、环己基、环庚基、苯基、哌嗪基、哌啶基、吗啉基、吡咯烷基、吡咯基、吗啉基、吡啶基、吡唑基各自任选地被1或2个R1a取代，且R1a独立选自卤素、-OH、-NO2、-CN、氧代、C1-4烷基、C1-4卤代烷基和C1-4烷氧基。
在一些优选的实施方式中，R1选自H、甲基、甲基哌嗪基、吡咯烷基、甲基哌嗪基、羟基环丁基、甲基吡唑基、羟乙基、羟丙基、甲基哌啶基、吗啉基、羟基吡咯烷基。
应当理解，任何上述R1的实施方式可以与如上文和下文所述的任何R2、R3、L、n和环A的实施方式以任意方式组合在一起。
在如上所述的式(I)中，R2可以选自H、卤素、-CN、-OH、-NO2、-NR7R8、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C3-6脂环基和4-6元杂脂环基。
在一些实施方式中，R2为H。
在一些实施方式中，R2为卤素，例如R2选自F、Cl、Br、I。
在一些实施方式中，R2为-CN。
在一些实施方式中，R2为-NO2。
在一些实施方式中，R2为C1-3烷基或C1-3卤代烷基，例如，R2选自任选地被一个或多个卤素原子(例如氟、氯、溴、碘)取代的甲基、乙基、丙基、异丙基。
在一些实施方式中，R2为C1-3烷氧基，例如，R2选自甲氧基、乙氧基、丙氧基、异丙氧基。
在一些实施方式中，R2为C3-6脂环基，例如，R2选自环丙基、环丁基、环戊基、环己基、环己烯基。
在一些实施方式中，R2为4-6元杂脂环基，例如，R2选自氧杂环丁烷基、硫杂环丁烷基、氮杂环丁烷基、四氢呋喃基、四氢噻吩基、吡咯烷基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、哌嗪基。
在一些实施方式中，R2为-NR7R8，其中R7和R8各自在每次出现时独立地选自：H、C1-3烷基(例如甲基、乙基、丙基、异丙基等)、C1-3卤代烷基(例如被被一个或多个选自氟、氯、溴、碘的卤原子取代的甲基、乙基、丙基、异丙基)、C1-3烷氧基(例如甲氧基、乙氧基、丙氧基、异丙氧基)，或者R7、R8以及与它们相连的N原子共同形成3-6元环(例如吡咯、吡啶、嘧啶、咪唑、吡唑、吡咯烷、六氢吡啶等)。
应当理解，任何上述R2的实施方式可以与如上文和下文所述的任何R1、R3、L、n和环A的实施方式以任意方式组合在一起。
在如上所述的式(I)中，R3可以选自H、卤素、-CN、-OH、-NO2、-NR7R8、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C3-6脂环基和4-6元杂脂环基。
在一些实施方式中，R3为H。
在一些实施方式中，R3为卤素，例如R3选自F、Cl、Br、I。
在一些实施方式中，R3为-CN。
在一些实施方式中，R3为-NO2。
在一些实施方式中，R3为C1-3烷基或C1-3卤代烷基，例如，R3选自任选地被一个或多个卤素原子(例如氟、氯、溴、碘)取代的甲基、乙基、丙基、异丙基。
在一些实施方式中，R3为C1-3烷氧基，例如，R3选自甲氧基、乙氧基、丙氧基、异丙氧基。
在一些实施方式中，R3为C3-6脂环基，例如，R3选自环丙基、环丁基、环戊基、环己基、环己烯基。
在一些实施方式中，R3为4-6元杂脂环基，例如，R3选自氧杂环丁烷基、硫杂环丁烷基、氮杂环丁烷基、四氢呋喃基、四氢噻吩基、吡咯烷基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、哌嗪基。
在一些实施方式中，R3为-NR7R8，其中R7和R8各自在每次出现时独立地选自：H、C1-3烷基(例如甲基、乙基、丙基、异丙基等)、C1-3卤代烷基(例如被被一个或多个选自氟、氯、溴、碘的卤原子取代的甲基、乙基、丙基、异丙基)、C1-3烷氧基(例如甲氧基、乙氧基、丙氧基、异丙氧基)，或者R7、R8以及与它们相连的N原子共同形成3-6元环(例如吡咯、吡啶、嘧啶、咪唑、吡唑、吡咯烷、六氢吡啶等)。
应当理解，任何上述R3的实施方式可以与如上文和下文所述的任何R1、R2、L、n和环A的实施方式以任意方式组合在一起。
在一些实施方式中，R3和R2可以是相同的。例如，R3和R2均为卤素，例如Cl；再例如，R3和R2均为甲基。在一个优选的实施方式中，R3和R2均为Cl。在一个优选的实施方式中，R3和R2均为H。
在另一些实施方式中，R3和R2可以是不同的。
在如上所述的式(I)中，L可以为(C＝O)、(O＝S＝O)、((C＝O)-CH2)、CH2或连接键。
在一些实施方式中，L为(C＝O)。
在一些实施方式中，L为(O＝S＝O)。
在一些实施方式中，L为((C＝O)-CH2)。
在一些实施方式中，L为CH2。
在一些实施方式中，L为连接键(即，R1和N原子直接以共价键相连)。
应当理解，任何上述L的实施方式可以与如上文和下文所述的任何R1、R2、R3、环A和n的的实施方式以任意方式组合在一起。
在如上所述的式(I)中，n为1、2或3。
在一些实施方式中，n为1。
在一些实施方式中，n为2。
在一些实施方式中，n为3。
应当理解，任何上述n的实施方式可以与如上文和下文所述的任何R1、R2、R3、L和环A的的实施方式以任意方式组合在一起。
在如上所述的式(I)中，环A为含氮的芳香环并满足：1)G1＝NR4，G2＝CR5；或者2)G1＝CR4，G2＝NR5；或者3)G1＝CR4，G2＝O或S；其中R4和R5各自独立地选自H、卤素、-CN、-OH、-NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基(R4和R5可以相同或不同)；或者R4和R5以及与它们相连的原子一起形成3-8元环。
因此，本申请中的式(I)化合物可以具有如下结构之一：
其中n、L、R1、R2、R3、R4、R5如上所定义；
其中n、L、R1、R2、R3、R4、R5如上所定义；
其中n、L、R1、R2、R3、R4如上所定义；
其中n、L、R1、R2、R3如上所定义；环B为含有1个N原子的3至8元环，Ra选自H、卤素、-CN、-OH、-NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基。
在上文中对于式(I)给出的R1、R2、R3、环A、L和n等的实施方式和优选项同样适用于式(I-1)、式(I-2)、式(I-3)和式(I-4)。
在一些具体实施方式中，本申请的式(I)化合物选自相应的各实施例所示的化合物。
二、化合物的制备方法
本申请的式(I)化合物可以由本领域技术人员根据化合物具体结构由常规的有机合成方法合成得到。
另外，本领域技术人员可以参照本申请具体实施例的具体化合物的合成路线，对反应原料和反应条件进行适当调整而得到其它化合物的合成方法。
三、化合物的用途和含有化合物的组合物
实验表明，本申请的式(I)化合物可以抑制TGF-β的活性，即可以作为TGF-β抑制剂使用。具体地，本申请的式(I)化合物尤其可以用于抑制TGF-βI型受体(TGFβRl)，即作为TGF-β1抑制剂使用。
在第二个方面，本申请提供了一种药物组合物，其含有如上文所述的本申请的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，以及一种或多种药学上可接受的载体、佐剂或赋形剂。
本申请的药物组合物可以按制药领域中熟知的方式制备，并且可以通过多种途径施用，这取决于期望局部治疗还是全身性治疗并且取决于有待治疗的部位。给药可以是局部的(包括眼科的和至粘膜，包括鼻内、阴道和直肠递送)、肺部的(例如，通过吸入或吹入粉末或气溶胶，包括通过喷雾器；气管内、鼻内、表皮和经皮肤)、眼部的、经口的或肠胃外的。用于眼部递送的方法可以包括局部给药(滴眼剂)，结膜下、眼周或玻璃体内注射或者通过用手术方法放置在结膜囊中的气囊式导管或眼科插入件引入。肠胃外给药包括静脉内、动脉内、皮下、腹膜内或肌内注射或输注；或颅内(例如，鞘内或脑室内)给药。肠胃外给药可以处于单次推注剂量的形式，或者可以例如通过连续灌注泵。用于局部给药的医药组合物和配制物可以包括透皮贴剂、软膏剂、洗剂、乳膏剂、凝胶剂、滴剂、栓剂、喷雾剂、液体以及粉剂。
如果使用固体载剂，则该制剂可以成片，以粉末或颗粒形式置于硬质凝胶胶囊中，或以糖锭或锭剂形式。固体载剂可以包括常规的赋形剂，诸如粘合剂、填料、成片润滑剂、崩解剂、润湿剂等等。如果需要可以通过常规技术膜包衣该片剂。如果使用液体载剂，则该制剂可以是糖浆、乳液、膏剂、软凝胶胶囊、用于注射的无菌载体、水性或非水性液体悬浮液形式的，或者可以是在使用前用水或其他适当载体复原的干品。液体制剂可以包含常规添加剂，诸如悬浮剂、乳化剂、润湿剂、非水性载体(包括可食用油)、防腐剂以及香味剂和/或着色剂。为了胃肠外施予，通常载体至少大部分包括无菌水，但也可以使用盐水溶液、葡萄糖溶液等。也可以使用可注射悬浮液，在这种情况下，可以使用常规悬浮剂。常规防腐剂、缓冲试剂等也可以添加到胃肠外剂型中。药物组合物通过对包含适量的活性成分(即本申请的化合物)的所需制剂合适的常规技术制备。
适于非肠道注射的组合物可以包括生理学上可接受无菌水性或非水性溶液、分散液、悬浮液或乳液和用于无菌可注射溶液或分散液的无菌粉末。合适的水性和非水性载体、稀释剂、溶剂的实例包括水、乙醇、多元醇(丙二醇、聚乙二醇、丙三醇等)、其合适的混合物、植物油(例如，橄榄油)和可注射有机酯(例如，油酸乙酯)。
这些组合物还可以包含各种赋形剂，例如，防腐剂、润湿剂、乳化剂和分散剂。可以通过各种抗菌剂和抗真菌剂(例如，对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸等)来确保对微生物的作用的抑制。还可以包括等渗剂，例如，糖、氯化钠等。可以通过使用延迟吸收试剂(例如，单硬脂酸铝和凝胶)来延长可注射药学剂型的吸收。
用于口服的固体剂型包括胶囊、药片、药丸、粉末和颗粒。在这种固体剂型中，将活性化合物与至少一种惰性赋型剂(或载体)(例如，柠檬酸钠或磷酸二钙)混合，其中还可以包括：(a)填料或混合剂(例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸)；(b)粘结剂(例如，羧基甲基纤维素、褐藻酸酯、凝胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯树胶)；(c)保湿剂(例如，丙三醇)；(d)崩解剂(例如，琼脂-琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、某些合成的硅酸酯、碳酸钠)； (e)溶液阻滞剂(例如，石蜡)；(f)吸收促进剂(例如，季铵化合物)；(I)润湿剂(例如，十六烷醇和单硬脂酸丙三醇酯)；(h)吸附剂(例如，高岭土和斑脱土)和(i)润滑剂(例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠)或其混合物混合。
类似类型的固体组合物还可以在使用例如乳糖以及高分子量聚乙二醇等作为赋型剂的软填充和硬填充凝胶胶囊中作为填料。
固体剂型(例如，药片、糖衣丸、胶囊、药丸和颗粒)可以采用涂层和外壳(例如，肠道涂层和本领域已知的其它)来制备。它们可以包含遮光剂，它们还可以是以延迟方式在肠道的某一部分中释放活性化合物或各种活性化合物的组合物。可用的包埋组合物的实例是聚合物质和蜡。活性组分还可以以微胶囊化形式，如果适当的话，可以具有一种或更多种上述赋型剂。
用于口服的液体剂型包括药学上可接受乳液、溶液、分散液、糖浆和酏剂。除了活性化合物以外，液体剂型可以包含本领域中通常所用的惰性稀释剂(例如，水或其它溶剂)、增溶剂和乳化剂(例如，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3丁二醇、二甲基甲酰铵)、油(具体为，棉花子油、落花生油、玉米油、橄榄油、蓖麻油、芝麻油)、丙三醇、四氢呋喃醇、聚乙二醇和山梨聚糖的脂肪酸酯或这些物质的混合物等。
除了这些惰性稀释剂，组合物还可以包括，例如，润湿剂、乳化和悬浮剂、香化剂、调味剂和加香剂。
除了活性化合物，悬浮液可以包含悬浮剂，例如乙氧基化异十八烷醇、聚氧化乙烯山梨醇、山梨聚糖酯、微晶纤维、偏氢氧化铝、斑脱土、琼脂-琼脂和黄芪胶或这些物质的混合物等。
本申请的化合物的局部给药用剂型包括膏剂、粉末、喷雾和吸入剂。该活性组分在无菌条件下与生理学上可接受载体和任何所需要的防腐剂、缓冲剂或推进剂混合。眼用配方、眼药膏、粉末和溶液也包括在本申请的范围内。
本申请的化合物在药物组合物和剂型中的量可以由本领域技术人员根据需要适当地确定，例如本申请的化合物可以治疗有效量存在于药物组合物或剂型中。
在第三个方面，本申请提供了本申请的式(I)化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，或如上文所述的药物组合物在制备用于治疗与TGF-β相关(尤其是与TGF-β1相关)的疾病或病症的药物中的用途。
在第四个方面，本申请也提供了治疗与TGF-β相关(尤其是与TGF-β1相关)的疾病或病症的方法，所述方法包括向有此需要的患者施用治疗有效量的本申请的式(I)化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，或如上文所述的药物组合物。其中，所述患者优选是哺乳动物，更优选是人类患者。其中给药途径可以是口服、外用(包括但不限于外敷、喷涂等)、胃肠外(包括皮下、肌肉、皮层和静脉)施予、支气管施予或鼻施予等。所施用的量为治疗有效量，可由本领域技术人员根据实际需要予以确定。
在本申请中，“与TGF-β相关(尤其是与TGF-β1相关)的疾病或病症”可以是癌症、病毒感染、慢性肾炎、急性肾炎、糖尿病肾病、骨质疏松症、关节炎、伤口愈合、疤痕、溃疡、角膜创伤、心脏瓣膜狭窄、充血性心脏坏死、神经功能损伤、阿尔兹海默综合征、腹膜或皮下粘连、动脉硬化症、皮肤纤维化和脂肪流失导致的皮肤老化、骨骼障碍或软骨细胞障碍、低磷血症障碍和器官纤维化疾病，尤其是肝细胞癌、乳腺癌、膀胱癌、结肠直肠癌、黑色素瘤、间皮瘤、肺癌、前列腺癌、膜腺癌、睾丸癌、甲状腺癌、鳞状细胞癌、神经胶母细胞瘤、成神经细胞瘤、子宫癌、横纹肌肉瘤、肾纤维化、肝纤维化、肺纤维化、皮肤疤痕、皮肤纤维化和脂肪流失导致的皮肤老化等。
在一些实施方案中，所述与TGF-β相关的疾病或病症是癌症。本申请的化合物可例如用于抑制癌细胞的增殖、转移等。
示例性癌症包括膀胱癌、乳腺癌、子宫颈癌、结肠直肠癌、小肠癌、结肠癌、直肠癌、肛门癌、子宫内膜癌、头颈癌(例如，喉、喉咽、鼻咽、口咽、唇部和口腔的癌症)、肾癌、肝癌(例如，肝细胞癌、胆管细胞癌)、肺癌(例如，腺癌、小细胞肺癌和非小细胞肺癌、小细胞癌和非小细胞癌、支气管癌、支气管腺瘤、胸膜肺母细胞瘤)、卵巢癌、前列腺癌、睾丸癌、子宫癌、食管癌、胆囊癌、胰腺癌(例如外分泌胰腺癌)、甲状腺癌、副甲状腺癌、皮肤癌(例如，鳞状细胞癌、卡波西肉瘤、梅克尔(Merkel)细胞皮肤癌)以及脑癌(例如，星状细胞瘤、神经管胚细胞瘤、室管膜瘤、神经外胚层肿瘤、松果体肿瘤)。
另外的示例性癌症包括造血系统恶性肿瘤，如白血病或淋巴瘤、多发性骨髓瘤、慢性淋巴细胞性淋巴瘤、成人T细胞白血病、B细胞淋巴瘤、皮肤T细胞淋巴瘤、急性骨髓性白血病、霍奇金或非霍奇金淋巴瘤、骨髓增生性肿瘤(例如，真性红细胞增多症、原发性血小板增多症和原发性骨髓纤维化)、瓦登斯特隆巨球蛋白血症、毛细胞淋巴瘤、慢性骨髓性淋巴瘤、急性淋巴母细胞性淋巴瘤、AIDS相关的淋巴瘤以及柏基特淋巴瘤。
另外的示例性癌症包括眼睛肿瘤、神经胶母细胞瘤、黑色素瘤、横纹肌肉瘤、淋巴肉瘤以及骨肉瘤。
在一些优选的实施方式中，所述与TGF-β相关的疾病或病症选自肝细胞癌、乳腺癌、膀胱癌、结肠直肠癌、黑色素瘤、间皮瘤、肺癌、前列腺癌、膜腺癌、睾丸癌、甲状腺癌、鳞状细胞癌、神经胶母细胞瘤、成神经细胞瘤、子宫癌以及横纹肌肉瘤。
在另一些实施方式中，所述与TGF-β相关的疾病或病症选自骨骼障碍和软骨细胞障碍，此类骨骼障碍和软骨细胞障碍包括但不限于软骨发育不全、软骨生成减退、侏儒症、致死性软骨发育不全(TD)(临床形式TD I和TD II)、阿佩尔(Apert)综合症、克鲁宗(Crouzon)综合症、杰克逊-威斯(Jackson-Weiss)综合症、比尔-史蒂文森皮肤旋纹综合症(Beare-Stevenson cutis gyrate syndrome)、斐弗(Pfeiffer)综合症以及颅缝线封闭过早综合症。
在另一些实施方式中，所述与TGF-β相关的疾病或病症为低磷血症障碍，所述低磷血症障碍包括例如X连锁低磷酸盐血性佝偻病(X-Iinked  hypophosphatemic rickets)、常染色体隐性低磷酸盐血性何偻病(autosomal recessive hypophosphatemic rickets)、常染色体显性低磷酸盐血性佝偻病(autosomaI dominant hypophosphatemic rickets)以及肿瘤诱发的骨软化症(tumor-induced osteromaIacia)。
在另一些实施方式中，所述与TGF-β相关的疾病或病症选自纤维化疾病。示例性纤维化疾病包括肝硬化、肾小球肾炎、肺纤维化、系统性纤维化、类风湿性关节炎以及伤口愈合。
在一些优选实施方式中，所述与TGF-β相关的疾病或病症是皮肤疾病，尤其是皮肤疤痕、皮肤纤维化和脂肪流失导致的皮肤老化等。
下面结合具体实施例对本申请做进一步的说明和描述。
实施例
以下在本文中阐述的实施例仅仅为了说明目的，用以举例说明本发明的各个方面以及实施方式，并不意欲以任何方式限制本发明所要求保护的范围。
除非另有声明，所有反应物原料均从商业途径获得。合成实验和产物分析检测中所用仪器设备等均为有机合成中通常使用的常规仪器和设备。凡是未特别注明的反应条件和检测条件均为有机合成和药学领域常规采用的反应条件和检测条件。
实施例1:1-(2-(4-(2-(6-甲基吡啶-2-基)-6,7-二氢-5H-吡咯并[1,2-a]咪唑-3- 基)吡啶-2-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)乙烷-1-酮
化合物1的合成路线：
合成方法：
合成中间体1-b:2-溴-1-(6-甲基吡啶-2-基)乙烷-1-酮
将原料1-a(2.0g,14.8mmol)溶于40ml乙腈中，加入对甲苯磺酸(3.8g,22.2mmol)，随后升温至80后，分批加入NBS(2.6g，14.8mmol)，持续2小时，加完后80完反应3小时。TLC监测原料反应完，然后向反应液中加入饱和碳酸氢钠溶液淬灭，用EA萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，硅胶柱纯化得到中间体1-b 1.8g，收率57.2％。LC-MS m/z(ESI)[M+H]+针对C8H9BrNO的计算值为:214.1；测量值为:214.1。
合成中间体1-c:2-(6-甲基吡啶-2-基)-6,7-二氢-5H-吡咯并[1,2-a]咪唑
将中间体1-b(800.0mg,3.7mmol)溶于40ml甲苯中，加入碳酸氢钠(942.4mg,11.2mmol)和2-氨基吡咯烷盐酸盐(896.4mg,7.5mmol)，升温至80至反应过夜。TLC监测原料反应完，向反应液中加水淬灭，用DCM萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，硅胶柱纯化得到中间体1-c 313.8mg，收率41.9％。LC-MS m/z(ESI)[M+H]+针对C12H14N3的计算值为:200.1；测量值为:200.2。
合成中间体1-d:3-溴-2-(6-甲基吡啶-2-基)-6,7-二氢-5H-吡咯并[1,2-a]咪唑将中间体1-c(313.8mg,1.6mmol)溶于20ml DCM中，室温下分批加入NBS(279.5mg,1.6mmol)，持续5分钟。立即TLC监测，原料反应完全，向反应液中加水淬灭，用DCM萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，硅胶柱纯化得到中间体1-d 289.7mg，收率66.4％。LC-MS m/z(ESI)[M+H]+针对C12H13N3Br的计算值为:278.0；测量值为:278.0。
合成中间体1-1:2-(4-溴吡啶-2-基)-3a,4,6,6a-四氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将2-醛基-4-溴吡啶(0.8g,4.3mmol)溶于30ml叔丁醇中，加入3,4-二氨基吡咯烷-1-羧酸叔丁酯(1.1g,5.6mmol)，碘(1.6g,6.5mmol)，碳酸钾(1.2g,8.6mmol)，升温至70℃反应3小时。反应完全后，降至室温，加5％的硫代硫酸钠水溶液淬灭反应，加EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体1-1 1.4g，收率88.9％。LC-MS m/z(ESI)[M+H]+针对C15H20BrN4O2的计算值为:367.1；测量值为:367.1。
合成中间体1-2:2-(4-溴吡啶-2-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将中间体1-1(1.4g,3.8mmol)溶于20ml DMSO中，加入IBX(2.1g,7.6mmol)，升温50℃反应过夜。反应完成后，降至室温，加饱和碳酸氢钠溶液淬灭反应，加EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体1-2 1.2g，收率84.7％。LC-MS m/z(ESI)[M+H]+针对C15H18BrN4O2的计算值为:365.1；测量值为:365.1。
合成中间体1-3:2-(4-溴吡啶-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将中间体1-2(1.2g,3.2mmol)溶于20ml THF中，降温至0℃，加入NaH(60％)(0.2g,4.9mmol)，搅拌0.5小时，加入SEMCl(0.8g,4.9mmol)。加入完毕后升至室温搅拌，反应完成后，加水淬灭，加EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体1-31.2g，收率75.2％。LC-MS m/z(ESI)[M+H]+针对C21H32BrN4O3Si的计算值为:495.1；测量值为:495.1。
合成中间体1-4:(2-(5-(叔丁氧基羰基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)吡啶-4-基)硼酸
将中间体1-3(200.0mg,0.4mmol)溶于10ml二氧六环中，加入联硼酸频那醇酯(207.5mg,0.8mmol)和Pd(dppf)Cl2(29.7mg,0.04mmol)，氮气置换，加入醋酸钾(120.5mg,1.2mmol)，再次氮气置换，升至80次反应过夜。将反应液冷却至室温，得到中间体1-4的粗品，直接用于下一步反应。
合成中间体1-5:2-(4-(2-(6-甲基吡啶-2-基)-6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基)吡啶-2-基)-1-(2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
在中间体1-4的反应瓶中加入2ml水和碳酸钾(111.6mg,0.8mmol)，再加入溶于10ml二氧六环的中间体1-d(114.1mg,0.8mmol)和Pd(dppf)Cl2(29.7mg,0.04mmol)，氮气置换，升至100℃反应过夜。将反应液冷却至室温，浓缩后硅胶柱纯化，得到中间体1-5 86.5mg，收率35.2％。LC-MS m/z(ESI)[M+H]+针对C33H44N7O3Si的计算值为:614.3；测量值为:614.3。
合成中间体1-6:2-(4-(2-(6-甲基吡啶-2-基)-6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基)吡啶-2-基)-1-(2-(三甲基甲硅烷基)乙氧基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑
将中间体1-5(60.0mg,0.1mmol)溶于10ml DCM，加入溴化锌(44.1mg,0.2mmol)，氮气置换，室温反应过夜。将反应液浓缩除去溶剂，随后溶于20ml THF，再加入饱和碳酸氢钠溶液与饱和食盐水各洗涤一次，浓缩后得 到中间体1-6粗品46.4mg，收率92.8％。LC-MS m/z(ESI)[M+H]+针对C28H36N7OSi的计算值为:514.3；测量值为:514.3。
合成中间体1-7:1-(2-(4-(2-(6-甲基吡啶-2-基)-6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基)吡啶-2-基)-1-(2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)乙烷-1-酮
将中间体1-6(46.4mg,0.1mmol)溶于10ml DCM中，室温下加入三乙胺(18.4mg,0.2mmol)，再加入乙酰氯(14.2mg,0.2mmol)，室温搅拌0.5小时。反应完成后，加水淬灭，加DCM萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，制备板纯化，得中间体1-7 27.4mg，收率54.8％。LC-MS m/z(ESI)[M+H]+针对C30H38N7O2Si的计算值为:556.3；测量值为:556.3。
合成化合物1:1-(2-(4-(2-(6-甲基吡啶-2-基)-6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基)吡啶-2-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)乙烷-1-酮
将中间体1-7(27.4mg,0.1mmol)溶于4ml甲醇中，加入2ml浓盐酸，50℃反应3小时，浓缩，溶于5ml甲醇，加0.5ml氨水，浓缩，再用反向硅胶柱纯化，得到最终产物6.2mg,收率29.6％。LC-MS m/z(ESI)[M+H]+针对C24H24N7O的计算值为:426.2；测量值为:426.2。
实施例2:2-(4-(2-(6-甲基吡啶-2-基)-6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基)吡 啶-2-基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑
化合物2的合成路线：
合成方法：
合成化合物2:2-(4-(2-(6-甲基吡啶-2-基)-6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基)吡啶-2-基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑
将中间体1-5(36.5mg,0.1mmol)溶于4ml甲醇中，加入2ml浓盐酸，50℃反应3小时，浓缩，溶于5ml甲醇，加0.5ml氨水，浓缩，再用反向硅胶柱纯化，得到最终产物4.1mg,收率17.9％。LC-MS m/z(ESI)[M+H]+针对C22H22N7的计算值为:384.2；测量值为:384.2。
实施例3：5-甲基-2-(4-(2-(6-甲基吡啶-2-基)-6,7-二氢-5H-吡咯并[1,2-a]咪唑 -3-基)吡啶-2-基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑
化合物3的合成路线：
合成方法：
合成化合物3:5-甲基-2-(4-(2-(6-甲基吡啶-2-基)-6,7-二氢-5H-吡咯[1,2-a]咪唑-3-基)吡啶-2-基)-1,4,5,6-四氢吡咯[3,4-d]咪唑
将中间体1-6(50.0mg,0.1mmol)和30％甲醛水溶液(11.7mg,0.4mmol)溶于5ml DCM中，室温搅拌0.5小时，降温至0℃加入三乙酰基硼氢化钠(82.8mg,0.4mmol)，室温反应2小时，加水淬灭，用DCM萃取，合并有机相，用饱和食盐水洗涤，浓缩。将浓缩物溶于4ml甲醇中，加入2ml浓盐酸，50℃反应2小时，浓缩，溶于5ml甲醇，加0.5ml氨水，浓缩，制备板纯化，得到最终产物3.2mg,收率8.3％
1H NMR(400MHz,CD3OD)δ8.61(d,J＝4.0Hz,1H),8.14(s,1H),7.74-7.70(m,1H),7.54(d,J＝8.0Hz,1H),7.43-7.41(m,1H),7.19(d,J＝8.0Hz,1H),4.59(s,4H),4.27-4.23(m,2H),3.21(s,3H),3.07-3.03(m,2H),2.79-2.72(m,2H),2.36(s,3H).
实施例4：(4-甲基哌嗪-1-基)(2-(4-(2-(6-甲基吡啶-2-基)-6,7-二氢-5H-吡咯并 [1,2-a]咪唑-3-基)吡啶-2-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲酮 (MDI-980)
化合物4的合成路线：
合成方法：
合成化合物4:(4-甲基哌嗪-1-基)(2-(4-(2-(6-甲基吡啶-2-基)-6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基)吡啶-2-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲酮
将中间体1-6(40.0mg,0.1mmol)溶于10ml的DCM，向体系中加入三光气(23.1mg,0.1mmol),将体系降温至0℃，滴加三乙胺(80.8mg,0.8mmol)，反应0.5小时，向体系中加入N-甲基哌啶(8.0mg,0.1mmol)，升至室温反应。反应完成后，加水淬灭，用DCM萃取，合并有机相，用饱和食盐水洗涤，浓缩。将浓缩物溶于4ml甲醇中，加入2ml浓盐酸，50℃反应2小时，浓缩，溶于5ml甲醇，加0.5ml氨水，浓缩，制备板纯化，得到最终产物2.2mg,收率5.5％。LC-MS m/z(ESI)[M+H]+针对C28H32N9O的计算值为:510.3；测量值为:510.3。
实施例6:(2-(4-(4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)吡啶-2-基)-4,6-二氢吡咯 并[3,4-d]咪唑-5(1H)-基)(吡咯烷-1-基)甲酮
化合物6的合成路线：
合成方法
合成中间体6-1:2-(1H-咪唑-4-基)-6-甲基吡啶
将中间体1-b(0.8g,3.7mmol)，溶于30ml乙二醇,加入醋酸甲脒(2.0g,18.7mmol)，氮气保护，130l反应2小时。冷却至室温，加水，调节pH为10，用EA萃取，饱和食盐水洗涤,无水硫酸钠干燥,浓缩得中间体6-1 400.0mg。LC-MS m/z(ESI)[M+H]+针对C9H10N3的计算值为：160.1；测量值为：160.1。
合成中间体6-2：2-甲基-6-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-4-基)吡啶
将中间体6-1(400.0mg,2.5mmol)溶于10ml THF，加入NaH(120.0mg,3.0mmol，60％)，在0℃反应0.5小时，加入SEMCl(628.4mg,3.8mmol)，室温反应2小时,加饱和氯化铵溶液淬灭，用EA萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩过柱得中间体6-2 140.0mg，收率：19.3％。
合成中间体6-3：2-(5-溴-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-4-基)-6-甲基吡啶
将中间体6-2(140.0mg,0.5mmol)溶于10ml DCM，分批加入NBS(77.5mg,0.4mmol)，室温反应10分钟。加饱和碳酸氢钠溶液淬灭，用DCM萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩过柱，得中间体6-3 90.0mg，收率：50.5％。LC-MS m/z(ESI)[M+H]+针对C15H23BrN3OSi的计算值为：368.1；测量值为：368.1。
合成中间体6-4：2-(4-(4-(6-甲基吡啶-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-5-基)吡啶-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将中间体1-3(300.0mg,0.6mmol)溶于10ml 1,4-二氧六环，加入醋酸钾(178.0mg,1.8mmol)，联硼酸频那醇酯(184.0mg,0.7mmol)，氮气保护，加入Pd(dppf)Cl2(45.0mg,0.1mmol)，在85℃反应过夜,加入中间体6-3(90.0mg,0.2mmol),醋酸钾(178.0mg,1.8mmol)，1ml H2O，Pd(dppf)Cl2(45.0mg,0.1mmol)，100℃反应6小时，过滤浓缩纯化得中间体6-4 50.0mg，收率：11.5％。
合成中间体6-5：(2-(4-(4-(6-甲基吡啶-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-5-基)吡啶-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)(吡咯烷-1-基)甲酮
将中间体6-4(50.0mg,0.1mmol)溶于10ml DCM，氮气保护,加入ZnBr2(32.0mg,0.1mmol)，室温反应过夜。加三乙胺(1ml)，室温反应0.5小时，加入吡咯烷-1-羰基氯(10.0mg,0.1mmol)，室温反应2小时，加水，用DCM萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩纯化得中间体6-5 20.0mg， 收率:42.9％。LC-MS m/z(ESI)[M+H]+针对C36H53N8O3Si2的计算值为：701.4；测量值为：701.4。
合成化合物6：(2-(4-(4-(6-甲基吡啶-2-基)-1H-咪唑-5-基)吡啶-2-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)(吡咯烷-1-基)甲酮
将中间体6-5(20.0mg,0.03mmol)，溶于2ml甲醇，加入1ml盐酸，在50℃反应3小时。浓缩，加氨水调碱，浓缩纯化得到产物4.7mg，收率:37.4％。LC-MS m/z(ESI)[M+H]+针对C24H25N8O的计算值为：441.2；测量值为：441.2。
实施例7:(4-甲基哌嗪-1-基)(2-(4-(3-(6-甲基吡啶-2-基)-1H-吡唑-4-基)吡啶- 2-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲酮
化合物7的合成路线：
合成方法：
合成中间体7-1:2-甲基-6-(1H-吡唑-3-基)吡啶
将1-(6-甲基吡啶-2-基)乙烷-1-酮(1.0g,7.4mmol)溶于10ml DMF-DMA中，110℃搅拌20小时。反应液冷却至室温，浓缩至黄色固体。固体溶于8ml乙醇，加入4ml水合肼，90℃反应30分钟，向反应液中加水，用EA萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得粗品中间体7-1共1.1g，收率90.2％。
合成中间体7-2:2-甲基-6-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)吡啶
将中间体7-1(1.1g,6.7mmol)溶于10ml DCM中，加入对甲苯磺酸(1.3g,6.7mmol)，室温滴加DHP(0.7ml,8.0mmol)，室温反应2小时。向反应液中加水，用DCM萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体7-2共1.6g，收率95.5％。
1H NMR(400MHz,CDCl3)δ7.79(d,J＝7.8Hz,1H),7.70-7.67(m,1H),7.63-7.59(m,1H),7.08(d,J＝7.5Hz,1H),6.96(d,J＝2.5Hz,1H),5.51-5.48(m,1H),4.15-4.11(m,1H),3.77-3.72(m,1H),2.62(s,3H),2.16-2.11(m,3H),1.77-1.71(m,3H).
合成中间体7-3:2-(4-溴-1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-基)-6-甲基吡啶
将中间体7-2(250.0mg,1.0mmol)溶于10ml DCM中，加入对NBS(274.3mg,1.5mmol)，室温搅拌15分钟，反应完毕。向反应液中加水，用DCM萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体7-3共223.2mg，收率67.4％。
1H NMR(400MHz,CDCl3)δ7.77-7.74(m,2H),7.66(t,J＝7.7Hz,1H),7.15(d,J＝7.8Hz,1H),5.51-5.48(m,1H),4.12-4.08(m,1H),3.77-3.69(m,1H),2.67(s,3H),2.17-2.00(m,3H),1.74-1.64(m,3H).
合成中间体7-4:2-(4-(3-(6-甲基吡啶-2-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)吡啶-2-基)-1-(2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁基酯
将2-(4-溴吡啶-2-基)-1-(2-(三甲基硅基)乙氧基)甲基)-4,6-二氢吡咯[3,4-d]咪唑-5(1H)-羧酸叔丁酯(300.0mg,0.6mmol)和联硼酸频那醇酯(184.5mg,0.7mmol)溶于8ml二氧六环中，向溶液中加入醋酸钾(118.9mg,1.2mmol)，Pd(dppf)Cl2(45.0mg,0.1mmol)，置换氮气，90℃反应16小时。将反应液降至室温，向反应液中加入中间体7-3(195.1mg,0.6mmol)，碳酸钾(251.1mg,1.8mmol)，补加Pd(dppf)Cl2(45.0mg,0.1mmol)，加入2ml水，置换氮气，100℃反应24小时。反应液过滤，滤液中加水，用EA萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体7-4共203.6mg，收率50.8％。
1H NMR(400MHz,CDCl3)δ8.38(t,J＝5.7Hz,1H),8.32-8.27(m,1H),8.03(d,J＝5.2Hz,1H),7.58(t,J＝7.7Hz,1H),7.46-7.43(m,1H),7.23-7.20(m,1H),7.11(d,J＝7.7Hz,1H),6.07-6.02(m,2H),5.51-5.47(m,1H),4.61-4.44(m,4H),4.13-4.10(m,1H),3.73(t,J＝10.8Hz,1H),3.62-3.54(m,2H),2.53(s,3H),2.22-2.07(m,3H),1.72-1.64(m,3H),1.53(s,9H),0.95-0.85(m,2H),-0.06(s,9H).
合成中间体7-5:2-(4-(3-(6-甲基吡啶-2-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)吡啶-2-基)-1-(2-(三甲基甲硅烷基)乙氧基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑
将中间体7-4(65.0mg,0.1mmol)溶于10ml DCM中，加入ZnBr2(110.9mg,0.5mmol)，室温下搅拌。反应完成后，加氨水淬灭，加DCM萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得中间体7-5共55.1mg，收率99.7％。
合成中间体7-6:(4-甲基哌嗪-1-基)(2-(4-(3-(6-甲基吡啶-2-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)吡啶-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲酮
将中间体7-5(55.0mg,0.1mmol)和三光气(29.2mg,0.1mmol)溶于10ml DCM中，降温至0℃向溶液中加入三乙胺(99.5mg,0.1mmol)，反应5分钟，向体系中加入N-甲基哌嗪(19.7mg,0.2mmol),升至室温搅拌。反应完成后，加水淬灭，用DCM萃取，合并有机相，用饱和食盐水洗涤，浓缩。硅胶柱纯化，得中间体7-6共35.2mg，收率51.9％。
合成化合物7:(4-甲基哌嗪-1-基)(2-(4-(3-(6-甲基吡啶-2-基)-1H-吡唑-4-基)吡啶-2-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲酮
将中间体7-6(35.2mg,0.1mmol)溶于4ml甲醇中，加入2ml浓盐酸，45℃反应6小时，浓缩，溶于5ml甲醇，加0.5ml氨水调至碱性，浓缩，纯化，得到最终产物5.0mg,收率20.8％。LC-MS m/z(ESI)[M+H]+针对C25H28N9O的计算值为:470.2；测量值为:470.2。
实施例9至11
以下实施例根据实施例1的合成路线，使用合适的起始原料进行制备。

实施例12至13
以下实施例根据实施例3的合成路线，使用合适的起始原料进行制备。

实施例14至15
以下实施例根据实施例4的合成路线，使用合适的起始原料进行制备。

实施例22至23
以下各实施例的化合物根据实施例7的合成路线，使用合适的起始原料进行制备。

实施例25至26
以下各实施例的化合物根据实施例3的合成路线，使用合适的起始原料进行制备。

实施例27至34
以下各实施例的化合物根据实施例4的合成路线，使用合适的起始原料进行制备。




实施例37至60
以下各实施例的化合物根据实施例7的合成路线，使用合适的起始原料进行制备。










实施例61：(4-甲基哌嗪-1-基)(2-(4-(2-(6-甲基吡啶-2-基)-5,6-二氢-8H-咪唑 并[2,1-c][1,4]恶嗪-3-基)吡啶-2-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲 酮
化合物61的合成路线：
合成方法：
合成中间体61-1:2-(6-甲基吡啶-2-基)-5,6-二氢-8H-咪唑并[2,1-c][1,4]恶嗪
将2-溴-1-(6-甲基吡啶-2-基)乙烷-1-酮(500.0mg,2.3mmol)，吗啉-3-亚胺盐酸盐(318.0mg,2.3mmol)和碳酸钠(1.2g,11.7mmol)溶于10ml DMF中，加热到80℃反应过夜。反应完成后，加水淬灭，用EA萃取2次，合并有机相，用饱和食盐水洗涤，浓缩，硅胶柱纯化得到中间体61-1共282.0mg,收率56.1％。LC-MS m/z(ESI)[M+H]+针对C12H14N3O的计算值为:216.1；测量值为:216.1。
1H NMR(400MHz,CDCl3)δ7.70(d,J＝8.0Hz,1H),7.62-7.58(m,2H),7.03(d,J＝8.0Hz,1H),4.94(s,2H),4.11(s,4H),2.58(s,3H).
合成中间体61-2:3-碘-2-(6-甲基吡啶-2-基)-5,6-二氢-8H-咪唑并[2,1-c][1,4]恶嗪
将中间体61-1(20.0mg,0.1mmol)和NIS(48.2mg,0.3mmol)溶于1ml DMF中，加热到60℃反应4小时。反应完成后，加水淬灭，用EA萃取2次，合并有机相，用饱和食盐水洗涤，浓缩，纯化得到中间体61-2共23.0mg,收率72.6％。LC-MS m/z(ESI)[M+H]+针对C12H13IN3O的计算值为:342.0；测量值为:342.0。
1H NMR(400MHz,CDCl3)δ7.76(d,J＝8.0Hz,1H),7.63(t,J＝8.0Hz,1H),7.09(d,J＝8.0Hz,1H),4.92(s,2H),4.14(t,J＝4.0Hz,2H),3.96(t,J＝8.0Hz,1H),2.64(s,3H).
合成中间体61-3:2-(4-(2-(6-甲基吡啶-2-基)-5,6-二氢-8H-咪唑并[2,1-c][1,4]恶嗪-3-基)吡啶-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将2-(4-溴吡啶-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯(76.3mg,0.2mmol)溶于10ml 1,4-二氧六环，加入醋酸钾(20.1mg,0.2mmol)，联硼酸频那醇酯(58.6mg,0.2mmol)和Pd(dppf)Cl2(7.5mg,0.01mmol)，氮气保护下100℃反应过夜。冷却到室温，加入中间体61-2(35.0mg,0.1mmol),碳酸钾(28.4mg,0.2mmol)，2ml H2O和Pd-127(7.8mg,0.01mmol)，氮气保护下100℃反应5小时，冷却到室温，加水，用EA萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，纯化得中间体61-3 42.0mg，收率：65.0％。LC-MS m/z(ESI)[M+H]+针对C33H44N7O4Si的计算值为:630.3；测量值为:630.3。
合成中间体61-4:2-(6-甲基吡啶-2-基)-3-(2-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)吡啶-4-基)-5,6-二氢-8H-咪唑并[2,1-c][1,4]恶嗪
将中间体61-3(42.0mg,0.1mmol)溶于10ml DCM，加入溴化锌(60.3mg,0.3mmol)，室温反应过夜。加入饱和碳酸氢钠溶液搅拌10分钟，用DCM萃取，用饱和食盐水洗涤一次，无水硫酸钠干燥，浓缩后得到中间体61-4粗品35.0mg，收率99.1％。
合成中间体61-5:(4-甲基哌嗪-1-基)(2-(4-(2-(6-甲基吡啶-2-基)-5,6-二氢-8H-咪唑并[2,1-c][1,4]恶嗪-3-基)吡啶-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲酮
将中间体61-4(35.0mg,0.1mmol)溶于10ml的DCM，冷却到0℃向，加入三光气(24.5mg,0.1mmol),反应5分钟，滴加三乙胺(66.9mg,0.7mmol)，反应0.5小时，向体系中加入N-甲基哌啶(7.9mg,0.1mmol)，升至室温反应。反应完成后，加水淬灭，用DCM萃取，合并有机相，用饱和食盐水洗涤，浓缩纯化得中间体61-5 31.0mg，收率：71.5％。
合成化合物61:(4-甲基哌嗪-1-基)(2-(4-(2-(6-甲基吡啶-2-基)-5,6-二氢-8H-咪唑并[2,1-c][1,4]恶嗪-3-基)吡啶-2-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲酮
将中间体61-5(31.0mg,0.05mmol)溶于4ml甲醇中，加入2ml浓盐酸，50℃反应2小时，浓缩，溶于5ml甲醇，加0.5ml氨水调至碱性，浓缩，制备板纯化，得到最终产物4.6mg,收率18.5％。LC-MS m/z(ESI)[M+H]+针对C28H32N9O2的计算值为:526.3；测量值为:526.3。
实施例62:(4-甲基哌嗪-1-基)(2-(4-(2-(6-甲基吡啶-2-基)-5,6-二氢-4H-吡咯 并[1，2-b]吡唑-3-基)吡啶-2-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲酮
化合物62的合成路线：
合成方法：
合成中间体62-1:3-(6-甲基吡啶-2-基)-3-氧代丙酸乙酯
将乙酸乙酯(874.3mg，9.9mmol)溶于10ml甲苯中，加入乙醇钠(450.0mg，6.6mmol)，室温搅拌1小时，加入6-甲基吡啶甲酸甲酯(500.0mg，3.3mmol)，95℃搅拌16小时。反应完毕，反应液冷却至室温，加醋酸调pH至7。向反应液中加水，用乙酸乙酯萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得粗品中间体62-1共530.3mg，收率77.3％。LC-MS m/z(ESI)[M+H]+针对C11H13NO3的计算值为:208.1；测量值为:208.2。
合成中间体62-2:3-(6-甲基吡啶-2-基)-3-((2-氧代吡咯烷-1-基)亚氨基)丙酸乙酯
将中间体62-1(430.0mg，2.1mmol)溶于10ml吡啶中，加入2-亚氨基吡咯烷盐酸盐(275.2mg，2.3mmol)，室温反应16小时，反应完毕。反应液浓缩除去吡啶，向浓缩液中加水，用乙酸乙酯萃取2次，合并有机相， 用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得粗品中间体62-2共580.1mg，收率96.6％。
合成中间体62-3:2-(6-甲基吡啶-2-基)-5,6-二氢-4H-吡咯并[1，2-b]吡唑-3-羧酸
将中间体62-2(580.0mg，2.0mmol)溶于10ml甲苯中，加入乙醇钠(272.7mg，4.0mmol)，100℃搅拌15小时。反应液冷却至室温，向反应液中加水，搅拌20分钟，用浓盐酸调pH至4，用二氯甲烷：异丙醇＝10:1萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得粗品中间体62-3共340.2mg，收率69.4％。LC-MS m/z(ESI)[M+H]+针对C13H13N3O2的计算值为:244.1；测量值为:244.1。
合成中间体62-4:3-溴-2-(6-甲基吡啶-2-基)-5,6-二氢-4H-吡咯并[1，2-b]吡唑
将中间体62-3(340.0mg，1.4mmol)溶于10ml DMF中，加入NBS(272.1mg，1.5mmol)，室温搅拌16小时，反应完毕。向反应液中加水，用乙酸乙酯萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体62-4共350.1mg，收率90.0％。LC-MS m/z(ESI)[M+H]+针对C12H12BrN3的计算值为:278.0；测量值为:278.0。
合成中间体62-5:2-(4-(2-(6-甲基吡啶-2-基)-5,6-二氢-4H-吡咯并[1，2-b]吡唑-3-基)吡啶-2-基]-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二羟基吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将2-(4-溴吡啶-2-基)-1-(2-(三甲基硅基)乙氧基)甲基)-4,6-二氢吡咯[3,4-d]咪唑-5(1H)-羧酸叔丁酯(106.9mg，0.2mmol)和联硼酸频那醇酯(109.6mg，0.4mmol)溶于8ml二氧六环中，向溶液中加入醋酸钾(42.3mg，0.4mmol)，Pd(dppf)Cl2(16.0mg，0.02mmol)，置换氮气，90℃反应16小时。将反应液降至室温，将中间体62-4(60.0mg，0.2mmol)溶于4m二氧六环中，和碳酸钾(89.2mg，0.6mmol)一起加入反应液，补加Pd(dppf)Cl2(16.0mg，0.02mmol)，加入3ml水，置换氮气，100℃反应20小时。反应液过滤，滤液中加水，用乙酸乙酯萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体62-5共70.6mg，收率 52.9％。LC-MS m/z(ESI)[M+H]+针对C33H43N7O3Si的计算值为:614.3；测量值为:614.5。
合成中间体62-6:2-(4-(2-(6-甲基吡啶-2-基)-5,6-二氢-4H-吡咯并[1，2-b]吡唑-3-基)吡啶-2-基]-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑
将中间体62-5(26.0mg，0.04mmol)溶于5ml二氯甲烷中，加入溴化锌(38.0mg，0.17mmol)，室温下搅拌16小时，反应液加氨水淬灭，二氯甲烷萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得粗品中间体62-6共16.3mg，收率73.5％。
合成中间体62-7:(4-甲基哌嗪-1-基)(2-(4-(2-(6-甲基吡啶-2-基)-5,6-二氢-4H-吡咯并[1，2-b]吡唑-3-基)吡啶-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲酮
将N-甲基哌嗪(6.2mg，0.06mmol)溶于5ml二氯甲烷，降温至0℃，加入三光气18.4mg，0.06mmol)，向反应液中缓慢加入三乙胺(62.9mg，0.6mmol)，反应5分钟，向反应液中加入62-6(16.3mg，0.03mmol)的二氯甲烷溶液，升至室温搅拌。反应完成后，加水淬灭，用二氯甲烷萃取，合并有机相，用饱和食盐水洗涤，浓缩。硅胶柱纯化，得中间体62-7共15.2mg，收率37.7％。
合成化合物62:(4-甲基哌嗪-1-基)(2-(4-(2-(6-甲基吡啶-2-基)-5,6-二氢-4H-吡咯并[1，2-b]吡唑-3-基)吡啶-2-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲酮
将中间体62-7(15.2mg，0.02mmol)溶于4ml甲醇中，加入2ml浓盐酸，45℃反应1小时，浓缩，溶于5ml甲醇，加0.5ml氨水调至碱性，浓缩，硅胶板纯化，得到最终产物5.3mg,收率44.4％。LC-MS m/z(ESI)[M+H]+针对C28H31N9O的计算值为:510.3；测量值为:510.3。
实施例63:2-(4-(2-(6-甲基吡啶-2-基)-6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基) 吡啶-2-基)-5-(甲基磺酰基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶
化合物63的合成路线：
合成方法：
合成中间体63-2:3-溴联苯胺甲酯
将中间体63-1(5.0g,27.5mmol)溶于50ml甲醇中，向反应液加入甲醇钠(3.0g,55.4mmol)，室温反应16小时，将反应液浓缩除去甲醇，浓缩物 中加水，用乙酸乙酯萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到中间体63-2粗品4.8g，收率81.4％。
合成中间体63-3:3-溴苯并咪唑盐酸盐
将中间体63-2(4.8g,22.3mmol)溶于40ml乙醇，加入NH4Cl(3.6g,67.2mmol)，在80℃反应2小时。反应完后浓缩得3.2g中间体63-3，收率57.1％。
合成中间体63-4:2-(4-溴吡啶-2-基)-3，4，6，7-四氢-5H-咪唑并[4，5-c]吡啶-5-羧酸叔丁酯
将中间体63-3(3.2g,13.6mmol)溶于40ml甲苯中，加入N-Boc-3-溴-4-氧代哌啶(7.5g,27.2mmol)和碳酸氢钠(3.4g,40.8mmol)，升温至80℃反应过夜。次日冷却后TLC监测，原料反应完全，向反应液中加水淬灭，用EA萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，硅胶柱纯化得到中间体63-4 2.9g，收率56.6％。LC-MS m/z(ESI)[M+H]+针对C16H20BrN4O2的计算值为:379.1；测量值为:379.0。
合成中间体63-5:2-(4-溴吡啶-2-基)-3-((2-(三甲基甲硅烷基)乙氧基)甲基)-3，4，6，7-四氢-5H-咪唑并[4，5-c]吡啶-5-羧酸叔丁酯
将中间体63-4(2.9g,7.6mmol)溶于30ml THF中，降温至0℃，加入NaH(60％)(0.6g,15.2mmol)，搅拌0.5小时，加入SEMCl(1.9g,11.4mmol)。加入完毕后升至室温搅拌，反应完成后，加水淬灭，加EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体63-52.7g，收率68.8％。LC-MS m/z(ESI)[M+H]+针对C22H34BrN4O3Si的计算值为:509.2；测量值为:509.1。
合成中间体63-6:(2-(5-(叔丁氧基羰基)-3-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-2-基)吡啶-4-基)硼酸
将中间体63-5(2.7g,5.2mmol)溶于30ml DME中，加入联硼酸频那醇酯(2.6g,10.4mmol)和二溴化镍并二甲氧基乙烷(393.3mg,0.5mmol)，氮气置换，加入醋酸钾(1.6g,15.6mmol)，再次氮气置换，升温至90℃反应过夜。次日将反应液冷却至室温，浓缩后硅胶柱纯化，得到中间体63-6 1.2 g，收率48.1％。LC-MS m/z(ESI)[M+H]+针对C22H36BN4O5Si的计算值为:475.3；测量值为:475.3。
合成中间体63-7:2-(4-(2-(6-甲基吡啶-2-基)-6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基)吡啶-2-基)-3-((2-(三甲基甲硅烷基)乙氧基)甲基)-3,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-羧酸叔丁酯
将3-溴-2-(6-甲基吡啶-2-基)-6,7-二氢-5H-吡咯并[1,2-a]咪唑(100.0mg,0.4mmol)溶于10ml DME和1ml水中，加入中间体63-6(256.5mg,0.5mmol)，碳酸钠(76.2mg,0.7mmol)和二溴化镍并二甲氧基乙烷(27.2mg,0.04mmol)，氮气置换，升至80℃反应过夜。加入水，萃取，饱和食盐水洗洗，无水硫酸钠干燥，浓缩后硅胶柱纯化，得到中间体63-7 89.4mg，收率39.6％。LC-MS m/z(ESI)[M+H]+针对C34H46N7O3Si的计算值为:628.3；测量值为:628.3。
合成中间体63-8:2-(4-(2-(6-甲基吡啶-2-基)-6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基)吡啶-2-基)-3-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶
将中间体63-7(89.4mg,0.2mmol)溶于10ml DCM，加入溴化锌(128.3mg,0.6mmol)，氮气置换，室温反应过夜。次日反应完后往反应液中加入0.5ml氨水，随后加水，加DCM萃取两次，合并有机相，再加入饱和碳酸氢钠溶液与饱和食盐水各洗涤一次，浓缩后得到中间体63-8粗品75.0mg，收率100％。
合成中间体63-9:(2-(4-(2-(6-甲基吡啶-2-基)-6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基)吡啶-2-基)-5-(甲基磺酰基)-3-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶
将中间体63-8(32.0mg,0.1mmol)溶于5ml DCM中，加入三乙胺(20.2mg,0.2mmol)，加入甲磺酰氯(8.3mg,0.1mmol)，室温反应1小时，向反应液中加水，用DCM萃取，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得到粗品中间体63-9 33.0mg，收率89.9％。
合成化合物63:2-(4-(2-(6-甲基吡啶-2-基)-6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基)吡啶-2-基)-5-(甲基磺酰基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶
将中间体63-9(33.0mg,0.1mmol)溶于2ml甲醇中，加入1ml浓盐酸，50℃反应2小时，浓缩，溶于5ml甲醇，加0.5ml氨水，浓缩，纯化，得到最终产物5.2mg，收率20.1％。LC-MS m/z(ESI)[M+H]+针对C24H26N7O2S的计算值为:476.2；测量值为:476.2。
实施例64
以下实施例的化合物根据实施例1的合成路线，使用合适的起始原料进行制备。
实施例65至74
以下各实施例的化合物根据实施例62的合成路线，使用合适的起始原料进行制备。




实施例75至76
以下各实施例的化合物根据实施例63的合成路线，使用合适的起始原料进行制备。
实施例77：化合物的活性检测
1.试剂和耗材
2.实验方法
2.1制备1x激酶反应缓冲液:
2.2激酶反应条件：
2.3活性测试步骤:
活性测试的原理是TGFβR1磷酸化底物TGFβR1tide而消耗ATP，本实验采用ADP-Glo方法检测激酶活性测试测定IC50值来评价受试化合物对人TGFβR1的抑制能力。实验中，以DSM作为阴性对照，以LY364947作为阳性对照。具体实验步骤如下。在稀释板中用DMSO对化合物进行4倍稀释，化合物最终起始浓度为10μM，10个浓度梯度点。将化合物50倍稀释到激酶反应缓冲液中，在振荡器上震荡20分钟。用酶反应缓冲液配制准备激酶，向反应板中每孔加入2μl激酶。向每孔加入1μl在缓冲液中稀释好的化合物，用封板膜封住板子1000g离心30秒，室温放置10分钟。用酶反应缓冲液配制TGFβR1tide和ATP溶液，向反应板中加入2μl TGFβR1tide/ATP溶液。用封板膜封住板子1000g离心30秒，室温反应60分钟。转移4μL ADP-Glo到384反应板中1000rpm/min,离心1min，25℃孵育40min。转移8μL Detection溶液到384反应板中1000rpm/min，离心1min，25℃孵育40min。使用BMG酶标仪读取RLU(Relative luminescence unit)信号，信号强度用于表征激酶的活性程度。
3.数据分析
3.1抑制率计算如下:
化合物抑制率(％inh)＝100％-(化合物-阳性对照)/(阴性对照-阳性对照)*100％。
3.2计算IC50并绘制化合物的抑制曲线：
利用以下非线性拟合公式来得到化合物的IC50(半数抑制浓度)：用Graphpad 7.0软件进行数据分析。
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*Hill Slope))
X:化合物浓度log值   Y:抑制率(％inhibition)
3.3报告二次检查
3.3.1一位实验员结束报告撰写后，由另一位实验员再次进行检查，以确保数据分析的准确性。
3.3.2数据从BMG中导出，人工分析。
3.3.2.1比值转化为抑制率，IC50通过抑制率由Prism GraphPad7.0计算。
3.3.2.2 IC50通过比值再次计算，以验证结果准确性。
3.4质量控制
Z factor>0.5；S/B>2
阳性对照IC50在历次平均值3倍以内
4.活性测试结果


以上结果表明，本申请的化合物表现出与阳性对照LY364947相当或更好的抑制TGFβR1的效果，因此可以用于治疗与TGF-β相关(尤其是与 TGF-β1相关)的疾病或病症。
虽然已经阐明并描述了本发明的特定实施方式，但并不意味着这些实施方式阐明了并描述了本发明的所有可能形式。更确切地，用在本说明书中的文字仅仅是描述性的文字并非限制性的。对于本领域技术人员明显的是，在不脱离本公开的一般范围的情况下，可以进行各种其他改变和修改。因此，在所附权利要求中，旨在包括在本发明范围内的所有这些改变和修改。

Claims (10)

  1. 一种式(I)的化合物：
    或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，其中：
    n＝1、2或3；
    L为(C＝O)、(O＝S＝O)、((C＝O)-CH2)、CH2或连接键；
    R1选自H、卤素、-OH、-NO2、-CN、-SF5、-SH、-S-C1-4烷基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-8烯基、C2-8炔基、C3- 7脂环基、3-10元杂脂环基、C6-12双环脂环基、6-12元双环杂脂环基、C8-15元三环脂环基、8-15元三环杂脂环基、C5-8芳基、5-10元杂芳基、C7-11双环芳基、7-11元双环杂芳基、-C1-4烷基-(C3-7脂环基)、-C1-4烷基-(3-10元杂脂环基)、-C1-4烷基-(C6-12双环脂环基)、-C1-4烷基-(6-12元双环杂脂环基)、-C1-4烷基-(C8-15元三环脂环基)、-C1-4烷基-(8-15元三环杂脂环基)、-C1-4烷基-(C5-8芳基)、-C1-4烷基-(5-10元杂芳基)、-N(R10)(R11)、-N(R10)(C(＝O)R11)、-N(R10)(C(＝O)-OR11)、-N(R12)(C(＝O)-N(R10)(R11))、-C(＝O)-N(R10)(R11)、-C(＝O)-R12、-C(＝O)-OR12、-OC(＝O)R12、-N(R10)(S(＝O)2R11)、-S(＝O)2-N(R10)(R11)、-SR12和-OR12，其中所述-S-C1-4烷基、C1-6烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-8烯基、C2-8炔基、C3-7脂环基、3-10元杂脂环基、C6-12双环脂环基、6-12元双环杂脂环基，C8-15元三环脂环基、8-15元三环杂脂环基、C5-8芳基、5-7元杂芳基、C7-11双环芳基、7-11元双环杂芳基、-C1-4烷基-(C3-7脂环基)、-C1-4烷基-(3-10元杂脂环基)、-C1- 4烷基-(C6-12双环脂环基)、-C1-4烷基-(6-12元双环杂脂环基)-C1-4烷基-(C8-15元三环脂环基)、-C1-4烷基-(8-15元三环杂脂环基)、-C1-4烷基-(C5-8芳基)和-C1-4烷基-(5-10元杂芳基)各自任选地被0、1、2、3或4个R1a取代，且R1a独立选自卤素、-OH、-NO2、-CN、-SF5、-SH、-S-C1-4烷基、氧代、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C2-8烯基、C2-8炔基、C3- 7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基、-N(R13)(R14)、-N(R13)(C(＝O)R14)、-N(R13)(C(＝O)-OR14)、-N(R15)(C(＝O)-N(R13)(R14))、-C(＝O)-N(R13)(R14)、-C(＝O)-R15、-C(＝O)-OR15、-OC(＝O)R15、-N(R13)(S(＝O)2R14)、-S(＝O)2-N(R13)(R14)、-SR15和-OR15；且
    R10、R11、R12、R13、R14、和R15各自在每次出现时独立地选自：H、C1-6烷基、C1-6卤代烷基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基、C7-11双环芳基、7-11元双环杂芳基、-C1-4烷基-(C3-7脂环基)、-C1- 4烷基-(3-10元杂脂环基)、-C1-4烷基-(C6-12双环脂环基)、-C1-4烷基-(6-12元双环杂脂环基)、-C1-4烷基-(C8-15元三环脂环基)、-C1-4烷基-(8-15元三环杂脂环基)、-C1-4烷基-(C5-8芳基)和-C1-4烷基-(5-10元杂芳基)，其中该群组内的各个选项任选地被0、1、2、3或4个各自独立选自以下群组的取代基所取代：卤素、-OH、-NH2、-NH(CH3)、-N(CH3)2、-CN、-NO2、-SF5、-SH、-S-C1-4烷基、氧代、C1-4烷基、C2-6烯基、C2-6炔基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基、C7-11双环芳基、7-11元双环杂芳基、C1- 4羟烷基、-S-C1-4烷基、-C(＝O)H、-C(＝O)-C1-4烷基、-C(＝O)-O-C1-4烷基、-C(＝O)-NH2、-C(＝O)-N(C1-4烷基)2、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基；或者R10、R11以及与它们相连的原子共同形成3-14元环；或者R13、R14以及与它们相连的原子共同形成3-14元环；
    R2的个数为1、2、3或4个，且每个R2各自独立地选自H、卤素、-CN、-OH、-NO2、-NR7R8、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C3-6脂环基和4-6元杂脂环基；
    R3的个数为1、2或3个，且每个R3各自独立地选自H、卤素、-CN、-OH、-NO2、-NR7R8、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C3-6脂环基和4-6元杂脂环基；
    R7和R8各自在每次出现时独立地选自：H、C1-6烷基、C1-4卤代烷基、C1-4烷氧基，或者R7、R8以及与它们相连的N原子共同形成3-6元环；
    环A为含氮的芳香环并满足：1)G1＝NR4，G2＝CR5；或者2)G1＝CR4，G2＝NR5；或者3)G1＝CR4，G2＝O或S；其中R4和R5各自独立地选自H、卤素、-CN、-OH、-NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基；或者R4和R5以及与它们相连的原子一起形成3-8元环。
  2. 根据权利要求1所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，其中式(I)化合物具有如下结构之一：
    其中n、L、R1、R2、R3、R4、R5如权利要求1所定义；
    其中n、L、R1、R2、R3、R4、R5如权利要求1所定义；
    其中n、L、R1、R2、R3、R4如权利要求1所定义；
    其中n、L、R1、R2、R3如权利要求1所定义；环B为含有1个N原子的3至8元环，Ra选自H、卤素、-CN、-OH、-NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基。
  3. 根据权利要求1或2所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，其中n＝1或2。
  4. 根据权利要求1-3中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，其中R2和R3各自独立地选自：H、CH3、F、Cl和Br。
  5. 根据权利要求1-3中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，其中R1选自H、卤素、-OH、-NO2、-CN、-SF5、-SH、-S-C1-4烷基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6 卤代烷氧基、C3-6脂环基、4-6元杂脂环基、C5-8芳基、5-10元杂芳基、-C1- 4烷基-(C3-7脂环基)、-C1-4烷基-(3-10元杂脂环基)、-C1-4烷基-(C5-8芳基)、-C1-4烷基-(5-10元杂芳基)、-N(R10)(R11)，其中所述-S-C1-4烷基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-6脂环基、4-6元杂脂环基、C5-8芳基、5-10元杂芳基、-C1-4烷基-(C3-7脂环基)、-C1-4烷基-(3-10元杂脂环基)、-C1-4烷基-(C5-8芳基)、-C1-4烷基-(5-10元杂芳基)各自任选地被0、1、2、3或4个R1a取代，且R1a独立选自卤素、-OH、-NO2、-CN、氧代、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C3-7脂环基、3-10元杂脂环基、C5-8芳基、5-7元杂芳基；
    且R10、R11和R12各自在每次出现时独立地选自：H、C1-6烷基、C1-6卤代烷基、C3-7脂环基、3-10元杂脂环基，其中该群组内的各个选项任选地被0、1、2、3或4个各自独立选自以下群组的取代基所取代：卤素、-OH、-NH2、氧代、C1-4烷基、C1-4羟烷基、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基；或者R10、R11以及与它们相连的原子共同形成3-8元环。
  6. 根据权利要求5所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，其中R1选自H、卤素、-OH、甲基、乙基、丙基、丁基、戊基、己基、甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基、环丙基、环丁基、环戊基、环己基、环庚基、苯基、哌嗪基、哌啶基、吗啉基、吡咯烷基、吡咯基、吗啉基、吡啶基和吡唑基，其中的甲基、乙基、丙基、丁基、戊基、己基、甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基、环丙基、环丁基、环戊基、环己基、环庚基、苯基、哌嗪基、哌啶基、吗啉基、吡咯烷基、吡咯基、吗啉基、吡啶基、吡唑基各自任选地被1或2个R1a取代，且R1a独立选自卤素、-OH、-NO2、-CN、氧代、C1-4烷基、C1-4卤代烷基和C1-4烷氧基；优选地R1选自H、甲基、甲基哌嗪基、吡咯烷基、甲基哌嗪基、羟基环丁基、甲基吡唑基、羟乙基、羟丙基、甲基哌啶基、吗啉基、羟基吡咯烷基。
  7. 根据权利要求1所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，其中所述化合物选自以下的化合物1-4、6-7、9-15、22-23、25-34、37-76：










  8. 一种药物组合物，其包含根据权利要求1-7中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异 构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，以及一种或多种药学上可接受的载体、佐剂或赋形剂。
  9. 根据权利要求1-7中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物或者根据权利要求8所述的药物组合物在制备用于治疗与TGF-β相关(优选与TGF-β1相关)的疾病或病症的药物中的用途。
  10. 根据权利要求9所述的用途，其中所述与TGF-β相关的疾病和病症选自：癌症、病毒感染、慢性肾炎、急性肾炎、糖尿病肾病、骨质疏松症、关节炎、伤口愈合、疤痕、溃疡、角膜创伤、心脏瓣膜狭窄、充血性心脏坏死、神经功能损伤、阿尔兹海默综合征、腹膜或皮下粘连、动脉硬化症、皮肤纤维化和脂肪流失导致的皮肤老化、骨骼障碍或软骨细胞障碍、低磷血症障碍和器官纤维化疾病；优选地，所述与TGF-β相关的疾病和病症选自肝细胞癌、乳腺癌、膀胱癌、结肠直肠癌、黑色素瘤、间皮瘤、肺癌、前列腺癌、膜腺癌、睾丸癌、甲状腺癌、鳞状细胞癌、神经胶母细胞瘤、成神经细胞瘤、子宫癌、横纹肌肉瘤、肾纤维化、肝纤维化、肺纤维化、皮肤疤痕、皮肤纤维化和脂肪流失导致的皮肤老化。
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