WO2022184000A1 - 咪唑类化合物、其药物组合物及其用途 - Google Patents
咪唑类化合物、其药物组合物及其用途 Download PDFInfo
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- WO2022184000A1 WO2022184000A1 PCT/CN2022/078161 CN2022078161W WO2022184000A1 WO 2022184000 A1 WO2022184000 A1 WO 2022184000A1 CN 2022078161 W CN2022078161 W CN 2022078161W WO 2022184000 A1 WO2022184000 A1 WO 2022184000A1
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- WIPO (PCT)
- Prior art keywords
- alkyl
- independently
- heterocyclyl
- methylpyridin
- mmol
- Prior art date
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- -1 Imidazole compound Chemical class 0.000 title claims abstract description 184
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 34
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
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Classifications
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Definitions
- the invention relates to the field of medicinal chemistry, in particular to an imidazole compound as a TGF- ⁇ inhibitor, in particular to an imidazole compound as a Transforming Growth Factor Beta Receptor-1 (TGF ⁇ R-1) inhibitor, comprising the Pharmaceutical compositions of the compounds, and the use of the compounds and compositions to prevent and/or treat diseases, disorders, or conditions mediated by or involving TGF-beta.
- TGF ⁇ R-1 Transforming Growth Factor Beta Receptor-1
- TGF- ⁇ Transforming Growth Factor Beta
- TGF- ⁇ Transforming Growth Factor Beta
- TGF- ⁇ is a multifunctional cytokine, and many types of cells in the human body have the ability to produce and secrete this cytokine.
- TGF- ⁇ is involved in the mechanism of many diseases, playing a dual role in inhibiting or promoting diseases, including wound healing, tissue fibrosis, atherosclerosis, cancer development and metastasis, autoimmune diseases, diabetic complications, and Alzheimer's disease. Nerve damage caused by mutism is closely related to TGF- ⁇ .
- the TGF- ⁇ signaling pathway plays an important role in the regulation of tumorigenesis and development, immunity, inflammation, fibrosis and endocrine function, and is a promising drug target.
- TGF- ⁇ The various biological effects of TGF- ⁇ are accomplished through signal transduction through cell surface receptors. And its receptors can be divided into six types, of which TGF ⁇ R-1-3 types are widely expressed. At present, it has been found that the signal transduction of TGF- ⁇ is mostly mediated by the heterotetramer composed of TGF ⁇ R-1 and 2, and TGF ⁇ R-3 has the effect of promoting the polymerization of TGF ⁇ R-1 and 2. Therefore, TGF ⁇ R-1 ⁇ 3 receptors Research is the current hot spot.
- TGF ⁇ R-1 belongs to the serine/threonine kinase family, also known as activin receptor-like kinase 5 (activin receptor-like kinase 5). TGF- ⁇ and activin cannot directly interact with TGF ⁇ R-1.
- Activated TGF ⁇ R-2 is required to activate TGF ⁇ R-1 by transphosphorylating the GS region of TGF ⁇ R-1.
- TGF ⁇ R-1 in the receptor complex determines the nature of the signaling pathway.
- the regulation of TGF- ⁇ on cell proliferation is mainly through the activation of Smad2/3 by the heterotetramer composed of TGF ⁇ R-1 and 2, and the translocation of Smad2/3 and Smad4 into the nucleus to open the Smad-dependent signaling pathway.
- the Smad signaling pathway can inhibit the expression of c-myc and promote the expression of cell cycle inhibitory proteins P21 and P15, resulting in cell cycle arrest. This pathway enables TGF- ⁇ to inhibit cell proliferation; in addition, TGF ⁇ R-1 and 2 can inhibit cell proliferation.
- Activates non-Smad signaling pathways such as MAPK, Rho-like GTPases and PI3K. Previous studies have found that in these pathways, MAPK and PI3K can promote cell proliferation to a certain extent.
- TGF- ⁇ -mediated Smad signaling pathway mainly inhibits cell proliferation in the regulation of cell proliferation, while the non-Smad signaling pathway mainly promotes cell proliferation.
- TGF ⁇ R-1 kinase inhibitors and the signaling pathways involved in this target have been studied or proven effective in anti-tumor, myelodysplasia, anti-fibrosis and scarring.
- Eli Lilly's TGF ⁇ R-1 kinase inhibitor LY2109761 reduced the formation of tumor blood vessels through two ways to limit the occurrence and development of liver cancer: (1) reducing the number and tortuosity of blood vessels, These two are the morphological basis for the tumor to absorb oxygen and evacuate drugs; (2) to block the interaction between the tumor and the body in the microenvironment.
- Galunisertib can inhibit the progression of liver cancer by inhibiting the TGF- ⁇ signaling pathway to regulate Epithelial-Mesenchymal Transition (EMT).
- EMT Epithelial-Mesenchymal Transition
- Galunisertib showed significant antitumor activity in human non-small cell lung cancer cell Calu6 and breast cancer cell MX1 xenograft subcutaneous tumor-bearing nude mouse models.
- Galunisertib can dose-dependently inhibit TGF- ⁇ -mediated Smad2 protein activation and hematopoietic inhibition, and promote bone marrow hematopoiesis in patients with primary MDS.
- galunisertib ameliorated anemia in a transgenic mouse model of bone marrow hematopoietic failure overexpressing TGF- ⁇ .
- the application of the small molecule ALK5 inhibitor CP-639180 can inhibit the secretion of type I collagen and ⁇ -SMA from hypertrophic scar fibroblasts, and further inhibit the synthesis of collagen fibers. Offer new ideas.
- the present invention provides a new class of imidazole compounds, which can be used as TGF- ⁇ inhibitors, especially as TGF ⁇ R-1 inhibitors, and have great effects on diseases, disorders, or conditions mediated by or involving TGF- ⁇ . good curative effect.
- the compounds of the present invention have excellent efficacy, pharmacokinetic properties and/or toxicological properties, and have good clinical application prospects.
- the present invention provides a new class of TGF- ⁇ inhibitors, especially TGF ⁇ R-1 inhibitors, which can be used to prepare and prevent and/or treat mammalian diseases, disorders, or diseases mediated by or involving TGF- ⁇ . Medications for the condition.
- the present invention also provides methods of preparing the compounds of the present invention, methods of using these compounds to treat the above-mentioned diseases, disorders, or conditions in mammals, especially humans, and pharmaceutical compositions comprising these compounds.
- the present invention provides a new imidazole compound, which has the structure shown in formula (I),
- X 1 is N, or -C(R a )-;
- X 2 is N, or -C(R 2 )-; provided that X 1 and X 2 are not both carbon atoms;
- X 3 , X 4 and X 5 are each independently -C(R 3 )-, or N;
- X 6 is O, S, or -N(R 3 )-;
- W is optionally substituted with 0, 1, 2, 3 , 4 or 5 R;
- Y 1 , Y 2 , Y 3 and Y 4 are each independently -C(R 4 )-, or N;
- each Y 5 is independently O, S, or -N(R 4 )-;
- Z is optionally substituted with 0, 1, 2, 3, 4 or 5 R4;
- R 1 , R 2 and Ra are each independently H, -(C(R c )(R d )) m -LR 5 , C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, or C 1-6 alkane Amino, provided that R 1 and R 2 are not H at the same time; alternatively, R 1 and R 2 together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring of 5-8 atoms, or R 2 and R a are the same The atoms to which it is attached together form a carbocycle or heterocycle of 5-8 atoms, wherein the carbocycle or heterocycle of 5-8 atoms is optionally surrounded by 0, 1, 2, 3 or 4 R 6 to replace;
- R b is H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, or C 1-6 cyanoalkyl;
- R c and R d are independently H, C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 1-6 haloalkyl; alternatively, R c and R d are the same as The connected carbon atoms together form a carbocyclic or heterocyclic ring of 3-6 atoms;
- R 5 is H, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl, C 1-6 alkyl, C 1-9 heteroaryl, C 1-9 heteroaryl, C 1-6 alkyl, C 5 -12 spirobicyclic group, C 5-12 spiro heterobicyclic group, C 5-12 fused bicyclic group, or C 5-12 fused heterobicyclic group; wherein R 5 is optionally replaced by 0, 1, 2, 3, 4 or 5 R 5a substitutions;
- R h and R i are each independently H, or C 1-6 alkyl
- n 0, 1, 2, 3, or 4.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable adjuvant, diluent or carrier.
- compositions described herein further comprise additional therapeutic agents.
- the additional therapeutic agent comprises TGF-beta inhibitors and/or ALK5 inhibitors.
- the present invention provides the use of a compound of the present invention or a pharmaceutical composition of the present invention in the preparation for the prevention and/or treatment of a disease, disorder, or condition mediated by or involving TGF-beta use in medicines.
- the disease, disorder, or condition is pulmonary hypertension, chronic kidney disease, acute kidney disease, wound healing, arthritis, osteoporosis, kidney disease, congestive heart failure, ulcers, ocular disorders, corneal damage, Diabetic nephropathy, neurological impairment, Alzheimer's disease, atherosclerosis, peritoneal or subcutaneous adhesions, renal fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, hepatitis B, type C Hepatitis, alcohol-induced hepatitis, cancer, hemochromatosis, primary biliary cirrhosis, restenosis, retroperitoneal fibrosis, mesenteric fibrosis, endometriosis, keloids, cancer, bone dysfunction, inflammatory Disorders, scarring and skin photoaging.
- the disease, disorder, or condition is a benign or malignant tumor, brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, stomach cancer, stomach tumor, ovarian cancer, colon cancer, rectal cancer , prostate cancer, pancreatic cancer, lung cancer, vaginal or thyroid cancer, sarcoma, glioblastoma, multiple myeloma or gastrointestinal cancer, colon or colorectal cancer, head and neck tumors, epidermal hyperproliferation, melanoma, psoriasis , benign prostatic hyperplasia, neoplasia, epithelial neoplasia, leukemia, lymphoma, breast cancer or leukemia.
- the articles “a”, “an” and “the” are intended to include “at least one” or “one or more” unless stated otherwise or otherwise clearly contradicted by context.
- these articles refer to one or more than one (ie, at least one) object of the article.
- a component refers to one or more components, ie, there may be more than one component contemplated for use or use in the implementation of the described embodiments.
- Stereoisomers refer to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, etc. .
- Enantiomer refers to two nonsuperimposable, but mirror-image isomers of a compound.
- Diastereomer refers to a stereoisomer that has two or more chiral neutralities and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, eg HPLC.
- optically active compounds Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light.
- the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about one or more of its chiral centers.
- the prefixes d and 1 or (+) and (-) are symbols used to designate the rotation of plane polarized light by the compound, where (-) or 1 indicates that the compound is levorotatory.
- Compounds prefixed with (+) or d are dextrorotatory.
- a specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture.
- a 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
- any asymmetric atom (eg, carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched forms, such as (R)-, (S)- or (R,S)-configurations exist.
- each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 70% enantiomeric excess in the (R)- or (S)-configuration 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
- tautomer or "tautomeric form” refers to structural isomers having different energies that are interconvertible through a low energy barrier.
- a chemical equilibrium of tautomers can be achieved if tautomerism is possible (eg, in solution).
- protontautomers also known as prototropic tautomers
- Valence tautomers include interconversions by recombination of some of the bonding electrons.
- keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
- tautomerism is phenol-ketone tautomerism.
- a specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers.
- all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
- “Pharmaceutically acceptable” means compounds, materials, compositions, and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergy, or compatibility with reasonable The benefit/risk ratio is symmetric with other problems and complications and is effective for the intended use.
- the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or as in the Examples, subclasses, and subclasses encompassed by the present invention. a class of compounds.
- substituted means that one or more hydrogen atoms in a given structure have been replaced with a specified substituent.
- a substituted group may have a substituent at each substitutable position of the group.
- the substituents can be substituted identically or differently at each position.
- C1-6 alkyl specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl groups .
- linking substituents are described.
- the Markush variables recited for that group should be understood to be the linking group.
- the “alkyl” or “aryl” is recited for the definition of a Markush group for that variable, it should be understood that the "alkyl” or “aryl”, respectively Represents a linked alkylene or arylene group.
- alkyl or “alkyl group” used in the present invention refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally be is substituted with one or more substituents described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in yet another embodiment, the alkyl group contains 1 -4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms. The alkyl group may be optionally substituted with one or more substituents described herein.
- alkyl groups include, but are not limited to, methyl (Me, -CH3 ), ethyl (Et, -CH2CH3), n - propyl (n - Pr, -CH2CH2CH3 ) ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH ) (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2CH2CH2CH2CH3), 2 -pentyl (-CH( CH3 ) CH2CH2CH3 ) , 3 - pentyl (-CH( CH2CH3 ) 2 ) , 2 -methyl
- alkenyl refers to a straight or branched chain monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one site of unsaturation, i.e. a carbon-carbon sp double bond, which includes "cis” and “cis”Anti” positioning, or “E” and “Z” positioning.
- the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 -4 carbon atoms.
- the alkenyl group may be optionally substituted with one or more substituents described herein.
- alkynyl refers to a straight or branched chain monovalent hydrocarbon group containing 2 to 12 carbon atoms in which there is at least one site of unsaturation, ie, a carbon-carbon sp triple bond.
- the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 -4 carbon atoms.
- alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH2C ⁇ CH), 1 -propynyl (-C ⁇ C- CH3 ), and the like .
- the alkynyl group may be optionally substituted with one or more substituents described herein.
- alkoxy means that an alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the definition as described herein. Unless otherwise specified, the alkoxy groups contain 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy groups may be optionally substituted with one or more substituents described herein.
- alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butanyl Oxy (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1 -pentyloxy (n - pentyloxy, -OCH2CH2CH2CH2CH2
- hydroxyalkyl or “hydroxyalkyl” as used herein means that an alkyl group is substituted with one or more hydroxy groups, wherein the alkyl group is as defined herein, examples of which include , but not limited to hydroxyethyl, 2-hydroxypropyl, hydroxymethyl, etc.
- cycloalkyl refers to a monovalent saturated or partially unsaturated (but not aromatic) monocyclic or polycyclic hydrocarbon.
- the cycloalkyl groups can be bridged or unbridged, spirocyclic or non-spirocyclic, and/or fused or non-fused bicyclic groups.
- the cycloalkyl group includes 3-10 carbon atoms, ie, C3 to C10 cycloalkyl.
- the cycloalkyl group has 3-15 (C 3-15 ), 3-10 (C 3-10 ), or 3-7 (C 3-7 ) carbon atoms.
- the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is bicyclic. In some embodiments, the cycloalkyl group is tricyclic. In some embodiments, the cycloalkyl group is fully saturated. In some embodiments, the cycloalkyl group is partially saturated.
- the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, deca Hydronaphthyl, or adamantyl.
- a cycloalkyl group When a cycloalkyl group is substituted, it may be independently substituted with one or more substituents described herein on any ring, ie, on any aromatic or non-aromatic ring contained by the cycloalkyl group.
- heterocyclyl and “heterocycle” are used interchangeably herein, unless otherwise specified, to refer to a monovalent monocyclic non-aromatic ring system and/or polycyclic ring system comprising at least one non-aromatic ring; wherein the One or more (in certain embodiments, 1, 2, 3, or 4) of the non-aromatic monocyclic atoms are heteroatoms independently selected from O, S(O) 0-2 , and N, and the The remaining ring atoms are all carbon atoms; and wherein one or more (in certain embodiments, 1, 2, 3, or 4) of the ring atoms of the polycyclic ring system are independently selected from O, S(O ) heteroatoms of 0-2 and N, and the remaining ring atoms are all carbon atoms.
- the heterocycle contains 1 or 2 heteroatoms, all of which are nitrogen atoms.
- the heterocyclyl group is polycyclic and contains one heteroatom in a non-aromatic ring, or one heteroatom in an aromatic ring, or two heteroatoms in an aromatic ring, or two One of the heteroatoms is in an aromatic ring and the other is in a non-aromatic ring.
- the heterocyclyl group has 3-20, 3-15, 3-10, 3-8, 4-7, or 5-6 ring atoms.
- the heterocyclyl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system.
- the heterocyclyl group can be bridged or unbridged, spirocyclic or non-spirocyclic, and/or fused or non-fused bicyclic groups.
- One or more nitrogen and sulfur atoms may be optionally oxidized, one or more nitrogen atoms may be optionally quaternized, and one or more carbon atoms may be optionally replace.
- Some rings may be partially or fully saturated, or aromatic, provided that the heterocycle is not fully aromatic.
- the monocyclic and polycyclic heterocycles can be attached to the main structure at any heteroatom or carbon atom that results in a stable compound.
- the polycyclic heterocyclyl may be attached to the main structure through any of its rings, including any aromatic or non-aromatic ring, whether or not the ring contains a heteroatom.
- the heterocyclyl group is "heterocycloalkyl", which is 1) a saturated or partially unsaturated (but non-aromatic) monovalent monocyclic group as described herein containing at least one ring heteroatom , or 2) a saturated or partially unsaturated (but non-aromatic) monovalent bicyclic or tricyclic group wherein at least one ring contains at least one heteroatom as described herein.
- heterocyclyl and heterocycloalkyl When heterocyclyl and heterocycloalkyl are substituted, they may be substituted on either ring, ie, on any aromatic or non-aromatic ring contained by heterocyclyl and heterocycloalkyl.
- heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidine, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolane base, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetra
- oxidized sulfur atom in the heterocyclyl group include, but are not limited to, sulfolanyl, 1,1-dioxothiomorpholinyl.
- the heterocyclyl group may be optionally substituted with one or more substituents described herein.
- the heterocyclyl group is a heterocyclyl group consisting of 3-8 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 3-8 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and Oxygen atom.
- Ring sulfur atoms can optionally be oxidized to S-oxides.
- the nitrogen atoms of the rings can be optionally oxidized to N-oxygen compounds.
- heterocyclyl groups of 3-8 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrroline base, pyrazolinyl, pyrazolidine, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide Cyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine base, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl
- oxidized sulfur atom in the heterocyclyl group include, but are not limited to, sulfolanyl, 1,1-dioxothiomorpholinyl.
- Said heterocyclyl group consisting of 3-8 atoms can be optionally substituted by one or more substituents described in the present invention.
- the heterocyclyl group is a heterocyclyl group consisting of 3-6 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 3-6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and Oxygen atom.
- Ring sulfur atoms can optionally be oxidized to S-oxides.
- the nitrogen atoms of the rings can be optionally oxidized to N-oxygen compounds.
- the 3-6 atom heterocyclyl group can be optionally substituted by one or more substituents described in the present invention.
- the heterocyclyl group is a heterocyclyl group consisting of 5-6 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 5-6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms.
- Ring sulfur atoms can optionally be oxidized to S-oxides.
- the nitrogen atoms of the rings can be optionally oxidized to N-oxygen compounds.
- heterocyclic groups of 5-6 atoms include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidine base, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, 2-oxopyrrolidinyl, oxo-1,3 -Thiazolidinyl, sulfolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholine base, piperazinyl, dioxanyl, dithianyl, thioxanyl,
- cycloalkylalkyl means that an alkyl group may be substituted by one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined herein, examples of which include, but do not Limited to, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexyl Ethyl etc.
- heterocyclylalkyl includes a heterocyclyl-substituted alkyl group
- heterocyclylalkoxy includes a heterocyclyl-substituted alkoxy group in which the oxygen atom is attached to the remainder of the molecule
- heterocyclylalkoxy includes a heterocyclyl-substituted alkoxy group in which the oxygen atom is attached to the remainder of the molecule
- heterocyclylalkoxy “Alkylamino” includes heterocyclyl-substituted alkylamino groups in which the nitrogen atom is attached to the remainder of the molecule.
- heterocyclyl, alkyl, alkoxy and alkylamino are as defined herein, such examples include, but are not limited to, azetidin-1-ylmethyl, azetidine -1-ylethyl, azetidin-1-ylpropyl, pyrrol-1-ylmethyl, pyrrol-1-ylethyl, pyrrol-1-ylpropyl, morpholin-4-ylethyl group, morpholin-4-ylethoxy, piperazin-4-ylethoxy, piperidin-4-ylethylamino and the like.
- alkylthio includes a C 1-10 straight or branched chain alkyl group attached to a divalent sulfur atom.
- the alkylthio group is a lower C1-3 alkylthio group, examples of which include, but are not limited to, methylthio ( CH3S- ).
- haloalkylthio includes a C 1-10 haloalkyl group attached to a divalent sulfur atom.
- the haloalkylthio group is a lower C 1-3 haloalkylthio group, examples of which include, but are not limited to, trifluoromethylthio.
- fused bicyclic ring refers to a saturated or unsaturated fused ring system system, involving a non-aromatic bicyclic ring system, as shown in formula (a1) , that is, ring B shares a bond with ring B'.
- Such systems may contain independent or conjugated unsaturation, but their core structure does not contain aromatic or aromatic heterocycles (although aromatics may be used as substituents thereon).
- Each ring in the fused bicyclic ring is either carbocyclic or heteroalicyclic, examples of which include, but are not limited to, hexahydro-furo[3,2-b]furan, 2,3,3a,4 ,7,7a-hexahydro-1H-indene, 7-azabicyclo[2.3.0]heptane, fused bicyclo[3.3.0]octane, fused bicyclo[3.1.0]hexane, all of which contain within a fused bicyclic ring.
- the fused bicyclic group may be optionally substituted with one or more substituents described herein.
- fused heterobicyclyl denotes a saturated or unsaturated fused or bridged ring system, involving a non-aromatic bicyclic or bridged ring system. Such systems may contain independent or conjugated unsaturation, but their core structure does not contain aromatic or aromatic heterocycles (although aromatics may be used as substituents thereon).
- each ring system contains a 3-7 membered ring, that is, contains 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S , where S or P is optionally substituted by one or more oxygen atoms to obtain groups such as SO, SO 2 , PO, PO 2 , such examples include, but are not limited to, hexahydro-1H-furo[ 3,2-b]furan, hexahydro-1H-furo[3,4-c]pyrrole, 7-azabicyclo[2.3.0]heptane, 2-azabicyclo[2.2.1]heptane, Octahydropyrrole[3,2-b]pyrrole, octahydropyrrole[3,4-c]pyrrole, octahydro-1H-pyrrole[3,2-b]pyrrole, etc.
- the fused heterobicyclic group may be optionally substituted with one or more substituent
- spirocyclyl means that one ring originates from a particular cyclic carbon on another ring.
- Ring A and Ring B that share a carbon atom in two saturated ring systems are called “spiro”.
- Each ring within the spiro ring is either carbocyclic or heteroalicyclic.
- Such examples include, but are not limited to, 2,7-diazaspiro[4.4]nonan-2-yl, 7-oxo-2-azaspiro[4.5]decan-2-yl, 4-azaspiro[4.5]decan-2-yl spiro[2.4]heptan-5-yl, 4-oxaspiro[2.4]heptan-5-yl, 5-azaspiro[2.4]heptan-5-yl, spiro[2.4]heptanyl, spiro [4.4]Nonyl, 7-hydroxy-5-azaspiro[2.4]heptan-5-yl and the like.
- the spirobicyclyl can be optionally substituted with one or more substituents described herein.
- spiroheterobicyclyl means that one ring originates from a particular cyclic carbon on another ring.
- Ring A and Ring B sharing a carbon atom in two saturated ring systems are referred to as "spirocycles”.
- each ring system contains a 3-7 membered ring, that is, contains 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S , where S or P is optionally substituted by one or more oxygen atoms to obtain groups such as SO, SO 2 , PO, PO 2 , such examples include, but are not limited to 4-azaspiro[2.4] Heptan-5-yl, 4-oxaspiro[2.4]heptan-5-yl, 5-azaspiro[2.4]heptan-5-yl, 7-hydroxy-5-azaspiro[2.4]heptyl Alk-5-yl, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 1,6-diazaspiro[3.4]octane, 2, 7-diazaspiro[3.5]nonane, 1,7-diazaspiro[
- bridged ring group used in the present invention refers to a saturated or unsaturated bridged ring system, involving a non-aromatic bridged ring system, as shown in formula (a2), that is, ring A1 and ring A2 share an alkane chain or a heterocyclic ring system Alkane chains, wherein j is 1, 2, 3 or 4, and Y 5 have the definitions set forth herein.
- Such systems may contain independent or conjugated unsaturation, but their core structure does not contain aromatic or aromatic heterocycles (although aromatics may be used as substituents thereon).
- Each ring in the bridged ring is either carbocyclic or heteroalicyclic, examples of which include, but are not limited to, bicyclo[2.2.1]heptane, 2-azabicyclo[2.2.1]heptane, 1,2,3,4,4a,5,8,8a-octahydronaphthalene, all of which are included in the fused bicyclic or bridged ring system.
- the bridged ring group may be optionally substituted with one or more substituents described herein.
- bridged heterocyclyl refers to a saturated or unsaturated bridged ring system, involving a bridged ring system that is not aromatic. Such systems may contain independent or conjugated unsaturation, but their core structure does not contain aromatic or aromatic heterocycles (although aromatics may be used as substituents thereon). and at least one ring system contains one or more heteroatoms, wherein each ring system contains a 3-7 membered ring, that is, contains 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S , where S or P are optionally substituted by one or more oxygen atoms to obtain groups such as SO, SO 2 , PO, PO 2 , such examples include, but are not limited to 2-azabicyclo[2.2.
- a substituent drawing a bond to the central ring to form a ring system represents that the substituent may be substituted at any substitutable position on any ring.
- formula b represents any possible substituted position on ring A or ring B, such as formula c, d, e, f, g, h, i, j, k, l, m, n, o, p, q, etc.
- n typically describes the number of ring-forming atoms in a molecule where the number of ring-forming atoms is n.
- piperidinyl is a 6-atom heterocycloalkyl group
- 1,2,3,4-tetrahydronaphthalene is a 10-atom cycloalkyl group.
- halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
- azido or “N3” refers to an azide structure. Such groups can be attached to other groups, for example, to a methyl group to form azidomethane ( MeN3 ), or to a phenyl group to form azidobenzene ( PhN3 ).
- aryl refers to a monovalent C6 - C14 carbocyclic ring system comprising at least one aromatic ring, wherein the aromatic ring system is monocyclic, bicyclic, or tricyclic .
- the aryl group can be attached to the main structure through any of its rings, ie, any aromatic or non-aromatic ring.
- the aryl group is phenyl, naphthyl, bicyclo[4.2.0]oct-1,3,5-trienyl, indanyl, fluorenyl, or tetrahydronaphthyl.
- aryl group When an aryl group is substituted, it can be substituted on any ring, ie, on any aromatic or non-aromatic ring contained by the aryl group.
- aryl is phenyl, naphthyl, tetrahydronaphthyl, fluorenyl, or indanyl.
- the aryl groups can be independently optionally substituted with one or more substituents described herein.
- aralkyl or "arylalkyl” as used herein, unless otherwise specified, refers to an alkyl group substituted with one or two aryl groups as defined herein, wherein the The alkyl group is the point of attachment to the rest of the molecule.
- the aralkyl group is benzyl, phenet-1-yl, phenet-2-yl, diphenylmethyl, 2,2-diphenylethyl, 3,3-diphenyl propyl, or 3-phenylpropyl; the benzyl, phenethyl-1-yl, phenethyl-2-yl, diphenylmethyl, 2,2-diphenylethyl, 3,3 - Diphenylpropyl, and 3-phenylpropyl are each optionally substituted on the ring with one or more substituents described herein.
- heteroaryl refers to a monovalent monocyclic or polycyclic aromatic group wherein at least one (in certain embodiments, 1, 2, 3, or 4) Ring atoms are heteroatoms independently selected from O, S(O) 0-2 and N in the ring.
- the heteroaryl group is attached to the rest of the molecule through any atom in the ring system, where valence rules permit.
- each ring of a heteroaryl group can contain 1 or 2 O atoms, 1 or 2 S atoms, and/or 1 to 4 N atoms, or a combination thereof, provided that the The total number of heteroatoms is 4 or less, and each ring contains at least 1 carbon atom.
- the heteroaryl group has 5-20, 5-15, or 5-10 ring atoms. When a heteroaryl group is substituted, it can be substituted on either ring.
- monocyclic heteroaryl groups include, but are not limited to, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, Pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl and triazolyl.
- bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzoyl thiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridyl, imidazothiazolyl, indazinyl, indolyl, indazolyl, isobenzoyl furanyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridyl, phthalazinyl, pteridyl, purinyl, pyridopyridyl, pyrrole pyridyl, quinolinyl, quinoxalinyl, quinazolinyl
- tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, aziridinyl, phenanthroline, phenanthridine and phenazine groups.
- the heteroaryl group is indolyl, furanyl, pyridyl, pyrimidinyl, imidazolyl, or pyrazolyl; each of which may optionally be represented by one or more of the present invention on either ring. substituted with the described substituents.
- heteroarylalkyl refers to an alkyl group substituted with one or two heteroaryl groups as defined herein, wherein the alkyl group is the point of attachment to the rest of the molecule.
- heteroarylalkyl include, but are not limited to, imidazole-2-methyl, thiazole-2-methyl, furan-2-ethyl, indole-3-methyl, and the like; each of which is optionally Any ring may be substituted with one or more of the substituents described herein.
- alkylamino includes “N-alkylamino” and "N,N-dialkylamino” wherein the amino group is independently substituted with one or two alkyl groups, respectively.
- alkylamino is a lower alkylamino group with one or two C1-6 alkyl groups attached to a nitrogen atom.
- the alkylamino group is a C1-3 lower alkylamino group.
- Suitable alkylamino groups may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N -Diethylamino, etc.
- aminoalkyl includes a C 1-10 straight or branched chain alkyl group substituted with one or more amino groups.
- aminoalkyl is a C 1-6 "lower aminoalkyl” substituted with one or more amino groups, and in other embodiments, aminoalkyl is substituted by one or more amino groups C 1-4 "lower aminoalkyl" substituted with an amino group, such examples include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.
- cyanoalkyl includes C1-10 straight or branched chain alkyl groups substituted with one or more cyano groups.
- cyano-substituted alkyl is a C 1-6 "lower cyanoalkyl” substituted with one or more cyano groups
- cyano-substituted Alkyl is a C1-4 "lower cyanoalkyl” substituted with one or more cyano groups, examples of which include, but are not limited to, CNCH2- , CNCH2CH2- , CNCH 2 CH 2 CH 2 -, CNCH 2 CHCNCH 2 -, etc.
- pharmaceutically acceptable salts refer to organic and inorganic salts of the compounds of the present invention.
- Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
- Pharmaceutically acceptable non-toxic acid-formed salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods such as ion exchange method described in books and literature these salts.
- salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lacturonate, Lactate, Laurate, Lauryl Sulfate, Malonate, Malonate, Mesylate, 2-Naphthalenesulfonate, Nicotinate, Nitrate, Oleate, Palmitate, Pamoate, Pectate, Persulfate, 3 - Phenylpropionate, picrate, pivalate, propionate,
- Salts obtained by reaction with suitable bases include alkali metal, alkaline earth metal, ammonium and N + ( C1 -C4alkyl )4 salts .
- the present invention also contemplates quaternary ammonium salts formed from any compound containing an N-group. Water- or oil-soluble or dispersible products can be obtained by quaternization.
- Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that resist the formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 -8 Sulfonates and aromatic sulfonates.
- counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 -8 Sulfonates and aromatic sulfonates.
- a “solvate” of the present invention refers to an association of one or more solvent molecules with a compound of the present invention.
- Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
- hydrate refers to an association in which the solvent molecule is water.
- the term "hydrate" may be used.
- one molecule of a compound of the present invention may be associated with one molecule of water, such as a monohydrate; in other embodiments, a molecule of a compound of the present invention may be associated with more than one molecule of water, such as a dihydrate In yet other embodiments, one molecule of the compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the non-hydrated form of the compounds.
- any disease or disorder in some embodiments refers to ameliorating the disease or disorder (ie, slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating or improving at least one physical parameter, including a physical parameter that may not be perceived by a patient. In other embodiments, “treating” refers to modulating a disease or disorder physically (eg, stabilizing an observable symptom) or physiologically (eg, stabilizing a physical parameter), or both. In other embodiments, “treating” refers to preventing or delaying the onset, occurrence or worsening of a disease or disorder.
- the present invention provides a new class of TGF-beta inhibitors, which can be used to prepare medicaments for preventing and/or treating mammalian diseases, disorders, or conditions mediated by or involving TGF-beta.
- the present invention also provides methods for preparing the compounds of the present invention, pharmaceutical compositions comprising these compounds, and the use of these compounds and pharmaceutical compositions comprising these compounds to prevent and/or treat the above-mentioned diseases, disorders, or the method of the condition.
- the present invention provides an imidazole compound that can be used as a TGF- ⁇ inhibitor, especially a TGF ⁇ R-1 inhibitor, which is shown in formula (I):
- X 1 is N, or -C(R a )-;
- X 2 is N, or -C(R 2 )-; provided that X 1 and X 2 are not both carbon atoms;
- X 3 , X 4 and X 5 are each independently -C(R 3 )-, or N;
- X 6 is O, S, or -N(R 3 )-;
- W is optionally substituted with 0, 1, 2, 3 , 4 or 5 R;
- Y 1 , Y 2 , Y 3 and Y 4 are each independently -C(R 4 )-, or N;
- each Y 5 is independently O, S, or -N(R 4 )-;
- Z is optionally substituted with 0, 1, 2, 3, 4 or 5 R4;
- R 1 , R 2 and Ra are each independently H, -(C(R c )(R d )) m -LR 5 , C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, or C 1-6 alkane Amino, provided that R 1 and R 2 are not H at the same time; alternatively, R 1 and R 2 together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring of 5-8 atoms, or R 2 and R a are the same The atoms to which it is attached together form a carbocycle or heterocycle of 5-8 atoms, wherein the carbocycle or heterocycle of 5-8 atoms is optionally surrounded by 0, 1, 2, 3 or 4 R 6 to replace;
- R b is H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, or C 1-6 cyanoalkyl;
- R c and R d are independently H, C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 1-6 haloalkyl; alternatively, R c and R d are the same as The connected carbon atoms together form a carbocyclic or heterocyclic ring of 3-6 atoms;
- R 5 is H, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl, C 1-6 alkyl, C 1-9 heteroaryl, C 1-9 heteroaryl, C 1-6 alkyl, C 5 -12 spirobicyclic group, C 5-12 spiro heterobicyclic group, C 5-12 fused bicyclic group, or C 5-12 fused heterobicyclic group; wherein R 5 is optionally replaced by 0, 1, 2, 3, 4 or 5 R 5a substitutions;
- R h and R i are each independently H, or C 1-6 alkyl
- n 0, 1, 2, 3, or 4.
- the compounds of the present invention have the structure of formula (II):
- t 0, 1, 2, 3, 4, or 5;
- n 0, 1, 2, 3, 4 or 5.
- the compound of the present invention has the structure shown in formula (III):
- t 0, 1, 2, 3, 4 or 5.
- W is optionally substituted with 0, 1, 2, 3 , or 4 R3.
- the compounds of the present invention have the structure of formula (IV):
- L 1 is -(C(R c )(R d )) m -;
- t 0, 1, 2, 3, 4 or 5.
- the compounds of the present invention have the structure of formula (V):
- t 0, 1, 2, 3, 4, or 5;
- p 0, 1, 2, 3 or 4.
- R 1 and R 2 are each independently H, -(C(R c )(R d )) m -LR 5 , C 1-4 alkyl, or C 1-4 hydroxyalkyl , provided that R 1 and R 2 are not H at the same time; or, R 1 and R 2 together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring of 5-6 atoms, wherein the 5-6 atoms
- the constituent carbocycles or heterocycles are optionally substituted with 0, 1, 2, 3 or 4 R6.
- R1 and R2 are each independently H, - (C( Rc )( Rd )) m - LR5, methyl, ethyl, n-propyl, isopropyl, n - butyl, tert - butyl, -CF3 , -CH2CF3 , -OCF3 , -CH2CN , -CH2CH2CN , -CH2OH , -CH2OH , or -CH2CH 2 OH, provided that R 1 and R 2 are not H at the same time; or, R 1 and R 2 together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring of 5-6 atoms, wherein the 5-6 A carbocyclic or heterocyclic ring consisting of 2 atoms is optionally substituted with 0, 1, 2, 3 or 4 R 6 .
- Rc and Rd are independently H, methyl, ethyl; alternatively, Rc and Rd together with the carbon atom to which they are attached form a cyclopropyl;
- R b is H, or C 1-3 alkyl.
- R 5 is H, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-4 alkyl, C 3-6 heterocyclyl, C 3-6 heterocyclyl C 1-4 alkyl, C 6-12 aryl, C 6-12 aryl C 1-4 alkyl, C 1-9 heteroaryl, C 1-9 heteroaryl C 1 -4 alkyl, C 5-12 spirobicyclyl, C 5-12 spiroheterobicyclyl, C 5-12 fused bicyclyl, or C 5-12 fused heterobicyclyl; wherein R 5 is optionally 0 , 1, 2, 3 or 4 R 5a substitutions.
- R 5 is methyl, ethyl, propyl, wherein R5 is optionally substituted with 0 , 1, 2, 3 or 4 R5a .
- R 4a is and
- Re , Rf , and Rg are each independently H, methyl, or ethyl.
- Rh and Ri are each independently H, methyl, or ethyl.
- X 2 is N, or -C(R 2 )-;
- X 3 , X 4 and X 5 are each independently -C(R 3 )-, or N;
- X 6 is -N(R 3 )-;
- W is optionally substituted with 0, 1 or 2 R ;
- Y 1 , Y 2 , Y 3 are each independently -C(R 4 )-, or N; Y 4 is each independently -C(R 4 )-;
- each Y 5 is independently S, or -N(R 4 )-;
- Z is optionally substituted with 0, 1 or 2 R4;
- R 1 and R 2 are each independently H, -(C(R c )(R d )) m -LR 5 , or C 1-6 alkyl, provided that R 1 and R 2 are not both H; or, R 1 and R 2 together with the carbon atom to which it is attached form a carbocyclic or heterocyclic ring consisting of 5-8 atoms;
- R b is H, or C 1-6 alkyl
- Each R c and R d at each occurrence is independently H, or C 1-6 alkyl
- Each R 3 is independently F, Cl, C 1-6 alkyl, or C 3-8 cycloalkyl;
- R 5 is H, C 3-8 cycloalkyl, C 6-12 aryl, C 1-9 heteroaryl, C 2-7 heterocyclyl, or C 5-12 fused heterobicyclyl; wherein R 5 is optionally substituted with 0, 1, 2, 3, or 4 R 5a ;
- R h , R i are each independently H;
- n 0, 1 or 2.
- X 2 is -C(R 2 )-;
- X 3 , X 4 and X 5 are each independently -C(R 3 )-, or N;
- W is optionally substituted with 0, 1 or 2 R ;
- Y 1 , Y 2 , Y 3 are each independently -C(R 4 )-, or N; Y 4 is each independently -C(R 4 )-;
- each Y 5 is independently S, or -N(R 4 )-;
- Z is optionally substituted with 0, 1 or 2 R4;
- R 1 and R 2 are each independently H, -(C(R c )(R d )) m -LR 5 , or C 1-6 alkyl, provided that R 1 and R 2 are not both H; or, R 1 and R 2 together with the carbon atom to which it is attached form a carbocyclic or heterocyclic ring consisting of 5-8 atoms;
- R b is H, or C 1-6 alkyl
- each of R c and R d is independently H at each occurrence;
- Each R3 is independently F, Cl, or C1-6 alkyl
- R 5 is H, C 3-8 cycloalkyl, C 6-12 aryl, C 1-9 heteroaryl, C 2-7 heterocyclyl, or C 5-12 fused heterobicyclyl; wherein R 5 optionally substituted with 0, 1, 2, 3, or 4 R 5a ;
- Each R 4a at each occurrence is independently C 2-7 heterocyclyl, wherein C 2-7 heterocyclyl is independently optionally substituted with 0, or 1 -OH, or -NH 2 ; each R 4b and R 4c are independently H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 2-7 heterocyclyl, -C 1 at each occurrence.
- R h , R i are each independently H;
- n 0, 1 or 2.
- X 2 is -C(R 2 )-;
- X 3 , X 4 and X 5 are each independently -C(R 3 )-, or N; and one of X 3 , X 4 and X 5 is N, and the rest are -C(R 3 )-;
- W is optionally substituted with 0, 1 or 2 R ;
- Y 1 is -C(R 4 )-, or N; Y 2 and Y 4 are each independently -C(R 4 )-; Y 3 is N;
- each Y 5 is independently -N(R 4 )-;
- Z is optionally substituted with 0, 1 or 2 R4;
- R 1 and R 2 are each independently H, -(C(R c )(R d )) m -LR 5 , or C 1-6 alkyl, provided that R 1 and R 2 are not both H; or, R 1 and R 2 together with the carbon atom to which it is attached form a carbocyclic or heterocyclic ring consisting of 5-8 atoms;
- R b is H, or C 1-6 alkyl
- each of R c and R d is independently H at each occurrence;
- Each R 3 is, at each occurrence, independently F, or C 1-6 alkyl
- R 5 is C 3-8 cycloalkyl, C 6-12 aryl, C 1-9 heteroaryl, or C 2-7 heterocyclyl; wherein R 5 is optionally replaced by 0, 1, 2, 3, or 4 R 5a substitutions;
- m 0 or 1.
- the compound of the present invention has a compound of one of the following structures:
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.
- the pharmaceutical composition further comprises an additional therapeutic agent.
- the present invention provides a method for preventing and/or treating TGF- ⁇ -mediated or TGF- ⁇ -related diseases, disorders, or use in medicines for conditions.
- the disease, disorder, or condition is pulmonary hypertension, chronic kidney disease, acute kidney disease, wound healing, arthritis, osteoporosis, kidney disease, congestive heart failure, ulcers, ocular disorders, corneal damage, Diabetic nephropathy, neurological impairment, Alzheimer's disease, atherosclerosis, peritoneal or subcutaneous adhesions, renal fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, hepatitis B, type C Hepatitis, alcohol-induced hepatitis, cancer, hemochromatosis, primary biliary cirrhosis, restenosis, retroperitoneal fibrosis, mesenteric fibrosis, endometriosis, keloids, cancer, bone dysfunction, inflammatory Disorders, scarring, or photoaging of the skin.
- the disease, disorder, or condition is a benign or malignant tumor, brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, stomach cancer, stomach tumor, ovarian cancer, colon cancer, rectal cancer , prostate cancer, pancreatic cancer, lung cancer, vaginal or thyroid cancer, sarcoma, glioblastoma, multiple myeloma or gastrointestinal cancer, colon or colorectal cancer, head and neck tumors, epidermal hyperproliferation, melanoma, psoriasis , benign prostatic hyperplasia, neoplasia, epithelial neoplasia, leukemia, lymphoma, breast cancer, or leukemia.
- the compounds or pharmaceutical compositions described herein can be administered in combination with additional therapeutic agents.
- the uses of the present invention comprise administering to a mammal, particularly a human, an amount of a compound or pharmaceutical composition of the present invention sufficient to effect the treatment or prevention.
- the compounds of the present invention are usually administered in the form of a pharmaceutical composition.
- Said composition can be prepared in a manner well known in the art of pharmacy and comprises at least one compound of the invention according to formula I, II, III, IV or V.
- the compounds of the present invention are administered in a pharmaceutically effective amount.
- the amount of the compound of the present invention actually administered will generally be determined by the physician in light of the circumstances, including the condition to be treated, the route of administration chosen, the actual compound of the present invention administered, the age, weight and response of the individual patient, the patient's symptoms severity, etc.
- compositions of the present invention can be administered by a variety of routes, including oral, rectal, transdermal, subcutaneous, intraarticular, intravenous, intramuscular, and intranasal.
- routes including oral, rectal, transdermal, subcutaneous, intraarticular, intravenous, intramuscular, and intranasal.
- the compounds of the present invention are preferably formulated as injectable or oral compositions or as ointments, as lotions or as patches (all for transdermal administration).
- compositions for oral administration pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water or liquid paraffin can be used.
- inert diluents such as water or liquid paraffin
- These compositions may also contain substances other than diluents, and in some embodiments, wetting agents, sweeteners, or flavoring preparations.
- compositions for parenteral administration may be emulsions or sterile solutions.
- propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, or injectable organic esters can be used as a solvent or carrier, and in some embodiments, ethyl oleate can be used as a solvent or carrier.
- These compositions may also contain adjuvants, especially wetting agents, isotonic agents, emulsifying agents, dispersing agents and stabilizing agents.
- Sterilization can be performed in several ways, in certain embodiments, by use of bacteriological filters, by radiation or by heat. They can also be prepared in the form of sterile solid compositions which, at the time of use, can be dissolved in sterile water or any other sterile injectable medium.
- the composition may also be an aerosol.
- the compositions may be stable sterile solutions or solid compositions dissolved in sterile pyrogen-free water, saline or any other pharmaceutically acceptable carrier at the time of use.
- the active ingredient is finely divided and combined with a water-soluble solid diluent or carrier, in certain embodiments, dextran, mannitol or lactose.
- compositions containing them may also be administered in the form of suppositories, eg for rectal administration of drugs.
- suppositories eg for rectal administration of drugs.
- suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- suitable non-irritating excipient include cocoa butter and polyethylene glycols.
- Typical pharmaceutical compositions and dosage forms contain one or more excipients.
- suitable excipients are well known to those skilled in the art of pharmacy, and in certain embodiments, suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, Glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene, glycol, water, ethanol, etc.
- a particular adjuvant is suitable for incorporation into a pharmaceutical composition or dosage form depends on various factors well known in the art, including but not limited to the manner in which the dosage form is administered to a subject and the particular active ingredient in the dosage form.
- the composition or single unit dosage form may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
- the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in medicine.
- the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and/or treatment of a disease, disorder, or condition mediated by or involving TGF-beta.
- the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutical composition comprising a compound of the present invention and other therapeutic agents, for use in the manufacture of a compound for the prevention and/or treatment of pulmonary hypertension, Chronic Kidney Disease, Acute Kidney Disease, Wound Healing, Arthritis, Osteoporosis, Kidney Disease, Congestive Heart Failure, Ulcers, Eye Conditions, Corneal Injury, Diabetic Kidney Disease, Neurological Impairment, Alzheimer's Disease, Atherosclerosis sclerosis, peritoneal or subcutaneous adhesions, renal fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, hepatitis B, hepatitis C, alcohol-induced hepatitis, cancer, hemochromatosis, primary bile cirrhosis, restenosis, retroperitoneal fibrosis, mesenteric fibrosis, end
- Therapeutic doses of the compounds may vary depending on, for example, the particular use of the treatment being performed, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
- the ratio or concentration of a compound of the present application in a pharmaceutical composition may vary depending on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration.
- the compounds of the present application may be provided in an aqueous physiological buffer solution for parenteral administration containing from about 0.1 to about 10% w/v of the compound. Some typical dosage ranges are from about 1 ⁇ g/kg body weight to about 1 g/kg body weight per day.
- the dose ranges from about 0.01 mg/kg body weight to about 100 mg/kg body weight per day.
- the dosage may depend on variables such as the type and degree of progression of the disease or disorder, the general health status of the particular patient, the relative biological potency of the selected compound, the formulation of the excipient and its route of administration. Effective doses can be extrapolated from dose-response curves obtained from in vitro or animal model test systems.
- the present application includes combination therapies for the treatment of cancers including premalignant and malignant tumors.
- the application includes methods of treating cancer comprising administering to a subject a compound of the application in combination with therapeutic treatment of cancer.
- the compounds of the present application are used in combination with standard anti-proliferative treatment care for cancer.
- Compounds of the present application are used in combination therapy in amounts sufficient to inhibit signaling by members of the TGF-beta superfamily, such as Nodal and Activin, which promote survival and/or differentiation of cancer stem cells, and thereby enhance therapeutic efficacy effect of treatment.
- Treatment with the compounds of the present application thus blocks the ability of cancer stem cells to regenerate tumors destroyed by treatment with standard of care.
- Therapeutic effect can be determined by any method known in the art commonly used for the particular cancer being treated and includes, for example, arresting, inhibiting or regressing tumor growth.
- One embodiment of treating cancer in a subject comprises administering to a subject in need thereof the above-mentioned amounts of a compound of the present application and administering a therapeutically effective amount of one or more chemotherapeutic agents, wherein the one or Various chemotherapeutic agents selected from antimetabolites, alkylating agents, coordination compounds, platinum complexes, DNA cross-linking compounds, transcriptase inhibitors, tyrosine kinase inhibitors, protein kinase inhibitors, topoisomerases Inhibitors, DNA minor groove binding compounds, Vinca alkaloids, taxanes, antitumor antibiotics, hormones, aromatase inhibitors, enzymes, growth factor receptor antibodies, cytokines, cell surface marker antibodies, HDAC inhibitors , HSP 90 inhibitors, BCL-2 inhibitors, B-raf inhibitors, MEK inhibitors, mTOR inhibitors, proteasome inhibitors and monoclonal antibodies.
- chemotherapeutic agents selected from antimetabolites, alkylating agents
- chemotherapeutic agents are independently selected from nitrogen mustard, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethyleneimine, methylmelamine, procarbazine, dacarbazine, temozolomide, busulfan , carmustine, lomustine, methotrexate, fluorouracil, capecitabine, cytarabine, gemcitabine, cytarabine, mercaptopurine, fludarabine, cladribine, thioguanine , azathioprine, vinblastine, vincristine, paclitaxel, docetaxel, colchicine, actinomycin D, daunorubicin, bleomycin
- co-administration includes any means of delivering two or more therapeutic agents to a patient as part of the same treatment regimen.
- two or more active agents may be administered simultaneously in a single formulation (ie, as a single pharmaceutical composition), this is not required.
- the active agents may also be administered in different formulations and at different times.
- the compounds of the present invention can be prepared by the methods described herein, where the substituents are as defined in formula I, II, III, IV or V unless otherwise specified.
- the following reaction schemes and examples serve to further illustrate the content of the present invention.
- Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether were obtained by refluxing and drying with metallic sodium.
- Anhydrous dichloromethane and chloroform were obtained by refluxing with calcium hydride.
- Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.
- reaction flasks are plugged with suitable rubber stoppers, and the substrate is injected through a syringe. Glassware is dry.
- the chromatographic column is a silica gel column.
- Silica gel 300-400 mesh was purchased from Qingdao Ocean Chemical Factory.
- 1 H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz nuclear magnetic resonance spectrometer. 1H NMR spectra were performed with CDC13, DMSO - d6, CD3OD or acetone - d6 as solvent (in ppm) and TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiplets are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened) peak), dd (doublet of doublets, double doublet), dt (doublet of triplets, double triplet). Coupling constant, expressed in Hertz (Hz).
- MS mass spectrometry
- Intermediate 1-1 reacts with alcohol solution of hydrogen chloride and then reacts with ammonia methanol solution or ammonium chloride to obtain intermediate 1-2; intermediate 1-2 and intermediate 1-3 undergo nucleophilic substitution under alkaline and heating conditions The reaction obtains intermediate 1-4; intermediate 1-4 undergoes an intramolecular ring-closure reaction under acidic and heating conditions to obtain intermediate 1-5; intermediate 1-5 can be tautomeric to intermediate 1-6, and then Metal-catalyzed coupling reaction with intermediates 1-7 affords compounds 1-8.
- W, R 1 , R 2 and Z all have the definitions described in the present invention; X is halogen; E 1 is halogen, boronic acid group or pinacol boronate group.
- Intermediate 1-2 and intermediate 2-1 undergo nucleophilic substitution reaction under alkaline and heating conditions to obtain intermediate 2-2;
- Intermediate 2-2 undergoes intramolecular ring closure reaction under acidic and heating conditions to obtain intermediate 2-3;
- Intermediate 2-3 and intermediate 1-7 undergo metal-catalyzed coupling reaction to obtain compound 2-4.
- W, R 6 , p and Z all have the definitions described in the present invention;
- X is halogen;
- E 1 is halogen, boronic acid group or pinacol boronate group.
- Intermediate 1-2 and 1,3-dihydroxyacetone dimer are heated and reacted in ammonia water to obtain intermediate 3-1; intermediate 3-1 can be obtained by corresponding halogenation reaction or nucleophilic substitution reaction to obtain intermediate 3- 2; Intermediate 3-2 undergoes nucleophilic substitution reaction with corresponding amine or phenol to obtain Intermediate 3-3; Intermediate 3-3 undergoes metal-catalyzed coupling reaction with Intermediate 1-7 to obtain compound 3-4.
- W, Z, L 1 , L and R 5 all have the definitions described in the present invention; E 1 is halogen, boronic acid group or pinacol boronate group; E 2 is halogen or methanesulfonyloxy group.
- Intermediate 1-1 reacts with hydrogen chloride alcohol solution to obtain intermediate 4-1; intermediate 4-1 and corresponding amine 4-2 undergo nucleophilic substitution reaction under alkaline conditions to obtain intermediate 4-3; intermediate 4- 3 was reacted with the corresponding haloaldehyde 4-4 under weak base and heating conditions to obtain compound 4-5.
- W, R 1 , and Z all have the definitions described herein; X is halogen.
- the hydrazide 5-1 reacts with the corresponding acid chloride to obtain the intermediate 5-2; the intermediate 5-2 reacts with phosphorus pentachloride to obtain the intermediate 5-3, and then reacts with the corresponding amine to obtain the triazole compound 5-4 .
- W, R 1 , and Z all have the definitions described in the present invention.
- Compound 6-1 is oxidized with hydrogen peroxide under basic conditions to obtain compound 6-2.
- X 3 , X 4 , X 5 , Y 1 , Y 4 , R 1 , R 2 , R 3 and t all have the definitions described in the present invention.
- Compound 6-1 is hydrolyzed under basic or acidic conditions to obtain intermediate 7-1, and then undergoes condensation reaction with the corresponding amine to obtain compound 7-3.
- X 3 , X 4 , X 5 , Y 1 , Y 4 , R 1 , R 2 , R 3 , R 4b , R 4c and t all have the definitions described in the present invention.
- Intermediate 8-1 is oxidized by manganese dioxide to obtain intermediate 8-2; intermediate 8-2 and 8-3 are subjected to metal-catalyzed coupling reaction to obtain intermediate 8-4; intermediate 8-4 is oxidized to obtain acid 8-5, and then condensed with the corresponding amine to obtain the intermediate 8-6; the intermediate 8-6 is oxidized with hydrogen peroxide under basic conditions to obtain the compound 8-7.
- X 3 , X 4 , X 5 , Y 1 , Y 4 , R 1 , R 2 , R 3 , R 5 , E 1 , R 4b , R 4c and t all have the definitions described in the present invention.
- 6-(2-(5-Fluoro-6-methylpyridin-2-yl)-5,6-dihydrocyclopentadieno[d]imidazol-1(4H)-yl)imidazo[1,2 -b] The preparation method of pyridazine-3-carboxamide refers to Example 2, except that 6-(2-(5-fluoro-6-methylpyridin-2-yl)-5,6-dihydrocyclopentane is used Eno[d]imidazol-1(4H)-yl)imidazo[1,2-b]pyridazine-3-carbonitrile instead of 6-(2-(6-methylpyridin-2-yl)-5, 6-Dihydrocyclopentadieno[d]imidazol-1(4H)-yl)imidazo[1,2-b]pyridazine-3-carbonitrile to give the title compound as a white solid (23 mg, 61%) .
- Phosphorus tribromide (5.62 g, 20.8 mmol) was slowly added dropwise to a solution of 4-hydroxyquinoline-6-carbonitrile (2.94 g, 17.3 mmol) in DMF (35 mL) at -5 °C. React at -5°C for 10 minutes. TLC detection showed that the reaction was complete, and ice water (35 mL) was added to the reaction solution to quench the reaction, and the pH was adjusted to about 8 with an aqueous sodium bicarbonate solution. After stirring for 0.5 hours, suction filtration was performed. The obtained filter cake was purified by silica gel column chromatography (eluting dichloromethane) to give the title compound as a yellow solid (2.14 g, 53%).
- Step 5 4-(2-(6-Methylpyridin-2-yl)-5,6-dihydrocyclopentadieno[d]imidazol-1(4H)-yl)quinoline-6-carbonitrile
- Step 2) 2-(2-(3-Chloro-4-fluorophenyl)-5,6-dihydrocyclopentadieno[d]imidazol-1(4H)-yl)-6-methylimidazo [2,1-b][1,3,4]thiadiazole
- 6-Bromo-[1,2,4]triazolo[1,5-a]pyridine (0.51 g, 2.56 mmol)
- boronic acid pinacol ester (1.95 g, 7.68 mmol)
- Pd(dppf)Cl2 (0.12 g , 0.16 mmol)
- potassium acetate (0.50 g, 5.14 mmol)
- dioxane 10 mL
- reaction solution was poured into ice water, the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (25 mL x 2), the organic phases were combined, and saturated brine (20 mL x 2) was used for extraction. Washed, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow solid (300 mg, 82%).
- 1-b][1,3,4]thiadiazole 5-carboxamide refer to Example 2, except that 6-methyl-2-(2-(6-methylpyridin-2-yl)- 5,6-Dihydrocyclopentadieno[d]imidazol-1(4H)-yl)imidazo[2,1-b][1,3,4]thiadiazole 5-carbonitrile instead of 6-( 2-(6-Methylpyridin-2-yl)-5,6-dihydrocyclopentadieno[d]imidazol-1(4H)-yl)imidazo[1,2-b]pyridazine-3 -carbonitrile to give the title compound as a pale yellow solid product (7 mg, 31%).
- Step 2) 6-(2-(3-Chloro-4-fluorophenyl)-4-methyl-1H-imidazol-1-yl)imidazo[1,2-b]pyridazine-3-carbonitrile
- Step 2) N-(2-Hydroxyethyl)-6-(2-(6-methylpyridin-2-yl)-5,6-dihydrocyclopentadieno[d]imidazole-1(4H) -yl)imidazo[1,2-a]pyridine-3-carboxamide
- 6-Bromo-4(3H)-quinazolinone (675 mg, 3 mmol) and DMF (15 mL) were added to the reaction flask, under nitrogen, cooled to 0°C, and 60% sodium hydride (240 mg, 6 mmol) was added. The reaction was stirred at room temperature for 1 hour, 1,2-dibromoethane (5.6 g, 30 mmol) was added, and the reaction was stirred for 2 hours.
- 6-(2-(5-fluoro-6-methylpyridin-2-yl) -5,6-Dihydrocyclopentadieno[d]imidazol-1(4H)-yl)imidazo[1,2-b]pyridazine-3-carbonitrile instead of 6-(2-(6-methylcarbonitrile pyridin-2-yl)-5,6-dihydrocyclopentadieno[d]imidazol-1(4H)-yl)imidazo[1,2-a]pyridine-3-carbonitrile to give the title compound As an off-white solid (6 mg, 10%).
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Abstract
作为TGF-β抑制剂,尤其是作为TGFβR-1抑制剂的一类新的咪唑类化合物,包含所述化合物的药物组合物,以及使用所述化合物和组合物预防和/或治疗TGF-β介导或涉及TGF-β的疾病、病症、或病况,其中所述化合物具有式(I)所示结构,或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、区域异构体、氮氧化物、或混合物:其中,X 1、X 2、R 1、W和Z均具有所述定义。
Description
本发明涉及药物化学领域,具体涉及作为TGF-β抑制剂,尤其涉及作为乙型转化生长因子受体-1(Transforming Growth Factor Beta Receptor-1,TGFβR-1)抑制剂的咪唑类化合物,包含所述化合物的药物组合物,以及使用所述化合物和组合物预防和/或治疗TGF-β介导或涉及TGF-β的疾病、病症、或病况。
乙型转化生长因子(Transforming Growth Factor Beta,TGF-β)是一种具有多功能的细胞激素,在人体内众多类型的细胞皆具有产生并分泌此种细胞激素的能力。TGF-β参与许多疾病的机转,扮演抑制或促进疾病的双重角色,包括伤口愈合、组织纤维化、粥状动脉硬化、癌症的发生与转移、自体免疫疾病、糖尿病并发症,以及阿兹海默症造成的神经损伤等,皆和TGF-β息息相关。TGF-β信号通路在肿瘤发生和发展、免疫、炎症、纤维化和内分泌功能调节过程中起重要作用,是一个有良好发展前景的药物靶点。
TGF-β的各种不同生物学作用是通过细胞表面受体来转导信号而完成的。而其受体可分为六型,其中TGFβR-1~3型表达广泛。目前发现,TGF-β的信号转导大都通过TGFβR-1和2构成的异四聚体来介导,而TGFβR-3具有促进TGFβR-1、2聚合作用,因此,TGFβR-1~3受体研究是当前的热点。TGFβR-1属于丝氨酸/苏氨酸激酶家族成员,也被称为活化素受体样激酶5(activin receptor-like kinase 5)。TGF-β和activin不能和TGFβR-1直接作用,需要激活的TGFβR-2通过转磷酸化TGFβR-1的GS区才能将其激活,受体复合物中TGFβR-1决定信号通路的性质。
TGF-β对细胞增殖的调节主要是通过TGFβR-1、2构成的异四聚体激活Smad2/3,Smad2/3与Smad4转入细胞核,开启Smad依赖信号通路。Smad信号通路具有抑制c-myc表达和促进细胞周期抑制蛋白P21、P15表达等作用,导致细胞周期的停滞,这条通路使TGF-β具有抑制细胞增殖的作用;另外,TGFβR-1、2可以激活非Smad信号通路,如MAPK、Rho-like GTPases和PI3K等途径。而已有研究发现,在这些途径中,MAPK和PI3K对细胞增殖有一定的促进作用。虽然也有研究发现,在某些上皮细胞中TGF-β激活Ras和MAPK途径可抑制细胞增殖,不过这个作用有赖于TGFβR-1、2和Smad蛋白的共同作用。因此,总体看来,TGF-β介导的Smad信号通路在细胞增殖调节上以抑制细胞增殖为主,而非Smad信号通路则以促进细胞增殖为主。
TGFβR-1激酶抑制剂以及该靶点涉及的信号通路已在抗肿瘤、骨髓增生异常、抗纤维化和瘢痕生成中被研究或证实有效。在肝癌细胞株HLE和HLF的研究中发现,礼来公司的TGFβR-1激酶抑制剂LY2109761通过两种途径减少肿瘤血管的形成从而限制肝癌的发生发展:(1)减少血管的数目和弯曲度,这两者是肿瘤汲取氧气和疏散药物的形态学基础;(2)阻断微环境中肿瘤与机体的相互作用。此外,在鸡胚模型中也同样发现LY2109761对肿瘤生长、侵袭和转移的抑制作用。TGFβR-1异常在肝癌中报道很少,其保守稳定的性质给药物靶向治疗提供了保障。礼来公司的另一款TGFβR-1激酶抑制剂Galunisertib在治疗肝癌患者的2期临床试验中,约23%的患者血清甲胎蛋白(α-fetoprotein,AFP)水平下降20%以上,与无AFP应答反应的患者相比,肿瘤进展较慢且生存期更久。在这些患者体内也发现上皮细胞钙粘蛋白表达增加,由此说明Galunisertib可以通过抑制TGF-β信号通路来调节上皮间质转化(Epithelial-Mesenchymal Transition,EMT)来抑制肝癌进展。在人非小细胞肺癌细胞Calu6和乳腺癌细胞MX1异种移植皮下荷瘤裸鼠模型中,Galunisertib显示出显著的抗肿瘤活性。对于初级造血干细胞,Galunisertib可剂量依赖性地抑制TGF-β介导的Smad2蛋白活化和造血抑制,促进原发性MDS患者的骨髓造血功能。体内研究中,针对TGF-β过度表达的转基因骨髓造血功能衰竭小鼠模型,Galunisertib可改善贫血。在抗纤维化和瘢痕生成研究中,应用小分子ALK5抑制剂CP-639180可以抑制增生性瘢痕成纤维细胞分泌I型胶原蛋白和α-SMA,进一步抑制胶原纤维的合成,为增生性瘢痕治疗研究提供新的思路。
本发明提供了一类新的咪唑类化合物,其可作为TGF-β抑制剂,尤其可作为TGFβR-1抑制剂,对TGF-β介导或涉及TGF-β的疾病、病症、或病况有很好的疗效。本发明化合物具有优异的药效、药代性质和/或毒理性质,具备较佳的临床应用前景。
发明摘要
以下仅概括说明本发明的一些方面,但并不局限于此。这些方面和其他部分将在后面有更完整的说明。本说明书中所有参考文献均通过引用其整体并入本文。当本说明书公开内容与引用文献有差异时,以本说明书公开内容为准。
本发明提供了一类新的TGF-β抑制剂,尤其是TGFβR-1抑制剂,其可用于制备预防和/或治疗哺乳动物有关TGF-β介导或涉及TGF-β的疾病、病症、或病况的药物。本发明还提供了制备本发明所述化合物的方法,使用这些化合物治疗哺乳动物尤其是人类的上述疾病、病症、或病况的方法以及包含这些化合物的药物组合物。
一方面,本发明提供了一种新的咪唑类化合物,其具有式(I)所示结构,
或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、区域异构体、氮氧化物、或混合物,其中,
X
1是N、或-C(R
a)-;
X
2是N、或-C(R
2)-;条件是X
1和X
2不同时为碳原子;
W是
X
3、X
4和X
5各自独立地为-C(R
3)-、或N;
X
6是O、S、或-N(R
3)-;
其中所述W任选地被0、1、2、3、4或5个R
3取代;
Z是
Y
1、Y
2、Y
3和Y
4各自独立地为-C(R
4)-、或N;
各Y
5分别独立地为O、S、或-N(R
4)-;
其中所述Z任选地被0、1、2、3、4或5个R
4取代;
R
1、R
2和R
a各自独立地为H、-(C(R
c)(R
d))
m-L-R
5、C
1-6烷基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
1-6烷氧基、C
1-6卤代烷氧基、C
1-6烷硫基、或C
1-6烷氨基,条件是R
1和R
2不同时为H;或者,R
1和R
2同与之连接的碳原子一起形成5-8个原子组成的碳环或杂环,或R
2和R
a同与之连接的原子一起形成5-8个原子组成的碳环或杂环,其中所述5-8个原子组成的碳环或杂环任选地被0、1、2、3或4 个R
6取代;
L不存在,或L是-N(R
b)-、O、S、-C(=O)-或-C(=O)-NH-;
R
b是H、C
1-6烷基、C
1-6羟基烷基、C
1-6卤代烷基、或C
1-6氰基烷基;
各R
c和R
d在每次出现时,分别独立地为H、C
1-6烷基、C
1-6羟基烷基、或C
1-6卤代烷基;或者,R
c和R
d同与之连接的碳原子一起形成3-6个原子组成的碳环或杂环;
各R
3在每次出现时,分别独立地为H、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
1-6烷氧基、C
1-6卤代烷氧基、C
1-6烷硫基、C
1-6烷氨基、C
1-6卤代烷氨基、C
3-8环烷基、C
3-8环烷基C
1-6烷基、C
2-7杂环基、或C
2-7杂环基C
1-6烷基;
各R
4在每次出现时,分别独立地为H、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
1-6烷氧基、C
1-6卤代烷氧基、C
1-6烷硫基、C
1-6烷氨基、C
1-6卤代烷氨基、C
1-6亚烷基C
2-7杂环基、-S(=O)
1-2R
4a、-C(=O)R
4a、-C(=O)OR
4b、-OS(=O)
1-2R
4a、-OC(=O)R
4a、-S(=O)
1-2OR
4b、-N(R
4b)C(=O)R
4a、-C(=O)NR
4bR
4c、-OC(=O)NR
4bR
4c、-NR
4bR
4c、-N(R
4b)S(=O)
1-2R
4a、-S(=O)
1-2NR
4bR
4c、或-N(R
4b)C(=O)NR
4bR
4c;
R
5是H、C
1-6烷基、C
3-8环烷基、C
3-8环烷基C
1-6烷基、C
2-7杂环基、C
2-7杂环基C
1-6烷基、C
6-12芳基、C
6-12芳基C
1-6烷基、C
1-9杂芳基、C
1-9杂芳基C
1-6烷基、C
5-12螺双环基、C
5-12螺杂双环基、C
5-12稠合双环基、或C
5-12稠合杂双环基;其中R
5任选地被0、1、2、3、4或5个R
5a取代;
各R
5a在每次出现时,分别独立地为H、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
1-6烷氧基、C
1-6卤代烷氧基、C
1-6烷硫基、C
1-6烷氨基、C
1-6卤代烷氨基、C
2-7杂环基C
1-6烷基、-C
1-6亚烷基-NR
fR
g、-NR
fR
g、-C(=O)OR
e、或-C(=O)NR
fR
g;
各R
6在每次出现时,分别独立地为H、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
1-6烷氧基、C
1-6卤代烷氧基、C
1-6烷硫基、C
1-6烷氨基、C
1-6卤代烷氨基、C
3-8环烷基、C
3-8环烷基C
1-6烷基、C
2-7杂环基、C
2-7杂环基C
1-6烷基、C
6-12芳基、C
6-12芳基C
1-6烷基、C
1-9杂芳基、C
1-9杂芳基C
1-6烷基、-C
1-6亚烷基-NR
fR
g、-NR
fR
g、-C(=O)OR
e、或-C(=O)NR
fR
g;
各R
4a、R
4b、R
4c、R
e、R
f和R
g在每次出现时,分别独立地为H、C
1-6烷基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
3-8环烷基、C
3-8环烷基C
1-6烷基、C
2-7杂环基、C
2-7杂环基C
1-6烷基、C
5-12螺双环基、C
5-12螺杂双环基、C
5-12稠合双环基、C
5-12稠合杂双环基、-C
1-6亚烷基-OP(=O)(OR
h)(OR
i)、或-C
1-6亚烷基-C(=O)OR
i;其中C
3-8环烷基、C
3-8环烷基C
1-6烷基、C
2-7杂环基、C
2-7杂环基C
1-6烷基、C
5-12螺双环基、C
5-12螺杂双环基、C
5-12稠合双环基、和C
5-12稠合杂双环基独立任选地被0、1、2、3或4个独立选自H、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
1-6烷氧基、C
1-6卤代烷氧基、C
1-6烷硫基、C
1-6烷氨基、和C
1-6卤代烷氨基的基团取代;
R
h和R
i各自独立地为H、或C
1-6烷基;和
m是0、1、2、3、或4。
另一方面,本发明提供了药物组合物,其包含本发明所述的化合物,以及药学上可以接受的辅料、稀释剂或载体。
在一些实施方案,本发明所述的药物组合物进一步包含附加治疗剂。
在一些实施方案,所述附加治疗剂包含TGF-β抑制剂类和/或ALK5抑制剂类。
另一方面,本发明提供了使用本发明所述的化合物或本发明所述的药物组合物在制备用于预防和/或治疗TGF-β介导或涉及TGF-β的疾病、病症、或病况的药物中的用途。
在一些实施方案,所述疾病、病症、或病况是肺动脉高压、慢性肾病、急性肾病、伤口愈合、关节炎、骨质疏松症、肾病、充血性心力衰竭、溃疡、眼部病症、角膜损伤、糖尿病性肾病、神经功能受损、阿尔茨海默病、动脉粥样硬化、腹膜或皮下粘连、肾纤维化、肺纤维化、特发性肺纤维化、肝纤维化、乙型肝炎、丙型肝炎、由酒精诱导型肝炎、癌症、血色病、原发性胆汁性肝硬化、再狭窄、腹膜后纤维化、肠系 膜纤维化、子宫内膜异位、瘢痕疙瘩、癌症、骨功能异常、炎性病症、瘢痕形成和皮肤光老化。
在一些实施方案,所述疾病、病症、或病况是良性或恶性肿瘤、脑癌、肾癌、肝癌、肾上腺癌、膀胱癌、乳腺癌、胃癌、胃部肿瘤、卵巢癌、结肠癌、直肠癌、前列腺癌、胰腺癌、肺癌、阴道癌或甲状腺癌、肉瘤、成胶质细胞瘤、多发性骨髓瘤或胃肠癌症、结肠癌或结肠直肠癌、头颈肿瘤、表皮过度增殖、黑色素瘤、牛皮癣、前列腺增生、瘤形成、上皮性状瘤形成、白血病、淋巴瘤、乳腺癌或白血病。
发明详述
定义和一般术语
除非另外说明,本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
除非另有说明或者上下文中有明显的冲突,本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此,本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如,“一组分”指一个或多个组分,即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
术语“包含/包括”为开放式表达,即包括本发明所指明的内容,但并不排除其他方面的内容。“立体异构体”是指具有相同化学构造,但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体,等等。
“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
“非对映异构体”是指有两个或多个手性中性并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质,如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱,例如HPLC来分离。
许多有机化合物以光学活性形式存在,即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时,使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号,其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体,这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体,当在化学反应或过程中没有立体选择性或立体特异性时,可出现这种情况。
本发明公开化合物的任何不对称原子(例如,碳等)都可以以外消旋或对映体富集的形式存在,例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中,各不对称原子在(R)-或(S)-构型方面具有至少50%对映体过量,至少60%对映体过量,至少70%对映体过量,至少80%对映体过量,至少90%对映体过量,至少95%对映体过量,或至少99%对映体过量。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中),则可以达到互变异构体的化学平衡。例如,质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化,如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出,本发明化合物的所有互变异构体形式都在本发明的范围之内。“药学上可接受的”是指这样一些化合物、原料、组合物和/或剂型,它们在合理医学判断的范围内,适用于与患者组织接触而无过度毒性、刺激性、变态反应或与合理的利益/风险比相对称的其他问题和并发症,并有效用于既定用途。
像本发明所描述的,本发明的化合物可以任选地被一个或多个取代基所取代,如上面的通式化合物,或者像实施例里面特殊的例子,子类,和本发明所包含的一类化合物。
一般而言,术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明,一个取代的基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代,那么取代基可以相同或不同地在各个位置取代。
术语“未取代的”,表示指定基团不带有取代基。
术语“任选地被…….所取代”,可以与术语“未取代或被…..所取代”交换使用,即所述结构是未取代的或者被一个或多个本发明所述的取代基取代,本发明所述的取代基包括,但不限于H、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
1-6烷氧基、C
1-6卤代烷氧基、C
1-6烷硫基、C
1-6烷氨基、C
1-6卤代烷氨基、C
3-8环烷基、C
3-8环烷基C
1-6烷基、C
2-7杂环基、C
2-7杂环基C
1-6烷基、C
6-12芳基、C
6-12芳基C
1-6烷基、C
1-9杂芳基、C
1-9杂芳基C
1-6烷基、-C
1-6亚烷基-NR
fR
g、-NR
fR
g、-C(=O)OR
e、-C(=O)NR
fR
g、-C
1-6亚烷基-OP(=O)(OR
h)(OR
i)、-C
1-6亚烷基-C(=O)OR
i、-S(=O)
1-2R
4a、-C(=O)R
4a、-C(=O)OR
4b、-OS(=O)
1-2R
4a、-OC(=O)R
4a、-S(=O)
1-2OR
4b、-N(R
4b)C(=O)R
4a、-C(=O)NR
4bR
4c、-OC(=O)NR
4bR
4c、-NR
4bR
4c、-N(R
4b)S(=O)
1-2R
4a、-S(=O)
1-2NR
4bR
4c、或-N(R
4b)C(=O)NR
4bR
4c等等,其中R
e、R
f、R
g、R
h、R
i、R
4a、R
4b和R
4c均具有本发明所述定义。
另外,需要说明的是,除非以其他方式明确指出,在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换,均应做广义理解,其既可以是指在不同基团中,相同符号之间所表达的具体选项之间互相不影响,也可以表示在相同的基团中,相同符号之间所表达的具体选项之间互相不影响。
在本说明书的各部分,本发明公开化合物的取代基按照基团种类或范围公开。特别指出,本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如,术语“C
1-6烷基”特别指独立公开的甲基、乙基、C
3烷基、C
4烷基、C
5烷基和C
6烷基。
在本发明的各部分,描述了连接取代基。当所述结构清楚地需要连接基团时,针对所述基团所列举的马库什变量应理解为连接基团。例如,如果所述结构需要连接基团并且针对所述变量的马库什基团定义列举了“烷基”或“芳基”,则应理解,所述“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
本发明使用的术语“烷基”或“烷基基团”,表示含有1至20个碳原子,饱和的直链或支链一价烃基基团,其中,所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。除非另外详细说明,烷基基团含有1-20个碳原子。在一实施方案中,烷基基团含有1-12个碳原子;在另一实施方案中,烷基基团含有1-6个碳原子;在又一实施方案中,烷基基团含有1-4个碳原子;还在一实施方案中,烷基基团含有1-3个碳原子。所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。
烷基基团的实例包含,但并不限于,甲基(Me、-CH
3),乙基(Et、-CH
2CH
3),正丙基(n-Pr、-CH
2CH
2CH
3),异丙基(i-Pr、-CH(CH
3)
2),正丁基(n-Bu、-CH
2CH
2CH
2CH
3),异丁基(i-Bu、-CH
2CH(CH
3)
2),仲丁基(s-Bu、-CH(CH
3)CH
2CH
3),叔丁基(t-Bu、-C(CH
3)
3),正戊基(-CH
2CH
2CH
2CH
2CH
3),2-戊基(-CH(CH
3)CH
2CH
2CH
3),3-戊基(-CH(CH
2CH
3)
2),2-甲基-2-丁基(-C(CH
3)
2CH
2CH
3),3-甲基-2-丁基(-CH(CH
3)CH(CH
3)
2),3-甲基-1-丁基(-CH
2CH
2CH(CH
3)
2),2-甲基-1-丁基(-CH
2CH(CH
3)CH
2CH
3),正己基(-CH
2CH
2CH
2CH
2CH
2CH
3),2-己基(-CH(CH
3)CH
2CH
2CH
2CH
3),3-己基(-CH(CH
2CH
3)(CH
2CH
2CH
3)),2-甲基-2-戊基(-C(CH
3)
2CH
2CH
2CH
3),3-甲基-2-戊基(-CH(CH
3)CH(CH
3)CH
2CH
3),4-甲基-2-戊基(-CH(CH
3)CH
2CH(CH
3)
2),3-甲基-3-戊基(-C(CH
3)(CH
2CH
3)
2),2-甲基-3-戊基(-CH(CH
2CH
3)CH(CH
3)
2),2,3-二甲基-2-丁基(-C(CH
3)
2CH(CH
3)
2),3,3-二甲基-2-丁基(-CH(CH
3)C(CH
3)
3),正庚基,正辛基,等等。
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基,其中至少有一个不饱和位点,即有一个碳-碳sp
2双键,其包括“顺”和“反”的定位,或者“E”和“Z”的定位。在一实施方案中,烯基基团包含2-8个碳原子;在另一实施方案中,烯基基团包含2-6个碳原子;在又一实施方案中,烯基基团包含2-4个碳原子。烯基基团的实例包括,但并不限于,乙烯基(-CH=CH
2)、烯丙基(-CH
2CH=CH
2)等等。所述烯基基团可以任选地被一个或多个本发明描述的取代基所取代。
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基,其中至少有一个不饱和位点,即有一个碳-碳sp三键。在一实施方案中,炔基基团包含2-8个碳原子;在另一实施方案中,炔基基团包含2-6个碳原子;在又一实施方案中,炔基基团包含2-4个碳原子。炔基基团的实例包括,但并不限于,乙炔基(-C≡CH)、炔丙基(-CH
2C≡CH)、1-丙炔基(-C≡C-CH
3)等等。所述炔基基团可以任选地被一个或多个本发明描述的取代基所取代。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连,其中烷基基团具有如本发明所述的定义。除非另外详细说明,所述烷氧基基团含有1-12个碳原子。在一实施方案中,烷氧基基团含有1-6个碳原子;在另一实施方案中,烷氧基基团含有1-4个碳原子;在又一实施方案中,烷氧基基团含有1-3个碳原子。 所述烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。
烷氧基基团的实例包括,但并不限于,甲氧基(MeO、-OCH
3),乙氧基(EtO、-OCH
2CH
3),1-丙氧基(n-PrO、n-丙氧基、-OCH
2CH
2CH
3),2-丙氧基(i-PrO、i-丙氧基、-OCH(CH
3)
2),1-丁氧基(n-BuO、n-丁氧基、-OCH
2CH
2CH
2CH
3),2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH
2CH(CH
3)
2),2-丁氧基(s-BuO、s-丁氧基、-OCH(CH
3)CH
2CH
3),2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH
3)
3),1-戊氧基(n-戊氧基、-OCH
2CH
2CH
2CH
2CH
3),2-戊氧基(-OCH(CH
3)CH
2CH
2CH
3),3-戊氧基(-OCH(CH
2CH
3)
2),2-甲基-2-丁氧基(-OC(CH
3)
2CH
2CH
3),3-甲基-2-丁氧基(-OCH(CH
3)CH(CH
3)
2),3-甲基-l-丁氧基(-OCH
2CH
2CH(CH
3)
2),2-甲基-l-丁氧基(-OCH
2CH(CH
3)CH
2CH
3),等等。
术语“卤代烷基”或“卤代烷氧基”表示烷基、或烷氧基基团被一个或多个卤素原子所取代,这样的实例包含,但并不限于,三氟甲基、三氟乙基、2,2,3,3-四氟丙基、三氟甲氧基、三氟乙氧基等。
本发明使用的术语“羟烷基”或“羟基烷基”表示烷基基团被一个或多个羟基基团所取代,其中烷基基团具有如本发明所述的定义,这样的实例包括,但并不限于羟乙基,2-羟基丙基,羟甲基等。
本发明使用的术语“环烷基”,除非另有说明,是指一价饱和或部分不饱和(但非芳香族)的单环或多环烃。在一些实施方案,所述环烷基基团可以是桥接的或非桥接的、螺环的或非螺环的、和/或稠合的或非稠合的双环基团。在一些实施方案,所述环烷基基团包括3-10个碳原子,即C
3至C
10环烷基。在一些实施方案,所述环烷基具有3-15(C
3-15)、3-10(C
3-10)、或3-7(C
3-7)个碳原子。在一些实施方案,所述环烷基基团是单环或双环。在一些实施方案,所述环烷基基团是单环。在一些实施方案,所述环烷基基团是双环。在一些实施方案,所述环烷基基团是三环。在一些实施方案,所述环烷基基团是完全饱和的。在一些实施方案,所述环烷基基团是部分饱和的。在一些实施方案,所述环烷基基团是环丙基、环丁基、环戊基、环己基、环庚基、双环[2.1.1]己基、双环[2.2.1]庚基、十氢萘基、或金刚烷基。当环烷基被取代时,其可在任一环上,即在由环烷基包含的任何芳香环或非芳香环上,可独立地被一个或多个本发明所描述的取代基所取代。
术语“杂环基”和“杂环”在此处可交换使用,除非另有说明,是指包含至少一个非芳香环的一价单环非芳香环体系和/或多环体系;其中所述非芳香单环原子中的一个或多个(在某些实施方案,1、2、3或4个)是独立地选自O、S(O)
0-2和N的杂原子,和所述其余环原子均为碳原子;和其中所述多环体系的环原子中的一个或多个(在某些实施方案,1、2、3或4个)是独立地选自O、S(O)
0-2和N的杂原子,和所述其余环原子均为碳原子。在一些实施方案,所述杂环包含1或2个杂原子,所述杂原子均为氮原子。在一些实施方案,所述杂环基是多环的并且在非芳香环中包含一个杂原子,或者在芳香环中包含一个杂原子,或者在芳香环中包含两个杂原子,或者包含两个杂原子其中一个在芳香环中,而另一个在非芳香环中。在一些实施方案,所述杂环基基团具有3-20、3-15、3-10、3-8、4-7、或5-6个环原子。在一些实施方案,所述杂环基是单环、双环、三环、或四环体系。在一些实施方案,所述杂环基基团可以是桥接的或非桥接的、螺环的或非螺环的、和/或稠合的或非稠合的双环基团。一个或多个氮原子和硫原子可任选地被氧化,一个或多个氮原子可任选地被季铵化,一个或多个碳原子可任选地被
替换。一些环可以是部分或完全饱和的,或者是芳香族的,条件是杂环是非完全芳香性的。所述单环杂环和多环杂环可在任何导致稳定化合物的杂原子或碳原子上与所述主结构连接。所述多环杂环基可通过其任一环,包括任何芳香环或非芳香环,而不管所述环是否含有杂原子,连接至所述主结构上。在一些实施方案,杂环基为“杂环烷基”,其为1)如本发明所述的含有至少一个环杂原子的饱和或部分不饱和(但非芳香族)一价单环基团,或2)饱和或部分不饱和(但非芳香族)一价双环基团或三环基团,其中至少一个环含有至少一个如本发明所述的杂原子。当杂环基和杂环烷基被取代时,其可在任一环上,即在由杂环基和杂环烷基所包含的任何芳香环或非芳香环上被取代。在一些实施方案,此类杂环基包括,但不限于,环氧乙烷基、氮杂环丁基,氧杂环丁基,硫杂环丁基,吡咯烷基,2-吡咯啉基,3-吡咯啉基,吡唑啉基,吡唑烷基,咪唑啉基,咪唑烷基,四氢呋喃基,二氢呋喃基,四氢噻吩基,二氢噻吩基,1,3-二氧环戊基,二硫环戊基,四氢吡喃基,二氢吡喃基,2H-吡喃基,4H-吡喃基,四氢噻喃基,哌啶基,吗啉基,硫代吗啉基,哌嗪基,二噁烷基,二噻烷基,噻噁烷基,高哌嗪基,高哌啶基,氧杂环庚烷基,硫杂环庚烷基,氧氮杂
基,二氮杂
基,硫氮杂
基, 苯并二噁烷基,苯并二氧杂环戊烯基,苯并呋喃酮基,苯并吡喃酮基,苯并吡喃基,二氢苯并呋喃基,苯并四氢噻吩基,苯并噻喃基,苯并噁嗪基,β-咔啉基,苯并二氢吡喃基,色酮基,噌啉基,香豆素基,十氢喹啉基,十氢异喹啉基,二氢苯并异噻嗪基,二氢苯并异噁嗪基,二氢呋喃基,二氢异吲哚基,二氢吡喃基,二氢吡唑基,二氢吡嗪基,二氢吡啶基,二氢嘧啶基,二氢吡咯基,二氧戊环基,1,4-二噻喃基,呋喃酮基,咪唑烷基,2,4-二氧-咪唑烷基,咪唑啉基,吲哚啉基,2-氧-吲哚啉基,异苯并四氢呋喃基,异苯并四氢噻吩基,异苯并二氢吡喃基,异香豆素基,异二氢吲哚基(异吲哚啉基),1-氧-异二氢吲哚基,1,3-二氧-异二氢吲哚基,异噻唑烷基,异噁唑烷基,3-氧-异噁唑烷基,吗啉基,3,5-二氧-吗啉基,八氢吲哚基,八氢异吲哚基,1-氧-八氢异吲哚基,1,3-二氧-六氢异吲哚基,噁唑烷酮基,噁唑烷基,环氧乙烷基,哌嗪基,2,6-二氧-哌嗪基,哌啶基,2,6-二氧-哌啶基,4-哌啶酮基,2-氧吡咯烷基,2,5-二氧吡咯烷基,奎宁环基,四氢异喹啉基,3,5-二氧-硫代吗啉基,噻唑烷基,2,4-二氧-噻唑烷基,四氢喹啉基,吩噻嗪基,吩噁嗪基,氧杂蒽基和1,3,5-三硫杂环己烷基。杂环基中-CH
2-基团被-C(=O)-替代的实例包括,但不限于,2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基。杂环基中硫原子被氧化的实例包括,但不限于,环丁砜基、1,1-二氧代硫代吗啉基。所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
在一实施方案,杂环基为3-8个原子组成的杂环基,是指包含3-8个环原子的饱和或部分不饱和的单环,其中至少一个环原子选自氮、硫和氧原子。除非另外说明,3-8个原子组成的杂环基可以是碳基或氮基,且-CH
2-基团可以任选地被-C(=O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。3-8个原子组成的杂环基的实例包括,但不限于:氮杂环丁基,氧杂环丁基,硫杂环丁基,吡咯烷基,2-吡咯啉基,3-吡咯啉基,吡唑啉基,吡唑烷基,咪唑啉基,咪唑烷基,四氢呋喃基,二氢呋喃基,四氢噻吩基,二氢噻吩基,1,3-二氧环戊基,二硫环戊基,四氢吡喃基,二氢吡喃基,2H-吡喃基,4H-吡喃基,四氢噻喃基,哌啶基,吗啉基,硫代吗啉基,哌嗪基,二噁烷基,二噻烷基,噻噁烷基,高哌嗪基,高哌啶基,氧杂环庚烷基,硫杂环庚烷基,氧氮杂
基,二氮杂
基,硫氮杂
基。杂环基中-CH
2-基团被-C(=O)-替代的实例包括,但不限于,2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基。杂环基中硫原子被氧化的实例包括,但不限于,环丁砜基、1,1-二氧代硫代吗啉基。所述的3-8个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
在一实施方案,杂环基为3-6个原子组成的杂环基,是指包含3-6个环原子的饱和或部分不饱和的单环,其中至少一个环原子选自氮、硫和氧原子。除非另外说明,3-6个原子组成的杂环基可以是碳基或氮基,且-CH
2-基团可以任选地被-C(=O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。所述的3-6个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
在另一实施方案,杂环基为5-6个原子组成的杂环基,是指包含5-6个环原子的饱和或部分不饱和的单环,其中至少一个环原子选自氮、硫和氧原子。除非另外说明,5-6个原子组成的杂环基可以是碳基或氮基,且-CH
2-基团可以任选地被-C(=O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。5-6个原子组成的杂环基的实例包括,但不限于:吡咯烷基,2-吡咯啉基,3-吡咯啉基,吡唑啉基,吡唑烷基,咪唑啉基,咪唑烷基,四氢呋喃基,二氢呋喃基,四氢噻吩基,二氢噻吩基,1,3-二氧环戊基,二硫环戊基、2-氧代吡咯烷基、氧代-1,3-噻唑烷基、环丁砜基、四氢吡喃基,二氢吡喃基,2H-吡喃基,4H-吡喃基,四氢噻喃基,哌啶基,吗啉基,硫代吗啉基,哌嗪基,二噁烷基,二噻烷基,噻噁烷基、2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基、1,1-二氧代硫代吗啉基。所述的5-6个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
术语“环烷基烷基”表示烷基基团可被一个或多个环烷基基团所取代,其中环烷基和烷基具有如本发明所述定义,这样的实例包括,但并不限于,环丙基甲基、环丙基乙基、环丙基丙基、环丁基甲基、环丁基乙基、环戊基甲基,环戊基乙基、环戊基丙基、环己基乙基等。
术语“杂环基烷基”包括杂环基取代的烷基;术语“杂环基烷氧基”包括杂环基取代的烷氧基,其中氧原子与分子的其余部分相连;术语“杂环基烷氨基”包括杂环基取代的烷氨基,其中氮原子与分子的其余部分相连。其中杂环基、烷基、烷氧基和烷氨基均具有如本发明所述定义,这样的实例包括,但并不限于,氮 杂环丁烷-1-基甲基、氮杂环丁烷-1-基乙基、氮杂环丁烷-1-基丙基、吡咯-1-基甲基,吡咯-1-基乙基、吡咯-1-基丙基、吗啉-4-基乙基、吗啉-4-基乙氧基、哌嗪-4-基乙氧基、哌啶-4-基乙基氨基等。
术语“烷硫基”包括C
1-10直链或支链的烷基连接到二价的硫原子上。其中一些实施方案是,烷硫基是较低级的C
1-3烷硫基,这样的实例包括,但并不限于甲硫基(CH
3S-)。
术语“卤代烷硫基”包括C
1-10的卤代烷基连接到二价硫原子上。其中一些实施方案是,卤代烷硫基是较低级的C
1-3卤代烷硫基,这样的实例包括,但并不限于三氟甲硫基。术语“稠合双环”,“稠环”,“稠合双环基”,“稠环基”表示饱和或不饱和的稠环体系体系,涉及非芳香族的双环体系,如式(a1)所示,即环B与环B’共有一个键。这样的体系可以包含独立的或共轭的不饱和状态,但其核心结构不包含芳香环或芳杂环(但是芳香族可以作为其上的取代基)。稠合双环中的每一个环要么是碳环要么是杂脂环族,这样的实例包括,但并不限于,六氢-呋喃并[3,2-b]呋喃,2,3,3a,4,7,7a-六氢-1H-茚,7-氮杂双环[2.3.0]庚烷,稠合双环[3.3.0]辛烷,稠合双环[3.1.0]己烷,这些都包含在稠合双环之内。并且所述稠合双环基可以任选地被一个或多个本发明描述的取代基所取代。
术语“稠合杂双环基”表示饱和或不饱和的稠环体系或桥环体系,涉及非芳香族的双环体系或桥环体系。这样的体系可以包含独立的或共轭的不饱和状态,但其核心结构不包含芳香环或芳杂环(但是芳香族可以作为其上的取代基)。且至少一个环体系包含一个或多个杂原子,其中每一个环体系包含3-7元环,即包含1-6个碳原子和选自N,O,P,S的1-3个杂原子,在此S或P任选地被一个或多个氧原子所取代得到例如SO,SO
2,PO,PO
2的基团,这样的实例包括,但并不限于六氢-1H-呋喃并[3,2-b]呋喃,六氢-1H-呋喃并[3,4-c]吡咯,7-氮杂双环[2.3.0]庚烷,2-氮杂双环[2.2.1]庚烷,八氢吡咯[3,2-b]吡咯,八氢吡咯[3,4-c]吡咯,八氢-1H-吡咯[3,2-b]吡啶等。并且所述稠合杂双环基可以任选地被一个或多个本发明描述的取代基所取代。
术语“螺环基”,“螺环”,“螺双环基”,“螺双环”表示一个环起源于另一个环上特殊的环状碳。例如,环A和环B在两个饱和的环体系中共享一个碳原子,则被称为“螺环”。螺环里面的每一个环要么是碳环要么是杂脂环族。这样的实例包括,但并不限于2,7-二氮杂螺[4.4]壬烷-2-基,7-氧-2-氮杂螺[4.5]癸烷-2-基,4-氮杂螺[2.4]庚烷-5-基,4-氧杂螺[2.4]庚烷-5-基,5-氮杂螺[2.4]庚烷-5-基,螺[2.4]庚烷基,螺[4.4]壬烷基,7-羟基-5-氮杂螺[2.4]庚烷-5-基等。并且所述螺双环基可以任选地被一个或多个本发明描述的取代基所取代。
术语“螺杂双环基”表示一个环起源于另一个环上特殊的环状碳。例如,如上面所描述的,环A和环B在两个饱和的环体系中共享一个碳原子,则被称为“螺环”。且至少一个环体系包含一个或多个杂原子,其中每一个环体系包含3-7元环,即包含1-6个碳原子和选自N,O,P,S的1-3个杂原子,在此S或P任选地被一个或多个氧原子所取代得到例如SO,SO
2,PO,PO
2的基团,这样的实例包括,但并不限于4-氮杂螺[2.4]庚烷-5-基,4-氧杂螺[2.4]庚烷-5-基,5-氮杂螺[2.4]庚烷-5-基,7-羟基-5-氮杂螺[2.4]庚烷-5-基,2,6-二氮杂螺[3.3]庚烷,2,6-二氮杂螺[3.4]辛烷,1,6-二氮杂螺[3.4]辛烷,2,7-二氮杂螺[3.5]壬烷,1,7-二氮杂螺[3.5]壬烷,3,9-二氮杂螺[5.5]十一烷,2-氧杂-6-氮杂螺[3.3]庚烷-6基等。并且所述螺杂双环基可以任选地被一个或多个本发明描述的取代基所取代。
本发明使用的术语“桥环基”表示饱和或不饱和的桥环体系,涉及非芳香族的桥环体系,如式(a2)所示,即环A1与环A2共有一个烷链或一个杂烷链,其中j为1,2,3或4,和Y
5具有本发明所述定义。这样的体系可以包含独立的或共轭的不饱和状态,但其核心结构不包含芳香环或芳杂环(但是芳香族可以作为其上的取代基)。桥接环中的每一个环要么是碳环要么是杂脂环族,这样的实例包括,但并不限于,双环[2.2.1] 庚烷,2-氮杂双环[2.2.1]庚烷,1,2,3,4,4a,5,8,8a-八氢萘,这些都包含在稠合双环或桥环的体系之内。并且所述桥环基可以任选地被一个或多个本发明描述的取代基所取代。
术语“桥杂环基”表示饱和或不饱和的桥环体系,涉及非芳香族的桥环体系。这样的体系可以包含独立的或共轭的不饱和状态,但其核心结构不包含芳香环或芳杂环(但是芳香族可以作为其上的取代基)。且至少一个环体系包含一个或多个杂原子,其中每一个环体系包含3-7元环,即包含1-6个碳原子和选自N,O,P,S的1-3个杂原子,在此S或P任选地被一个或多个氧原子所取代得到例如SO,SO
2,PO,PO
2的基团,这样的实例包括,但并不限于2-氮杂双环[2.2.1]庚烷,(1R,5S)-3,6-二氮杂双环[3.1.1]庚烷,2,5-二氮杂双环[2.2.1]庚烷,(1R,5S)-8-氮杂双环[3.2.1]辛烷等。并且所述桥杂环基可以任选地被一个或多个本发明描述的取代基所取代。
如本发明所描述的,环体系中有一个不定连接点与分子其余部分相连,如式(a3)或(a4)所示,表示所述连接点可以是环体系的各个环上任一个氢原子被取代后可适合与分子其余部分相连的附着点。
像本发明所描述的,取代基画一个键连接到中心的环上形成的环体系(如下所示)代表取代基可在任一环上任何可取代的位置取代。例如,式b代表A环或B环上任何可能被取代的位置均可被取代,如式c、d、e、f、g、h、i、j、k、l、m、n、o、p、q等所示。
术语“n个原子组成的”,其中n是整数,典型地描述分子中成环原子的数目,在所述分子中成环原子的数目是n。例如,哌啶基是6个原子组成的杂环烷基,而1,2,3,4-四氢萘是10个原子组成的环烷基基团。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“叠氮基”或“N
3”表示一个叠氮结构。这种基团可以与其他基团相连接,例如,可与一个甲基相连形成叠氮甲烷(MeN
3),或者与一个苯基相连形成叠氮苯(PhN
3)。
本发明使用的术语“芳基”,除非另有说明,是指包含至少一个芳环的一价C
6-C
14碳环体系,其中所述芳环体系是单环、二环、或三环。所述芳基可通过其任何环即任何芳香环或非芳香环连接至主结构上。在一些实施方案,芳基是苯基、萘基、二环[4.2.0]辛-1,3,5-三烯基、茚满基、芴基、或四氢萘基。当芳基被取 代时,其可在任何环上即在由芳基包含的任何芳香环或非芳香环上被取代。在一些或任一实施方案,芳基是苯基、萘基、四氢萘基、芴基、或茚满基。所述芳基基团可以独立任选地被一个或多个本发明所描述的取代基所取代。
本发明使用的术语“芳烷基”或“芳基烷基”,除非另有说明,是指被如本发明所定义的一个或两个芳基基团取代的烷基基团,其中所述烷基基团是与分子其余部分连接的点。在一些实施方案,芳烷基是苯甲基、苯乙-1-基、苯乙-2-基、二苯基甲基、2,2-二苯基乙基、3,3-二苯基丙基、或3-苯基丙基;所述苯甲基、苯乙-1-基、苯乙-2-基、二苯基甲基、2,2-二苯基乙基、3,3-二苯基丙基、和3-苯基丙基各自任选地在环上被一个或多个本发明所描述的取代基所取代。
本发明使用的术语“杂芳基”,除非另有说明,是指一价单环或多环芳香基团,其中所述至少一个(在某些实施方案,1、2、3或4个)环原子是独立地选自所述环中的O、S(O)
0-2和N的杂原子。所述杂芳基基团是通过环体系中的任何原子,其化合价规则允许情况下,连接至分子其余部分。在一些实施方案,杂芳基基团的每个环可含有1或2个O原子、1或2个S原子、和/或1至4个N原子、或其组合,条件是每个环中杂原子的总数为4或更少,以及每个环含有至少1个碳原子。在一些实施方案,所述杂芳基具有5-20、5-15、或5-10个环原子。当杂芳基被取代时,其可在任一环上进行取代。在某些实施方案,单环杂芳基基团包括但不限于,呋喃基,咪唑基,异噻唑基,异噁唑基,噁二唑基,噁唑基,吡嗪基,吡唑基,哒嗪基,吡啶基,嘧啶基,吡咯基,噻二唑基,噻唑基,噻吩基,四唑基,三嗪基和三唑基。在某些实施方案,双环杂芳基基团包括,但不限于,苯并呋喃基,苯并咪唑基,苯并异噁唑基,苯并吡喃基,苯并噻二唑基,苯并噻唑基,苯并噻吩基,苯并三唑基,苯并噁唑基,呋喃并吡啶基,咪唑并吡啶基,咪唑并噻唑基,吲嗪基,吲哚基,吲唑基,异苯并呋喃基,异苯并噻吩基,异吲哚基,异喹啉基,异噻唑基,萘啶基,噁唑并吡啶基,酞嗪基,蝶啶基,嘌呤基,吡啶并吡啶基,吡咯并吡啶基,喹啉基,喹喔啉基,喹唑啉基,噻二唑并嘧啶基和噻吩并吡啶基。在某些实施方案,三环杂芳基基团包括,但不限于,吖啶基,苯并吲哚基,咔唑基,二苯并呋喃基,咟啶基,菲咯啉基,菲啶基和吩嗪基。在一些或任一实施方案,杂芳基是吲哚基,呋喃基,吡啶基,嘧啶基,咪唑基或吡唑基;其各自任选地可在任一环上被一个或多个本发明所描述的取代基所取代。
本发明使用的术语“杂芳基烷基”,除非另有说明,是指被如本发明所定义的一个或两个杂芳基基团取代的烷基基团,其中所述烷基基团是与分子其余部分连接的点。所述杂芳基烷基的实例包括,但并不限于咪唑-2-甲基、噻唑-2-甲基、呋喃-2-乙基、吲哚-3-甲基等;其各自任选地可在任一环上被一个或多个本发明所描述的取代基所取代。
术语“烷基氨基”包括“N-烷基氨基”和“N,N-二烷基氨基”,其中氨基基团分别独立地被一个或两个烷基基团所取代。其中一些实施例是,烷基氨基是一个或两个C
1-6烷基连接到氮原子上的较低级的烷基氨基基团。另外一些实施例是,烷基氨基是C
1-3的较低级的烷基氨基基团。合适的烷基氨基基团可以是单烷基氨基或二烷基氨基,这样的实例包括,但并不限于,N-甲氨基,N-乙氨基,N,N-二甲氨基,N,N-二乙氨基等等。
术语“氨基烷基”包括被一个或多个氨基所取代的C
1-10直链或支链烷基基团。其中一些实施例是,氨基烷基是被一个或多个氨基基团所取代的C
1-6“较低级的氨基烷基”,另一些实施例是,氨基烷基是被一个或多个氨基基团所取代的C
1-4“较低级的氨基烷基”,这样的实例包括,但并不限于,氨甲基,氨乙基,氨丙基,氨丁基和氨己基。
术语“氰基烷基”包括被一个或多个氰基所取代的C
1-10直链或支链烷基基团。其中一些实施例是,氰基取代的烷基是被一个或多个氰基基团所取代的C
1-6“较低级的氰基烷基”,另一些实施例是,氰基取代的烷基是被一个或多个氰基基团所取代的C
1-4“较低级的氰基烷基”,这样的实例包括,但并不限于,CNCH
2-、CNCH
2CH
2-、CNCH
2CH
2CH
2-、CNCH
2CHCNCH
2-等。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的,如文献:S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括,但并不限于,与氨基基团反应形成的无机酸盐如盐酸盐,氢溴酸盐,磷酸盐,硫酸盐,高氯酸盐,和有机酸盐如乙酸盐,草酸盐,马来酸盐,酒石酸盐,柠檬酸盐,琥珀酸盐,丙二酸盐,或通过书籍文献上所记载的其他方法如 离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐,藻酸盐,抗坏血酸盐,天冬氨酸盐,苯磺酸盐,苯甲酸盐,重硫酸盐,硼酸盐,丁酸盐,樟脑酸盐,樟脑磺酸盐,环戊基丙酸盐,二葡萄糖酸盐,十二烷基硫酸盐,乙磺酸盐,甲酸盐,反丁烯二酸盐,葡庚糖酸盐,甘油磷酸盐,葡萄糖酸盐,半硫酸盐,庚酸盐,己酸盐,氢碘酸盐,2-羟基-乙磺酸盐,乳糖醛酸盐,乳酸盐,月桂酸盐,月桂基硫酸盐,苹果酸盐,丙二酸盐,甲磺酸盐,2-萘磺酸盐,烟酸盐,硝酸盐,油酸盐,棕榈酸盐,扑酸盐,果胶酸盐,过硫酸盐,3-苯基丙酸盐,苦味酸盐,特戊酸盐,丙酸盐,硬脂酸盐,硫氰酸盐,对甲苯磺酸盐,十一酸盐,戊酸盐,等等。通过与适当的碱反应得到的盐包括碱金属,碱土金属,铵和N
+(C
1-C
4烷基)
4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠,锂,钾,钙,镁,等等。药学上可接受的盐进一步包括适当的、无毒的铵,季铵盐和抗平衡离子形成的胺阳离子,如卤化物,氢氧化物,羧化物,硫酸化物,磷酸化物,硝酸化物,C
1-8磺酸化物和芳香磺酸化物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括,但并不限于,水,异丙醇,乙醇,甲醇,二甲亚砜,乙酸乙酯,乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
当所述溶剂为水时,可以使用术语“水合物”。在一些实施例中,一个本发明化合物分子可以与一个水分子相结合,比如一水合物;在另外一些实施例中,一个本发明化合物分子可以与多于一个的水分子相结合,比如二水合物,还有一些实施例中,一个本发明化合物分子可以与少于一个的水分子相结合,比如半水合物。应注意,本发明所述的水合物保留有非水合形式的所述化合物的生物有效性。
如本发明所使用的术语“治疗”任何疾病或病症,在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中,“治疗”指缓和或改善至少一种身体参数,包括可能不为患者所察觉的身体参数。在另一些实施方案中,“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案,“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
发明内容
本发明提供了一类新的TGF-β抑制剂,可用于制备预防和/或治疗哺乳动物有关TGF-β介导或涉及TGF-β的疾病、病症、或病况的药物。本发明还提供了制备本发明所述化合物的方法,包含这些化合物的药物组合物,以及使用这些化合物和包含这些化合物的药物组合物预防和/或治疗哺乳动物尤其是人类的上述疾病、病症、或病况的方法。
一方面,本发明提供了一种可作为TGF-β抑制剂,特别是可作为TGFβR-1抑制剂的咪唑类化合物,其如式(I)所示:
或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、区域异构体、氮氧化物、或混合物,其中,
X
1是N、或-C(R
a)-;
X
2是N、或-C(R
2)-;条件是X
1和X
2不同时为碳原子;
W是
X
3、X
4和X
5各自独立地为-C(R
3)-、或N;
X
6是O、S、或-N(R
3)-;
其中所述W任选地被0、1、2、3、4或5个R
3取代;
Z是
Y
1、Y
2、Y
3和Y
4各自独立地为-C(R
4)-、或N;
各Y
5分别独立地为O、S、或-N(R
4)-;
其中所述Z任选地被0、1、2、3、4或5个R
4取代;
R
1、R
2和R
a各自独立地为H、-(C(R
c)(R
d))
m-L-R
5、C
1-6烷基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
1-6烷氧基、C
1-6卤代烷氧基、C
1-6烷硫基、或C
1-6烷氨基,条件是R
1和R
2不同时为H;或者,R
1和R
2同与之连接的碳原子一起形成5-8个原子组成的碳环或杂环,或R
2和R
a同与之连接的原子一起形成5-8个原子组成的碳环或杂环,其中所述5-8个原子组成的碳环或杂环任选地被0、1、2、3或4个R
6取代;
L不存在,或L是-N(R
b)-、O、S、-C(=O)-或-C(=O)-NH-;
R
b是H、C
1-6烷基、C
1-6羟基烷基、C
1-6卤代烷基、或C
1-6氰基烷基;
各R
c和R
d在每次出现时,分别独立地为H、C
1-6烷基、C
1-6羟基烷基、或C
1-6卤代烷基;或者,R
c和R
d同与之连接的碳原子一起形成3-6个原子组成的碳环或杂环;
各R
3在每次出现时,分别独立地为H、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
1-6烷氧基、C
1-6卤代烷氧基、C
1-6烷硫基、C
1-6烷氨基、C
1-6卤代烷氨基、C
3-8环烷基、C
3-8环烷基C
1-6烷基、C
2-7杂环基、或C
2-7杂环基C
1-6烷基;
各R
4在每次出现时,分别独立地为H、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
1-6烷氧基、C
1-6卤代烷氧基、C
1-6烷硫基、C
1-6烷氨基、C
1-6卤代烷氨基、C
1-6亚烷基C
2-7杂环基、-S(=O)
1-2R
4a、-C(=O)R
4a、-C(=O)OR
4b、-OS(=O)
1-2R
4a、-OC(=O)R
4a、-S(=O)
1-2OR
4b、-N(R
4b)C(=O)R
4a、-C(=O)NR
4bR
4c、-OC(=O)NR
4bR
4c、-NR
4bR
4c、-N(R
4b)S(=O)
1-2R
4a、-S(=O)
1-2NR
4bR
4c、或-N(R
4b)C(=O)NR
4bR
4c;
R
5是H、C
1-6烷基、C
3-8环烷基、C
3-8环烷基C
1-6烷基、C
2-7杂环基、C
2-7杂环基C
1-6烷基、C
6-12芳基、C
6-12芳基C
1-6烷基、C
1-9杂芳基、C
1-9杂芳基C
1-6烷基、C
5-12螺双环基、C
5-12螺杂双环基、C
5-12稠合双环基、或C
5-12稠合杂双环基;其中R
5任选地被0、1、2、3、4或5个R
5a取代;
各R
5a在每次出现时,分别独立地为H、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
1-6烷氧基、C
1-6卤代烷氧基、C
1-6烷硫基、C
1-6烷氨基、C
1-6卤代烷氨基、C
2-7杂环基C
1-6烷基、-C
1-6亚烷基-NR
fR
g、-NR
fR
g、-C(=O)OR
e、或-C(=O)NR
fR
g;
各R
6在每次出现时,分别独立地为H、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
1-6烷氧基、C
1-6卤代烷氧基、C
1-6烷硫基、C
1-6烷氨基、C
1-6卤代烷氨基、C
3-8环烷基、C
3-8环烷基C
1-6烷基、C
2-7杂环基、C
2-7杂环基C
1-6烷基、C
6-12芳基、C
6-12芳基C
1-6烷基、C
1-9杂芳基、C
1-9杂芳基C
1-6烷基、-C
1-6亚烷基-NR
fR
g、-NR
fR
g、-C(=O)OR
e、或-C(=O)NR
fR
g;
各R
4a、R
4b、R
4c、R
e、R
f和R
g在每次出现时,分别独立地为H、C
1-6烷基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
3-8环烷基、C
3-8环烷基C
1-6烷基、C
2-7杂环基、C
2-7杂环基C
1-6烷基、C
5-12螺双环基、C
5-12螺杂双环基、C
5-12稠合双环基、C
5-12稠合杂双环基、-C
1-6亚烷基-OP(=O)(OR
h)(OR
i)、或-C
1-6亚烷基-C(=O)OR
i;其中C
3-8环烷基、C
3-8环烷基C
1-6烷基、C
2-7杂环基、C
2-7杂环基C
1-6烷基、C
5-12螺双环基、C
5-12螺杂双环基、C
5-12稠合双环基、和C
5-12稠合杂双环基独立任选地被0、1、2、3或4个独立选自H、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
1-6烷氧基、C
1-6卤代烷氧基、C
1-6烷硫基、C
1-6烷氨基、和C
1-6卤代烷氨基的基团取代;
R
h和R
i各自独立地为H、或C
1-6烷基;和
m是0、1、2、3、或4。
在一些实施方案,本发明所述化合物具有式(II)所示结构:
其中,
t是0、1、2、3、4或5;和
n是0、1、2、3、4或5。
在一些实施方案,本发明所述化合物具有式(III)所示结构:
其中,
t是0、1、2、3、4或5。
在一些实施方案,其中W是
在一些实施方案,其中Z是
在一些实施方案,本发明所述化合物具有具有式(IV)所示结构:
其中,
L
1是-(C(R
c)(R
d))
m-;
t是0、1、2、3、4或5。
在一些实施方案,本发明所述化合物具有式(V)所示结构:
其中,
t是0、1、2、3、4或5;和
p是0、1、2、3或4。
在一些实施方案,其中,R
1和R
2各自独立地为H、-(C(R
c)(R
d))
m-L-R
5、C
1-4烷基、或C
1-4羟基烷基,条件是R
1和R
2不同时为H;或者,R
1和R
2同与之连接的碳原子一起形成5-6个原子组成的碳环或杂环,其中所述5-6个原子组成的碳环或杂环任选地被0、1、2、3或4个R
6取代。
在一些实施方案,其中,R
1和R
2各自独立地为H、-(C(R
c)(R
d))
m-L-R
5、甲基、乙基、n-丙基、异丙基、n-丁基、叔丁基、-CF
3、-CH
2CF
3、-OCF
3、-CH
2CN、-CH
2CH
2CN、-CH
2OH、-CH
2OH、或-CH
2CH
2OH,条件是R
1和R
2不同时为H;或者,R
1和R
2同与之连接的碳原子一起形成5-6个原子组成的碳环或杂环, 其中所述5-6个原子组成的碳环或杂环任选地被0、1、2、3或4个R
6取代。
在一些实施方案,其中,
各R
c和R
d在每次出现时,分别独立地为H、甲基、乙基;或者,R
c和R
d同与之连接的碳原子一起形成环丙基;
L不存在,或L是-N(R
b)-、O、S、-C(=O)-或-C(=O)-NH-;和
R
b是H、或C
1-3烷基。
在一些实施方案,其中,R
5是H、C
1-4烷基、C
3-6环烷基、C
3-6环烷基C
1-4烷基、C
3-6杂环基、C
3-6杂环基C
1-4烷基、C
6-12芳基、C
6-12芳基C
1-4烷基、C
1-9杂芳基、C
1-9杂芳基C
1-4烷基、C
5-12螺双环基、C
5-12螺杂双环基、C
5-12稠合双环基、或C
5-12稠合杂双环基;其中R
5任选地被0、1、2、3或4个R
5a取代。
在一些实施方案,其中,各R
5a在每次出现时,分别独立地为H、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-4烷基、C
2-4烯基、C
2-4炔基、C
1-4羟基烷基、C
1-4卤代烷基、C
1-4氨基烷基、C
1-4氰基烷基、C
1-4烷氧基、C
1-4卤代烷氧基、C
1-4烷氨基、C
3-6杂环基C
1-3烷基、-C
1-4亚烷基-NR
fR
g、-NR
fR
g、-C(=O)OR
e、或-C(=O)NR
fR
g。
在一些实施方案,其中,各R
5a在每次出现时,分别独立地为H、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、甲基、乙基、乙烯基、乙炔基、-CF
3、-OCF
3、-OCH
2CF
3、-OCH
3、-OCH
2CH
3、-CH
2-NR
fR
g、-NR
fR
g、-C(=O)NR
fR
g、
在一些实施方案,其中,各R
3在每次出现时,分别独立地为H、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-4烷基、C
1-4羟基烷基、C
1-4卤代烷基、C
1-4氰基烷基、C
1-4烷氧基、C
1-4卤代烷氧基、或C
3-6环烷基。
在一些实施方案,其中,各R
3在每次出现时,分别独立地为H、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、甲基、乙基、丙基、异丙基、丁基、或环丙基。
在一些实施方案,其中,各R
4在每次出现时,分别独立地为H、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-4烷基、C
1-4羟基烷基、C
1-4卤代烷基、C
1-4氨基烷基、C
1-4氰基烷基、C
1-4烷氧基、C
1-4卤代烷氧基、-C(=O)R
4a、-C(=O)OR
4b、-N(R
4b)C(=O)R
4a、或-C(=O)NR
4bR
4c。
在一些实施方案,其中,各R
4a、R
4b和R
4c分别独立地为H、C
1-4烷基、C
1-4羟基烷基、C
1-4卤代烷基、C
1-4氰基烷基、C
3-6环烷基、C
3-6环烷基C
1-4烷基、C
3-6杂环基、C
3-6杂环基C
1-4烷基、C
5-12螺双环基、C
5-12螺杂双环基、C
5-12稠合双环基、C
5-12稠合杂双环基、-C
1-4亚烷基-OP(=O)(OR
h)(OR
i)、或-C
1-4亚烷基 -C(=O)OR
i;其中C
3-6环烷基、C
3-6环烷基C
1-4烷基、C
3-6杂环基、C
3-6杂环基C
1-4烷基、C
5-12螺双环基、C
5-12螺杂双环基、C
5-12稠合双环基、和C
5-12稠合杂双环基独立任选地被0、1、2、3或4个独立选自H、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-4烷基、C
2-4烯基、C
2-4炔基、C
1-4羟基烷基、C
1-4卤代烷基、C
1-4氨基烷基、C
1-4氰基烷基、C
1-4烷氧基、C
1-4卤代烷氧基、C
1-4烷硫基、C
1-4烷氨基、和C
1-4卤代烷氨基的基团取代。
在一些实施方案,其中,
在一些实施方案,其中,R
e、R
f和R
g分别独立地为H、甲基、或乙基。
在一些实施方案,其中,R
h和R
i各自独立地为H、甲基、或乙基。
在一些实施方案,其中,X
1是N;
X
2是N、或-C(R
2)-;
W是
X
3、X
4和X
5各自独立地为-C(R
3)-、或N;
X
6是-N(R
3)-;
其中所述W任选地被0、1或2个R
3取代;
Z是
Y
1、Y
2、Y
3各自独立地为-C(R
4)-、或N;Y
4各自独立地为-C(R
4)-;
各Y
5分别独立地为S、或-N(R
4)-;
其中所述Z任选地被0、1或2个R
4取代;
R
1和R
2各自独立地为H、-(C(R
c)(R
d))
m-L-R
5、或C
1-6烷基,条件是R
1和R
2不同时为H;或者,R
1和R
2同与之连接的碳原子一起形成5-8个原子组成的碳环或杂环;
L不存在,或L是-N(R
b)-、O、或-C(=O)-NH-;
R
b是H、或C
1-6烷基;
各R
c和R
d在每次出现时,分别独立地为H、或C
1-6烷基;
各R
3在每次出现时,分别独立地为F、Cl、C
1-6烷基、或C
3-8环烷基;
各R
4在每次出现时,分别独立地为H、-CN、C
1-6烷基、-C
1-6亚烷基C
2-7杂环基、-C(=O)R
4a、或-C(=O)NR
4bR
4c;R
5是H、C
3-8环烷基、C
6-12芳基、C
1-9杂芳基、C
2-7杂环基、或C
5-12稠合杂双环基;其中R
5任选地被0、1、2、3、或4个R
5a取代;
各R
5a在每次出现时,分别独立地为F、Cl、Br、-OH、C
1-6烷基、C
1-6卤代烷基、C
2-6炔基、C
1-6烷氧基、C
1-6卤代烷氧基、C
2-7杂环基C
1-6烷基、-NR
fR
g、或-C(=O)NR
fR
g;
各R
4a在每次出现时,分别独立地为C
2-7杂环基,其中C
2-7杂环基独立任选地被0、或1个-OH、-NH
2、或C
1-6烷基取代;各R
4b、R
4c在每次出现时,分别独立地为H、C
1-6烷基、C
1-6羟基烷基、C
3-8环烷基、C
2-7杂环基、-C
1-6亚烷基-OP(=O)(OR
h)(OR
i)、或-C
1-6亚烷基-C(=O)OR
i,其中C
3-8环烷基独立任选地被0、或1个-OH取代;各R
f和R
g在每次出现时,分别独立地为H、或C
1-6烷基;
R
h、R
i各自独立地为H;和
m是0、1或2。
在一些实施方案,其中,X
1是N;
X
2是-C(R
2)-;
W是
X
3、X
4和X
5各自独立地为-C(R
3)-、或N;
其中所述W任选地被0、1或2个R
3取代;
Z是
Y
1、Y
2、Y
3各自独立地为-C(R
4)-、或N;Y
4各自独立地为-C(R
4)-;
各Y
5分别独立地为S、或-N(R
4)-;
其中所述Z任选地被0、1或2个R
4取代;
R
1和R
2各自独立地为H、-(C(R
c)(R
d))
m-L-R
5、或C
1-6烷基,条件是R
1和R
2不同时为H;或者,R
1和R
2同与之连接的碳原子一起形成5-8个原子组成的碳环或杂环;
L不存在,或L是-N(R
b)-、O、或-C(=O)-NH-;
R
b是H、或C
1-6烷基;
各R
c和R
d在每次出现时,分别独立地为H;
各R
3在每次出现时,分别独立地为F、Cl、或C
1-6烷基;
各R
4在每次出现时,分别独立地为H、-CN、C
1-6烷基、-C(=O)R
4a、或-C(=O)NR
4bR
4c;
R
5是H、C
3-8环烷基、C
6-12芳基、C
1-9杂芳基、C
2-7杂环基、或C
5-12稠合杂双环基;其中R
5任选地被0、1、2、3、或4个R
5a取代;
各R
5a在每次出现时,分别独立地为F、Cl、Br、-OH、C
1-6烷基、C
1-6卤代烷基、C
2-6炔基、C
1-6烷氧基、C
1-6卤代烷氧基、C
2-7杂环基C
1-6烷基、-NR
fR
g、或-C(=O)NR
fR
g;
各R
4a在每次出现时,分别独立地为C
2-7杂环基,其中C
2-7杂环基独立任选地被0、或1个-OH、或-NH
2取代;各R
4b、R
4c在每次出现时,分别独立地为H、C
1-6烷基、C
1-6羟基烷基、C
3-8环烷基、C
2-7杂环基、-C
1-6亚烷基-OP(=O)(OR
h)(OR
i)、或-C
1-6亚烷基-C(=O)OR
i,其中C
3-8环烷基独立任选地被0、或1个-OH取代;各R
f和R
g在每次出现时,分别独立地为H、或C
1-6烷基;
R
h、R
i各自独立地为H;和
m是0、1或2。
在一些实施方案,其中,X
1是N;
X
2是-C(R
2)-;
W是
X
3、X
4和X
5各自独立地为-C(R
3)-、或N;且X
3、X
4和X
5中的一个为N,其余为-C(R
3)-;
其中所述W任选地被0、1或2个R
3取代;
Z是
Y
1为-C(R
4)-、或N;Y
2、Y
4各自独立地为-C(R
4)-;Y
3为N;
各Y
5分别独立地为-N(R
4)-;
其中所述Z任选地被0、1或2个R
4取代;
R
1和R
2各自独立地为H、-(C(R
c)(R
d))
m-L-R
5、或C
1-6烷基,条件是R
1和R
2不同时为H;或者,R
1和R
2同与之连接的碳原子一起形成5-8个原子组成的碳环或杂环;
L不存在,或L是-N(R
b)-、O、或-C(=O)-NH-;
R
b是H、或C
1-6烷基;
各R
c和R
d在每次出现时,分别独立地为H;
各R
3在每次出现时,分别独立地为F、或C
1-6烷基;
各R
4在每次出现时,分别独立地为H、-C(=O)R
4a、或-C(=O)NR
4bR
4c;
R
5是C
3-8环烷基、C
6-12芳基、C
1-9杂芳基、或C
2-7杂环基;其中R
5任选地被0、1、2、3、或4个R
5a取代;
各R
5a在每次出现时,分别独立地为F、Cl、Br、C
1-6烷基、C
1-6卤代烷基、C
2-6炔基、C
1-6烷氧基、C
1-6卤代烷氧基、C
2-7杂环基C
1-6烷基、或-C(=O)NR
fR
g;
各R
4a在每次出现时,分别独立地为C
2-7杂环基,其中C
2-7杂环基独立任选地被0、或1个-OH、或-NH
2取代;各R
4b、R
4c在每次出现时,分别独立地为H、C
1-6烷基、C
1-6羟基烷基、或C
3-8环烷基,其中C
3-8环烷基独立任选地被0、或1个-OH取代;各R
f和R
g在每次出现时,分别独立地为H;和
m是0、或1。
在一些实施方案,其中,本发明所述化合物具有以下结构之一的化合物:
或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、区域异构体、氮氧化物、或混合物。
另一方面,本发明提供了一种药物组合物,所述药物组合物包含本发明所述的化合物或其药学上可接受的盐,以及药学上可接受的辅料、稀释剂或载体。
在一些实施方案,所述的药物组合物进一步包含附加治疗剂。
另一方面,本发明提供了一种使用本发明所述的化合物或本发明所述的药物组合物在制备用于预防和/或治疗TGF-β介导或涉及TGF-β的疾病、病症、或病况的药物中的用途。
在一些实施方案,所述疾病、病症、或病况是肺动脉高压、慢性肾病、急性肾病、伤口愈合、关节炎、骨质疏松症、肾病、充血性心力衰竭、溃疡、眼部病症、角膜损伤、糖尿病性肾病、神经功能受损、阿尔茨海默病、动脉粥样硬化、腹膜或皮下粘连、肾纤维化、肺纤维化、特发性肺纤维化、肝纤维化、乙型肝炎、丙型肝炎、由酒精诱导型肝炎、癌症、血色病、原发性胆汁性肝硬化、再狭窄、腹膜后纤维化、肠系膜纤维化、子宫内膜异位、瘢痕疙瘩、癌症、骨功能异常、炎性病症、瘢痕形成、或皮肤光老化。
在一些实施方案,所述疾病、病症、或病况是良性或恶性肿瘤、脑癌、肾癌、肝癌、肾上腺癌、膀胱癌、乳腺癌、胃癌、胃部肿瘤、卵巢癌、结肠癌、直肠癌、前列腺癌、胰腺癌、肺癌、阴道癌或甲状腺癌、肉瘤、成胶质细胞瘤、多发性骨髓瘤或胃肠癌症、结肠癌或结肠直肠癌、头颈肿瘤、表皮过度增殖、黑色素瘤、牛皮癣、前列腺增生、瘤形成、上皮性状瘤形成、白血病、淋巴瘤、乳腺癌、或白血病。
在一些实施方案,本发明所述化合物或药物组合物可与另外的治疗剂组合施用。
在一些实施方案,本发明所述用途包括对哺乳动物尤其是人类施用足以实现所述治疗或预防的量的本 发明所述化合物或药物组合物。
药物组合物、制剂和用途
当用作药物时,本发明化合物通常以药物组合物形式施用。所述组合物可以以制药技术中熟知的方式制备并且包含至少一个根据式I、II、III、IV或V的本发明所述化合物。通常,本发明化合物以药物有效量施用。实际施用的本发明化合物的量通常将由医师根据相关情形决定,所述情形包括待治疗病症、所选的施用途径、所施用的本发明的实际化合物、个别患者的年龄、体重和响应、患者症状的严重程度等。
本发明的药物组合物可以通过多种途径施用,包括口服、直肠、经皮、皮下、关节内、静脉内、肌内和鼻内。取决于预期的递送途径,本发明化合物优选配制为可注射或口服组合物或作为药膏、作为洗剂或作为贴剂(均用于经皮施用)。
作为用于口服给药的液体组合物,可使用含有惰性稀释剂如水或液体石蜡的药学上可接受的溶液、悬浮液、乳液、糖浆剂和酏剂。所述这些组合物还可包含稀释剂以外的物质,在一些实施方案,包含润湿剂、甜味剂或调味剂制品。
用于肠胃外给药的组合物可以是乳剂或无菌溶液。在某些实施方案,可使用丙二醇、聚乙二醇、植物油、特别是橄榄油或可注射的有机酯作为溶剂或载体,在一些实施方案,使用油酸乙酯作为溶剂或载体。所述这些组合物还可包含佐剂,特别是润湿剂,等渗剂,乳化剂,分散剂和稳定剂。可以几种方式进行灭菌,在某些实施方案,使用细菌学过滤器,通过辐射或通过加热进行灭菌。它们也可以无菌固体组合物的形式进行制备,其可在使用时溶于无菌水或任何其他可注射的无菌介质中。
所述组合物还可以是气雾剂。为了以液体气雾剂的形式使用,所述组合物可以是稳定的无菌溶液或在使用时溶于无热源无菌水、盐水或任何其他药学上可接受的载体中的固体组合物。为了以旨在直接吸入的干气雾剂形式使用,将所述活性成分精细分开并与水溶性固体稀释剂或载体组合,在某些实施方案,与葡聚糖、甘露醇或乳糖组合。
式(I)-(V)所示化合物或包含所述化合物的组合物也可按栓剂形式施用,例如用于直肠施用药物。这些组合物可通过将化合物与适宜的无刺激性的辅料混合来制备,所述辅料在常温为固体,但是在直肠温度为液体且由此将在直肠中融化以释放药物。上述材料包括可可脂及聚乙二醇。
典型的药物组合物和剂型包含一种或多种辅料。合适的辅料对药学领域的技术人员而言是熟知的,在某些实施方案,合适的辅料包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸钠、甘油单硬脂酸酯、滑石粉、氯化钠、脱脂奶粉、甘油、丙烯、乙二醇、水、乙醇等。特定的辅料是否适合掺入药物组合物或剂型,取决于本领域众所周知的各种因素,包括但不限于将所述剂型施用于受试者的方式以及所述剂型中的特定活性成分。若需要,所述组合物或单一单位剂型还可含有少量润湿剂或乳化剂,或pH缓冲剂。
另一方面,本发明提供了本发明化合物或包含本发明化合物的药物组合物,其用于医学。在具体实施方案中,本发明提供了本发明化合物或包含本发明化合物的药物组合物,其用于预防和/或治疗TGF-β介导或涉及TGF-β的疾病、病症、或病况。
在一些实施方案,本发明提供了本发明化合物或包含本发明化合物的药物组合物、或包含本发明化合物以及其它治疗剂的药物组合物,其用于制备用于预防和/或治疗肺动脉高压、慢性肾病、急性肾病、伤口愈合、关节炎、骨质疏松症、肾病、充血性心力衰竭、溃疡、眼部病症、角膜损伤、糖尿病性肾病、神经功能受损、阿尔茨海默病、动脉粥样硬化、腹膜或皮下粘连、肾纤维化、肺纤维化、特发性肺纤维化、肝纤维化、乙型肝炎、丙型肝炎、由酒精诱导型肝炎、癌症、血色病、原发性胆汁性肝硬化、再狭窄、腹膜后纤维化、肠系膜纤维化、子宫内膜异位、瘢痕疙瘩、癌症、骨功能异常、炎性病症、瘢痕形成、皮肤光老化、良性或恶性肿瘤、脑癌、肾癌、肝癌、肾上腺癌、膀胱癌、乳腺癌、胃癌、胃部肿瘤、卵巢癌、结肠癌、直肠癌、前列腺癌、胰腺癌、肺癌、阴道癌或甲状腺癌、肉瘤、成胶质细胞瘤、多发性骨髓瘤或胃肠癌症、结肠癌或结肠直肠癌、头颈肿瘤、表皮过度增殖、黑色素瘤、牛皮癣、前列腺增生、瘤形成、上皮性状瘤形成、白血病、淋巴瘤、乳腺癌、或白血病的药物。其它疾病、病症或病况包括Cowden综合征、Lhermitte-Dudos病和Bannayan-Zonana综合征或其中PI3K/PKB通路异常活化的疾病。
化合物的治疗剂量可根据例如所进行的治疗的具体用途、化合物的施用方式、患者的健康和状况及开具处方的医生的判断而变化。本申请化合物在药物组合物中的比例或浓度可取决于多种因素(包括剂量、化 学性质(例如疏水性)及施用途径)而变化。例如,本申请化合物可按含有约0.1至约10%w/v所述化合物的用于胃肠外施用的水性生理缓冲溶液形式提供。一些典型的剂量范围为每天约1μg/kg体重至约1g/kg体重。在一些实施方案,剂量范围为每天约0.01mg/kg体重至约100mg/kg体重。剂量可能取决于疾病或病症的类型和进展程度、具体患者的总体健康状态、所选化合物的相对生物效能、辅料的配制及其施用途径等变量。可根据由体外或动物模型测试系统获得的剂量-响应曲线外推有效剂量。
另一方面,本申请包括用于治疗包括恶性前和恶性肿瘤在内的癌症的组合疗法。在此方面,本申请包括治疗癌症的方法,其包括向受试者施用本申请化合物与癌症治疗性处置的组合。在本申请一些实施方案中,本申请化合物用于与癌症标准抗增殖治疗护理组合。本申请化合物用于组合疗法的量为以下量,其足以抑制由TGF-β超家族的成员例如Nodal和Activin(其促进癌症干细胞的存活和/或分化)进行的信号传导且由此提高治疗性处置的效果。用本申请化合物进行的治疗由此阻断癌症干细胞使通过用标准护理进行治疗而破坏的肿瘤得以重新生成的能力。治疗效果可通过本领域知晓的针对所治疗的具体癌症所通常使用的任何方法来确定且包括例如使肿瘤生长得以阻滞、抑制或消退。
对受试者中的癌症进行治疗的一个实施方案包括向有此需要的受试者施用上述量的本申请化合物及施用治疗有效量的一种或多种化学治疗剂,其中所述一种或多种化学治疗剂选自抗代谢剂、烷化剂、配位化合物、铂络合物、DNA交联化合物、转录酶抑制剂、酪氨酸激酶抑制剂、蛋白激酶抑制剂、拓扑异构酶抑制剂、DNA小沟结合化合物、长春花生物碱、紫杉烷类、抗肿瘤抗生素、激素、芳香酶抑制剂、酶、生长因子受体抗体、细胞因子、细胞表面标志物抗体、HDAC抑制剂、HSP 90抑制剂、BCL-2抑制剂、B-raf抑制剂、MEK抑制剂、mTOR抑制剂、蛋白酶体抑制剂和单克隆抗体。
对受试者进行治疗的方法的其它实施方案包括向受试者施用一定量(如上所述)的本申请化合物及施用治疗有效量的一种或多种化学治疗剂,所述一种或多种化学治疗剂独立选自氮芥、环磷酰胺、异环磷酰胺、美法仑、苯丁酸氮芥、乙烯亚胺、甲基三聚氰胺、丙卡巴肼、达卡巴嗪、替莫唑胺、白消安、卡莫司汀、洛莫司汀、甲氨蝶呤、氟尿嘧啶、卡培他滨、阿糖胞苷、吉西他滨、阿糖胞苷、巯嘌呤、氟达拉滨、克拉屈滨、硫鸟嘌呤、硫唑嘌呤、长春碱、长春新碱、紫杉醇、多西他赛、秋水仙碱、放线菌素D、柔红霉素、博来霉素、L-天冬酰胺酶、顺铂、卡铂、奥沙利铂、泼尼松、地塞米松、氨鲁米特、福美坦、阿那曲唑、己酸羟孕酮、甲羟孕酮、他莫昔芬、安吖啶、米托蒽醌、托泊替康、伊立替康、喜树碱、阿法替尼、阿西替尼、博舒替尼、硼替佐米、卡非佐米、卡博替尼、西地尼布、克唑替尼、达沙替尼、达拉菲尼、依罗莫司、依鲁替尼、LDK378、LGX818、MEK162、瑞格菲尼、鲁索替尼、司美替尼、索拉非尼、曲美替尼、维罗非尼、厄洛替尼、吉非替尼、伊马替尼、拉帕替尼、来他替尼、尼罗替尼、帕博西尼、帕唑帕尼、普纳替尼、司马沙尼、西罗莫司、舒尼替尼、替西罗莫司、瓦他拉尼、凡德他尼、抗Her2抗体、干扰素-α、干扰素-γ、白细胞介素2、GM CSF、抗CTLA 4抗体、利妥昔单抗、抗CD33抗体、MGCD0103、伏立诺他、17-AAG、沙利度胺、来那度胺、雷帕霉素、CCI-779、阿霉素、吉西他滨、美法仑、NPI052、吉妥单抗、阿仑单抗、西妥昔单抗、替伊莫单抗、托西莫单抗、碘-131托西莫单抗、曲妥单抗、阿多曲妥单抗依酯、奥妥珠单抗、贝伐单抗、利妥昔单抗和抗TRAIL死亡受体抗体。
如本领域技术人员显而易见的是,共同施用包括递送两种或多种治疗剂至患者作为同一治疗方案的一部分的任何方式。虽然两种或多种活性剂可以同时在单一制剂(即作为单一药物组合物)中施用,但此并非必要的。所述活性剂也可在不同制剂中、在不同时间施用。
为描述本发明,以下列出了实施例。但需要理解,本发明不限于这些实施例,只是提供实践本发明的方法。
一般地,本发明的化合物可以通过本发明所描述的方法制备得到,除非有进一步的说明,其中取代基的定义如式I、II、III、IV或V所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。
所属领域的专业人员将认识到:本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物,且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如,根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成,如适当的保护干扰基团,通过利用其他已知的试剂除了本发明所描述的,或将反应条件做一些常规的修改。另外,本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
下面所描述的实施例,除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company,使用时都没有经过进一步纯化,除非其他方面表明。一般的试剂从汕头西陇化工厂,广东光华化学试剂厂,广州化学试剂厂,天津好寓宇化学品有限公司,天津市福晨化学试剂厂,武汉鑫华远科技发展有限公司,青岛腾龙化学试剂有限公司,和青岛海洋化工厂购买得到。
无水四氢呋喃,二氧六环,甲苯,乙醚是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯,石油醚,正己烷,N,N-二甲基乙酰胺和N,N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明),反应瓶都塞上合适的橡皮塞,底物通过注射器打入。玻璃器皿都是干燥过的。
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。
1H NMR谱使用Bruker 400MHz或600MHz核磁共振谱仪记录。
1H NMR谱以CDC1
3、DMSO-d
6、CD
3OD或丙酮-d
6为溶剂(以ppm为单位),用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候,将使用下面的缩写:s(singlet,单峰)、d(doublet,双峰)、t(triplet,三重峰)、m(multiplet,多重峰)、br(broadened,宽峰)、dd(doublet of doublets,双二重峰)、dt(doublet of triplets,双三重峰)。偶合常数,用赫兹(Hz)表示。
低分辨率质谱(MS)数据的测定条件是:Agilent 6120四级杆HPLC-M(柱子型号:Zorbax SB-C18,2.1x30mm,3.5微米,6min,流速为0.6mL/min。流动相:5%-95%((含0.1%甲酸的CH
3CN)在(含0.1%甲酸的H
2O)中的比例),采用电喷雾电离(ESI),在210nm/254nm下,用UV检测。
纯的化合物的使用Agilent 1260pre-HPLC或Calesep pump 250pre-HPLC(柱子型号:NOVASEP 50/80mm DAC),在210nm/254nm用UV检测。
制备本发明公开化合物的典型合成步骤如以下合成方案1-7所示。
合成方案1:
中间体1-1与氯化氢醇溶液反应后再与氨甲醇溶液或氯化铵反应得到中间体1-2;中间体1-2与中间体1-3在碱性及加热条件下发生亲核取代反应得到中间体1-4;中间体1-4在酸性及加热条件下发生分子内关环反应得到中间体1-5;中间体1-5可互变异构为中间体1-6,再与中间体1-7发生金属催化偶联反应得到化合物1-8。其中W、R
1、R
2和Z均具有本发明所述定义;X为卤素;E
1为卤素、硼酸基或频哪醇硼酸酯基。
合成方案2:
中间体1-2与中间体2-1在碱性及加热条件下发生亲核取代反应得到中间体2-2;中间体2-2在酸性及加热条件下发生分子内关环反应得到中间体2-3;中间体2-3与中间体1-7发生金属催化偶联反应得到化合物2-4。其中W、R
6、p和Z均具有本发明所述定义;X为卤素;E
1为卤素、硼酸基或频哪醇硼酸酯基。
合成方案3:
中间体1-2与1,3-二羟基丙酮二聚体在氨水中加热反应得到中间体3-1;中间体3-1可通过相应的卤代反应或亲核取代反应得到中间体3-2;中间体3-2与相应的胺或酚发生亲核取代反应得到中间体3-3;中间体3-3与中间体1-7发生金属催化偶联反应得到化合物3-4。其中W、Z、L
1、L和R
5均具有本发明所述定义;E
1为卤素、硼酸基或频哪醇硼酸酯基;E
2为卤素或甲磺酰氧基。
合成方案4:
中间体1-1与氯化氢醇溶液反应得到中间体4-1;中间体4-1与相应的胺4-2在碱性条件下发生亲核取代反应得到中间体4-3;中间体4-3与相应的卤代醛4-4在弱碱性及加热条件下反应得到化合物4-5。其中W、R
1、和Z均具有本发明所述定义;X是卤素。
合成方案5:
酰肼5-1与相应的酰氯反应得到中间体5-2;中间体5-2与五氯化磷反应得到中间体5-3,再与相应的胺反应得到三氮唑类化合物5-4。其中W、R
1、和Z均具有本发明所述定义。
合成方案6:
化合物6-1在碱性条件下经双氧水氧化得到化合物6-2。其中其中X
3、X
4、X
5、Y
1、Y
4、R
1、R
2、R
3和t均具有本发明所述定义。
合成方案7:
化合物6-1在碱性或酸性条件下水解得到中间体7-1,再与相应的胺发生缩合反应得到化合物7-3。其中X
3、X
4、X
5、Y
1、Y
4、R
1、R
2、R
3、R
4b、R
4c和t均具有本发明所述定义。
合成方案8:
中间体8-1经二氧化锰氧化得到中间体8-2;中间体8-2与8-3经金属催化的偶联反应得到中间体8-4;中间体8-4经氧化反应得到酸8-5,再与相应的胺缩合得到中间体8-6;中间体8-6在碱性条件下经双氧水氧化得到化合物8-7。其中X
3、X
4、X
5、Y
1、Y
4、R
1、R
2、R
3、R
5、E
1、R
4b、R
4c和t均具有本发明所述定义。
实施例1
6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-b]哒嗪-3-甲腈
步骤1)N'-(6-氯哒嗪-3-基)-N,N-二甲基甲脒
向100mL单口瓶中加入3-氨基-6-氯哒嗪(5g,38.6mmol)和N,N-二甲基甲酰胺二甲缩醛(27.59g,231.58mmol),所得混合物于100℃加热反应2小时。待反应液冷至室温,减压浓缩,所得固体经石油醚(15mL)打浆,过滤,烘干,得标题化合物为灰褐色固体(6.8g,95%)。LCMS[M+1]
+:185.1。
步骤2)6-氯咪唑并[1,2-b]哒嗪-3-甲腈
向N'-(6-氯哒嗪-3-基)-N,N-二甲基甲脒(5g,27.1mmol)的乙腈(40mL)溶液中加入溴乙腈(9.7g,81.2mmol)和三乙胺(5.48g,54.2mmol),所得混合物于85℃加热反应过夜。待反应液冷至室温,减压浓缩,所得残余物经硅胶柱层析纯化(洗脱剂:二氯甲烷)得标题化合物为淡黄色固体(4.1g,85%)。LCMS[M+1]
+:179.1。
步骤3)6-甲基吡啶-2-甲脒
室温下,向2-氰基-6-甲基吡啶(4.42g,37.3mmol)的甲醇溶液(25mL)中缓慢加入甲醇钠(4.05g,75mmol)的甲醇溶液(30mL),加完后升温至65℃反应4小时。待反应液冷至室温,加入氯化铵(20g,0.37mol),所得混合物于45℃搅拌反应0.5小时。反应完全后,将混合物减压浓缩,向所得残余物中加入二氯甲烷(54mL)和异丙醇(18mL),搅拌10分钟后,过滤,所得滤饼再加入二氯甲烷(40mL)和异丙醇(40mL),继续搅拌10分钟,过滤,合并滤液,减压浓缩,得粗产品5.81g,直接用于下一步反应。LCMS[M+1]
+:136.2。
步骤4)6-甲基吡啶-2-(N-(2-氧代环戊基))甲脒
向6-甲基吡啶-2-甲脒(1.99g,15.0mmol)的THF(38mL)溶液中加入2-氯环戊酮(1.37g,11.55mmol)和碳酸钾水溶液(2.1g,15.2mmol,溶于4.8mL水中),所得混合物于65℃反应3小时。待反应液冷却至室温后,减压浓缩,向所得残余物中加入甲醇(20mL),溶解后过滤,所得滤液经减压浓缩,硅胶柱层析纯化(二氯甲烷:甲醇=20:1),得标题化合物为浅黄色固体(834mg,33%)。LCMS[M+1]
+:218.1。
步骤5)2-(6-甲基吡啶-2-基)-1,4,5,6-四氢环戊二烯并[d]咪唑
向6-甲基吡啶-2-(N-(2-氧代环戊基))甲脒(834mg,3.84mmol)的二氧六环(25mL)溶液中加入无水对甲苯磺酸(1.32g,7.68mmol),所得混合物于85℃加热反应过夜。待反应液冷却至室温,减压浓缩,所得残余物加入乙酸乙酯(25mL)和水(20mL),用饱和碳酸氢钠水溶液调节pH至8左右,分层,水相再用乙酸乙酯(25mL)萃取,合并有机相,用饱和食盐水(25mL)洗涤,无水硫酸钠干燥,减压浓缩,得标题化合物为褐色固体(700mg,92%)。LCMS[M+1]
+:200.2。
步骤6)6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-甲腈
向25mL单口瓶中加入2-(6-甲基吡啶-2-基)-1,4,5,6-四氢环戊二烯并[d]咪唑(80mg,0.4mmol)、6-氯咪唑并[1,2-b]哒嗪-3-甲腈(72.2mg,0.4mmol)、邻非罗啉(21.6mg,0.12mmol)、碘化亚铜(11.3mg,0.06mmol)、碳酸钾(110mg,0.8mmol)和二甲基亚砜(6mL),置换氮气,升温至95℃反应过夜。待反应液冷却至室温,减压浓缩,所得残余物用二氯甲烷和甲醇混合溶剂充分溶解后,再用硅藻土过滤,滤液经减压浓缩,厚制备板纯化(石油醚:乙酸乙酯=1:1),得标题化合物为类白色固体(12mg,8.8%)。LCMS[M+1]
+:342.2。
1H NMR(500MHz,DMSO)δ8.66(s,1H),8.44(d,J=9.6Hz,1H),7.86(d,J=7.8Hz,1H),7.77(t,J=7.7Hz,1H),7.63(d,J=9.5Hz,1H),7.13(d,J=7.6Hz,1H),2.79(t,J=6.6Hz,2H),2.71(t,J=6.6Hz,2H),2.54(d,J=8.0Hz,2H),1.94(s,3H)。
实施例2
6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-b]哒嗪-3-甲酰胺
向6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)哒嗪并[1,2-a]吡啶-3-甲腈(20mg,0.059mmol)的二氧六环(0.6mL)和水(0.1mL)溶液中加入氢氧化锂一水合物(2.6mg,0.062mmol)和30%过氧化氢(54μL,0.48mmol),所得混合物室温搅拌10分钟。减压浓缩,所得残余物经厚制备板纯化(二氯甲烷:甲醇=25:1)得标题化合物为淡黄色固体产物(10mg,48%)。LCMS[M+1]
+:360.4。
1H NMR(500MHz,CDCl
3)δ:8.66(s,1H),8.43(s,1H),7.89(d,J=8.0Hz,1H),7.77(d,J=9.4Hz,1H),7.59(t,J=7.7Hz,1H),7.53(d,J=9.4Hz,1H),6.96(d,J=7.6Hz,1H),2.85(t,J=6.4Hz,2H),2.72(t,J=6.3Hz,2H),2.63–2.54(m,2H),2.05(s,3H)。
实施例3
6-(2-(3-氯-4-氟苯基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-b]哒嗪-3-甲腈
步骤1)3-氯-4-氟苯甲亚胺酸乙酯盐酸盐
向100mL单口瓶中加入3-氯-4-氟苯腈(3g,19.3mmol)和30%氯化氢乙醇溶液(20mL),所得混合物室温反应过夜。减压浓缩,经异丙醚打浆得白色固体(4.22g,92%)。
步骤2)3-氯-4-氟苯甲脒
向3-氯-4-氟苯甲亚胺酸乙酯盐酸盐(4.22g,17.8mmol)的甲醇(10mL)悬浮液中加入4M氨甲醇溶液(10mL),所得混合物室温搅拌2天后,TLC检测显示反应完全,减压浓缩,用异丙醚打浆得粗品3.9g,直接用于下一步反应。LCMS[M+1]
+:173.1。
步骤3)3-氯4-氟-N-(2-氧代环戊基)苯甲脒
向3-氯-4-氟苯甲脒(2.82g,16.3mmol)的四氢呋喃(50mL)悬浮液中加入2-氯环戊酮(1.94g,16.3mmol)。将碳酸钾(4.5g,32.6mmol)溶于水(10mL)中,再加入至上述反应液中,所得混合物加热至80℃反应3小时。待反应液冷至室温,加入水(30mL)和乙酸乙酯(30mL),析出部分固体,过滤,滤饼经烘干后得白色固体0.9g。滤液分层,水层用乙酸乙酯萃取(50mL),合并有机层,经饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,所得残余物经异丙醚打浆得白色固体0.6g。LCMS[M+1]
+:255.1。
步骤4)2-(3-氯-4-氟苯基)-1,4,5,6-四氢环戊二烯并[d]咪唑
向3-氯4-氟-N-(2-氧代环戊基)苯甲脒(1.5g,5.89mmol)的1,4-二氧六环(40mL)溶液中加入无水对甲苯磺酸(1.01g,5.89mmol),所得混合物加热回流反应过夜。待反应液冷却,减压浓缩,加水(35mL),用饱和碳酸氢钠调pH至8左右,用乙酸乙酯(30mL x 3)萃取,合并有机层,经无水硫酸钠干燥,减压浓缩,所得残余物经硅胶柱层析纯化(二氯甲烷:甲醇=50:1),得标题化合物为棕色固体(1.3g,93%)。LCMS[M+1]
+:237.1。
步骤5)6-(2-(3-氯-4-氟苯基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-b]哒嗪-3-甲腈
向25mL单口瓶中加入2-(3-氯-4-氟苯基)-1,4,5,6-四氢环戊二烯并[d]咪唑(59mg,0.25mol)、6-氯咪唑并[1,2-b]哒嗪-3-甲腈(54mg,0.30mmol)、碘化亚铜(4.8mg,0.025mmol)、L-脯氨酸(5.8mg,0.05mmol)、碳酸钾(86mg,0.62mmol)和DMF(2mL),置换氮气后,所得混合物加热至100℃反应2小时。待反应液冷却至室温,硅藻土过滤,加水(10mL),用乙酸乙酯(10mL x 3)萃取,合并有机层,再用饱和食盐水洗涤,无水硫酸干燥,减压浓缩,所得残余物经厚制备板纯化(石油醚:乙酸乙酯=1:1)得淡黄色固体(24mg,24%)。LCMS[M+1]
+:379.2。
1H NMR(400MHz,CDCl
3)δ:8.30(s,1H),8.01(m,1H),7.63(m,1H),7.26(m,1H),7.13(m,1H),6.93(m,1H),2.99(m,2H),2.81(m,2H),2.59(m,2H)。
实施例4
6-(2-(5-氟-6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-b]哒嗪-3-甲腈
6-(2-(5-氟-6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-b]哒嗪-3-甲腈的制备方法参照实施例1,除了用5-氟-6-甲基-2-氰基吡啶代替2-氰基-6-甲基吡啶,得标题化合物为黄色固体(166mg,46%)。LCMS[M+1]
+:360.2。
1H NMR(500MHz,CDCl
3)δ:8.30(s,1H),8.02(d,J=9.2Hz,2H),7.40(t,J=8.8Hz,1H),7.27(d,J=11.2Hz,1H),2.89(t,J=6.7Hz,2H),2.83(t,J=6.5Hz,2H),2.66–2.55(m,2H),2.08(s,3H)。
实施例5
6-(2-(5-氟-6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-b]哒嗪-3-甲酰胺
6-(2-(5-氟-6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-b]哒嗪-3-甲酰胺的制备方法参照实施例2,除了用6-(2-(5-氟-6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-b]哒嗪-3-甲腈代替6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-b]哒嗪-3-甲腈,得标题化合物为白色固体(23mg,61%)。LCMS[M+1]
+:378.3。
1H NMR(500MHz,CDCl
3)δ:8.58(s,1H),8.12(t,J=9.8Hz,1H),8.00(d,J=8.5Hz,1H),7.93(s,1H),7.40(t,J=8.7Hz,1H),7.21(d,J=9.5Hz,1H),5.97(s,1H),2.89–2.75(m,4H),2.65–2.57(m,2H),2.03(s,3H)。
实施例6
6-(2-(1-环丙基-1H-吡唑-3-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-b]哒嗪-3-甲腈
6-(2-(1-环丙基-1H-吡唑-3-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-b]哒嗪-3-甲腈的制备方法参照实施例1,除了用1-环丙基-1H-吡唑-3-甲腈代替2-氰基-6-甲基吡啶,得标题化合物为得黄色固体产物(35mg,16%)。LCMS[M+1]
+:357.3。
1H NMR(500MHz,CDCl
3)δ:8.28(s,1H),7.99(d,J=9.7Hz,1H),7.47(s,1H),7.30(s,1H),6.73(s,1H),3.52–3.42(m,1H),2.94(t,J=6.3Hz,2H),2.81(t,J=6.2Hz,2H),2.64–2.52(m,2H),0.89(m,4H)。
实施例7
6-(2-(1-环丙基-1H-吡唑-3-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-b]哒嗪-3-甲酰胺
6-(2-(1-环丙基-1H-吡唑-3-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-b]哒嗪-3-甲酰胺的制备方法参照实施例2,除了用6-(2-(1-环丙基-1H-吡唑-3-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-b]哒嗪-3-甲腈代替6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-b]哒嗪-3-甲腈,得标题化合物为淡黄色固体产物(8mg,51%)。LCMS[M+1]
+:375.2。
1H NMR(500MHz,CDCl
3)δ:8.58(s,1H),8.12(m,1H),7.95(s,1H),7.45(s,1H),7.23(m,1H),6.70(s,1H),5.83(s,1H),3.43(m,1H),2.84(m,4H),2.60(m,2H),0.87-0.81(m,4H)。
实施例8
4-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)喹啉-6-甲腈
步骤1)4-(((2,2-二甲基-4,6-二氧代-1,3-二氧杂-5-亚基)甲基)氨基)苯腈
向4-氨基苯腈(2.88g,25mmol)的二氯甲烷(70mL)溶液中滴加5-(乙氧基甲烯基)-2,2-二甲基-1,3-二氧六环-4,6-二酮(10g,50mmol)的二氯甲烷(20mL)溶液,所得混合物室温搅拌0.5小时。TLC检测显示反应完全,过滤,滤饼经乙酸乙酯洗涤,烘干得标题化合物为白色固体(5.6g,81%)。LCMS[M+1]
+:273.1。
步骤2)4-羟基喹啉-6-甲腈
向250mL单口瓶中加入4-(((2,2-二甲基-4,6-二氧代-1,3-二氧杂-5-亚基)甲基)氨基)苯腈(5.6g,0.02mol)和二苯醚(56mL),升温至220℃左右反应1小时。待反应液冷却至室温,缓慢加入石油醚(100mL),加完继续搅拌10分钟,过滤,滤饼用石油醚和二氯甲烷的混合溶液(1:1)洗涤,烘干,得标题化合物为褐色固体(3.3g,95%)。LCMS[M+1]
+:171.1。
步骤3)4-溴喹啉-6-甲腈
在-5℃下,向4-羟基喹啉-6-甲腈(2.94g,17.3mmol)的DMF(35mL)溶液中缓慢滴加三溴化磷(5.62g,20.8mmol),加完继续在-5℃下反应10分钟。TLC检测显示反应完全,向反应液中加入冰水(35mL)淬灭反应,用碳酸氢钠水溶液调节pH至8左右,搅拌0.5小时后抽滤,所得滤饼经硅胶柱层析纯化(洗脱剂为二氯甲烷)得标题化合物为黄色固体(2.14g,53%)。
步骤4)6-氰基喹啉-4-硼酸频哪醇酯
向100mL单口瓶中加入4-溴喹啉-6-甲腈(1.8g,7.7mmol)、联硼酸频哪醇酯(5.88g,23.17mmol)、Pd(dppf)Cl
2(0.3g,0.41mmol)、乙酸钾(1.51g,15.4mmol)和二氧六环(50mL),置换氮气,升温至100℃反应1小时。待反应液冷却至室温,用硅藻土过滤,滤液经减压浓缩,所得残余物经硅胶柱层析纯化(石油醚:乙酸乙酯=5:1),得到标题化合物为淡黄色固体(2.08g,96%)。LCMS[M+1]
+:199.3。
步骤5)4-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)喹啉-6-甲腈
向50mL单口瓶中加入2-(6-甲基吡啶-2-基)-1,4,5,6-四氢环戊二烯并[d]咪唑(400mg,2mmol)、6-氰基喹啉-4-硼酸频哪醇酯(1.12g,4mmol)、无水醋酸铜(363mg,2mmol)、DMF(25mL)、三乙胺(505mg,5mmol)和分子筛(1.5g),置换氧气,所得混合物加热至50℃反应5小时。待反应液冷至室温,减压浓缩,向残余物中加入二氯甲烷/甲醇混合溶液,搅拌10分钟后,过滤,滤液经减压浓缩,所得残余物经硅胶柱层析纯化(乙酸乙酯:石油醚=1:2),得棕红色粗产物(120mg,17%)。取粗品35mg经厚制 备板再纯化(二氯甲烷:甲醇=25:1),得标题化合物为淡黄色固体产物25mg。LCMS[M+1]
+:352.2。
1H NMR(500MHz,CDCl
3)δ:9.12(t,J=5.0Hz,1H),8.30(t,J=6.6Hz,1H),8.00–7.94(m,1H),7.91(s,1H),7.87(d,J=8.7Hz,1H),7.55(t,J=7.6Hz,1H),7.41(d,J=4.5Hz,1H),6.81(d,J=7.5Hz,1H),2.93(dd,J=15.1,8.1Hz,2H),2.61(dd,J=12.9,6.2Hz,2H),2.27–2.19(m,1H),2.10–2.03(m,1H),1.59(s,3H)。
实施例9
4-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)喹啉-6-甲酰胺
4-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)喹啉-6-甲酰胺的制备方法参照实施例2,除了用4-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)喹啉-6-甲腈代替6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-b]哒嗪-3-甲腈,得标题化合物为淡黄色固体产物(16mg,25%)。LCMS[M+1]
+:370.2。
1H NMR(500MHz,DMSO)δ:9.04(s,1H),8.19(q,J=9.0Hz,3H),7.99(s,1H),7.83(d,J=7.8Hz,1H),7.62(t,J=7.8Hz,1H),7.55(d,J=4.4Hz,1H),7.49(s,1H),6.88(d,J=7.6Hz,1H),2.84-2.71(m,2H),2.62(dd,J=14.1,7.0Hz,1H),2.48-2.39(m,1H),1.54-1.44(m,3H),1.24(s,2H)。
实施例10
2-(2-(3-氯-4-氟苯基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)-6-甲基咪唑并[2,1-b][1,3,4]噻二唑
步骤1)2-溴-6-甲基咪唑并[2,1-b][1,3,4]噻二唑
向5-溴-1,3,4噻二唑-2-胺(540mg,3mmol)的乙醇(10mL)悬浮液中加入氯丙酮(555mg,6mmol),所得混合物加热回流反应2天。待反应液冷至室温,减压浓缩,加水(20mL),用饱和碳酸氢钠溶液调pH至8左右后,用乙酸乙酯(20mL x 2)萃取,合并有机层,经无水硫酸干燥,减压浓缩,所得残余物经硅胶柱层析纯化(石油醚:乙酸乙酯=4:1),得标题化合物为淡黄色固体(270mg,41%)。LCMS[M+1]
+:217.9,219.9。
步骤2)2-(2-(3-氯-4-氟苯基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)-6-甲基咪唑并[2,1-b][1,3,4]噻二唑
向25mL单口瓶中加入2-(3-氯-4-氟苯基)-1,4,5,6-四氢环戊二烯并[d]咪唑(97mg,0.41mol)、2-溴-6-甲基咪唑并[2,1-b][1,3,4]噻二唑(60mg,0.28mmol)、碘化亚铜(8.0mg,0.042mmol)、1,10-邻菲罗啉(15mg,0.084mmol)、碳酸钾(97mg,0.70mmol)和DMF(2mL),置换氮气后,所得混合物于85℃加热反应过夜。待反应液冷却至室温,用硅藻土过滤,加水(10mL),用乙酸乙酯(10mL x 3)萃取,合并有机层,再用饱和食盐水洗涤,无水硫酸干燥,减压浓缩,所得残余物经厚制备板纯化(石油醚:乙酸乙酯=1:1)得标题化合物为白色固体(15mg,14%)。LCMS[M+1]
+:374.2。
实施例11
6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)-[1,2,4]三氮唑并[1,5-a]吡啶
步骤1)N'-(5-溴吡啶-2-基)-N,N-二甲基甲脒
向2-氨基-5-溴吡啶(5.19g,0.03mmol)的乙醇(30mL)溶液中加入N,N-二甲基甲酰胺二甲基缩醛(7.15g,0.06mmol),所得混合物加热至回流反应4小时。待反应液冷却至室温,减压浓缩,所得残余物经硅胶柱层析纯化(石油醚:乙酸乙酯=3:1)得标题化合物为类白色固体(5.3g,78%)。LCMS[M+1]
+:228.2。
步骤2)N'-(5-溴吡啶-2-基)-N-羟基甲脒
向N'-(5-溴吡啶-2-基)-N,N-二甲基甲脒(1.44g,4.5mmol)的甲醇(20mL)溶液中加入盐酸羟胺(0.52g,7.5mmol),所得混合物室温搅拌反应1小时。减压浓缩,向所得残余物中加入水(15mL),用乙酸乙酯(20mL x 2)萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩得标题化合物为白色固体(0.8g,83%)。LCMS[M+1]
+:216.1。
步骤3)6-溴-[1,2,4]三氮唑并[1,5-a]吡啶
向N'-(5-溴吡啶-2-基)-N-羟基甲脒(0.79g,3.64mmol)的甲苯(7mL)溶液中加入乙酸酐(4.1mL,29mmol),所得混合物加热至85℃反应2小时。待反应液冷却至室温,加入甲醇(4mL),搅拌1小时后,减压浓缩,所得残余物经硅胶柱层析纯化(二氯甲烷:甲醇=50:1)得标题化合物为浅褐色固体(0.52g,72%)。LCMS[M+1]
+:198.1。
步骤4)[1,2,4]三氮唑并[1,5-a]吡啶-6-硼酸频哪醇酯
向50mL反应瓶中加入6-溴-[1,2,4]三氮唑并[1,5-a]吡啶(0.51g,2.56mmol)、硼酸频哪醇酯(1.95g,7.68mmol)、Pd(dppf)Cl
2(0.12g,0.16mmol)、乙酸钾(0.50g,5.14mmol)和二氧六环(10mL)。体系置换氮气后,加热至100℃反应1小时。待反应液冷却,过滤,减压浓缩,所得残余物经硅胶柱层析纯化(二氯甲烷:石油醚=10:1)得标题化合物为棕色胶状物(0.6g,95%)。LCMS[M+1]
+:164.1。
步骤5)6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)-[1,2,4]三氮唑并[1,5-a]吡啶
6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)-[1,2,4]三氮唑并[1,5-a]吡啶的制备方法参照实施例8,除了用[1,2,4]三氮唑并[1,5-a]吡啶-6-硼酸频哪醇酯代替6-氰基喹啉-4-硼酸频哪醇酯,得标题化合物为黄色固体(21mg,收率:13%)。LCMS[M+1]
+:317.3。
1H NMR(500MHz,CDCl
3)δ:8.66(s,1H),8.43(s,1H),7.89(d,J=8.0Hz,1H),7.77(d,J=9.4Hz,1H),7.59(t,J=7.7Hz,1H),7.53(d,J=9.4Hz,1H),6.96(d,J=7.6Hz,1H),2.85(t,J=6.4Hz,2H),2.72(t,J=6.3Hz,2H),2.63–2.54(m,2H),2.05(s,3H)。
实施例12
6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-甲腈
步骤1)6-溴咪唑并[1,2-a]吡啶-3-甲腈
向封管中加入N'-(5-溴吡啶-2-基)-N,N-二甲基甲脒(1.2g,4.16mmol)、溴乙腈(0.9mL,12.9mmol)、碳酸氢钠(1.05g,12.48mmol)和异丙醇(13mL),所得混合物加热至100℃左右反应14小时。待反应液冷却,过滤,减压浓缩,所得残余物经硅胶柱层析纯化(二氯甲烷:石油醚=20:3),得标题化合物为黄色固体(760mg,82%)。LCMS[M+1]
+:222.2,224.1。
步骤2)3-氰基咪唑并[1,2-a]吡啶-6-硼酸频哪醇酯
3-氰基咪唑并[1,2-a]吡啶-6-硼酸频哪醇酯的制备方法参照实施例11,除了用6-溴咪唑并[1,2-a]吡啶-3-甲腈代替6-溴-[1,2,4]三氮唑并[1,5-a]吡啶,得标题化合物为淡黄色固体(0.9g,100%)。LCMS[M+1]
+: 188.0。
步骤3)6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-甲腈
6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-甲腈的制备方法参照实施例8,除了用3-氰基咪唑并[1,2-a]吡啶-6-硼酸频哪醇酯代替6-氰基喹啉-4-硼酸频哪醇酯,得标题化合物为黄色固体(26mg,17%)。LCMS[M+1]
+:341.2。
1H NMR(500MHz,CDCl
3)δ:8.66(s,1H),8.43(s,1H),7.89(d,J=8.0Hz,1H),7.77(d,J=9.4Hz,1H),7.59(t,J=7.7Hz,1H),7.53(d,J=9.4Hz,1H),6.96(d,J=7.6Hz,1H),2.85(t,J=6.4Hz,2H),2.72(t,J=6.3Hz,2H),2.63–2.54(m,2H),2.05(s,3H)。
实施例13
6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例2,除了用6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-甲腈代替6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-b]哒嗪-3-甲腈,得标题化合物为淡黄色固体产物(10mg,16%)。LCMS[M+1]
+:359.3。
1H NMR(500MHz,DMSO)δ:9.52(s,1H),8.41(s,1H),8.11–7.92(m,1H),7.80(d,J=7.7Hz,1H),7.75(d,J=9.4Hz,1H),7.69(t,J=7.8Hz,1H),7.46(d,J=9.4Hz,2H),7.05(d,J=7.5Hz,1H),2.67(dd,J=15.9,6.9Hz,4H),2.48(d,J=6.3Hz,2H),1.94(s,3H)。
实施例14
6-甲基-2-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[2,1-b][1,3,4]噻二唑
6-甲基-2-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[2,1-b][1,3,4]噻二唑的制备方法参照实施例10,除了用2-(6-甲基吡啶-2-基)-1,4,5,6-四氢环戊二烯并[d]咪唑代替2-(3-氯-4-氟苯基)-1,4,5,6-四氢环戊二烯并[d]咪唑,得到标题化合物为白色固体(17mg,34%)。LCMS[M+1]
+:337.2。
1H NMR(500MHz,CDCl
3)δ:7.89(d,J=7.7Hz,1H),7.64(t,J=7.7Hz,1H),7.50(s,1H),7.04(d,J=7.5Hz,1H),2.83(dd,J=13.6,6.8Hz,4H),2.66–2.51(m,2H),2.42(s,3H),2.21(s,3H)。
实施例15
6-甲基-2-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[2,1-b][1,3,4]噻二唑5-甲腈
步骤1)6-甲基-2-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[2,1-b][1,3,4]噻二唑5-甲醛
向氮气保护的反应瓶中加入DMF(0.73g,10mmol),冷至0℃,再缓慢滴加三氯氧磷(1.55g,10mmol), 加完后,于0℃左右搅拌10分钟,再滴加6-甲基-2-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[2,1-b][1,3,4]噻二唑(337mg,1.0mmol)的DMF(5mL)溶液,所得混合物升温至70℃反应1小时。待反应液冷却,将反应液倒入冰水中,用饱和碳酸氢钠水溶液调节pH至7~8,用乙酸乙酯(25mL x 2)萃取,合并有机相,用饱和食盐水(20mL x 2)洗涤,无水硫酸钠干燥,减压浓缩,得标题化合物为黄色固体(300mg,82%)。
步骤2)6-甲基-2-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[2,1-b][1,3,4]噻二唑5-甲醛肟
向6-甲基-2-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[2,1-b][1,3,4]噻二唑5-甲醛(300mg,0.82mmol)的甲醇(25mL)溶液中加入盐酸羟胺(114mg,0.82mmol),所得混合物在室温下搅拌0.5小时。减压浓缩,加水(20mL),向混合物中加入碳酸氢钠水溶液至pH为7~8,用乙酸乙酯(20mL x 2)萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,得标题化合物为黄色固体(308mg,99%)。
步骤3)6-甲基-2-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[2,1-b][1,3,4]噻二唑5-甲腈
向25mL反应瓶中加入6-甲基-2-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[2,1-b][1,3,4]噻二唑5-甲醛肟(90mg,0.24mmol)和乙酸酐(6mL),所得混合物加热至130℃反应2小时。待反应液冷至室温,减压浓缩,向所得残余物中加入冰水,用饱和碳酸氢钠溶液调节pH至7~8,用乙酸乙酯萃取(25mL x 2),合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,得标题化合物为浅棕色固体产物(83mg,97%)。LCMS[M+1]
+:362.2。
1H NMR(500MHz,CDCl
3)δ:7.92(d,J=7.8Hz,1H),7.68(t,J=7.8Hz,1H),7.10(d,J=7.5Hz,1H),2.93(t,J=6.4Hz,2H),2.82(t,J=6.4Hz,2H),2.64–2.58(m,2H),2.57(s,3H),2.31(s,3H)。
实施例16
6-甲基-2-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[2,1-b][1,3,4]噻二唑5-甲酰胺
6-甲基-2-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[2,1-b][1,3,4]噻二唑5-甲酰胺的制备方法参照实施例2,除了用6-甲基-2-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[2,1-b][1,3,4]噻二唑5-甲腈代替6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-b]哒嗪-3-甲腈,得标题化合物为淡黄色固体产物(7mg,31%)。LCMS[M+1]
+:380.2。
1H NMR(500MHz,CDCl
3)δ:8.12(t,J=7.8Hz,1H),7.97(d,J=7.8Hz,1H),7.78(s,1H),7.61(d,J=7.8Hz,1H),7.22(s,1H),3.12–2.98(m,4H),2.86–2.74(m,5H),2.63(s,3H)。
实施例17
3-甲基-6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)喹唑啉-4(3H)-酮
步骤1)6-溴-3-甲基喹唑啉-4(3H)-酮
向6-溴-4-羟基喹唑啉(1.12mg,5.0mmol)的DMF(20mL)溶液中加入钠氢(500mg,12.5mmol),室温搅拌10分钟后,加入碘甲烷(620μL,10.0mmol),室温反应2小时。冷却至0℃,向混合物中滴加水淬灭反应,加水(40mL),用乙酸乙酯萃取(40mL x 3),合并有机层,经饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,所得残余物经乙醚打浆得淡黄色固体(0.85g,62%)。LCMS[M+1]
+:239.0,241.0。
步骤2)3-甲基喹唑啉-4(3H)-酮-6-硼酸频哪醇酯
向50mL反应瓶中加入6-溴-3-甲基喹唑啉-4(3H)-酮(0.8g,3.35mmol)、联硼酸频哪醇酯(2.12g,8.37mmol)、Pd(dppf)Cl
2(127mg,0.17mmol)、乙酸钾(658mg,6.70mmol)和1,4-二氧六环(15mL),反应体系置换氮气后,于100℃加热反应2小时。待反应液冷却至室温,用硅藻土过滤,减压浓缩,所得残余物经硅胶柱层析纯化(石油醚:乙酸乙酯=4:1至1.5:1),得标题化合物为淡黄色固体(820mg,80%)。LCMS[M+1]
+:287.1。
步骤3)3-甲基-6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)喹唑啉-4(3H)-酮
向3-甲基喹唑啉-4(3H)-酮-6-硼酸频哪醇酯(129mg,0.45mmol)的1,2-二氯乙烷(4mL)溶液中加入2-(6-甲基吡啶-2-基)-1,4,5,6-四氢环戊二烯并[d]咪唑(60mg,0.3mmol)、醋酸铜(54mg,0.3mmol)、2,2'-联吡啶(47mg,0.3mmol)和碳酸钠(64mg,0.6mmol)。反应体系置换氧气后,于70℃反应过夜。待反应液冷至室温,用硅藻土过滤,减压浓缩,所得残余物经厚制备板纯化(二氯甲烷:甲醇=30:1),得标题化合物为淡黄色固体(21mg,20%)。LCMS[M+1]
+:358.2。
1H NMR(400MHz,CDCl
3)δ:8.20(s,1H),8.10(s,1H),7.76(m,1H),7.71(m,1H),7.62(m,1H),7.55(m,1H),6.94(m,1H),3.64(s,3H),2.84(m,2H),2.72(m,2H),2.55(m,2H),2.10(s,3H)。
实施例18
6-(2-(3-氯-4-氟苯基)-4-甲基-1H-咪唑-1-基)咪唑并[1,2-b]哒嗪-3-甲酰胺
步骤1)2-(3-氯-4-氟苯基)-4-甲基-1H-咪唑
向3-氯-4-氟苯甲脒(1g,5.81mmol)的四氢呋喃(15mL)溶液中依次加入水(3mL),碳酸钾(1.6g,11.62mmol)和氯代丙酮(538mg,5.81mmol),升温至70℃反应18小时。待反应液冷至室温,向反应液中加入水(30mL),用乙酸乙酯(30mL x 2)萃取,合并有机相,经饱和氯化钠溶液洗,无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化(DCM:MeOH=30:1)得到标题化合物为淡黄色固体(870mg,71%)。LCMS[M+H]
+:211.1。
步骤2)6-(2-(3-氯-4-氟苯基)-4-甲基-1H-咪唑-1-基)咪唑并[1,2-b]哒嗪-3-甲腈
6-(2-(3-氯-4-氟苯基)-4-甲基-1H-咪唑-1-基)咪唑并[1,2-b]哒嗪-3-甲腈的制备方法参照实施例1,除了用2-(3-氯-4-氟苯基)-4-甲基-1H-咪唑代替2-(6-甲基吡啶-2-基)-1,4,5,6-四氢环戊二烯并[d]咪唑,得标题化合物为淡黄色浆状物(250mg,75%)。LCMS[M+H]
+:353.1。
步骤3)6-(2-(3-氯-4-氟苯基)-4-甲基-1H-咪唑-1-基)咪唑并[1,2-b]哒嗪-3-甲酰胺
6-(2-(3-氯-4-氟苯基)-4-甲基-1H-咪唑-1-基)咪唑并[1,2-b]哒嗪-3-甲酰胺的制备方法参照实施例2,除了 用6-(2-(3-氯-4-氟苯基)-4-甲基-1H-咪唑-1-基)咪唑并[1,2-b]哒嗪-3-甲腈代替6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-b]哒嗪-3-甲腈,得标题化合物为白色固体(22mg,22%)。LCMS[M+H]
+:371.1。
1H NMR(500MHz,CDCl
3)δ:8.60(s,1H),8.18(m,1H),7.69(m,1H),7.59(s,1H),7.22-7.18(m,2H),7.13(m,1H),7.08(m,1H),5.78(s,1H),2.39(s,3H)。
实施例19
6-(4-甲基-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈
步骤1)2-甲基-6-(4-甲基-1H-咪唑-2-基)吡啶
向6-甲基吡啶-2-甲脒(1.2g,8.9mmol)的四氢呋喃(12mL)溶液中加入碳酸钾(1.25g,9mmol)的水溶液(1.2mL)和氯丙酮(0.7g,7.6mmol),加完升温至55℃左右反应3.5小时。待反应液冷至室温,过滤,滤液经减压浓缩,所得残余物经硅胶柱层析纯化(二氯甲烷:甲醇=30:1),得标题化合物为黄色固体(750mg,57%)。LC-MS[M+H
]+:174.1。
步骤2)6-(4-甲基-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈
向25mL反应瓶中加入2-甲基-6-(4-甲基-1H-咪唑-2-基)吡啶(104mg,0.6mmol)、3-氰基咪唑并[1,2-a]吡啶-6-硼酸频哪醇酯(242mg,0.9mmol)、醋酸铜(109mg,0.6mmol)、2,2’-联吡啶(93.8mg,0.6mmol)、碳酸钠(127.2mg,1.2mmol)和1,2-二氯乙烷(4mL)。反应体系置换氧气后,所得混合物加热至70℃左右反应18小时。待反应液冷至室温,过滤,滤液经减压浓缩,所得残余物经硅胶柱层析纯化(二氯甲烷:甲醇=25:1)得油状粗品400mg。取油状粗品150mg用厚制备板纯化(二氯甲烷:甲醇=25:1),得标题化合物为黄色固体(47mg,66%)。LC-MS[M+H]
+:315.25。
1H-NMR(500MHz,CDCl
3)δ:8.52(s,1H),8.24(s,1H),7.94(d,J=7.5Hz,1H),7.76(d,J=9.5Hz,1H),7.63(t,J=7.5Hz,1H),7.48(d,J=9.5Hz,1H),7.02(d,J=7.5Hz,1H),6.94(s,1H),2.39(s,3H),2.12(s,3H)。
实施例20
6-(4-甲基-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-甲基-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例2,除了6-(4-甲基-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈代替6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-b]哒嗪-3-甲腈,得标题化合物为白色固体(20mg,24%)。LC-MS[M+H]
+:333.2。
1H NMR(500MHz,DMSO)δ:9.54(s,1H),8.42(s,1H),8.05(m,1H),7.81(d,J=8.0Hz,1H),7.72(dd,J=17.0,9.5Hz,2H),7.46(d,J=2.0Hz,1H),7.44(d,J=2.0Hz,1H),7.35(s,1H),7.10(d,J=7.5Hz,1H),2.26(s,3H),1.99(s,3H)。
实施例21
N-(2-羟基乙基)-6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-甲酰胺
步骤1)6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-甲酸
向25mL反应瓶中依次加入水(680μL)、浓硫酸(170μL)、乙酸(340μL)和6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-甲腈(34mg,0.1mmol),所得混合物升温至100℃反应7小时。待反应液冷至室温,减压浓缩以去除大部分乙酸,再用饱和碳酸氢钠水溶液调节pH至5~6,减压浓缩,所得残余物直接用于下一步反应。
步骤2)N-(2-羟基乙基)-6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-甲酰胺
向上述装有6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-甲酸的反应瓶中加入乙腈(3mL)、EDCI(30mg,0.16mmol)、HOBt(21mg,0.16mmol)、乙醇胺(12μL,0.19mmol)和三乙胺(50μL,0.36mmol),所得混合物室温搅拌反应48小时。减压浓缩,向所得残余物中加入水(8mL),用乙酸乙酯萃取(8mL x 2),合并有机相,用饱和氯化钠水溶液(10mL)洗涤,无水硫酸钠干燥,减压浓缩,所得残余物经厚制备板纯化(二氯甲烷:甲醇=15:1),得标题化合物为淡黄色固体(7mg,17%)。LC-MS[M+H]
+:403.3。
1H-NMR(500MHz,DMSO)δ:9.54(s,1H),8.60(t,J=5.5Hz,1H),8.43(s,1H),7.78(d,J=8.0Hz,1H),7.76(d,J=9.5Hz,1H),7.70(t,J=7.5Hz,1H),7.46(dd,J=9.5,2.0Hz,1H),7.08(d,J=7.5Hz,1H),4.77(m,1H),3.52(t,J=6.0Hz,2H),3.33(t,J=6.0Hz,2H),2.78–2.62(m,4H),2.47(m,2H),1.97(s,3H)。
实施例22
6-(4-(2-羟基乙基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈
步骤1)4-(三苯基甲氧基)-1-丁醇
向干燥的反应瓶中加入分子筛(2.5g),置换氮气,用注射器加入1,4-丁二醇(1.2g,13.3mmol)的二氯甲烷溶液(5mL)、三苯基氯甲烷(0.97g,3.5mmol)的二氯甲烷溶液(3mL)和吡啶(0.32g,4.0mmol),所得混合物室温搅拌过夜。过滤,向滤液中加入二氯甲烷(10mL)和水(10mL),分层后有机相再用饱和食盐水洗涤(15mL),无水硫酸钠干燥,减压浓缩,所得残余物经硅胶柱层析纯化(石油醚:乙酸乙酯=5:1),得标题化合物为白色固体(690mg,61%)。
1H-NMR(500MHz,CDCl
3)δ:7.47(d,J=7.8Hz,6H),7.32(t,J=7.5Hz,6H),7.26(t,J=7.2Hz,3H),3.66(d,J=5.6Hz,2H),3.14(t,J=5.3Hz,2H),1.76–1.64(m,5H)。
步骤2)4-(三苯基甲氧基)丁醛
氮气保护下,向50mL双口圆底烧瓶中加入草酰氯(228μL,2.70mmol)的二氯甲烷溶液3mL,冷却至-78℃左右,再慢慢滴加DMSO(365μL,5.14mmol)的二氯甲烷熔液(2mL),加完搅拌10分钟后,再加入4-(三苯基甲氧基)-1-丁醇(570mg,1.77mmol)的二氯甲烷溶液(3mL)和三乙胺(715μL,5.14mmol)。所得混合物在-78℃下继续反应1小时。加入水(15mL),用二氯甲烷(3×10mL)萃取,合并有机相,用饱和食盐水洗,无水硫酸钠干燥,减压浓缩,得标题化合物为油状粗品(600mg,95%)。不纯化直接用于下一步反应。
1H-NMR(500MHz,CDCl
3)δ:9.81(s,1H),7.45(d,J=7.5Hz,6H),7.32(t,J=7.4Hz,6H),7.29–7.25(m,3H),3.16(t,J=6.0Hz,2H),2.56(t,J=7.1Hz,2H),1.96(p,J=6.5Hz,2H)。
步骤3)2-氯-4-(三苯基甲氧基)丁醛
氮气保护下,向50mL双口圆底烧瓶中加入L-脯氨酸(70mg,0.57mmol)和4-(三苯基甲氧基)丁醛(1.8g,5.6mmol)的二氯甲烷溶液(8mL),冷却至0℃左右,加入NCS(695mg,5.2mmol)的二氯甲烷混悬液(4mL),所得混合物于0℃搅拌过夜。向反应液中加入饱和碳酸氢氢钠水溶液(20mL),并转移至室温搅拌15分钟,分液,水相用二氯甲烷(15mL x 2)萃取,合并有机相,有机相用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,得标题化合物为浅棕色油状物(2g,98%),不纯化直接用于下一步反应。
步骤4)2-甲基-6-(4-(2-(三苯基甲氧基)乙基)-1H-咪唑-2-基)吡啶
向6-甲基吡啶-2-甲脒(0.37g,2.74mmol)的四氢呋喃(8mL)溶液中加入碳酸钾(0.49g,3.5mmol)的水溶液(1mL)和2-氯-4-(三苯基甲氧基)丁醛(1g,2.75mmol),所得混合物升温至65℃反应过夜。待反应液冷至室温,加水(10mL),用乙酸乙酯萃取(10mL x 2),合并有机相,用饱和食盐水洗,无水硫酸钠干燥,减压浓缩,将所得残余物溶于二氧六环(10mL),加热至85℃反应4.5小时。待反应液冷至室温,减压浓缩,所得残余物经硅胶柱层析纯化(二氯甲烷:甲醇=100:1),得标题化合物为棕色固体(316mg,26%)。LC-MS[M+H]
+:445.8。
步骤5)6-(2-(6-甲基吡啶-2-基)-4-(2-(三苯基甲氧基)乙基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈
向25mL反应瓶中加入2-甲基-6-(4-(2-(三苯基甲氧基)乙基)-1H-咪唑-2-基)吡啶(316mg,0.7mmol)、3-氰基咪唑并[1,2-a]吡啶-6-硼酸频哪醇酯(258mg,0.96mmol)、醋酸铜(116mg,0.64mmol)、2,2’-联吡啶(100mg,0.64mmol)、碳酸钠(150mg,1.4mmol)和1,2-二氯乙烷(7mL),置换氧气,所得混合物加热至80℃反应过夜。待反应液冷至室温,用硅藻土过滤,减压浓缩,所得残余物经硅胶柱层析纯化(二氯甲烷:甲醇=50:1),得含标题化合物的粗品(270mg,65.8%)。LC-MS[M+H]
+:587.2。
步骤6)6-(4-(2-羟基乙基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈
向6-(2-(6-甲基吡啶-2-基)-4-(2-(三苯基甲氧基)乙基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈粗品(270mg,0.46mmol)的四氢呋喃(3mL)溶液中加入1N HCl(3.5mL),所得混合物加热至60℃反应2小时。待反应液冷至室温,用饱和碳酸氢钠水溶液调节pH至中性,减压浓缩,所得残余物经硅胶柱层析纯化(二氯甲烷:甲醇=20:1)得粗品,再经厚制备板(二氯甲烷:甲醇=20:1)纯化得标题化合物为浅橙色固体(14mg,9%),LC-MS[M+H]
+:345.3。
1H-NMR(500MHz,DMSO)δ:8.95(s,1H),8.55(s,1H),7.85(t,J=9.5Hz,2H),7.74(t,J=7.8Hz,1H),7.58(dd,J=9.5,1.9Hz,1H),7.42(s,1H),7.14(d,J=7.6Hz,1H),4.69(s,1H),3.75(t,J=7.0Hz,2H),2.78(t,J=7.0Hz,2H),2.03(s,3H)。
实施例23
6-(4-(2-羟基乙基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
向25mL反应瓶中加入6-(4-(2-羟基乙基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈(14mg,0.041mmol)和二氯甲烷(1.5mL),降温至5℃,再加入20%的氢氧化钠溶液(85μL)、四丁基硫酸氢铵(5mg)和30%H
2O
2(80μL),加完室温搅拌反应20分钟。减压浓缩,向所得残余物中加入水(5mL),搅拌5分钟,过滤,滤饼再用水(5mL)打浆一次,过滤,烘干得标题化合为浅橙色固体(9mg,61%),LC-MS[M+H]
+:363.3。
1H-NMR(500MHz,DMSO)δ:9.53(d,J=1.0Hz,1H),8.42(s,1H),8.05(s,1H),7.83(d,J=7.5Hz,1H),7.72(m,2H),7.44(dd,J=9.5,2.0Hz,2H),7.36(s,1H),7.10(d,J=7.6Hz,1H),4.69(s,1H),3.74(t,J=6.5Hz,2H),2.76(t,J=7.0Hz,2H),1.98(s,3H)。
实施例24
6-(3-(3-氯-4-氟苯基)-5-乙基-4H-1,2,4-三氮唑-4-基)咪唑并[1,2-a]吡啶-3-甲腈
步骤1)N,N-二甲基-N'-(5-硝基吡啶-2-基)甲脒
向5-硝基吡啶-2-胺(5.0g,36.0mmol)的乙醇(60mL)溶液中,加入N,N-二甲基甲酰胺二甲基缩醛(8.6g,72.0mmol),加热回流反应4小时。待反应液冷却至室温,过滤,滤饼经烘干得标题化合物为黄色固体(6.7g,96%)。LC-MS[M+H]
+:195.1。
步骤2)N'-(5-氨基吡啶-2-基)-N,N-二甲基甲脒
向N,N-二甲基-N'-(5-硝基吡啶-2-基)甲脒(6.5g,33.5mmol)的乙醇(40mL)和乙酸乙酯(40mL)混合溶液中,加入10%钯碳(700mg),置换氢气,室温搅拌反应8小时。所得混合物经硅藻土过滤,用乙酸乙酯淋洗滤饼,滤液经减压浓缩,所得残余物用石油醚(150mL)和乙酸乙酯(15mL)打浆纯化,得到标题化合物为棕黄色固体(5.3g,96%)。LC-MS[M+H]
+:165.1。
步骤3)(6-((二甲氨基)亚甲基)氨基)吡啶-3-基)氨基甲酸叔丁酯
向N'-(5-氨基吡啶-2-基)-N,N-二甲基甲脒(5.7g,34.7mmol)的四氢呋喃(100mL)溶液中,加入Boc酸酐(11.4g,52.0mmol)和三乙胺(6.7g,69.2mmol),室温搅拌反应16小时。减压浓缩,加入石油醚(100mL)打浆纯化得标题化合物为棕黄色固体(6.0g,65%)。LC-MS[M+H]
+:265.2。
步骤4)(3-氰基咪唑并[1,2-a]吡啶-6-基)氨基甲酸叔丁酯
向(6-((二甲氨基)亚甲基)氨基)吡啶-3-基)氨基甲酸叔丁酯(6.0g,22.7mmol)的异丙醇(60mL)溶液中,加入溴乙腈(5.4g,45.4mmol)和碳酸氢钠(5.7g,68.1mmol),所得混合物加热回流反应16小时。待反应液冷至室温,减压浓缩,用二氯甲烷(100mL)溶解,过滤,滤液经减压浓缩,再用石油醚(100mL)和乙酸乙酯(10mL)打浆纯化,得到标题化合物为淡黄色固体(4.5g,77%)。LC-MS[M+H]
+:259.1。
步骤5)6-氨基咪唑[1,2-a]吡啶-3-甲腈
冰浴下,向(3-氰基咪唑并[1,2-a]吡啶-6-基)氨基甲酸叔丁酯(5.5g,21.3mmol)的四氢呋喃(60mL)溶液中,滴加盐酸(18.0mL,0.21mol),然后移至室温搅拌反应16小时。将反应液用冰浴冷却,再用15%氢氧化钠溶液调pH为8左右,所得混合物用乙酸乙酯(50mL x 3)萃取,合并有机相,经饱和盐水洗,无水硫酸钠干燥,过滤,减压浓缩,得标题化合物为黄色固体(3.0g,89%)。LC-MS[M+H]
+:159.1。
步骤6)3-氯-4-氟苯甲酸
向3-氯-4-氟苯甲酸乙酯(500mg,2.47mmol)的乙醇(3mL)溶液中加入氢氧化锂(114mg,2.71mmol)的水溶液(850μL),所得混合物室温搅拌反应2.5小时。减压浓缩除去溶剂,向残余物中加水(10mL),滴加2N HCl调节pH至3左右,有大量固体析出,过滤,滤饼用水洗,真空干燥后得标题化合物为粉红色固体(400mg,93%)。LC-MS[M-H]
-:173.0。
步骤7)2-(3-氯-4-氟苯甲酰基)肼-1-氨基甲酸叔丁酯
向3-氯-4-氟苯甲酸(400mg,2.3mmol)的二氯甲烷(4mL)溶液中加入HATU(956mg,2.5mmol)、三乙胺(475μL,3.43mmol)和叔丁氧羰基肼(302mg,2.29mmol),所得混合物室温反应2小时。减压浓缩除去溶剂,所得残余物经水(6mL)打浆纯化,过滤,滤饼用水洗,真空干燥后得标题化合物为粉红色固体(570mg,86%)。LC-MS[M+H
]+:288.0。
步骤8)3-氯-4-氟苯甲酰肼
向2-(3-氯-4-氟苯甲酰基)肼-1-氨基甲酸叔丁酯(570mg,2mmol)的二氧六环(4mL)溶液中缓慢加入浓盐酸(0.4mL,4mmol),室温反应3小时,再补加浓盐酸(0.4mL,4mmol),继续搅拌过夜。减压浓缩,向所得残余物中加入水(15mL)和乙酸乙酯(15mL),用饱和碳酸氢钠水溶液调节pH至7~8,分液,水相用乙酸乙酯(10mL x 3)萃取,合并有机相,有机相经饱和食盐水洗,无水硫酸钠干燥,减压浓缩,得浅绿色固体粗品(370mg,98%)。LC-MS[M+H]
+:189.2。
步骤9)3-氯-4-氟-N'-丙酰基苯甲酰肼
向3-氯-4-氟苯甲酰肼(370mg,1.97mmol)的二氯甲烷(4mL)溶液中加入N,N-二异丙基乙胺(305mg,2.36mmol),冰水浴冷却,缓慢滴加丙酰氯(182mg,1.97mmol),所得混合物升至室温反应40分钟。减压浓缩,所得残余物经硅胶柱层析纯化(乙酸乙酯:甲醇=100:1),得标题化合物为白色固体(347mg,72%)。LC-MS[M+H]
+:245.1。
步骤10)6-(3-(3-氯-4-氟苯基)-5-乙基-4H-1,2,4-三氮唑-4-基)咪唑并[1,2-a]吡啶-3-甲腈
向3-氯-4-氟-N'-丙酰基苯甲酰肼(347mg,1.42mmol)的甲苯(3mL)溶液中加入五氯化磷(296mg,1.42mmol),所得混合物加热至100℃反应1小时。待反应液冷至室温,减压浓缩彻底除去溶剂和五氯化磷,向所得残余物中加入二甲基苯胺(2mL)和6-氨基咪唑[1,2-a]吡啶-3-甲腈(224mg,158mmol),所得混合物加热至130℃反应5小时。待反应液冷至室温,减压浓缩,所得残余物经硅胶柱层析纯化(二氯甲烷:甲醇=30:1)得油状粗品110mg(主要含目标产物和二甲基苯胺)。取油状粗品55mg,经厚制备板纯化(二氯甲烷:甲醇=20:1)得标题化合物为淡黄色固体(20mg,7.6%)。LC-MS[M+H]
+:367.2。
1H-NMR(500MHz,DMSO)δ:9.26(d,J=1.0Hz,1H),8.58(s,1H),7.98(d,J=9.5Hz,1H),7.82–7.75(m,1H),7.65(dd,J=9.5,2.0Hz,1H),7.40–7.37(m,1H),7.37(s,1H),2.65(m,2H),1.20(t,J=7.5Hz,3H)。
实施例25
6-(3-(3-氯-4-氟苯基)-5-乙基-4H-1,2,4-三氮唑-4-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(3-(3-氯-4-氟苯基)-5-乙基-4H-1,2,4-三氮唑-4-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例23,除了用6-(3-(3-氯-4-氟苯基)-5-乙基-4H-1,2,4-三氮唑-4-基)咪唑并[1,2-a]吡啶-3-甲腈代替6-(4-(2-羟基乙基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈,得标题化合物为白色固体(15mg,25%)。LC-MS[M+H]
+:385.3。
1H NMR(500MHz,DMSO)δ:9.65(d,J=1.0Hz,1H),8.45(s,1H),8.11(s,1H),7.89(d,J=9.5Hz,1H),7.75(dd,J=7.1,1.9Hz,1H),7.58(dd,J=9.5,2.0Hz,1H),7.53(s,1H),7.40(t,J=8.9Hz,1H),7.38–7.32(m,1H),2.62(q,J=7.5Hz,2H),1.22(t,J=7.5Hz,3H)。
实施例26
6-(3-乙基-5-(6-甲基吡啶-2-基)-4H-1,2,4-三氮唑-4-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(3-乙基-5-(6-甲基吡啶-2-基)-4H-1,2,4-三氮唑-4-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例25,除了用6-甲基-2-吡啶甲酸甲酯代替3-氯-4-氟苯甲酸乙酯,得标题化合物为淡黄色固体(15mg,57%)。LC-MS[M+H]
+:348.3。
1H-NMR(500MHz,DMSO)δ:9.58(d,J=1.0Hz,1H),8.44(s,1H),8.07(m,1H),7.90(d,J=7.5Hz,1H),7.83(d,J=9.5Hz,1H),7.78(t,J=7.5Hz,1H),7.58(dd,J=9.5,2.0Hz,1H),7.48(m,1H),7.19(d,J=8.0Hz,1H),2.64(q,J=7.5Hz,2H),1.97(s,3H),1.22(t,J=7.5Hz,3H)。
实施例27
6-(5-甲基-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
步骤1)2-溴丙醛
冰浴下,向正丙醛(1.0g,17.2mmol)的二氯甲烷(10mL)溶液中加入溴素(2.48g,15.5mmol),同温度下继续搅拌4小时。向反应液中加水(10mL),分液,有机层用饱和碳酸氢钠溶液洗,饱和食盐水洗,无水硫酸钠干燥,过滤,减压浓缩得无色油状物1.8g,不纯化直接用于后续反应。
步骤2)6-甲基吡啶-2-甲亚胺酸甲酯
向6-甲基吡啶-2-甲腈(1.5g,12.7mmol)的甲醇(20mL)溶液中,加入甲醇钠(1.7g,31.75mmol),所得混合物加热回流反应3小时。待反应液冷却至室温,减压浓缩,所得残余物用二氯甲烷溶解,过滤,滤液经减压浓缩,所得残余物经硅胶柱层析纯化(石油醚:乙酸乙酯=3:1),得标题化合物为类白色固体(1.0g,52%)。LC-MS[M+H]
+:151.1。
步骤3)N-(3-氰基咪唑并[1,2-a]吡啶-6-基)-6-甲基吡啶甲脒
氮气保护下,向6-氨基咪唑[1,2-a]吡啶-3-甲腈(1.0g,6.6mmol)的DMF(7mL)溶液中加入60%氢化钠(390mg,9.8mmol),加热至60℃搅拌30分钟。待反应液冷至室温,再滴加6-甲基吡啶-2-甲亚胺酸甲酯(700mg,4.43mmol)的DMF(5mL)溶液,加完后升温至60℃搅拌反应2小时。反应液用冰浴冷却,滴加水直至不冒气泡,再加水(20mL),用乙酸乙酯(20mL x 3)萃取,合并有机层,用饱和盐水(30mL x 3)洗,无水硫酸钠干燥,过滤,减压浓缩,所得残余物经硅胶柱层析纯化(二氯甲烷:甲醇=50:1)得标题化合物为灰色固体(200mg,11%)。LC-MS[M+H]
+:277.1。
步骤4)6-(5-甲基-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈
向N-(3-氰基咪唑并[1,2-a]吡啶-6-基)-6-甲基吡啶甲脒(400mg,1.45mmol)的异丙醇(10mL)溶液中加入2-溴丙醛(800mg,5.80mmol)和碳酸氢钠(730mg,8.7mmol),所得混合物加热回流反应72小时。待反应液冷至室温,过滤,减压浓缩,所得残余物经厚制备板纯化(二氯甲烷:甲醇=50:1)得标题化合物为淡黄色固体(25mg,5.5%)。LC-MS[M+H]
+:315.2。
步骤5)6-(5-甲基-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(5-甲基-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例23,除了用6-(5-甲基-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈代替6-(4-(2-羟基乙基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈,得标题化合物为白色固体(12mg,45%)。LC-MS[M+H]
+:333.2。
1H-NMR(400MHz,CDCl
3)δ:9.49(s,1H),8.16(s,1H),7.89(d,J=6.0Hz,1H),7.80(d,J=7.6Hz,1H),7.57(t,J=6.0Hz,1H),7.45(d,J=7.6Hz,1H),7.06(s,1H),6.92(d,J=6.0Hz,1H),5.79-5.63(m,2H),2.16(s,3H),2.00(s,3H)。
实施例28
6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈
步骤1)(2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)甲醇
向100mL反应瓶中加入25%氨水溶液(40mL)、6-甲基吡啶-2-甲脒(1.2g,8.9mmol)、1,3-二羟基丙酮二聚体(3.2g,17.8mmol)和氯化铵(5.35g,0.1mol),所得混合物加热至80℃反应4小时。待反应液冷至室温,减压浓缩,再加入二氯甲烷(100mL),搅拌溶解,过滤除去无机盐,滤液经减压浓缩,所得残余物经硅胶柱层析纯化(二氯甲烷:甲醇=50:1)得棕色稠状物(1.2g,71%)。LC-MS[M+H]
+:190.1。
步骤2)2-(4-(氯甲基)-1H-咪唑-2-基)-6-甲基吡啶盐酸盐
向100mL反应瓶中加入(2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)甲醇(1.2g,6.3mmol))和氯化亚砜(20mL),加热回流反应5小时。待反应液冷至室温,减压浓缩彻底除去氯化亚砜,得粗产品2.0g,不纯化直接用于下一步反应。
步骤3)2-氟-N-((2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)甲基)苯胺
向上述2-(4-(氯甲基)-1H-咪唑-2-基)-6-甲基吡啶盐酸盐粗品的乙腈(25mL)溶液中加入二异丙基乙胺(2.44g,18.9mmol)和邻氟苯胺(840mg,7.6mmol),所得混合物室温搅拌反应2小时。减压浓缩,所得残余物经硅胶柱层析纯化(二氯甲烷:甲醇=100:1))得标题化合物为棕色稠状物(1.0g,两步收率:53%)。LC-MS[M+H]
+:283.1。
步骤4)6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈
向25mL反应瓶中加入2-氟-N-((2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)甲基)苯胺(284mg,1.0mmol)、3-氰基咪唑并[1,2-a]吡啶-6-硼酸频哪醇酯(323mg,1.2mmol)、醋酸铜(100mg,0.5mmol)、2,2-二联吡啶(156mg,1.0mmol)、碳酸钾(276mg,2.0mmol)、乙二醇二甲醚(8mL)和水(2mL),所得混合物加热回流反应4小时。待反应液冷至室温,过滤,用乙酸乙酯(50mL)淋洗滤饼,滤液用饱和盐水洗,无水硫酸钠干燥,减压浓缩,所得残余物经硅胶柱层析纯化(二氯甲烷:甲醇=100:1)得标题化合物为白色固体(140mg,33%)。LC-MS[M+H]
+:424.2。
1H-NMR(400MHz,CDCl
3)δ:8.54(s,1H),8.26(s,1H),7.99(d,J=6.4Hz,1H),7.79(d,J=7.6Hz,1H),7.69(t,J=6.4Hz,1H),7.49(d,J=7.6Hz,1H),7.15(s,1H),7.08-7.00(m,3H),6.85(t,J=6.4Hz,1H),6.71-6.67(m,1H),4.51(s,2H),2.14(s,3H)。
实施例29
6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例23,除了用6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈代替6-(4-(2-羟基乙基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈,得标题化合物为白色固体(30mg,36%)。LC-MS[M+H]
+:442.2。
1H-NMR(400MHz,CDCl
3)δ:9.63(s,1H),8.18(s,1H),7.91(d,J=6.4Hz,1H),7.72(d,J=7.6Hz,1H),7.62(t,J=6.4Hz,1H),7.46(d,J=7.6Hz,1H),7.15(s,1H),7.05-6.99(m,3H),6.86(t,J=6.4Hz,1H),6.69-6.65(m,1H),5.92-5.69(m,2H),4.48(s,2H),2.13(s,3H)。
实施例30
N-((1-([1,2,4]三氮唑并[1,5-a]吡啶-6-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)甲基)-2-氟苯胺
N-((1-([1,2,4]三氮唑并[1,5-a]吡啶-6-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)甲基)-2-氟苯胺的制备方法参照实施例28,除了用[1,2,4]三氮唑并[1,5-a]吡啶-6-硼酸频哪醇酯代替3-氰基咪唑并[1,2-a]吡啶-6-硼酸频哪醇酯,得标题化合物为白色固体(15mg,5.3%)。LC-MS[M+H]
+:400。
1H-NMR(400MHz,CDCl
3)δ:8.73(m,1H),8.46(m,1H),7.96(m,1H),7.80(m,1H),7.67(m,1H),7.57(m,1H),7.15(s,1H),7.07-7.00(m,3H),6.84(m,1H),6.71-6.67(m,1H),4.52(s,2H),2.11(s,3H)。
实施例31
6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)-3-(2-吗啉基乙基)喹唑啉-4(3H)-酮
1)6-溴-3-(2-溴乙基)喹唑啉-4(3H)-酮
向反应瓶中加入6-溴-4(3H)-喹唑啉酮(675mg,3mmol)和DMF(15mL),氮气保护,冷却至0℃,加入60%氢化钠(240mg,6mmol)。升至室温搅拌反应1小时,加入1,2-二溴乙烷(5.6g,30mmol),继续搅拌反应2小时。将反应液倒入到冰水(30mL)中淬灭,用乙酸乙酯萃取(50mL x 2),合并有机层,用饱和氯化钠水溶液洗涤(80mL x 2),无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化(DCM),得标题化合物为白色固体(720mg,73%)。LC-MS[M+H]
+:333.0。
2)6-溴-3-(2-吗啉基乙基)喹唑啉-4(3H)-酮
向6-溴-3-(2-溴乙基)喹唑啉-4(3H)-酮(498mg,1.5mmol)的DMF(8mL)溶液中加入吗啉(144mg,1.65mmol)和碳酸钾(311mg,2.25mmol),所得混合物加热至70℃过夜。待反应液冷至室温,加入水(30mL),用乙酸乙酯萃取(30mL x 2),合并有机层,用饱和氯化钠水溶液洗涤(50mL x 2),无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化(二氯甲烷:甲醇=25:1),得标题化合物为浆状物(400mg,79%)。LC-MS[M+H]
+:338.0。
3)3-(2-吗啉基乙基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)喹唑啉-4(3H)-酮
向6-溴-3-(2-吗啉基乙基)喹唑啉-4(3H)-酮(400mg,1.18mmol)的1,4-二氧六环(8mL)溶液中加入联硼酸频那醇酯(900mg,3.55mmol)、Pd(dppf)Cl
2(69mg,0.094mmol)和乙酸钾(235mg,2.36mmol)),氮气保护,所得混合物加热至100℃反应2.5小时。待反应液冷至室温后,减压浓缩,所得残余物经柱层析纯化(二氯甲烷:甲醇=25:1),得标题化合物为浅棕色浆状物(394mg,87%)。LC-MS[M+H]
+:386.3。
4)6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)-3-(2-吗啉基乙基)喹唑啉-4(3H)-酮
向6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)-3-(2-吗啉基乙基)喹唑啉-4(3H)-酮(116mg,0.3mmol)的1,2-二氯乙烷(1.5mL)溶液中加入2-(6-甲基吡啶-2-基)-1,4,5,6-四氢环戊二烯并[d]咪唑(40mg,0.2mmol)、醋酸铜(37mg,0.2mmol)、2,2'-联吡啶(32mg,0.2mmol)和碳酸钠(42.5mg,0.4mmol),反应体系置换氧气后,于70℃反应过夜。待反应液冷至室温,用硅藻土过滤,减压浓缩,所得残余物经厚制备板纯化(二氯甲烷:甲醇=25:1),得标题化合物为淡黄色固体(24mg,26%)。LC-MS[M+H]
+:457.3。1H-NMR(500MHz,CDCl
3)δ:8.20(d,J=1.7Hz,1H),8.12(s,1H),7.78(d,J=7.8Hz,1H), 7.71(d,J=8.6Hz,1H),7.63(dd,J=8.6,2.1Hz,1H),7.56(t,J=7.8Hz,1H),6.95(d,J=7.6Hz,1H),4.14(t,J=5.9Hz,2H),3.71(d,J=3.9Hz,4H),2.85(t,J=6.8Hz,2H),2.75(m,4H),2.56(s,6H),2.10(s,3H)。
实施例32
N,N-双(2-羟乙基)-6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-甲酰胺
1)6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-甲酸
向反应瓶中加入6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-甲腈(3g,8.82mmol),再加入由浓硫酸(15mL)、醋酸(30mL)和水(60mL)配成的混合溶液,搅拌升温至100℃左右反应过夜。待反应液冷至室温,减压浓缩至剩余40~50mL溶剂,冰水浴冷却,用固体碳酸氢钠调节pH至5左右,减压浓缩,所得残余物用甲醇(100mL)溶解,过滤,滤液经减压浓缩,得含标题化合物的棕色固体粗品(2.6g,82%)。LC-MS[M+H]
+:360.3。
2)N,N-双(2-羟乙基)-6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-甲酰胺
向6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-甲酸(72mg,0.20mmol)的二氯甲烷(1.5mL)溶液中加入三乙胺(50μL,0.36mmol)、HATU(83.6mg,0.22mmol)和二乙醇胺(25.3mg,0.24mmol),所得混合物室温搅拌反应4小时。将反应液倒入水(10mL)中,用DCM萃取(10mL x 3),合并有机层,用无水硫酸钠干燥,减压浓缩,所得残余物经制备板制备纯化(二氯甲烷:甲醇=15:1),得标题化合物为浅棕色固体(24mg,27%)。LC-MS[M+H]
+:447.3。
1H-NMR(500MHz,DMSO)δ:9.05(s,1H),8.28(s,1H),7.80(d,J=9.5Hz,1H),7.75-7.71(m,2H),7.53(m,1H),7.15(m,1H),4.95(s,2H),3.65(s,4H),3.09(m,4H),2.77(t,J=6.9Hz,2H),2.70(s,2H),2.56-2.52(m,2H),2.08(s,3H)。
实施例33
N-(1,3-二羟基-2-(羟甲基)丙烷-2-基)-6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-甲酰胺
N-(1,3-二羟基-2-(羟甲基)丙烷-2-基)-6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例32,除了用三羟甲基氨基甲烷代替二乙醇胺,得标题化合物为浅棕色固体(26mg,28%)。LC-MS[M+H]
+:463.3。
1H-NMR(500MHz,CDCl
3)δ:9.51(d,J=1.5Hz,1H),8.18(s,1H),7.74(d,J=7.9Hz,1H),7.65(d,J=9.4Hz,1H),7.59(t,J=7.8Hz,1H),7.36(m,1H),7.20(s,1H),6.98(d,J=7.7Hz,1H),3.71(s,6H),2.84(t,J=7.0Hz,2H),2.73(t,J=6.8Hz,2H),2.58(m,2H),2.09(s,3H)。
实施例34
(6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-基)(吗啉基)甲酮
(6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-基)(吗啉基)甲酮的制备方法参照实施例32,除了用吗啉代替二乙醇胺,得标题化合物为浅棕色固体(38mg,44%)。LC-MS[M+H]
+:429.4。
1H-NMR(500MHz,DMSO)δ:8.98(d,J=1.4Hz,1H),8.12(s,1H),7.81(d,J=7.9Hz,1H),7.75(d,J=9.5Hz,1H),7.70(t,J=7.8Hz,1H),7.47(m,1H),7.07(d,J=7.6Hz,1H),3.72(d,J=4.3Hz,4H),3.69-3.63(m,4H),2.70(m,4H),2.48(m,2H),1.98(s,3H)。
实施例35
(4-甲基哌嗪-1-基)(6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-基)甲酮
(4-甲基哌嗪-1-基)(6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-基)甲酮的制备方法参照实施例32,除了用1-甲基哌嗪代替二乙醇胺,得标题化合物为浅棕色固体(25mg,28.3%)。LC-MS[M+H]
+:442.3。
1H-NMR(500MHz,CDCl
3)δ:9.10(d,J=1.5Hz,1H),7.92(s,1H),7.88(d,J=7.9Hz,1H),7.65(d,J=9.5Hz,1H),7.58(t,J=7.8Hz,1H),7.36(dd,J=9.5,2.0Hz,1H),6.95(d,J=7.6Hz,1H),3.91(s,4H),2.83(t,J=7.0Hz,2H),2.77(t,J=6.9Hz,2H),2.60-2.51(m,6H),2.40(s,3H),2.11(s,3H)。
实施例36
(6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-羰基)甘氨酸
1)(6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-羰基)甘氨酸甲酯
(6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-羰基)甘氨酸甲酯的制备方法参照实施例32,除了用甘氨酸甲酯盐酸盐代替二乙醇胺,得标题化合物为棕色油状物(71mg,55%)。LC-MS[M+H]
+:431.4。
2)(6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-羰基)甘氨酸
向(6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-羰基)甘氨酸甲酯(71mg,0.16mmol)的甲醇(1mL)溶液中,加入氢氧化锂一水合物(39mg,0.93mmol)的水溶液(400μL),室温搅拌反应0.5小时,减压浓缩,所得残余物用水(2mL)溶解,用1N盐酸调pH至6左右,有固体析出,过滤,水洗,滤饼经真空干燥后得标题化合物为浅橙色固体(25mg,37%)。LC-MS[M+H]
+:417.3。
1H-NMR(500MHz,DMSO)δ:12.68(s,1H),9.49(d,J=1.5Hz,1H),8.98(t,J=5.9Hz,1H),8.47(s,1H),7.80(m,2H),7.69(t,J=7.8Hz,1H),7.48(m,1H),7.05(d,J=7.6Hz,1H),3.96(d,J=5.9Hz,2H),2.73-2.61(m,4H),2.48(d,J=6.8Hz,2H),1.94(s,3H)。
实施例37
6-(2-(5-氟-6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)-N-(2-羟基乙基)咪唑并[1,2-b]哒嗪-3-甲 酰胺
6-(2-(5-氟-6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)-N-(2-羟基乙基)咪唑并[1,2-b]哒嗪-3-甲酰胺的制备方法参照实施例21,除了用6-(2-(5-氟-6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-b]哒嗪-3-甲腈代替6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-甲腈,得标题化合物为类白色固体(6mg,10%)。LC-MS[M+H]
+:422.3。
1H-NMR(500MHz,DMSO)δ:8.39-8.35(m,2H),8.32(t,J=5.4Hz,1H),7.95(m,1H),7.75(t,J=9.1Hz,1H),7.46(d,J=9.6Hz,1H),3.49(m,2H),3.40(m,2H),2.88(t,J=6.7Hz,2H),2.71(t,J=6.9Hz,2H),2.49(m,2H),1.96(m,3H)。
实施例38
6-(2-(5-氟-6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)-N-(2-羟基乙基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(2-(5-氟-6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)-N-(2-羟基乙基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例21,除了用5-氟-6-甲基-2-氰基吡啶代替2-氰基-6-甲基吡啶,得标题化合物为类白色固体(22mg,19%)。LC-MS[M+H]
+:421.2。
1H-NMR(500MHz,DMSO)δ:9.54(d,J=1.5Hz,1H),8.59(t,J=5.7Hz,1H),8.44(s,1H),7.89(m,1H),7.79-7.73(m,1H),7.66(t,J=9.1Hz,1H),7.47(m,1H),3.52(t,J=6.1Hz,2H),3.39(d,J=6.1Hz,2H),2.73-2.63(m,4H),2.48(d,J=7.3Hz,2H),1.95(m,3H)。
实施例39
磷酸二氢-2-(6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)-N-(2-羟基乙基)咪唑并[1,2-a]吡啶-3-甲酰胺基)乙酯
氮气保护及0℃下,向N-(2-羟基乙基)-6-(2-(6-甲基吡啶-2-基)-5,6-二氢环戊二烯并[d]咪唑-1(4H)-基)咪唑并[1,2-a]吡啶-3-甲酰胺(100mg,0.25mmol)的磷酸三甲酯(1.5mL)溶液中滴加三氯氧磷(230μL,3.8mmol)。所得混合物于0℃继续反应4小时,滴加水(2mL)淬灭反应,用饱和碳酸氢钠水溶液调pH至8左右,用二氯甲烷(3mL)洗涤,收集水相并浓缩至干,所得残余物用甲醇(2mL)溶解,过滤,滤液经减压浓缩,所得残余物用水(1mL)溶解,用1N盐酸调pH至6左右,有固体慢慢析出,室温搅拌过夜,过滤,收集滤饼,水洗,烘干得标题化合物为浅橙色固体(19mg,16%)。LC-MS[M+H]
+:483.3。
1H-NMR(500MHz,MeOD)δ:9.58(d,J=1.3Hz,1H),8.39(d,J=12.3Hz,1H),7.80(m,2H),7.58(d,J=7.8Hz,1H),7.50(m,1H),7.32(d,J=7.8Hz,1H),4.04(m,2H),3.63(t,J=5.2Hz,2H),2.93(t,J=6.8Hz,2H),2.88-2.79(m,2H),2.68(m,2H),2.26(s,3H)。
实施例40
6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-b]哒嗪-3-甲酰胺
1)6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-b]哒嗪-3-甲腈
向反应瓶中加入2-氟-N-((2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)甲基)苯胺(84mg,0.3mmol)、6-氯咪唑并[1,2-b]哒嗪-3-甲腈(69mg,0.39mmol)、碘化亚铜(10mg,0.05mmol)、1,10-邻菲罗啉(17mg,0.09mmol)、碳酸钾(84mg,0.6mmol)和DMSO(3mL)。所得混合物于氮气保护下,加热至95℃搅拌反应过夜。待反应液冷至室温,加入水(15mL),用乙酸乙酯萃取(15mL x 2),合并有机层,用饱和食盐水洗涤(20mL x 3),无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化(二氯甲烷:甲醇=80:1)得粗品,再经厚制备板纯化(二氯甲烷:甲醇=25:1),得标题化合物为淡黄色固体(45mg,36%)。LC-MS[M+H]
+:425.2。
2)6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-b]哒嗪-3-甲酰胺
6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-b]哒嗪-3-甲酰胺的制备方法参照实施例23,除了用6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-b]哒嗪-3-甲腈代替6-(4-(2-羟基乙基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈,得标题化合物为类白色固体(10mg,45.2%)。LC-MS[M+H]
+:443.2。
1H-NMR(500MHz,CDCl
3)δ:9.45(d,J=1.3Hz,1H),8.16(s,1H),7.94(d,J=7.9Hz,1H),7.64(t,J=7.8Hz,1H),7.27(m,1H),7.15(s,1H),7.08-6.97(m,3H),6.90-6.82(m,1H),6.72-6.64(m,1H),5.86(s,2H),4.47(s,3H),2.16(s,3H)。
实施例41
8-氟-6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
8-氟-6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用8-氟-3-氰基咪唑并[1,2-a]吡啶-6-硼酸频哪醇酯代替3-氰基咪唑并[1,2-a]吡啶-6-硼酸频哪醇酯,得标题化合物为类白色固体(15mg,48%)。LC-MS[M+H]
+:460.2。
1H-NMR(500MHz,CDCl
3)δ:8.58(s,1H),8.11(d,J=9.5Hz,1H),8.01(d,J=7.8Hz,1H),7.82(s,1H),7.71(t,J=7.8Hz,1H),7.33(s,1H),7.24(d,J=9.5Hz,1H),7.09(d,J=7.7Hz,1H),7.02(m,2H),6.85(t,J=8.4Hz,1H),6.69(m,1H),5.84(s,1H),4.58(s,1H),4.50(s,2H),2.09(s,3H)。
实施例42
6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)-8-甲基咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)-8-甲基咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用8-甲基-3-氰基咪唑并[1,2-a]吡啶-6-硼酸频哪醇酯代替3-氰基咪唑并[1,2-a]吡啶-6-硼酸频哪醇酯,得标题化合物为类白色固体(10mg,44%)。LC-MS[M+H]
+:456.1。
1H-NMR(500MHz,CDCl
3)δ:9.47(d,J=1.3Hz,1H),8.13(s,1H),7.87(d,J=7.8Hz,1H),7.61(t,J=7.8Hz,1H),7.30(s,1H),7.14(s,1H),7.06-6.96(m,3H),6.87(m,1H),6.67(m,1H),5.77(s,2H),4.55(s,1H),4.47(s,2H),2.67(s,3H),2.14(s,3H)。
实施例43
6-(4-(1-((2-氟苯基)氨基)乙基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
1)2-(6-甲基吡啶-2-基)-1H-咪唑-4-甲醛
向(2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)甲醇(1g,5.28mmol)的二氯甲烷(10mL)和四氢呋喃(10mL)溶液中加入二氧化锰(3.68g,42.2mmol),加热至50℃反应过夜。待反应液冷却至室温,用硅藻土过滤,滤液经减压浓缩,用(石油醚:乙酸乙酯=4:1)的混合溶液打浆得标题化合物为灰白色固体(0.8g,81%)。LCMS[M+1]
+:188.1。
2)1-(2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)乙醇
0℃下,向2-(6-甲基吡啶-2-基)-1H-咪唑-4-甲醛(0.6g,3.21mmol)的四氢呋喃(10mL)溶液中滴加3M甲基溴化镁(3.74mL,11.2mmol),加完升至室温反应。2小时后,TLC显示反应完全。将反应液冷至0℃,滴加氯化铵溶液淬灭反应,加水(15mL),用乙酸乙酯萃取(15mL x 2),合并有机层,用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩得标题化合物为棕色固体(0.62g,95%)。LCMS[M+1]
+:204.1。
3)2-(4-(1-叠氮基乙基)-1H-咪唑-2基)-6-甲基吡啶
0℃下,向1-(2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)乙醇(0.58g,2.86mmol)和DBU(609mg,4.0mmol)的四氢呋喃(10mL)中滴加DPPA(1.1g,4.0mmol),所得混合物升至室温反应过夜。将反应液倒入水(15mL)中,用乙酸乙酯萃取(15mL x 2),合并有机层,用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化得标题化合物为浆状物(330mg,51%)。LCMS[M+1]
+:229.1。
4)1-(2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)乙胺
0℃下,向2-(4-(1-叠氮基乙基)-1H-咪唑-2-基)-6-甲基吡啶(0.33g,1.45mmol)的乙醇(6mL)和四氢呋喃(6mL)溶液中加入10%Pd/C(100mg),通入氢气(气球)。所得混合物于30℃反应3小时后,TLC显示反应完全。反应液经硅藻土过滤,减压浓缩得标题化合物为灰白色固体(240mg,82%)。LCMS[M+1]
+:203.1。
5)(1-(2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)乙基)氨基甲酸叔丁酯
向1-(2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)乙胺(202mg,1.0mmol)的四氢呋喃(5mL)和二氯甲烷(5mL)溶液中加入Boc酸酐(283mg,1.3mmol)和三乙胺(202mg,2.0mmol),所得混合物于室温反应3小时。反应液经减压浓缩,所得残余经柱层析纯化(=100:1至50:1)得标题化合物为白色固体(241mg,81%)。LCMS[M+1]
+:303.1。
6)(1-(1-(3-氰基咪唑并[1,2-a]吡啶-6-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)乙基)氨基甲酸叔丁酯
向(1-(2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)乙基)氨基甲酸叔丁酯(241mg,0.8mmol)的DME(15mL)溶液中加入3-氰基咪唑并[1,2-a]吡啶-6-硼酸频哪醇酯(240mg,0.89mmol)、醋酸铜一水合物(80mg,0.4mmol)和碳酸钾(220mg,1.60mmol)的水溶液(1mL)。置换氧气后,将反应液加热至70℃反应,45 分钟后,补加3-氰基咪唑并[1,2-a]吡啶-6-硼酸频哪醇酯(200mg,0.74mmol),再反应40分钟后,继续补加3-氰基咪唑并[1,2-a]吡啶-6-硼酸频哪醇酯(100mg,0.37mmol)。所得混合物再反应1小时后,停止搅拌,待反应液冷至室温,用硅藻土过滤,减压浓缩,所得残余物经柱层析纯化(=50:1)得标题化合物为淡黄色固体(240mg,68%)。LCMS[M+1]
+:444.2。
7)6-(4-(1-氨基乙基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈
向(1-(1-(3-氰基咪唑并[1,2-a]吡啶-6-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)乙基)氨基甲酸叔丁酯(240mg,0.54mmol)的二氯甲烷溶液(5mL)中加入三氟乙酸(0.5mL),所得混合物于室温反应3小时。反应液经减压浓缩,加水(15mL),用饱和碳酸氢钠溶液调pH至8左右,用二氯甲烷萃取(15mL x 3),合并有机层,用无水硫酸钠干燥,减压浓缩得标题化合物为淡黄色固体(180mg,97%)。LCMS[M+1]
+:344.2。
8)6-(4-(1-((2-氟苯基)氨基)乙基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈
向6-(4-(1-氨基乙基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈(65mg,0.19mmol)、Pd
2(dba)
3(17.4mg,0.019mmol)、X-Phos(18.1mg,0.038mmol)和碳酸钾(79mg,0.57mol)的1,4-二氧六环(2.7mL)溶液中加入2-氟-1-碘苯(210mg,0.95mmol),体系置换氮气,于110℃反应24小时。待反应液冷至室温,用硅藻土过滤,减压浓缩,所得残余物经厚制备板纯化(=20:1)得标题化合物为黄色浆状物(22mg,27%)。LCMS[M+1]
+:438.2。
9)6-(4-(1-((2-氟苯基)氨基)乙基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
向6-(4-(1-((2-氟苯基)氨基)乙基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈(22mg,0.050mmol)的1,4-二氧六环(1mL)中加入30%双氧水(56μL,0.50mmol)和氢氧化锂一水合物(10.5mg,0.25mmol)的水溶液(0.2mL),所得混合物于室温搅拌反应。40分钟后,TLC显示反应完全,减压浓缩除去部分溶剂,加水(5mL),用二氯甲烷和异丙醇的混合物溶液萃取,合并有机层,无水硫酸钠干燥,减压浓缩,所得残余物经厚制备板纯化(=15:1)得标题化合物为米白色固体(11mg,48%)。LCMS[M+1]
+:456.0。
1H-NMR(500MHz,CDCl
3)δ:9.38(s,1H),8.04(s,1H),7.92(d,J=8.0Hz,1H),7.59(m,2H),7.43(m,1H),7.29(m,4H),7.10(s,1H),7.02-6.96(m,2H),5.66(br,2H),4.02(m,1H),2.08(s,3H),1.51(d,J=6.5Hz,3H)。
实施例44
6-(4-(1-(2-氟苯甲酰胺基)乙基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
1)N-(1-(1-(3-氰基咪唑并[1,2-a]吡啶-6-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)乙基)-2-氟苯甲酰胺
向6-(4-(1-氨基乙基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈(35mg,0.10mmol)的二氯甲烷(1mL)溶液中加入三乙胺(28μL,0.20mmol)和2-氟苯甲酰氯(24μL,0.20mmol),所得混合物于室温反应1小时。减压浓缩,所得残余物经厚制备板纯化(二氯甲烷:甲醇=25:1)得标题化合物为泡沫状固体(47mg,100%)。LCMS[M+1]
+:466.2。
2)6-(4-(1-(2-氟苯甲酰胺基)乙基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(1-(2-氟苯甲酰胺基)乙基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例43,除了用N-(1-(1-(3-氰基咪唑并[1,2-a]吡啶-6-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)乙基)-2-氟苯甲酰胺代替6-(4-(1-((2-氟苯基)氨基)乙基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈,得标题化合物为白色固体(29mg,59%)。LCMS[M+1]
+:484.3。
1H-NMR(500MHz,CDCl
3)δ: 9.63(s,1H),8.14(m,2H),7.94(d,J=7.5Hz,1H),7.70(d,J=9.5Hz,1H),7.62(t,J=7.5Hz,1H),7.55(m,1H),7.47(m,2H),7.29(m,1H),7.15(m,2H),7.00(m,1H),5.77(br,2H),5.47(m,1H),2.11(s,3H),1.75(d,J=6.0Hz,3H)。
实施例45
6-(4-(2-(2-氟苯甲酰胺基)丙烷-2-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
1)2-(6-甲基吡啶-2-基)-1H-咪唑-4-甲酸
0℃下,向2-(6-甲基吡啶-2-基)-1H-咪唑-4-甲醛(0.6g,3.21mmol)的四氢呋喃(15mL)、叔丁醇(8mL)和水(8mL)溶液中加入2-甲基-2丁烯(2.7mL,32.1mmol)、磷酸二氢钠(2.50g,16.0mmol)和亚氯酸钠(1.45g,16.0mmol)。所得混合物搅拌5分钟后,升至室温反应。TLC显示反应完全后,旋干,加水,用1N盐酸调pH至5左右,过滤,烘干得标题化合物为白色固体(0.6g,91%)。LCMS[M+1]
+:204.1。
2)2-(6-甲基吡啶-2-基)-1H-咪唑-4-甲酸乙酯
0℃下,向2-(6-甲基吡啶-2-基)-1H-咪唑-4-甲酸(0.7g,3.45mmol)的乙醇(10mL)溶液中滴加氯化亚砜(1mL,13.8mmol)。所得混合物升至室温搅拌30分钟后,加热回流反应2天。待反应液冷至室温,旋干,加水,用碳酸氢钠饱和溶液调pH至8左右,再用乙酸乙酯萃取(15mL x 2),合并有机层,用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化(二氯烷基:甲醇=100:1为淡黄色固体(680mg,85%)。LCMS[M+1]
+:232.1。
3)2-(2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)丙-2-醇
0℃下,向2-(6-甲基吡啶-2-基)-1H-咪唑-4-甲酸乙酯(0.68g,2.94mmol)的四氢呋喃(12mL)溶液中滴加甲基溴化镁(4.9mL,14.7mol,3M in Et
2O)。所得混合物于60℃反应3小时,LCMS显示反应完全。反应液用冰浴冷却,再用饱和氯化铵溶液淬灭反应,加水(15mL),用乙酸乙酯(15mL0 x 2)萃取,合并有机层,用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,所得残余物经石油醚打浆得标题化合物为淡黄色固体(0.55g,86%)。LCMS[M+1]
+:218.1。
4)6-(4-(2-羟基丙烷-2-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈
向2-(2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)丙-2-醇(0.52g,2.40mmol)的DME(15mL)溶液中加入3-氰基咪唑并[1,2-a]吡啶-6-硼酸频哪醇酯(0.65mg,2.40mmol)、醋酸铜一水合物(478mg,2.40mmol)和碳酸钾(662mg,4.80mmol)的水溶液(3mL)。置换氧气后,反应液加热至70℃反应,30分钟后,补加3-氰基咪唑并[1,2-a]吡啶-6-硼酸频哪醇酯(391mg,1.44mmol),再反应30分钟后,继续补加3-氰基咪唑并[1,2-a]吡啶-6-硼酸频哪醇酯(261mg,0.96mmol)。所得混合物再反应1小时后,停止搅拌,待反应液冷至室温,用硅藻土过滤,减压浓缩,所得残余物经柱层析纯化(二氯甲烷:甲醇=100:1至50:1)得标题化合物为淡黄色固体(464mg,54%)。LCMS[M+1]
+:359.2。
5)6-(4-(2-叠氮基丙烷-2-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈
0℃下,向6-(4-(2-羟基丙烷-2-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈(464mg,1.29mmol)的四氢呋喃(10mL)溶液中滴加三氟化硼乙醚溶液(1.05mL,6.45mmol)和TMSN
3(258μL,2.58mmol),加完搅拌5分钟后,升至室温反应。TLC显示反应完全后,加水(15mL),用碳酸氢钠饱和溶液调pH至8左右,用乙酸乙酯(15mL x 2)萃取,合并有机层,用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化(石油醚:乙酸乙酯=2:1)得标题化合物为白色固体(360mg,73%)。LCMS[M+1]
+:384.2。
6)6-(4-(2-氨基丙烷-2-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈
向6-(4-(2-叠氮基丙烷-2-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈(350mg,0.91mmol)的四氢呋喃(9mL)和水(2mL)溶液中加入三甲基膦(1.37mL,1.37mmol,1M in THF),所得混合物于室温反应过夜。反应液经减压浓缩,所得残余物经柱层析纯化(二氯甲烷:甲醇=100:1至25:1)得标题化合物为白色固体(310mg,94%)。LCMS[M+1]
+:358.2。
7)N-(2-(1-(3-氰基咪唑并[1,2-a]吡啶-6-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)丙烷-2-基)-2-氟苯甲酰胺
N-(2-(1-(3-氰基咪唑并[1,2-a]吡啶-6-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)丙烷-2-基)-2-氟苯甲酰胺的制备方法参照实施例44,除了用6-(4-(2-氨基丙烷-2-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈代替6-(4-(1-氨基乙基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈,得到标题化合物为泡沫状固体(41mg,85%)。LCMS[M+1]
+:480.2。
8)6-(4-(2-(2-氟苯甲酰胺基)丙烷-2-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(2-(2-氟苯甲酰胺基)丙烷-2-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例43,除了用N-(2-(1-(3-氰基咪唑并[1,2-a]吡啶-6-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)丙烷-2-基)-2-氟苯甲酰胺代替6-(4-(1-((2-氟苯基)氨基)乙基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈,得标题化合物为米白色固体(19mg,42%)。LCMS[M+1]
+:498.3。
1H-NMR(500MHz,CDCl
3)δ:9.67(s,1H),8.22(m,1H),8.12(m,1H),8.05-7.97(m,2H),7.73(d,J=9.5Hz,1H),7.65(t,J=7.5Hz,1H),7.52-7.45(m,2H),7.27(m,1H),7.18-7.14(m,2H),7.01(d,J=8.0Hz,1H),5.76(br,2H),2.11(s,3H),1.98(s,6H)。
实施例46
6-(4-(((2-甲基苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((2-甲基苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用2-甲基苯胺代替2-氟苯胺,得标题化合物为白色固体(15mg,58%)。LCMS[M+1]
+:438.2。
1H-NMR(500MHz,CDCl
3)δ:9.64(s,1H),8.16(s,1H),8.02-7.93(m,1H),7.72-7.70(m,1H),7.66-7.62(m,1H),7.47-7.44(m,1H),7.20-7.15(m,2H),7.11-7.10(m,1H),7.04-7.02(m,1H),6.78-6.77(m,1H),6.73-6.70(m,1H),5.76-5.62(m,2H),4.51(s,2H),2.26(s,3H),2.13(s,3H)。
实施例47
6-(2-(6-甲基吡啶-2-基)-4-(((2-(三氟甲氧基)苯基)氨基)甲基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(2-(6-甲基吡啶-2-基)-4-(((2-(三氟甲氧基)苯基)氨基)甲基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用2-(三氟甲氧基)苯胺代替2-氟苯胺,得标题化合物为白色固体(24mg, 70%)。LCMS[M+1]
+:508.2。
1H-NMR(500MHz,CDCl
3)δ:9.63(s,1H),8.20(s,1H),7.94(d,J=6.4Hz,1H),7.73-7.71(m,1H),7.63(t,J=6.4Hz,1H),7.48-7.46(m,1H),7.20-7.17(m,2H),7.11(s,1H),7.03(d,J=6.4Hz,1H),6.89-6.87(m,1H),6.72-6.70(m,1H),5.79-5.64(m,2H),4.51(s,2H),2.12(s,3H)。
实施例48
6-(4-(((2,6-二甲基苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((2,6-二甲基苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用2,6-二甲基苯胺代替2-氟苯胺,得标题化合物为白色固体(29mg,82%)。LCMS[M+1]
+:452.2。
1H-NMR(500MHz,CDCl
3)δ:9.61(s,1H),8.16(s,1H),7.96(d,J=6.4Hz,1H),7.71-7.70(m,1H),7.63(t,J=6.4Hz,1H),7.44-7.42(m,1H),7.09(s,1H),7.06-7.04(m,2H),7.02(d,J=6.4Hz,1H),6.90-6.87(m,1H),5.78-5.68(m,2H),4.27(s,2H),2.41(s,3H),2.12(s,3H)。
实施例49
6-(4-(((2,4-二氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((2,4-二氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用2,4-二氟苯胺代替2-氟苯胺,得标题化合物为白色固体(13mg,65%)。LCMS[M+1]
+:446.2。
1H-NMR(500MHz,CDCl
3)δ:9.63(s,1H),8.19(s,1H),7.94(d,J=6.0Hz,1H),7.73-7.71(m,1H),7.63(t,J=6.0Hz,1H),7.47-7.45(m,1H),7.15(s,1H),7.03(d,J=6.0Hz,1H),6.85-6.81(m,1H),6.81-6.78(m,2H),5.82-5.66(m,2H),4.45(s,2H),2.13(s,3H)。
实施例50
6-(2-(6-甲基吡啶-2-基)-4-(((3-(三氟甲氧基)苯基)氨基)甲基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(2-(6-甲基吡啶-2-基)-4-(((3-(三氟甲氧基)苯基)氨基)甲基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用3-(三氟甲氧基)苯胺代替2-氟苯胺,得标题化合物为白色固体(11mg,48%)。LCMS[M+1]
+:508.2。
1H-NMR(500MHz,CDCl
3)δ:9.64(s,1H),8.20(s,1H),7.74-7.72(m,1H),7.97(d,J=6.4Hz,1H),7.64(t,J=6.4Hz,1H),7.47-7.44(m,1H),7.21-7.18(m,1H),7.16(s,1H),7.03(d,J=6.4Hz,1H),6.68-6.65(m,1H),6.61-6.57(m,2H),5.83-5.68(m,2H),4.44(s,2H),2.13(s,3H)。
实施例51
6-(4-(((2,5-二氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((2,5-二氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用2,5-二氟苯胺代替2-氟苯胺,得标题化合物为白色固体(14mg,79%)。LCMS[M+1]
+:460.2。
1H-NMR(500MHz,CDCl
3)δ:9.64(s,1H),8.21(s,1H),7.95(d,J=6.0Hz,1H),7.74-7.72(m,1H),7.64(t,J=6.0Hz,1H),7.49-7.46(m,1H),7.17(s,1H),7.04(d,J=6.0Hz,1H),6.95-6.90(m,1H),6.58-6.54(m,1H),6.34-6.30(m,1H),5.85-5.66(m,2H),4.45(s,2H),2.13(s,3H)。
实施例52
6-(4-(((4-氟-2-(三氟甲基)苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((4-氟-2-(三氟甲基)苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用4-氟-2-(三氟甲基)苯胺代替2-氟苯胺,得标题化合物为白色固体(15mg,48%)。LCMS[M+1]
+:510.2。
1H-NMR(500MHz,CDCl
3)δ:9.63(s,1H),8.21(s,1H),7.93(d,J=6.4Hz,1H),7.74-7.72(m,1H),7.63(t,J=6.4Hz,1H),7.48-7.46(m,1H),7.24-7.22(m,1H),7.17-7.13(m,1H),7.11(s,1H),7.03(d,J=6.4Hz,1H),6.87-6.84(m,1H),5.84-5.64(m,2H),4.95(m,1H),4.50(s,2H),2.12(s,3H)。
实施例53
6-(4-(((3-乙炔基苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((3-乙炔基苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用3-乙炔基苯胺代替2-氟苯胺,得标题化合物为白色固体(18mg,50%)。LCMS[M+1]
+:448.2。
1H-NMR(500MHz,CDCl
3)δ:9.63(m,1H),8.17(s,1H),7.94(d,J=6.4Hz,1H),7.72-7.70(m,1H),7.63(t,J=6.4Hz,1H),7.46-7.44(m,1H),7.18-7.16(m,1H),7.15(s,1H),7.03(d,J=6.4Hz,1H),6.91-6.88(m,2H),6.77-6.75(m,1H),5.76-5.66(m,2H),4.43(s,2H),3.04(s,1H),2.13(s,3H)。
实施例54
6-(2-(6-甲基吡啶-2-基)-4-((吡啶-2-基氨基)甲基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(2-(6-甲基吡啶-2-基)-4-((吡啶-2-基氨基)甲基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用2-氨基吡啶代替2-氟苯胺,得标题化合物为白色固体(5mg,48%)。LCMS[M+1]
+:425.2。
1H-NMR(500MHz,CDCl
3)δ:9.61(s,1H),8.15-8.12(m,2H),7.88(d,J=6.4Hz,1H),7.70-7.68(m,1H),7.61(t,J=6.4Hz,1H),7.50-7.47(m,1H),7.44-7.42(m,1H),7.16(s,1H),7.02(d,J=6.4Hz,1H),6.65-6.62(m,1H),6.60-6.58(m,1H),5.76-5.64(m,2H),4.63(m,2H),2.13(s,3H)。
实施例55
6-(4-(((2,3-二氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((2,3-二氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用2,3-二氟苯胺代替2-氟苯胺,得标题化合物为白色固体(20mg,74%)。LCMS[M+1]
+:460.2。
1H-NMR(500MHz,CDCl
3)δ:9.64(d,J=1.6Hz,1H),8.18(s,1H),7.93(d,J=6.4Hz,1H),7.73(d,J=7.6Hz,1H),7.63(t,J=6.4Hz,1H),7.47(m,1H),7.15(s,1H),7.03(d,J=6.4Hz,1H),6.97-6.92(m,1H),6.64-6.60(m,1H),6.55-6.50(m,1H),5.82-5.64(m,2H),4.48(s,2H),2.13(s,3H)。
实施例56
6-(4-(((3-氯-2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((3-氯-2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用3-氯-2-氟苯胺代替2-氟苯胺,得标题化合物为白色固体(25mg,81%)。LCMS[M+1]
+:476.1。
1H-NMR(500MHz,CDCl
3)δ:9.63(s,1H),8.17(s,1H),7.72-7.70(m,1H),7.92(d,J=6.4Hz,1H),7.63(t,J=6.4Hz,1H),7.46-7.44(m,1H),7.15(s,1H),7.03(d,J=6.4Hz,1H),6.97-6.94(m,1H),6.77-6.71(m,2H),5.84-5.67(m,2H),4.48(s,2H),2.13(s,3H)。
实施例57
6-(4-(((5-氯-2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((5-氯-2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用5-氯-2-氟苯胺代替2-氟苯胺,得标题化合物为白色固体(22mg,71%)。LCMS[M+1]
+:476.1。
1H-NMR(500MHz,CDCl
3)δ:9.64(m,1H),8.19(s,1H),7.93(d,J=6.4Hz,1H),7.73-7.71(m,1H)7.63(t,J=6.4Hz,1H),7.48-7.46(m,1H),7.16(s,1H),7.03(d,J=6.4Hz,1H),6.94-6.90(m,1H),6.84-6.82(m,1H),6.63-6.60(m,1H),5.83-5.68(m,2H),4.43(s,2H),2.13(s,3H)。
实施例58
6-(4-(((2,6-二氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((2,6-二氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用2,6-二氟苯胺代替2-氟苯胺,得标题化合物为白色固体(10mg,64%)。LCMS[M+1]
+:460.2。
1H-NMR(500MHz,CDCl
3)δ:9.61(s,1H),8.18(s,1H),7.96(d,J=6.0Hz,1H),7.72-7.70(m,1H),7.63(t,J=6.0Hz,1H),7.45-7.43(m,1H),7.14(s,1H),7.03(d,J=6.0Hz,1H),6.86-6.83(m,2H),6.72-6.66(m,1H),5.80-5.66(m,2H),4.61(s,2H),2.13(s,3H)。
实施例59
6-(4-(((2,3,4-三氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((2,3,4-三氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用2,3,4-三氟苯胺代替2-氟苯胺,得标题化合物为白色固体(11mg,53%)。LCMS[M+1]
+:478.2。
1H-NMR(500MHz,CDCl
3)δ:9.65(s,1H),8.25(s,1H),7.96(d,J=6.4Hz,1H),7.75-7.73(m,1H),7.64(t,J=6.4Hz,1H),7.49-7.46(m,1H),7.15(s,1H),7.03(d,J=6.4Hz,1H),6.88-6.83(m,1H),6.55-6.51(m,1H),5.88-5.71(m,2H),4.49(s,2H),2.13(s,3H)。
实施例60
6-(4-(((3,4-二氯苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((3,4-二氯苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用3,4-二氯苯胺代替2-氟苯胺,得标题化合物为白色固体(21mg,75%)。LCMS[M+1]
+:492.1。
1H-NMR(500MHz,CDCl
3)δ:9.64(d,J=1.6Hz,1H),8.18(s,1H),7.94(d,J=6.4Hz,1H),7.73(d,J=7.6Hz,1H),7.64(m,1H),7.46(m,1H),7.24(d,J=6.8Hz,1H),7.14(s,1H),7.05(d,J=6.4Hz,1H),6.84(d,J=2.4Hz,1H),6.60(m,1H),5.79-5.61(m,2H),4.40(s,2H),2.14(s,3H)。
实施例61
6-(4-(((4-氯-2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((4-氯-2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用4-氯-2-氟苯胺代替2-氟苯胺,得标题化合物为白色固体(24mg,83%)。LCMS[M+1]
+:476.1。
1H-NMR(500MHz,CDCl
3)δ:9.62(d,J=1.6Hz,1H),8.15(s,1H),7.90-7.88(m,1H),7.72(d,J=7.6Hz,1H),7.63-7.60(m,1H),7.45(m,1H),7.14(s,1H),7.05-7.00(m,3H),6.79-6.76(m,1H), 5.80-5.64(m,2H),4.44(s,2H),2.13(s,3H)。
实施例62
6-(4-(((4-溴-2,6-二氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((4-溴-2,6-二氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用4-溴-2,6-二氟苯胺代替2-氟苯胺,得标题化合物为白色固体(13mg,73%)。LCMS[M+1]
+:538.1。
1H-NMR(500MHz,CDCl
3)δ:9.63(s,1H),8.21(s,1H),7.97-7.92(m,1H),7.74-7.72(m,1H),7.65-7.62(m,1H),7.46-7.44(m,1H),7.13(s,1H),7.04-7.01(m,3H),5.81-5.67(m,2H),4.59(s,2H),2.12(s,3H)。
实施例63
6-(4-(((1-甲基-1H-吡唑-3-基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((1-甲基-1H-吡唑-3-基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用1-甲基-1H-吡唑-3-胺代替2-氟苯胺,得标题化合物为白色固体(15mg,48%)。LCMS[M+1]
+:428.2。
1H-NMR(500MHz,CDCl
3)δ:9.61(m,1H),8.15(s,1H),7.91(d,J=6.4Hz,1H),7.70-7.68(m,1H),7.61(t,J=6.4Hz,1H),7.44-7.42(m,1H),7.16(s,1H),7.14(m,1H),7.01(d,J=6.4Hz,1H),5.76-5.66(m,2H),5.65(m,1H),4.46(s,2H),3.77(s,3H),2.12(s,3H)。
实施例64
6-(2-(6-甲基吡啶-2-基)-4-(((6-(三氟甲氧基)-3a,7a-二氢苯并[d]噻唑-2-基)氨基)甲基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(2-(6-甲基吡啶-2-基)-4-(((6-(三氟甲氧基)-3a,7a-二氢苯并[d]噻唑-2-基)氨基)甲基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用6-(三氟甲氧基)-3a,7a-二氢苯并[d]噻唑-2-胺代替 2-氟苯胺,得标题化合物为白色固体(18mg,43%)。LCMS[M+1]
+:567.2。
1H-NMR(500MHz,CDCl
3)δ:9.64(m,1H),8.16(s,1H),7.89(d,J=6.4Hz,1H),7.73(d,J=7.2Hz,1H),7.63(m,1H),7.58(d,J=7.2Hz,1H),7.50-7.48(m,1H),7.46-7.43(m,1H),7.25(s,1H),7.21-7.17(m,1H),7.03(d,J=6.4Hz,1H),5.78-5.66(m,2H),4.76(s,2H),2.14(s,3H)。
实施例65
6-(4-(((3-甲酰胺基苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((3-甲酰胺基苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用3-氰基苯胺代替2-氟苯胺,得标题化合物为白色固体(15mg,46%)。LCMS[M+1]
+:467.2。
1H-NMR(500MHz,DMSO)δ:9.54(m,1H),8.42(s,1H),8.10-8.00(m,1H),7.88-7.86(m,1H),7.80-7.77(m,1H),7.75-7.72(m,2H),7.49(s,1H),7.49-7.46(m,1H),7.46-7.44(m,1H),7.21-7.17(m,2H),7.16-7.11(m,2H),7.07-7.05(m,1H),6.87-6.84(m,1H),6.18(t,J=4.4Hz,1H),4.31(d,J=4.4Hz,1H),1.99(s,3H)。
实施例66
6-(4-((二甲氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
1)6-(4-(羟甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈
向(2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)甲醇(7.0g,37.0mmol)的乙二醇二甲醚(240mL)溶液中加入3-氰基咪唑并[1,2-a]吡啶-6-硼酸频哪醇酯(6.5g,24.2mmol)、醋酸铜(4.8g,24.2mmol)、碳酸钾(6.7g,48.3mmol)和水(60mL),加热回流反应1小时。待反应液冷却,过滤,滤液经减压浓缩,向所得残余物中加入水(100mL),用乙酸乙酯萃取(100mL x 3),合并有机层,用饱和盐水洗,无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化(二氯甲烷:甲醇=20:1)得标题化合物为淡棕色固体(650mg,8.2%)。LCMS[M+1]
+:331.1。
2)6-(4-(氯甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈
向6-(4-(羟甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈(100mg,0.30mmol)的二氯甲烷(10mL)溶液中加入一滴N,N-二甲基甲酰胺,再滴加氯化亚砜(180mg,1.5mmol),所得混合物室温反应1小时。冰浴冷却,加水淬灭反应,用饱和碳酸氢钠溶液调溶液pH至7左右,用二氯甲烷(10mL x 2)萃取,合并有机层,用无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化(石油醚:乙酸乙酯=1:1)得标题化合物为白色固体(65mg,62%)。LCMS[M+1]
+:349.1。
3)6-(4-((二甲氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈
向6-(4-(氯甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈(35mg,0.1mmol)的DME(1mL)溶液中加入二甲胺盐酸盐(24mg,0.3mmol)、碳酸钾(70mg,0.5mmol)和碘化钾(17mg, 0.1mmol),所得混合物加热至70℃搅拌反应过夜。待反应液冷却至室温,倒入水(10mL)中,用二氯甲烷(5mL×3)萃取,合并有机层,有机层经无水硫酸钠干燥,减压浓缩,所得残余物经厚制备板纯化(二氯甲烷:甲醇=15:1)得标题化合物为黄色油状物(23mg,64%)。LCMS[M+H]
+:358.2。
4)6-(4-((二甲氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
向6-(4-(二甲氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈(23mg,0.06mmol)的二氯甲烷(3mL)溶液中加入依次加入20%氢氧化钠溶液(50μL,0.3mmol)、四丁基硫酸氢铵(8mg,0.02mmol)和30%双氧水(50μL,0.48mmol),所得混合物于室温下搅拌反应3小时。减压浓缩,所得残余物用二氯甲烷和甲醇溶解后,过滤,滤液经减压浓缩后,再用厚制备板纯化(二氯甲烷:甲醇=12:1)得标题化合物为白色固体(8mg,33%)。LCMS[M+H]
+:376.2。
1H NMR(500MHz,CDCl
3)δ:9.62(s,1H),8.18(s,1H),7.92(d,J=8.0Hz,1H),7.87(d,J=9.5Hz,1H),7.60(t,J=8.0Hz,1H),7.43(d,J=11.5Hz,1H),7.24(s,1H),6.99(d,J=8.0Hz,1H),5.78(s,2H),3.69(s,2H),2.49(s,6H),2.11(s,3H)。
实施例67
6-(2-(6-甲基吡啶-2-基)-4-(((四氢-2H-吡喃-4-基)氨基)甲基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(2-(6-甲基吡啶-2-基)-4-(((四氢-2H-吡喃-4-基)氨基)甲基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例66,除了用4-氨基四氢吡喃代替二甲胺盐酸盐,得标题化合物为白色固体(10mg,42%)。LCMS[M+H]
+:432.2。
1H NMR(500MHz,CDCl3)δ:9.62(s,1H),8.16(s,1H),7.85(d,J=7.5Hz,1H),7.69(d,J=9.5Hz,1H),7.60(t,J=8.0Hz,1H),7.42(d,J=11.5Hz,1H),7.15(s,1H),7.00(d,J=9.5Hz,1H),5.86(s,2H),4.04(d,J=11.0Hz,2H),3.93(s,2H),3.47(t,J=11.5Hz,2H),2.96-2.84(m,1H),2.13(s,3H),2.05-1.90(m,2H),1.60-1.50(m,2H)。
实施例68
6-(4-(((5-(二甲氨基)-2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((5-(二甲氨基)-2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例66,除了用5-(二甲氨基)-2-氟苯胺代替二甲胺盐酸盐,得标题化合物为白色固体(5mg,16%)。LCMS[M+H]
+:485.2。
1H NMR(500MHz,CDCl
3)δ:9.61(s,1H),8.15(s,1H),7.90(d,J=8.0Hz,1H),7.69(d,J=9.5Hz,1H),7.61(t,J=8.0Hz,1H),7.43(d,J=11.5Hz,1H),7.14(s,1H),7.00(d,J=9.5Hz,1H),6.83(t,J=9.5Hz,1H),6.60(d,J=14.5Hz,1H),6.54(d,J=8.0Hz,1H),5.78(s,2H),4.42(s,2H),2.86(s,6H),2.13(s,3H)。
实施例69
6-(4-((2-氟苯氧基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-((2-氟苯氧基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例66,除了用2-氟苯酚代替二甲胺盐酸盐,得标题化合物为白色固体(25mg,73%)。LCMS[M+H]
+:443.2。
1H NMR(500MHz,DMSO)δ:9.57(s,1H),8.43(s,1H),8.06(s,1H),7.88(d,J=8.0Hz,1H),7.83-7.71(m,3H),7.58-7.36(m,3H),7.32-7.09(m,3H),7.01-6.94(m,1H),5.16(s,2H),2.00(s,3H)。
实施例70
6-(4-(((2-氟-3-(吗啉基甲基)苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
1)(2-氟-3-甲基苯基)氨基甲酸叔丁酯
向2-氟-3-甲基苯胺(3g,23.9mmol)的四氢呋喃(25mL)溶液中加入Boc酸酐(5.5g,25.2mmol),升温至65℃搅拌反应过夜。待反应液冷至室温,减压浓缩,所得残余物经柱层析纯化(石油醚:乙酸乙酯=1:100)得到标题化合物为白色固体(4.1g,76%)。LCMS[M+H]
+:226.1。
2)(3-(溴甲基)-2-氟苯基)氨基甲酸叔丁酯
向(2-氟-3-甲基苯基)氨基甲酸叔丁酯(2.25g,10mmol)的四氯化碳(25mL)溶液中依次加入AIBN(200mg,1mmol)和NBS(1.87g,10.5mmol),体系置换氮气后升温至80℃反应过夜。所得混合液冷却至室温后经减压过滤,滤饼用四氯化碳洗(10mL×3),合并滤液,减压浓缩,得标题化合物的粗品为黄色固体(3g,99%),直接用于下一步反应。LCMS[M+H]
+:304.0。
3)(2-氟-3-(吗啉甲基)苯基)氨基甲酸叔丁酯
向(3-(溴甲基)-2-氟苯基)氨基甲酸叔丁酯(1g,3.3mmol)的乙腈(15mL)溶液中依次加入吗啉(575mg,6.6mmol)和碳酸钾(1.37g,9.9mmol),升温至60℃搅拌反应1小时。待反应液冷却至室温,倒入水(30mL)中,用乙酸乙酯萃取(20mL×3),合并有机相,有机相经饱和氯化钠溶液洗(30mL),无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化(石油醚:乙酸乙酯=2:1)得标题化合物为淡黄色油状物(800mg,78%)。LCMS[M+H]
+:311.2。
4)2-氟-3-(吗啉基甲基)苯胺
向(2-氟-3-(吗啉甲基)苯基)氨基甲酸叔丁酯(800mg,2.57mmol)的二氯甲烷(8mL)溶液中加入三氟乙酸(2mL)。所得反应液室温搅拌6小时后,减压浓缩,所得残余物用水(10mL)溶解,再用饱和碳酸氢钠溶液调pH至8左右,用乙酸乙酯萃取(20mL×3),合并有机相,有机相经饱和食盐水洗,无水硫酸钠干燥,减压浓缩得标题化合物为淡黄色油状物(530mg,98%)。LCMS[M+H]
+:211.2。
5)6-(4-(((2-氟-3-(吗啉基甲基)苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((2-氟-3-(吗啉基甲基)苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲 酰胺的制备方法参照实施例66,除了用2-氟-3-(吗啉基甲基)苯胺代替二甲胺盐酸盐,得标题化合物为白色固体(10mg,51%)。LCMS[M+H]
+:541.1。
1H NMR(500MHz,CDCl
3)δ:9.61(s,1H),8.15(s,1H),7.89(d,J=7.5Hz,1H),7.69(d,J=9.5Hz,1H),7.61(t,J=7.5Hz,1H),7.46-7.41(m,1H),7.15(s,1H),7.04-6.97(m,2H),6.79(t,J=8.0Hz,1H),6.71(t,J=7.0Hz,1H),5.79(s,2H),4.58(s,1H),4.46(s,2H),3.73(s,4H),3.60(s,2H),2.53(s,4H),2.13(s,3H)。
实施例71
6-(4-(((2-氟苯基)(甲基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((2-氟苯基)(甲基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例66,除了用N-甲基-2-氟苯胺代替二甲胺盐酸盐,得标题化合物为白色固体(20mg,48%)。LCMS[M+H]
+:456.2。
1H NMR(500MHz,CDCl
3)δ:9.59(s,1H),8.15(s,1H),7.89(d,J=8.0Hz,2H),7.68(d,J=9.5Hz,1H),7.60(t,J=7.5Hz,1H),7.42(d,J=9.5Hz,1H),7.10-6.91(m,5H),6.93-6.85(m,1H),5.77(s,2H),4.44(s,2H),3.00(s,3H),2.11(s,3H)。
实施例72
6-(4-((2-氧杂-6-氮杂螺[3.3]庚烷-6-基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-((2-氧杂-6-氮杂螺[3.3]庚烷-6-基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例66,除了用2-氧杂-6-氮杂螺[3.3]庚烷代替二甲胺盐酸盐,得标题化合物为白色固体(10mg,42%)。LCMS[M+H]
+:430.2。
1H NMR(500MHz,CDCl
3)δ:9.61(s,1H),8.16(s,1H),7.90(d,J=7.5Hz,1H),7.69(d,J=9.5Hz,1H),7.60(t,J=7.5Hz,1H),7.48-7.39(m,1H),7.09(s,1H),6.99(d,J=8.0Hz,1H),5.84(s,2H),4.79(s,4H),3.69(s,2H),3.59(s,4H),2.11(s,3H)。
实施例73
6-(2-(6-甲基吡啶-2-基)-4-((氧杂环丁烷-3-基氨基)甲基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(2-(6-甲基吡啶-2-基)-4-((氧杂环丁烷-3-基氨基)甲基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制 备方法参照实施例66,除了用3-氨基氧杂环丁烷代替二甲胺盐酸盐,得标题化合物为白色固体(20mg,64%)。LCMS[M+H]
+:404.1。
1H NMR(500MHz,CDCl
3)δ:9.59(s,1H),8.20(s,1H),7.77(d,J=7.5Hz,1H),7.64(d,J=9.5Hz,1H),7.60(t,J=7.5Hz,1H),7.38(m,2.0Hz,1H),7.18(s,1H),7.01(d,J=7.5Hz,1H),4.85(t,J=7.0Hz,2H),4.58(t,J=6.5Hz,2H),4.21(m,1H),3.87(s,2H),2.11(s,3H)。
实施例74
6-(2-(6-甲基吡啶-2-基)-4-(吗啉基甲基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(2-(6-甲基吡啶-2-基)-4-(吗啉基甲基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例66,除了用吗啉代替二甲胺盐酸盐,得标题化合物为白色固体(15mg,48%)。LCMS[M+H]
+:418.2。
1H NMR(500MHz,CDCl
3)δ:9.62(s,1H),8.17(s,1H),7.88(d,J=8.0Hz,1H),7.70(d,J=9.5Hz,1H),7.60(t,J=7.5Hz,1H),7.43(m,1H),7.24(s,1H),7.00(d,J=7.5Hz,1H),5.89(s,2H),3.92-3.78(m,6H),2.86(s,4H),2.11(s,3H)。
实施例75
6-(2-(6-甲基吡啶-2-基)-4-(((2,3,5,6-四氟苯基)氨基)甲基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(2-(6-甲基吡啶-2-基)-4-(((2,3,5,6-四氟苯基)氨基)甲基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例66,除了用2,3,5,6-四氟苯胺代替二甲胺盐酸盐,得标题化合物为白色固体(3mg,60%)。LCMS[M+H]
+:496.1。
1H-NMR(500MHz,CDCl
3)δ:9.61(s,1H),8.16(s,1H),7.90(d,J=6.4Hz,1H),7.73-7.71(m,1H),7.63(t,J=6.4Hz,1H),7.46-7.44(m,1H),7.16(s,1H),7.03(d,J=6.4Hz,1H),6.49-6.41(m,1H),5.78-5.63(m,2H),4.65(s,2H),2.12(s,3H)。
实施例76
6-(4-(((5-溴-2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((5-溴-2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例66,除了用5-溴-2-氟苯胺代替二甲胺盐酸盐,得标题化合物为白色固体(30mg,72%)。 LCMS[M+H]
+:520.1。
1H-NMR(500MHz,CDCl
3)δ:9.65(m,1H),8.20(s,1H),7.93-7.91(m,1H),7.74(d,J=6.4Hz,1H),7.63(m,1H),7.49-7.46(m,1H),7.16(s,1H),7.03(d,J=6.4Hz,1H),6.98-6.96(m,2H),6.89-6.85(m,1H),6.78-6.75(m,1H),5.88-5.68(m,2H),4.43(s,2H),2.13(s,3H)。
实施例77
N-((1-(1H-吲唑-5-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)甲基)-2-氟苯胺
1)5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑
向5-溴-1H-吲唑(5g,25.4mmol)的二氧六环(50mL)溶液中依次加入Pd(dppf)Cl
2(743mg,1.0mmol)、联硼酸频那醇酯(9.7g,38.1mmol)和醋酸钾(6.2g,63.5mmol),体系经氮气置换后加热至100℃反应过夜。待反应液冷至室温,过滤,滤液经减压浓缩,所得残余物经柱层析纯化(二氯甲烷)得标题化合物为黄色油状物(6.0g,97%)。LCMS[M+H]
+:245.2。
2)5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑-1-甲酸叔丁酯
向5-(4,4,5,5-四甲基-1,3,2-二氧杂硼-2-基)-1H-吲唑(2.4g,10mmol)的乙腈(30mL)溶液中依次加入Boc酸酐(6.24g,30mmol)和DMAP(122mg,1mmol)。所得混合物室温反应2小时后,减压浓缩,所得残余物经柱层析纯化(石油醚:乙酸乙酯=15:1)得标题化合物为无色油状物(1.4g,41%)。LCMS[M+H]
+:345.2。
3)5-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)-1H-吲唑-1-甲酸叔丁酯
向反应瓶中依次加入2-氟-N-((2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)甲基)苯胺(200mg,0.71mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑-1-甲酸叔丁酯(365mg,1.06mmol)、一水合醋酸铜(28.4mg,0.142mmol)、碳酸钾(294mg,2.13mmol)、水(80μL,4.44mmol)和DMF(10mL),体系经氧气置换后加热至65℃反应过夜。待反应液冷至室温,过滤,所得滤液经减压浓缩,残余物经柱层析纯化(石油醚:乙酸乙酯=1:1)得标题化合物为黄色油状物(120mg,34%)。LCMS[M+H]
+:499.1。
4)N-((1-(1H-吲唑-5-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)甲基)-2-氟苯胺
向5-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)-1H-吲唑-1-甲酸叔丁酯(30mg,0.06mmol)的二氯甲烷(2mL)溶液中加入三氟乙酸(0.3mL,4mmol),所得混合物室温搅拌反应过夜。减压浓缩,向残余物中加水(10mL),用饱和碳酸氢钠溶液调pH至8左右,用乙酸乙酯萃取(10mL×3),合并有机相,有机相经饱和食盐水洗,无水硫酸钠干燥,减压浓缩,所得残余物经厚制备板纯化(DCM:MeOH=20:1)得标题化合物为黄色固体(20mg,83%)。LCMS[M+H]
+:399.1。
1H NMR(500MHz,CDCl
3)δ:10.71(s,1H),8.26(s,0.73H),8.13(s,0.32H),7.86(s,0.74H),7.80(d,J=7.0Hz,0.74H),δ7.69(s,0.33H),7.45-7.60(m,1.60H),7.40-7.30(m,1.60H),7.19(s,1H),7.05-7.0(m,2H),6.85(t,J=8.5Hz,1H),6.68(s,1H),6.56(d,J=8.0Hz,0.67H),4.68(s,2.3H),4.50(s,0.79H),2.99(s,2.2H),2.25(s,0.86H)。
实施例78
2-氟-N-((1-(1-甲基-1H-吲唑-5-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)甲基)苯胺
1)1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑
向5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(500mg,2mmol)的DMF(10mL)溶液中依次加入碳酸钾(1.1g,8mmol)和碘甲烷(568mg,4mmol),所得混合物室温搅拌反应过夜。将反应液倒入水(20mL)中,用乙酸乙酯萃取(15mL×3),合并有机相,有机相经饱和食盐水洗,无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化(二氯甲烷)得标题化合物为白色固体(120mg,23%)。LCMS[M+H]
+:259.1。
2)2-氟-N-((1-(1-甲基-1H-吲唑-5-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)甲基)苯胺
向反应瓶中依次加入1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(100mg,0.39mmol)、2-氟-N-((2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)甲基)苯胺(100mg,0.35mmol)、一水合醋酸铜(70mg,0.35mmol)、碳酸钾(106mg,0.7mmol)、乙二醇二甲醚(7.5mL)和水(2.5mL),体系经氧气置换后加热至80℃搅拌反应1小时。待反应液冷至室温后,过滤,滤液经减压浓缩,所得残余物经厚制备板纯化得标题化合物为白色固体(5mg,3.4%)。LCMS[M+H]
+:413.1。
1H NMR(500MHz,CDCl
3)δ:8.16(s,1H),7.81(s,1H),7.65(d,J=9.0Hz,1H),7.53(t,J=8.0Hz,1H),7.35(t,J=9.0Hz,2H),7.19(s,1H),7.02-6.96(m,2H),6.85(t,J=8.5Hz,1H),6.69(m,1H),6.56(d,J=8.0Hz,1H),4.68(s,3H),4.23(s,3H),2.98(s,3H)。
实施例79
6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)-3-甲基喹唑啉-4(3H)-酮
6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)-3-甲基喹唑啉-4(3H)-酮的制备方法参照实施例17,除了用2-氟-N-((2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)甲基)苯胺代替2-(6-甲基吡啶-2-基)-1,4,5,6-四氢环戊二烯并[d]咪唑,得标题化合物为类白色固体(3mg,4%)。LC-MS[M+H]
+:441.2。
1H-NMR(500MHz,CDCl
3)δ:8.24(d,J=2.3Hz,1H),8.11(s,1H),7.78(d,J=7.4Hz,1H),7.71(d,J=8.7Hz,1H),7.65-7.58(m,2H),7.17(s,1H),7.06-6.97(m,3H),6.86(t,J=8.3Hz,1H),6.67(m,1H),5.37(m,1H),4.51(s,2H),3.64(s,3H),2.17(s,3H)。
实施例80
6-(4-苄基-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
1)2-溴-3-苯基丙醛
0℃下,向苯丙酮(268mg,2mmol)的二氯甲烷(3mL)溶液中加入溴素(320mg,2mmol),所得 混合物升至室温反应过夜。反应液经减压浓缩,所得粗品直接用于下一步反应。
2)2-(4-苄基-1H-咪唑-2-基)-6-甲基吡啶
向2-溴-3-苯基丙醛粗品的四氢呋喃(5mL)溶液中加入6-甲基吡啶-2-甲脒(216mg,1.6mmol)、碳酸钾(287mg,2.08mmol)和水(0.5mL),所得混合物加热至60℃反应2.5小时。待反应液冷至室温后,加入水(10mL),用乙酸乙酯萃取(10mL×2),合并有机相,用无水硫酸钠干燥,减压浓缩,所得残余物加入二氧六环(5mL),加热至85℃反应3小时,TLC监控反应结束后,待反应液冷至室温,减压浓缩,所得残余物经柱层析纯化(二氯甲烷:甲醇=50:1),得标题化合物为棕色油状物(240mg,60%)。LC-MS[M+H]
+:250.2。
3)6-(4-苄基-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-苄基-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用2-(4-苄基-1H-咪唑-2-基)-6-甲基吡啶代替2-氟-N-((2-(6-甲基吡啶-2-基)-1H-咪唑-4-基)甲基)苯胺,得标题化合物为类白色固体(20mg,70%)。LC-MS[M+H]
+:409.29。
1H-NMR(500MHz,CDCl
3)δ:9.57(s,1H),8.14(s,1H),7.90(d,J=7.7Hz,1H),7.66(d,J=9.3Hz,1H),7.60(t,J=7.7Hz,1H),7.40(d,J=6.5Hz,3H),7.35(t,J=7.4Hz,2H),7.25(t,J=7.0Hz,1H),6.99(d,J=7.6Hz,1H),6.77(s,1H),5.81(s,2H),4.09(s,2H),2.11(s,3H)。
实施例81
6-(4-((2-氟苯基)氨基甲酰基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
1)6-(4-甲酰基-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈
向反应瓶中加入2-(6-甲基吡啶-2-基)-1H-咪唑-4-甲醛(187mg,1mmol)、3-氰基咪唑并[1,2-a]吡啶-6-硼酸频哪醇酯(296mg,1mmol)、醋酸铜(23mg,0.126mmol)、碳酸钾(277mg,2mmol))、乙二醇二甲醚(14mL)和水(2mL),反应体系氧气置换后,加热至55℃反应过夜。待反应液冷至室温,过滤,减压浓缩,所得残余物经柱层析纯化(二氯甲烷:甲醇=100:1)得标题化合物为淡黄色固体(40mg,12%)。LC-MS[M+H]
+:329.2。2)1-(3-氰基咪唑并[1,2-a]吡啶-6-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-4-甲酸
0℃下,向6-(4-甲酰基-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈(40mg,0.12mmol)的四氢呋喃(2.5mL)、叔丁醇(1mL)和水(1mL)溶液中依次加入2-甲基-2-丁烯(86mg,1.22mmol)、磷酸二氢钠(95mg,0.61mmol)和亚氯酸钠(55mg,0.61mmol),加完后移至室温搅拌反应0.5小时。反应液经减压浓缩,所得残余物用水(1mL)溶解,用1N HCl调pH至5左右,过滤,收集滤饼,烘干,得标题化合物为淡黄色固体(32mg,76%)。LC-MS[M+H]
+:345.1。
3)6-(4-((2-氟苯基)氨基甲酰基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈
向1-(3-氰基咪唑并[1,2-a]吡啶-6-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-4-甲酸(29mg,0.08mmol)的二氯甲烷(2.5mL)溶液中加入三乙胺(18μL,0.13mmol)、HATU(32mg,0.08mmol)和邻氟苯胺(10.4mg,0.09mmol),室温搅拌反应过夜。将反应液倒入水(5mL)中,用二氯甲烷(8mL x 2)萃取,合并有机相,用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,减压浓缩,得标题化合物粗品为类白色固体。LC-MS[M+H]
+:438.2。
4)6-(4-((2-氟苯基)氨基甲酰基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
向1-(3-氰基咪唑并[1,2-a]吡啶-6-基)-N-(2-氟苯基)-2-(6-甲基吡啶-2-基)-1H-咪唑-4-甲酰胺粗品的二氧六环(2mL)溶液中加入氢氧化锂一水合物(5.3mg,0.13mmol)的水(0.2mL)溶液和30%的过氧化氢(76μL,0.67mmol),所得混合物室温搅拌反应3.5小时。反应完全后,减压浓缩,所得残余物用二氯甲 烷和甲醇(15:1)的混合溶液(25mL)溶解,过滤,滤液浓缩至干,所得残余物用乙腈(1mL)和水(0.3mL)打浆纯化,得标题化合物为类白色固体(22mg,58%)。LC-MS[M+H]
+:456.2。
1H-NMR(500MHz,DMSO)δ:9.72(s,1H),9.65(s,1H),8.45(s,1H),8.36(s,1H),8.04(t,J=6.7Hz,2H),7.99(d,J=7.8Hz,1H),7.87-7.76(m,2H),7.56(d,J=7.9Hz,1H),7.50(s,1H),7.40-7.30(m,1H),7.24(m,3H),2.03(s,3H)。
实施例82
6-(2-(5-氟-6-甲基吡啶-2-基)-4-(((2-氟苯基)氨基)甲基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(2-(5-氟-6-甲基吡啶-2-基)-4-(((2-氟苯基)氨基)甲基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例29,除了用5-氟-6-甲基吡啶-2-甲腈代替6-甲基-吡啶腈,得标题化合物为类白色固体(23mg,58.5%)。LC-MS[M+H]
+:460.2。
1H-NMR(500MHz,CDCl
3)δ:9.57(s,1H),8.14(s,1H),7.90(d,J=7.7Hz,1H),7.66(d,J=9.3Hz,1H),7.60(t,J=7.7Hz,1H),7.40(d,J=6.5Hz,3H),7.35(t,J=7.4Hz,2H),7.25(t,J=7.0Hz,1H),6.99(d,J=7.6Hz,1H),6.77(s,1H),5.81(s,2H),4.09(s,2H),2.11(s,3H)。
实施例83
6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)-N-甲基咪唑并[1,2-a]吡啶-3-甲酰胺
1)6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酸
向反应瓶瓶中加入6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈(470mg),再加入由浓硫酸(200μL)、醋酸(400μL)、水(800μL)配成的混合溶液,搅拌升温至100℃左右反应过夜。待反应液冷至室温,减压浓缩,加水(2mL),冰水冷却,用固体碳酸氢钠调节pH至6左右,减压浓缩,所得残余物用二氯甲烷和异丙醇溶解,过滤,减压浓缩,得含标题化合物的棕色固体粗品(367mg,75%)。LC-MS[M+H]
+:443.05。
2)6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)-N-甲基咪唑并[1,2-a]吡啶-3-甲酰胺
向6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酸(57mg,0.13mmol)的乙腈(4mL)溶液中加入三乙胺(75μL)、HATU(69mg,0.18mmol)和甲胺盐酸盐(23mg,0.34mmol)。室温搅拌反应4小时后,减压浓缩,向所得残余物中加入水(10mL),用二氯甲烷萃取(10mL x 2),合并有机层,用无水硫酸钠干燥,减压浓缩后经厚制备板纯化(二氯甲烷:甲醇=10:1)得标题化合物为类白色固体(12mg,15%)。LC-MS[M+H]
+:456.2。
1H-NMR(500MHz,CDCl
3)δ:9.63(s,1H),8.08(s,1H),7.89(d,J=7.9Hz,1H),7.67(d,J=9.5Hz,1H),7.61(t,J=7.8Hz,1H),7.40(m,1H),7.15(s,1H),7.02(m,3H),6.86(t,J=7.9Hz,1H),6.67(m,1H),6.13(s,1H),4.47(s,2H),3.04(d,J=4.8Hz,3H),2.13(s,3H)。
实施例84
6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)-N,N-二甲基咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)-N,N-二甲基咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例83,除了用二甲胺盐酸盐代替甲胺盐酸盐,得标题化合物为类白色固体(6mg,10%)。LC-MS[M+H]
+:470.1。
1H-NMR(500MHz,CDCl
3)δ:9.30(s,1H),8.01(s,1H),7.89(d,J=7.8Hz,1H),7.66(d,J=9.5Hz,1H),7.61(t,J=7.8Hz,1H),7.40(d,J=9.5Hz,1H),7.15(s,1H),7.02(m,3H),6.86(t,J=8.1Hz,1H),6.67(m,1H),4.46(s,2H),3.28(s,6H),2.16(s,3H)。
实施例85
6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)-N-异丙基咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)-N-异丙基咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例83,除了用异丙胺代替甲胺盐酸盐,得标题化合物为淡黄色固体(9mg,14%)。LC-MS[M+H]
+:484.2。
1H-NMR(500MHz,CDCl
3)δ:9.64(d,J=1.3Hz,1H),8.06(s,1H),7.89(d,J=7.9Hz,1H),7.69-7.58(m,2H),7.39(m,1H),7.15(s,1H),7.02(m,3H),6.86(t,J=8.1Hz,1H),6.67(m,1H),5.86(d,J=7.1Hz,1H),4.47(s,2H),4.31(m,1H),2.14(s,3H),1.36-1.24(m,6H)。
实施例86
N-环丙基-6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
N-环丙基-6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例83,除了用环丙胺代替甲胺盐酸盐,得标题化合物为淡黄色固体(14mg,22%)。LC-MS[M+H]
+:482.1。
1H-NMR(500MHz,CDCl
3)δ:9.66(s,1H),8.06(s,1H),7.90(d,J=7.8Hz,1H),7.66(d,J=9.5Hz,1H),7.61(t,J=7.8Hz,1H),7.40(m,1H),7.14(s,1H),7.08-6.98(m,3H),6.86(m,1H),6.71-6.63(m,1H),6.23(s,1H),4.47(s,2H),2.88(m,1H),2.13(s,3H),0.91(m,2H),0.72-0.62(m,2H)。
实施例87
(6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-基)(3-羟基氮杂环丁烷-1-基)甲酮
(6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-基)(3-羟基氮杂环丁烷-1-基)甲酮的制备方法参照实施例83,除了用氮杂环丁烷-3-醇盐酸盐代替甲胺盐酸盐,得标题化合物为类白色固体(7mg,10.6%)。LC-MS[M+H]
+:498.2。
1H-NMR(500MHz,CDCl
3)δ:9.70(s,1H),7.96(s,1H),7.89(d,J=7.8Hz,1H),7.68(d,J=9.3Hz,1H),7.61(t,J=7.8Hz,1H),7.42(d,J=9.4Hz,1H),7.14(s,1H),7.02(m,3H),6.86(t,J=8.1Hz,1H),6.67(d,J=5.5Hz,1H),4.84(s,1H),4.60(s,2H),4.47(s,2H),4.31(m,3H),2.13(s,3H)。
实施例88
6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)-N-(2-羟基乙基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)-N-(2-羟基乙基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例83,除了用乙醇胺代替甲胺盐酸盐,得标题化合物为类白色固体(12mg,20%)。LC-MS[M+H]
+:486.1。
1H-NMR(500MHz,CDCl
3)δ:9.61(s,1H),8.16(s,1H),7.87(d,J=7.8Hz,1H),7.68(d,J=9.4Hz,1H),7.61(t,J=7.8Hz,1H),7.40(d,J=9.4Hz,1H),7.15(s,1H),7.01(m,3H),6.86(t,J=8.2Hz,1H),6.74(s,1H),6.67(m,1H),4.46(s,2H),3.89-3.82(m,2H),3.64(m,2H),2.13(s,3H)。
实施例89
6-(2-(6-甲基吡啶-2-基)-4-(氧杂环丁烷-3-基氨基甲酰基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(2-(6-甲基吡啶-2-基)-4-(氧杂环丁烷-3-基氨基甲酰基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例81,除了用氧杂环丁烷-3-胺代替邻氟苯胺,得标题化合物为白色固体(20mg,55%)。LC-MS[M+H]
+:418.3。
1H-NMR(500MHz,CDCl
3+CD
4O)δ:9.62(d,J=2.0Hz,1H),8.21(d,J=3.8Hz,1H),7.82(d,J=4.0Hz,1H),7.76(m,1H),7.70-7.59(m,2H),7.43-7.36(m,1H),7.29(s,1H),7.05(m,1H),5.32-5.21(m,1H),5.00(m,2H),4.72(m,2H),2.13(s,3H)。
实施例90
6-(4-(环丙基氨基甲酰基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(环丙基氨基甲酰基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例81,除了用环丙胺代替邻氟苯胺,得标题化合物为白色固体(20mg,57%)。LC-MS[M+H]
+:402.4。
1H-NMR(500MHz,DMSO-d6)δ:9.58(d,J=1.5Hz,1H),8.43(s,1H),8.15(d,J=4.5Hz,1H),8.07(d,J=13.4Hz,2H),7.93(d,J=7.8Hz,1H),7.82–7.73(m,2H),7.50(dd,J=9.5,2.1Hz,2H),7.17(d,J=7.7Hz,1H),2.91-2.83(m,1H),2.00(s,3H),0.74-0.63(m,4H)。
实施例91
6-(4-((2-甲基-3-丁炔-2-基)氨基甲酰基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-((2-甲基丁-3-炔-2-基)氨基甲酰基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例81,除了用2-甲基-3-丁炔-2-胺代替邻氟苯胺,得标题化合物物为白色固体(28mg,75%)。LC-MS[M+H]
+:428.75。
1H-NMR(500MHz,CDCl
3)δ:9.64(d,J=1.4Hz,1H),8.19(s,1H),7.89(d,J=7.8Hz,1H),7.83(s,1H),7.72(d,J=9.5Hz,1H),7.63(m,1H),7.41(m,1H),7.39(s,1H),7.04(d,J=7.7Hz,1H),5.93(s,2H),2.43(s,1H),2.13(s,3H),1.83(s,6H)。
实施例92
6-(4-((3-氟吡啶-2-基)氨基甲酰基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
1)6-(4-((3-氟吡啶-2-基)氨基甲酰基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈
向1-(3-氰基咪唑并[1,2-a]吡啶-6-基)-2-(6-甲基吡啶-2-基)-1H-咪唑-4-甲酸(29mg,0.08mmol)的乙腈(2.5mL)溶液中加入三乙胺(18μL,0.13mmol)、HATU(32mg,0.08mmol)和2-氨基-3-氟吡啶(9.8mg,0.09mmol),所得混合物加热至75℃反应过夜。待反应液冷至室温,将反应液倒入水(5mL)中,用二氯甲烷(8mL x 2)萃取,合并有机相,用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,减压浓缩,得标题化合物为粗品,直接用于下一步反应。LC-MS[M+H]
+:439.2。
2)6-(4-((3-氟吡啶-2-基)氨基甲酰基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈
向6-(4-((3-氟吡啶-2-基)氨基甲酰基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲腈粗品的二氧六环(2mL)溶液中加入氢氧化锂一水合物(5.3mg,0.13mmol)的水(0.2mL)溶液和30%的过氧化氢(76μL,0.67mmol),所得混合物室温搅拌反应2小时。反应完全后,减压浓缩,所得残余物用二氯甲烷和甲醇(15:1)的混合溶液(25mL)溶解,过滤,滤液浓缩至干,所得残余物用乙腈(1mL)和 水(0.3mL)打浆,过滤,所得滤饼再用甲醇(0.5mL)打浆,过滤,烘干得标题化合物为类白色固体(22mg,58%)。LC-MS[M+H]
+:456.2。
1H-NMR(500MHz,DMSO)δ:9.72(s,1H),9.65(s,1H),8.45(s,1H),8.36(s,1H),8.04(t,J=6.7Hz,2H),7.99(d,J=7.8Hz,1H),7.87-7.76(m,2H),7.56(d,J=7.9Hz,1H),7.50(s,1H),7.40-7.30(m,1H),7.24(m,3H),2.03(s,3H)。
实施例93
6-(4-(4-甲基哌嗪-1-甲酰基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(4-甲基哌嗪-1-甲酰基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例81,除了用1-甲基哌嗪代替邻氟苯胺,得标题化合物为标题化合物为白色固体(17mg,44%)。LC-MS[M+H]
+:445.5。
1H-NMR(500MHz,CDCl
3+CD
4O)δ:9.60(s,1H),8.20(s,1H),7.83(d,J=7.6Hz,1H),7.75(s,1H),7.65(d,J=9.4Hz,1H),7.59(t,J=7.8Hz,1H),7.42(dd,J=9.4,2.0Hz,1H),7.00(d,J=7.6Hz,1H),4.40(s,2H),3.82(s,2H),2.59(s,4H),2.37(s,3H),2.05(s,3H)。
实施例94
6-(4-((5-氯-2-氟苯基)氨基甲酰基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-((5-氯-2-氟苯基)氨基甲酰基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例92,除了用5-氯-2-氟苯胺代替2-氨基-3-氟吡啶,得标题化合物为黄色固体(26mg,61%)。LC-MS[M+H]
+:490.3。
1H-NMR(500MHz,DMSO-d6)δ:9.78(s,1H),9.64(d,J=1.5Hz,1H),8.44(s,1H),8.39(s,1H),8.15(m,1H),8.07(s,1H),7.98(d,J=7.8Hz,1H),7.82(t,J=7.8Hz,1H),7.78(d,J=9.5Hz,1H),7.56(m,1H),7.50(s,1H),7.45-7.37(m,1H),7.34-7.26(m,1H),7.21(m,1H),2.02(s,3H)。
实施例95
6-(4-((2-氟-5-甲氧基苯基)氨基甲酰基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-((2-氟-5-甲氧基苯基)氨基甲酰基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例92,除了用2-氟-5-甲氧基苯胺代替2-氨基-3-氟吡啶,得标题化合物为黄色固体(28mg,66%)。LC-MS[M+H]
+:486.4。
1H-NMR(500MHz,DMSO-d6)δ:9.68-9.58(m,2H),8.44(s,1H),8.36(s,1H),8.07(s,1H),7.98(d,J=7.8Hz,1H),7.82(t,J=7.8Hz,1H),7.78(d,J=9.5Hz,1H),7.73(m,1H),7.56(m,1H),7.50(s,1H),7.32-7.24(m,1H),7.21(d,J=7.7Hz,1H),6.76(m,1H),3.77(s,3H),2.02(s,3H)。
实施例96
6-(4-((2-氟-3-甲氧基苯基)氨基甲酰基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-((2-氟-3-甲氧基苯基)氨基甲酰基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例92,除了用2-氟-3-甲氧基苯胺代替2-氨基-3-氟吡啶,得标题化合物为黄色固体(27mg,64%)。LC-MS[M+H]
+:486.4。
1H-NMR(500MHz,DMSO-d6)δ:9.66(d,J=19.0Hz,2H),8.44(s,1H),8.34(s,1H),8.07(s,1H),7.98(d,J=7.8Hz,1H),7.85-7.75(m,2H),7.64-7.53(m,2H),7.49(s,1H),7.21(d,J=7.6Hz,1H),7.16(t,J=8.2Hz,1H),7.02(t,J=7.9Hz,1H),3.88(s,3H),2.02(s,3H)。
实施例97
6-(4-((5-氟吡啶-2-基)氨基甲酰基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-((5-氟吡啶-2-基)氨基甲酰基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例92,除了用2-氨基-5-氟吡啶代替2-氨基-3-氟吡啶,得标题化合物为黄色固体(22mg,55%)。LC-MS[M+H]
+:457.4。
1H-NMR(500MHz,DMSO-d6)δ:9.92(s,1H),9.65(d,J=1.5Hz,1H),8.44(d,J=1.4Hz,2H),8.41(d,J=2.9Hz,1H),8.30(m,1H),8.05(t,J=10.2Hz,2H),7.85(m,1H),7.83-7.76(m,2H),7.57(m,1H),7.50(s,1H),7.21(d,J=7.7Hz,1H),2.01(s,3H)。
实施例98
6-(2-(6-甲基吡啶-2-基)-4-(嘧啶-4-基氨基甲酰基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(2-(6-甲基吡啶-2-基)-4-(嘧啶-4-基氨基甲酰基)-1H-咪唑-1-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例92,除了用4-氨基嘧啶代替2-氨基-3-氟吡啶,得标题化合物为白色固体(6mg,16%)。LC-MS[M+H]
+:440.2。
1H-NMR(500MHz,DMSO-d6)δ10.15(s,1H),9.65(s,1H),8.96(s,1H),8.76(d,J=5.7Hz,1H),8.53(s,1H),8.44(s,1H),8.25(d,J=5.7Hz,1H),8.13-8.02(m,2H),7.86-7.76(m,2H),7.75-7.65(m,1H),7.56(m,1H),7.22(d,J=7.7Hz,1H),2.01(s,3H)。
实施例99
6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)-N-(氧杂环丁烷-3-基)咪唑并[1,2-a]吡啶-3-甲酰胺
6-(4-(((2-氟苯基)氨基)甲基)-2-(6-甲基吡啶-2-基)-1H-咪唑-1-基)-N-(氧杂环丁烷-3-基)咪唑并[1,2-a]吡啶-3-甲酰胺的制备方法参照实施例83,除了用氧杂环丁烷-3-胺代替甲胺盐酸盐,得标题化合物为白色固体(9mg,14%)。LC-MS[M+H]
+:498.1。
1H-NMR(500MHz,CDCl
3)δ:9.57(d,J=1.3Hz,1H),8.23(s,1H),7.91(d,J=7.8Hz,1H),7.70(d,J=9.5Hz,1H),7.62(t,J=7.8Hz,1H),7.44(m,1H),7.13(s,1H),7.02(m,3H),6.85(t,J=8.3Hz,1H),6.77(d,J=5.8Hz,1H),6.67(m,1H),5.29-5.19(m,1H),5.04(t,J=7.1Hz,2H),4.67(t,J=6.5Hz,2H),4.47(s,2H),2.12(s,3H)。
生物试验
TGFβR-1体外抑制活性实验
实验方法:
1)待测化合物和阳性参照化合物LY364947采用10个稀释梯度点每个梯度三倍稀释的方法制备待测液,起始浓度为10μM;2)先后加入待测液和TGFβR-1(V-4092,Promega)到检测板中;3)加入TGFβR-1底物和ATP混合液(V-910B,Promega)开始反应;4)加入ADP-Glo试剂(V-9102,Promega)和激酶检测试剂(Envision 2104multi-label Reader,PerkinElmer)检测荧光信号。
实验结果见表1,表明本发明大部分化合物具有很好TGFβR-1抑制活性。
表1.TGFβR-1体外抑制活性实验结果
+:≥1000nM;++:500-1000nM;+++:100-500nM;++++:0.01-100nM
受试化合物 | TGFβR-1IC 50(nM) | 受试化合物 | TGFβR-1IC 50(nM) |
实施例1 | +++ | 实施例2 | +++ |
实施例3 | + | 实施例4 | + |
实施例5 | +++ | 实施例6 | + |
实施例7 | ++ | 实施例8 | + |
实施例9 | + | 实施例10 | +++ |
实施例11 | +++ | 实施例12 | +++ |
实施例13 | ++++ | 实施例14 | + |
实施例15 | + | 实施例16 | + |
实施例17 | ++++ | 实施例18 | + |
实施例19 | + | 实施例20 | ++++ |
实施例21 | ++++ | 实施例22 | + |
实施例23 | +++ | 实施例24 | ++ |
实施例25 | + | 实施例26 | + |
实施例27 | ++++ | 实施例28 | + |
受试化合物 | TGFβR-1IC 50(nM) | 受试化合物 | TGFβR-1IC 50(nM) |
实施例29 | ++++ | 实施例30 | ++ |
实施例31 | ++ | 实施例32 | + |
实施例33 | ++ | 实施例34 | +++ |
实施例35 | ++ | 实施例36 | +++ |
实施例37 | +++ | 实施例38 | ++++ |
实施例39 | +++ | 实施例40 | +++ |
实施例41 | + | 实施例42 | + |
实施例43 | + | 实施例44 | ++ |
实施例45 | + | 实施例46 | ++++ |
实施例47 | ++++ | 实施例48 | +++ |
实施例49 | ++++ | 实施例50 | ++++ |
实施例51 | ++++ | 实施例52 | ++++ |
实施例53 | ++++ | 实施例54 | ++++ |
实施例55 | ++++ | 实施例56 | ++++ |
实施例57 | ++++ | 实施例58 | ++++ |
实施例59 | ++++ | 实施例60 | ++++ |
实施例61 | ++++ | 实施例62 | ++++ |
实施例63 | ++++ | 实施例64 | +++ |
实施例65 | ++++ | 实施例66 | + |
实施例67 | + | 实施例68 | +++ |
实施例69 | ++++ | 实施例70 | ++++ |
实施例71 | ++++ | 实施例72 | + |
实施例73 | +++ | 实施例74 | ++ |
实施例75 | ++++ | 实施例76 | ++++ |
实施例77 | +++ | 实施例78 | ++ |
实施例79 | +++ | 实施例80 | ++++ |
实施例81 | ++++ | 实施例82 | ++++ |
实施例83 | ++++ | 实施例84 | +++ |
实施例85 | ++ | 实施例86 | ++++ |
实施例87 | ++++ | 实施例88 | ++++ |
受试化合物 | TGFβR-1IC 50(nM) | 受试化合物 | TGFβR-1IC 50(nM) |
实施例89 | +++ | 实施例90 | ++++ |
实施例91 | + | 实施例92 | + |
实施例93 | + | 实施例94 | +++ |
实施例95 | +++ | 实施例96 | ++++ |
实施例97 | ++++ | 实施例98 | +++ |
实施例99 | +++ | LY364947 | +++ |
从活性测试结果可看出:本发明化合物具有较好的TGFβR-1抑制活性,具有非常好的开发前景。
本说明书中引用的所有出版物、专利和专利申请均通过引用并入本发明,就如同每个单独的出版物、专利或专利申请被具体地和单独地指出通过引用并入。尽管已根据各种实施例/实施方案描述了所要求保护的主题,但本领域技术人员将认识到,可在不脱离本发明精神的情况下进行各种修改/修饰、替换、删减和改变/变化。因此,所要求保护的主题的范围旨在仅由所附权利要求的范围限定,包括其等同物。
Claims (29)
- 式(I)所示化合物:或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、区域异构体、氮氧化物、或混合物,其中,X 1是N、或-C(R a)-;X 2是N、或-C(R 2)-;条件是X 1和X 2不同时为碳原子;W是X 3、X 4和X 5各自独立地为-C(R 3)-、或N;X 6是O、S、或-N(R 3)-;其中所述W任选地被0、1、2、3、4或5个R 3取代;Z是Y 1、Y 2、Y 3和Y 4各自独立地为-C(R 4)-、或N;各Y 5分别独立地为O、S、或-N(R 4)-;其中所述Z任选地被0、1、2、3、4或5个R 4取代;R 1、R 2和R a各自独立地为H、-(C(R c)(R d)) m-L-R 5、C 1-6烷基、C 1-6羟基烷基、C 1-6卤代烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷硫基、或C 1-6烷氨基,条件是R 1和R 2不同时为H;或者,R 1和R 2同与之连接的碳原子一起形成5-8个原子组成的碳环或杂环,或R 2和R a同与之连接的原子一起形成5-8个原子组成的碳环或杂环,其中所述5-8个原子组成的碳环或杂环任选地被0、1、2、3或4个R 6取代;L不存在,或L是-N(R b)-、O、S、-C(=O)-或-C(=O)-NH-;R b是H、C 1-6烷基、C 1-6羟基烷基、C 1-6卤代烷基、或C 1-6氰基烷基;各R c和R d在每次出现时,分别独立地为H、C 1-6烷基、C 1-6羟基烷基、或C 1-6卤代烷基;或者,R c和R d同与之连接的碳原子一起形成3-6个原子组成的碳环或杂环;各R 3在每次出现时,分别独立地为H、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6羟基烷基、C 1-6卤代烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 1-6卤代烷氨基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、或C 2-7杂环基C 1-6烷基;各R 4在每次出现时,分别独立地为H、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6羟基烷基、C 1-6卤代烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 1-6卤代烷氨基、C 1-6亚烷基C 2-7杂环基、-S(=O) 1-2R 4a、-C(=O)R 4a、-C(=O)OR 4b、-OS(=O) 1-2R 4a、-OC(=O)R 4a、-S(=O) 1-2OR 4b、-N(R 4b)C(=O)R 4a、-C(=O)NR 4bR 4c、-OC(=O)NR 4bR 4c、-NR 4bR 4c、-N(R 4b)S(=O) 1-2R 4a、-S(=O) 1-2NR 4bR 4c、或-N(R 4b)C(=O)NR 4bR 4c;R 5是H、C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、C 1-9杂芳基C 1-6烷基、C 5-12螺双环基、C 5-12螺杂双环基、C 5-12稠合双环基、或C 5-12稠合杂双环基;其中R 5任选地被0、1、2、3、4或5个R 5a取代;各R 5a在每次出现时,分别独立地为H、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6羟基烷基、C 1-6卤代烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 1-6卤代烷氨基、C 2-7杂环基C 1-6烷基、-C 1-6亚烷基-NR fR g、-NR fR g、-C(=O)OR e、或-C(=O)NR fR g;各R 6在每次出现时,分别独立地为H、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6羟基烷基、C 1-6卤代烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 1-6卤代烷氨基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、C 1-9杂芳基C 1-6烷基、-C 1-6亚烷基-NR fR g、-NR fR g、-C(=O)OR e、或-C(=O)NR fR g;各R 4a、R 4b、R 4c、R e、R f和R g在每次出现时,分别独立地为H、C 1-6烷基、C 1-6羟基烷基、C 1-6卤代烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 5-12螺双环基、C 5-12螺杂双环基、C 5-12稠合双环基、C 5-12稠合杂双环基、-C 1-6亚烷基-OP(=O)(OR h)(OR i)、或-C 1-6亚烷基-C(=O)OR i;其中C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 5-12螺双环基、C 5-12螺杂双环基、C 5-12稠合双环基、和C 5-12稠合杂双环基独立任选地被0、1、2、3或4个独立选自H、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6羟基烷基、C 1-6卤代烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷硫基、C 1-6烷氨基、和C 1-6卤代烷氨基的基团取代;R h和R i各自独立地为H、或C 1-6烷基;和m是0、1、2、3、或4。
- 根据权利要求1-5任一项所述的化合物,其中,R 1和R 2各自独立地为H、-(C(R c)(R d)) m-L-R 5、C 1-4烷基、或C 1-4羟基烷基,条件是R 1和R 2不同时为H;或者,R 1和R 2同与之连接的碳原子一起形成5-6个原子组成的碳环或杂环,其中所述5-6个原子组成的碳环或杂环任选地被0、1、2、3或4个R 6取代。
- 根据权利要求1-5任一项所述的化合物,其中,R 1和R 2各自独立地为H、-(C(R c)(R d)) m-L-R 5、甲基、乙基、n-丙基、异丙基、n-丁基、叔丁基、-CF 3、-CH 2CF 3、-OCF 3、-CH 2CN、-CH 2CH 2CN、-CH 2OH、-CH 2OH、或-CH 2CH 2OH,条件是R 1和R 2不同时为H;或者,R 1和R 2同与之连接的碳原子一起形成5-6个原子组成的碳环或杂环,其中所述5-6个原子组成的碳环或杂环任选地被0、1、2、3或4个R 6取代。
- 根据权利要求1-6任一项所述的化合物,其中,各R c和R d在每次出现时,分别独立地为H、甲基、乙基;或者,R c和R d同与之连接的碳原子一起形成环丙基;L不存在,或L是-N(R b)-、O、S、-C(=O)-或-C(=O)-NH-;和R b是H、或C 1-3烷基。
- 根据权利要求1-6任一项所述的化合物,其中,R 5是H、C 1-4烷基、C 3-6环烷基、C 3-6环烷基C 1-4烷基、C 3-6杂环基、C 3-6杂环基C 1-4烷基、C 6-12芳基、C 6-12芳基C 1-4烷基、C 1-9杂芳基、C 1-9杂芳基C 1-4烷基、C 5-12螺双环基、C 5-12螺杂双环基、C 5-12稠合双环基、或C 5-12稠合杂双环基;其中R 5任选地被0、1、2、3或4个R 5a取代。
- 根据权利要求1-6任一项所述的化合物,其中,各R 5a在每次出现时,分别独立地为H、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4羟基烷基、C 1-4卤代烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 3-6杂环基C 1-3烷基、-C 1-4亚烷基-NR fR g、-NR fR g、-C(=O)OR e、或-C(=O)NR fR g。
- 根据权利要求1-7任一项所述的化合物,其中,各R 3在每次出现时,分别独立地为H、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、C 1-4烷基、C 1-4羟基烷基、C 1-4卤代烷基、C 1-4氰基烷基、C 1-4烷氧基、C 1-4卤代烷氧基、或C 3-6环烷基。
- 根据权利要求1-7任一项所述的化合物,其中,各R 3在每次出现时,分别独立地为H、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、甲基、乙基、丙基、异丙基、丁基、或环丙基。
- 根据权利要求1-7任一项所述的化合物,其中,各R 4在每次出现时,分别独立地为H、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、C 1-4烷基、C 1-4羟基烷基、C 1-4卤代烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 1-4烷氧基、C 1-4卤代烷氧基、-C(=O)R 4a、-C(=O)OR 4b、-N(R 4b)C(=O)R 4a、或-C(=O)NR 4bR 4c。
- 根据权利要求1-7任一项所述的化合物,其中,各R 4a、R 4b和R 4c分别独立地为H、C 1-4烷基、C 1-4羟基烷基、C 1-4卤代烷基、C 1-4氰基烷基、C 3-6环烷基、C 3-6环烷基C 1-4烷基、C 3-6杂环基、C 3-6杂环基C 1-4烷基、C 5-12螺双环基、C 5-12螺杂双环基、C 5-12稠合双环基、C 5-12稠合杂双环基、-C 1-4亚烷基-OP(=O)(OR h)(OR i)、或-C 1-4亚烷基-C(=O)OR i;其中C 3-6环烷基、C 3-6环烷基C 1-4烷基、C 3-6杂环基、C 3-6杂环基C 1-4烷基、C 5-12螺双环基、C 5-12螺杂双环基、C 5-12稠合双环基、和C 5-12稠合杂双环基独立任选地被0、1、2、3或4个独立选自H、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4羟基烷基、C 1-4卤代烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷硫基、C 1-4烷氨基、和C 1-4卤代烷氨基的基团取代。
- 根据权利要求1-7任一项所述的化合物,其中,R e、R f和R g分别独立地为H、甲基、或乙基。
- 根据权利要求1-7任一项所述的化合物,其中,R h和R i各自独立地为H、甲基、或乙基。
- 根据权利要求1所述的化合物,其中,X 1是N;X 2是N、或-C(R 2)-;W是X 3、X 4和X 5各自独立地为-C(R 3)-、或N;X 6是-N(R 3)-;其中所述W任选地被0、1或2个R 3取代;Z是Y 1、Y 2、Y 3各自独立地为-C(R 4)-、或N;Y 4各自独立地为-C(R 4)-;各Y 5分别独立地为S、或-N(R 4)-;其中所述Z任选地被0、1或2个R 4取代;R 1和R 2各自独立地为H、-(C(R c)(R d)) m-L-R 5、或C 1-6烷基,条件是R 1和R 2不同时为H;或者,R 1和R 2同与之连接的碳原子一起形成5-8个原子组成的碳环或杂环;L不存在,或L是-N(R b)-、O、或-C(=O)-NH-;R b是H、或C 1-6烷基;各R c和R d在每次出现时,分别独立地为H、或C 1-6烷基;各R 3在每次出现时,分别独立地为F、Cl、C 1-6烷基、或C 3-8环烷基;各R 4在每次出现时,分别独立地为H、-CN、C 1-6烷基、-C 1-6亚烷基C 2-7杂环基、-C(=O)R 4a、或-C(=O)NR 4bR 4c;R 5是H、C 3-8环烷基、C 6-12芳基、C 1-9杂芳基、C 2-7杂环基、或C 5-12稠合杂双环基;其中R 5任选地被0、1、2、3、或4个R 5a取代;各R 5a在每次出现时,分别独立地为F、Cl、Br、-OH、C 1-6烷基、C 1-6卤代烷基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-7杂环基C 1-6烷基、-NR fR g、或-C(=O)NR fR g;各R 4a在每次出现时,分别独立地为C 2-7杂环基,其中C 2-7杂环基独立任选地被0、或1个-OH、-NH 2、或C 1-6烷基取代;各R 4b、R 4c在每次出现时,分别独立地为H、C 1-6烷基、C 1-6羟基烷基、C 3-8环烷基、C 2-7杂环基、-C 1-6亚烷基-OP(=O)(OR h)(OR i)、或-C 1-6亚烷基-C(=O)OR i,其中C 3-8环烷基独立任选地被0、或1个-OH取代;各R f和R g在每次出现时,分别独立地为H、或C 1-6烷基;R h、R i各自独立地为H;和m是0、1或2。
- 根据权利要求1所述的化合物,其中,X 1是N;X 2是-C(R 2)-;W是X 3、X 4和X 5各自独立地为-C(R 3)-、或N;其中所述W任选地被0、1或2个R 3取代;Z是Y 1、Y 2、Y 3各自独立地为-C(R 4)-、或N;Y 4各自独立地为-C(R 4)-;各Y 5分别独立地为S、或-N(R 4)-;其中所述Z任选地被0、1或2个R 4取代;R 1和R 2各自独立地为H、-(C(R c)(R d)) m-L-R 5、或C 1-6烷基,条件是R 1和R 2不同时为H;或者,R 1和R 2同与之连接的碳原子一起形成5-8个原子组成的碳环或杂环;L不存在,或L是-N(R b)-、O、或-C(=O)-NH-;R b是H、或C 1-6烷基;各R c和R d在每次出现时,分别独立地为H;各R 3在每次出现时,分别独立地为F、Cl、或C 1-6烷基;各R 4在每次出现时,分别独立地为H、-CN、C 1-6烷基、-C(=O)R 4a、或-C(=O)NR 4bR 4c;R 5是H、C 3-8环烷基、C 6-12芳基、C 1-9杂芳基、C 2-7杂环基、或C 5-12稠合杂双环基;其中R 5任选地被0、1、2、3、或4个R 5a取代;各R 5a在每次出现时,分别独立地为F、Cl、Br、-OH、C 1-6烷基、C 1-6卤代烷基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-7杂环基C 1-6烷基、-NR fR g、或-C(=O)NR fR g;各R 4a在每次出现时,分别独立地为C 2-7杂环基,其中C 2-7杂环基独立任选地被0、或1个-OH、或-NH 2取代;各R 4b、R 4c在每次出现时,分别独立地为H、C 1-6烷基、C 1-6羟基烷基、C 3-8环烷基、C 2-7杂环基、-C 1-6亚烷基-OP(=O)(OR h)(OR i)、或-C 1-6亚烷基-C(=O)OR i,其中C 3-8环烷基独立任选地被0、或1个-OH取代;各R f和R g在每次出现时,分别独立地为H、或C 1-6烷基;R h、R i各自独立地为H;和m是0、1或2。
- 根据权利要求1所述的化合物,其中,X 1是N;X 2是-C(R 2)-;W是X 3、X 4和X 5各自独立地为-C(R 3)-、或N;且X 3、X 4和X 5中的一个为N,其余为-C(R 3)-;其中所述W任选地被0、1或2个R 3取代;Z是Y 1为-C(R 4)-、或N;Y 2、Y 4各自独立地为-C(R 4)-;Y 3为N;各Y 5分别独立地为-N(R 4)-;其中所述Z任选地被0、1或2个R 4取代;R 1和R 2各自独立地为H、-(C(R c)(R d)) m-L-R 5、或C 1-6烷基,条件是R 1和R 2不同时为H;或者,R 1和R 2同与之连接的碳原子一起形成5-8个原子组成的碳环或杂环;L不存在,或L是-N(R b)-、O、或-C(=O)-NH-;R b是H、或C 1-6烷基;各R c和R d在每次出现时,分别独立地为H;各R 3在每次出现时,分别独立地为F、或C 1-6烷基;各R 4在每次出现时,分别独立地为H、-C(=O)R 4a、或-C(=O)NR 4bR 4c;R 5是C 3-8环烷基、C 6-12芳基、C 1-9杂芳基、或C 2-7杂环基;其中R 5任选地被0、1、2、3、或4个R 5a取代;各R 5a在每次出现时,分别独立地为F、Cl、Br、C 1-6烷基、C 1-6卤代烷基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-7杂环基C 1-6烷基、或-C(=O)NR fR g;各R 4a在每次出现时,分别独立地为C 2-7杂环基,其中C 2-7杂环基独立任选地被0、或1个-OH、或-NH 2取代;各R 4b、R 4c在每次出现时,分别独立地为H、C 1-6烷基、C 1-6羟基烷基、或C 3-8环烷基,其中C 3-8环烷基独立任选地被0、或1个-OH取代;各R f和R g在每次出现时,分别独立地为H;和m是0、或1。
- 药物组合物,所述药物组合物包含权利要求1-25中任一项所述的化合物或其药学上可接受的盐,以及药学上可接受的辅料、稀释剂或载体。
- 使用权利要求1-25任一项所述的化合物或权利要求26所述的药物组合物在制备用于预防和/或治疗TGF-β介导或涉及TGF-β的疾病、病症、或病况的药物中的用途。
- 根据权利要求27所述的用途,其中所述疾病、病症、或病况是肺动脉高压、慢性肾病、急性肾病、伤口愈合、关节炎、骨质疏松症、肾病、充血性心力衰竭、溃疡、眼部病症、角膜损伤、糖尿病性肾病、神经功能受损、阿尔茨海默病、动脉粥样硬化、腹膜或皮下粘连、肾纤维化、肺纤维化、特发性肺纤维化、肝纤维化、乙型肝炎、丙型肝炎、由酒精诱导型肝炎、癌症、血色病、原发性胆汁性肝硬化、再狭窄、腹膜后纤维化、肠系膜纤维化、子宫内膜异位、瘢痕疙瘩、癌症、骨功能异常、炎性病症、瘢痕形成、或皮肤光老化。
- 根据权利要求27所述的用途,其中所述疾病、病症、或病况是良性或恶性肿瘤、脑癌、肾癌、肝癌、肾上腺癌、膀胱癌、乳腺癌、胃癌、胃部肿瘤、卵巢癌、结肠癌、直肠癌、前列腺癌、胰腺癌、肺癌、阴道癌或甲状腺癌、肉瘤、成胶质细胞瘤、多发性骨髓瘤或胃肠癌症、结肠癌或结肠直肠癌、头颈肿瘤、表皮过度增殖、黑色素瘤、牛皮癣、前列腺增生、瘤形成、上皮性状瘤形成、白血病、淋巴瘤、乳腺癌、或白血病。
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