WO2022100727A1 - 咪唑并噻唑类化合物、其药物组合物及其用途 - Google Patents

咪唑并噻唑类化合物、其药物组合物及其用途 Download PDF

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WO2022100727A1
WO2022100727A1 PCT/CN2021/130584 CN2021130584W WO2022100727A1 WO 2022100727 A1 WO2022100727 A1 WO 2022100727A1 CN 2021130584 W CN2021130584 W CN 2021130584W WO 2022100727 A1 WO2022100727 A1 WO 2022100727A1
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alkyl
compound
cycloalkyl
thiazol
ethyl
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PCT/CN2021/130584
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English (en)
French (fr)
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邹晴安
张健存
陈延维
张礼军
康宁
郭琛
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广州市恒诺康医药科技有限公司
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Priority to US18/037,101 priority Critical patent/US20240002401A1/en
Priority to AU2021378438A priority patent/AU2021378438B2/en
Priority to JP2023528336A priority patent/JP2023549203A/ja
Priority to CA3199039A priority patent/CA3199039A1/en
Priority to EP21891247.5A priority patent/EP4242211A4/en
Publication of WO2022100727A1 publication Critical patent/WO2022100727A1/zh

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D513/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to the field of medicinal chemistry, in particular to a new class of imidazothiazole compounds as ATX (Autotaxin) inhibitors, a pharmaceutical composition comprising the compounds, and the use of the compounds or compositions in the treatment of ATX (Autotaxin) ) in diseases expressing increased pathological features.
  • ATX Autotaxin
  • ATX Autotaxin
  • PDE phosphodiesterase
  • ENPP extracellular pyrophosphatase/phosphodiesterase
  • lysoPLD lysophospholipase D activity, which can catalyze the production of lysophosphatidic acid (LPA) with lysophosphatidylcholine (LPC) as a substrate.
  • LPA is not only a precursor of phospholipid synthesis, but also can cause a wide range of biological effects through various signaling pathways.
  • LPA1-6 cell surface-specific receptor proteins
  • GPCRs G protein-coupled receptors
  • LPA1-6 are named LPA1/Edg-2/VZG-1, LPA2/Edg-4, LPA3/Edg-7, LPA4/p2y9/GPR23, LPA5/GPR92, respectively, according to endothelial cell differentiation gene (Edg) and ventricular zone gene names and LPA6/p2Y5, each receptor is mediated by G ⁇ proteins (Gs, Gi, Gq, and G12/13), which in turn initiate a series of cellular signaling cascades.
  • GPCRs G protein-coupled receptors
  • the main pathways include hydrolysis of phosphatidylinositol diphosphate (PIP2), which in turn triggers intracellular calcium release and protein kinase C (PKC) activation; inhibition of adenylate cyclase (cAMP) signaling pathway; activation Ras-MAPK, MERK, ERK pathway regulates cell proliferation activity; activates phosphoinositide PI3K-AKT pathway, regulates cell survival and apoptosis; finally, activates Rho pathway to regulate cytoskeleton remodeling, shape change and cell migration activity.
  • PIP2 phosphatidylinositol diphosphate
  • PLC protein kinase C
  • cAMP adenylate cyclase
  • the concentration of LPA can be increased to 10 ⁇ mol/L, which is much higher than the normal level of 100 nmol/L.
  • Excessive LPA will increase the production of vascular endothelial growth factor (VEGF) and promote angiogenesis; reduce the expression of tumor suppressor p53 and increase the survival and metastasis of tumor cells.
  • VEGF vascular endothelial growth factor
  • the ATX-LPA signaling pathway is involved in many physiological and pathological processes, and thus has an important connection with many serious diseases, including cardiovascular diseases, autoimmune diseases, cancer, fibrotic diseases, inflammation, nervous system diseases, pain, etc.
  • LPA has multiple functions in tumorigenesis, promoting tumor cell growth, angiogenesis, metastasis and emergence of drug resistance. Therefore, reducing the concentration level of LPA is beneficial to the treatment and control of tumors.
  • inhibiting the activity of AXT and blocking the production pathway of LPA is a research hotspot in the treatment of many serious diseases.
  • Fibrotic diseases are mainly idiopathic pulmonary fibrosis (IPF) and liver fibrosis.
  • IPF idiopathic pulmonary fibrosis
  • IPF is a lethal disease characterized by diffuse alveolitis and alveolar structural disorder, leading to the progressive development of pulmonary interstitial fibrosis.
  • the prognosis is poor, with an average survival time of 2 to 5 years.
  • IPF is probably the disease most closely linked to the ATX-LPA pathway, because in lung tissue, ATX expression is most concentrated in bronchial epithelial cells and alveolar macrophages, which can juxtapose fibroblast foci.
  • GLPG-1690 as an Autotaxin inhibitor, has entered the clinical phase II trial for the treatment of idiopathic pulmonary fibrosis; serum ATX concentration is closely related to liver fibrosis and liver stiffness value, which is the best predictor of liver cirrhosis.
  • ATX is highly expressed in many tumor tissues, including melanoma, non-small cell lung cancer, liver cancer, kidney cancer, breast cancer, thyroid cancer, ovarian cancer, and Hodgkin lymphoma.
  • LPA/ATX can promote cell invasion and metastasis during tumor cell growth. Therefore, ATX inhibitors, which block the signal transduction pathway, provide a new way for clinical treatment of cancer and fibrotic diseases.
  • ATX inhibitors Compared with traditional kinase inhibitors, ATX inhibitors inhibit the activity of ATX and affect multiple signaling pathways related to cell proliferation, growth and apoptosis, and have a better inhibitory effect on some drug-resistant tumors.
  • the fibrosis of organs is closely related and is an important target for the research and development of new drugs for fibrotic diseases.
  • the present invention provides a new class of imidazothiazole compounds, which have good inhibitory activity on ATX, and are much better than Comparative Example 1 for in vitro enzymatic activity.
  • the compounds of the present invention have higher exposure and bioavailability.
  • 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 imidazothiazole compounds, which have very good inhibitory activity to ATX, and have high exposure and bioavailability in rats, and can be used to prepare and treat diseases with increased ATX expression.
  • Diseases with physical characteristics such as cancer, fibrotic diseases (eg, pulmonary fibrosis or liver fibrosis), metabolic diseases, myelodysplastic syndromes, cardiovascular diseases, autoimmune diseases, inflammation, neurological diseases, or pain medications .
  • 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 in mammals, especially humans, and pharmaceutical compositions comprising these compounds.
  • the present invention provides a new imidazothiazole compound, which has the structure shown in formula (I):
  • Z is H, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkane base, C 3-8 cycloalkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 6-10 Aryl, or C 1-9 heteroaryl; wherein said Z is optionally substituted with one or more R 5 ;
  • R 1b is H, C 1-4 alkyl, C 3-6 cycloalkyl, or C 3-6 cycloalkyl C 1-4 alkyl; wherein said R 1b is optionally replaced by 1, 2, 3 or 4 R 7 substitutions;
  • R 2 is H, -CN, -NO 2 , -OH, -NH 2 , -N 3 , F, Cl, Br, I, C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 hydroxyalkyl;
  • R 3 is H, -CN, -NO 2 , -OH, -NH 2 , -N 3 , F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkyne group, C 1-6 haloalkyl, C 1-6 cyanoalkyl, or C 1-6 hydroxyalkyl;
  • m1 is independently 1, 2, or 3;
  • m2 is independently 0, 1, 2, or 3;
  • m3 is independently 1, 2, or 3;
  • n1 0, 1, 2, 3 or 4;
  • t 0, 1, 2, 3, or 4;
  • t1 and t2 are each independently 1, 2, 3 or 4.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer thereof compounds, nitrogen oxides, metabolites, prodrugs, and pharmaceutically acceptable excipients, diluents or carriers.
  • compositions described herein further comprise additional therapeutic agents.
  • the present invention provides a use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention or treatment of a disease in a mammal having pathological characteristics of increased ATX expression .
  • the disease characterized by the pathology of increased ATX expression comprises: cancer, fibrotic disease, metabolic disease, myelodysplastic syndrome, cardiovascular disease, autoimmune disease, inflammation, neurological disease, or pain.
  • the disease pathologically characterized by increased ATX expression is pulmonary fibrosis or liver fibrosis.
  • 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. .
  • 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 .
  • 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
  • deuterated alkyl or “deuterated ethyl” refers to an alkyl group or ethyl group substituted with 1, 2, 3, 4, 5 or 6 D atoms, wherein the alkyl group is of the present invention said definition.
  • deuterated alkyl or deuterated ethyl include, but are not limited to, -CD3 , -CH2D , -CHD2 , -CD2CD3 , -CH2CD3 , -CD2CH3 , and the like.
  • 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
  • haloalkyl or “haloalkoxy” means that an alkyl or alkoxy group is substituted with one or more halogen atoms (such as F, Cl, Br, or I), examples of which include, but are not limited to, Trifluoromethyl, trifluoroethyl, 2,2,3,3-tetrafluoropropyl, trifluoromethoxy and the like.
  • halogen atoms such as F, Cl, Br, or I
  • 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, such examples 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 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.
  • 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 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.
  • 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.
  • 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.
  • heteroatom refers to O, S, N, P, and Si, including N, S, and P in any oxidation state; in the form of primary, secondary, tertiary amines, and quaternary ammonium salts; or on a nitrogen atom in a heterocyclic ring.
  • Hydrogen substituted form for example, N (like N in 3,4-dihydro-2H-pyrrolidinyl), NH (like NH in pyrrolidinyl) or NR (like in N-substituted pyrrolidinyl) NR).
  • cyano-substituted alkyl or “cyanoalkyl” includes a C1-10 straight or branched chain alkyl group 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.
  • the substituents draw a bond to the central ring to form a ring system (as shown in the figure below) to represent that the substituents can 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.
  • 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.
  • the imidazothiazole compounds provided by the present invention can effectively inhibit the activity of ATX, and the in vitro enzyme activity is much better than that of Comparative Example 1, and has higher exposure and bioavailability in rats, and can be used for the preparation of therapeutic agents with ATX Diseases expressing increased pathological features, eg, cancer, fibrotic diseases (eg, pulmonary fibrosis or liver fibrosis), metabolic diseases, myelodysplastic syndromes, cardiovascular diseases, autoimmune diseases, inflammation, neurological diseases or pain medication.
  • fibrotic diseases eg, pulmonary fibrosis or liver fibrosis
  • metabolic diseases eg, myelodysplastic syndromes, cardiovascular diseases, autoimmune diseases, inflammation, neurological diseases or pain medication.
  • the present invention provides a new imidazothiazole compound, which has the structure shown in formula (I):
  • Z is H, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkane base, C 3-8 cycloalkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 6-10 Aryl, or C 1-9 heteroaryl; wherein said Z is optionally substituted with one or more R 5 ;
  • R 1b is H, C 1-4 alkyl, C 3-6 cycloalkyl, or C 3-6 cycloalkyl C 1-4 alkyl; wherein said R 1b is optionally replaced by 1, 2, 3 or 4 R 7 substitutions;
  • R 2 is H, -CN, -NO 2 , -OH, -NH 2 , -N 3 , F, Cl, Br, I, C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 hydroxyalkyl;
  • R 3 is H, -CN, -NO 2 , -OH, -NH 2 , -N 3 , F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkyne group, C 1-6 haloalkyl, C 1-6 cyanoalkyl, or C 1-6 hydroxyalkyl;
  • m1 is independently 1, 2, or 3;
  • m2 is independently 0, 1, 2, or 3;
  • m3 is independently 1, 2, or 3;
  • n1 0, 1, 2, 3 or 4;
  • t 0, 1, 2, 3, or 4;
  • t1 and t2 are each independently 1, 2, 3 or 4.
  • the compounds of the present invention have the structure of formula (II):
  • R 1a is H, ethyl, deuterated ethyl, isopropyl, trifluoroethyl, trifluoromethyl, hydroxyethyl, cyclopropyl, or cyclopropylmethyl.
  • Cy is wherein X 3 is -NH-, or -(CH 2 ) 1-2 -; m3 is 1, 2, or 3; and n1 is 0, 1, 2, 3, or 4.
  • R 1b is H, methyl, or ethyl.
  • Z is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 3-6 heterocyclyl C 1-4 Alkyl, or C 3-6 cycloalkyl C 1-4 alkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkane group, C 3-6 heterocyclyl C 1-4 alkyl and C 3-6 cycloalkyl C 1-4 alkyl optionally substituted with one or more R 5 ; or Z is in
  • X 4 is N, or -CH 2 -;
  • X5 is -O-, -S-, -NH-, - ( CH2 ) m4 -NH-( CH2 ) m5- , -( CH2 ) m4 -O-( CH2 ) m5- , -(CH 2 ) m4 -S-(CH 2 ) m5 -, or -(CH 2 ) m6 -;
  • each m4 is independently 1, 2, 3 or 4;
  • each m5 is independently 0, 1, 2, 3 or 4;
  • each m6 is independently 1, 2, 3 or 4;
  • n2 is 0, 1, 2, 3 or 4.
  • Z is -CH2CH2OH , -CH2C ( CH3 ) 2OH, -CH2C ( CH3 ) 2CH2OH , -CH2CH2CN , -CH2CHF 2 , -CH( CH3 )CH2OH, -C ( CH3 ) 2CH2OH , -CH2C ( CH3 ) 3 ,
  • the compounds of the present invention are compounds having 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, hydrate, solvate, stereoisomer, tautomer thereof compounds, nitrogen oxides, metabolites, prodrugs, and pharmaceutically acceptable excipients, diluents, or carriers.
  • compositions described herein further comprise additional therapeutic agents.
  • the additional therapeutic agent is associated with fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, skin diseases
  • a therapeutic agent for diseases associated with biological disorders and/or abnormal angiogenesis is associated with fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, skin diseases.
  • the pharmaceutical composition of the present invention wherein the additional therapeutic agent includes, but is not limited to, immunomodulatory agents, analgesics, non-steroidal anti-inflammatory drugs, steroids, synthetic DMARDS, drugs for the treatment of proliferative diseases Drugs, glucocorticoids, cytostatics, alkylating agents, antimetabolites, cytotoxic antibiotics, antibodies, etc.
  • additional therapeutic agent includes, but is not limited to, immunomodulatory agents, analgesics, non-steroidal anti-inflammatory drugs, steroids, synthetic DMARDS, drugs for the treatment of proliferative diseases Drugs, glucocorticoids, cytostatics, alkylating agents, antimetabolites, cytotoxic antibiotics, antibodies, etc.
  • the present invention provides a use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention or treatment of a disease in a mammal having pathological characteristics of increased ATX expression .
  • the disease characterized by the pathology of increased ATX expression comprises: cancer, fibrotic disease, metabolic disease, myelodysplastic syndrome, cardiovascular disease, autoimmune disease, inflammation, neurological disease, or pain.
  • the disease pathologically characterized by increased ATX expression is pulmonary fibrosis or liver fibrosis.
  • a compound of the present invention or a pharmaceutical composition thereof may be administered in combination with an additional therapeutic agent.
  • the uses of the present invention comprise administering to a mammal 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.
  • the composition may be prepared in a manner well known in the pharmaceutical art and comprises at least one compound of the invention according to formula I, or II.
  • 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.
  • 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 compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention for use in the prevention and/or treatment of fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, Cardiovascular disease, neurodegenerative disease, dermatological disorders and/or disorders related to abnormal angiogenesis.
  • 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 manufacture of a compound for the prevention and/or treatment of fibrotic, proliferative, inflammatory, autoimmune, respiratory Drugs for diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders and/or disorders related to abnormal angiogenesis.
  • the present invention provides pharmaceutical compositions comprising a compound of the present invention and other therapeutic agents.
  • the other therapeutic agent is a disease associated with fibrotic disease, proliferative disease, inflammatory disease, autoimmune disease, respiratory disease, cardiovascular disease, neurodegenerative disease, dermatological disorder and/or abnormal angiogenesis therapeutic agent.
  • 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 fibrotic disease.
  • the fibrotic disease is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), cystic fibrosis, other diffuse parenchymal lung diseases of various etiologies (including iatrogenic drug-induced fibrosis, occupational and /or environment-induced fibrosis), granulomatous disease (sarcoidosis, hypersensitivity pneumonitis), collagen vascular disease, alveolar protein deposition, Langerhans cell granuloma, lymphangiopathy, genetic disease (Hermans Kipdrak syndrome, tuberous sclerosis, neurofibromatosis, metabolic accumulation disorder, familial interstitial lung disease), radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, blemishes Mycin-
  • IPPF id
  • 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 manufacture of a medicament for the prevention and/or treatment of fibrotic diseases.
  • the fibrotic disease is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), cystic fibrosis, other diffuse parenchymal lung diseases of various etiologies (including iatrogenic drug-induced fibrosis, occupational and/or environment-induced fibrosis), granulomatous disease (sarcoidosis, hypersensitivity pneumonitis), collagen vascular disease, alveolar protein deposition, Langerhans cell granuloma, lymphangiopathy, genetic disease (Hermann Sky-Pudelac syndrome, tuberous sclerosis, neurofibromatosis, metabolic accumulation disorder, familial interstitial lung disease), radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, Bleomycin-induced
  • PPF chronic o
  • the present invention provides a method of preventing and/or treating a mammal suffering from a fibrotic disease, the method comprising administering an effective amount of one of the compounds or pharmaceutical compositions of the present invention or more for the treatment or prevention of the condition.
  • the fibrotic disease is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), cystic fibrosis, other diffuse parenchymal lung diseases of various etiologies (including iatrogenic drug-induced fibrosis, occupational and /or environment-induced fibrosis), granulomatous disease (sarcoidosis, hypersensitivity pneumonitis), collagen vascular disease, alveolar protein deposition, Langerhans cell granuloma, lymphangiopathy, genetic disease (Hermans Ki-Pudelak syndrome, tuberous sclerosis, neurofibromatosis, metabolic accumulation disorder, familial interstitial lung disease), radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, rheumatoid arthritis Leomycin-induced pulmonary fibrosis, chronic asthma, silicosis, asbestos-induced pulmonary fibrosis, acute respiratory distress syndrome (ARDS), renal fibrosis, tubul
  • IPPF
  • Particular aspects of the methods of the invention include administering to an individual suffering from a fibrotic disease an effective amount of a compound of the invention of Formula I, Ia, II, or IIa for a period of time sufficient to reduce the level of fibrosis in the individual, and preferably The process causing the fibrosis is terminated.
  • Specific embodiments of the methods include administering to an individual patient suffering from developing idiopathic pulmonary fibrosis an effective amount of a compound of the invention of Formula I, Ia, II, or IIa for a period of time sufficient to reduce or prevent idiopathic pulmonary fibrosis in said patient, and preferably termination of the process causing said idiopathic pulmonary fibrosis.
  • 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 in the present invention, and unless otherwise specified, the definitions of the substituents are as shown in formula I, or II.
  • 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).
  • the measurement conditions for low-resolution mass spectrometry (MS) data are: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 microns, 6 min, flow rate 0.6 mL/min.
  • Mobile phase 5 %-95% (( CH3CN with 0.1% formic acid) in ( H2O with 0.1% formic acid)) using electrospray ionization (ESI) at 210 nm/254 nm with UV detection.
  • ESI electrospray ionization
  • E 1 is selected from Cl, Br or I
  • E 2 is selected from Cl, Br, I or B(OH) 2
  • E 3 is selected from Cl, Br, I, OMs, OTs or OTf
  • Pr 1 is selected from Boc, Cbz or PMB
  • Pr 2 is selected from tert-butyl or 2,4,4-trimethylpent-2-yl
  • R 1a , R 2 , R 3 , R 6 , Y, Z, Cy and t all have the present invention said definition.
  • Intermediate 1-1 reacts with NBS or phenyltrimethylammonium bromide to obtain intermediate 1-2; intermediate 1-2 undergoes ring closure reaction with thiourea to obtain intermediate 1-3; intermediate 1-3 reacts with Pr 2 NC and aldehyde R 2 CHO are catalyzed by Lewis acid to generate intermediates 1-4 through three-component reactions; intermediates 1-4 are reacted with acetic acid under heating conditions, and the obtained intermediates are then reacted with Boc anhydride or CbzCl to obtain Intermediate 1-5; Intermediate 1-5 is first reacted with a strong base, then undergoes a nucleophilic substitution reaction with intermediate 1-6, and then reacts with a substituted alkyl R 1a E 2 to obtain intermediate 1-7; Intermediates 1-7 can be hydrogenated under acidic conditions or palladium catalyzed or reacted with trimethyliodosilane to remove the protecting group Pr 1 to obtain intermediates 1-8; intermediates 1-8 and 2-7 are in alkaline and under heating conditions,
  • Step 2) Benzyl 4-(oxoethyl)piperidine-1-carboxylate
  • Step 7) 4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b] Thiazol-2-yl)piperidine-1-carboxylate tert-butyl ester
  • tert-butyl 4-(5-acetamido-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidine-1-carboxylate 150 mg, 0.38 mmol
  • 60% NaH 46 mg, 1.14 mmol
  • 2-chloro-4-(4-fluorophenyl)thiazole-5-carbonitrile 91 mg was slowly added dropwise , 0.38 mmol) in tetrahydrofuran (3 mL).
  • the mixture was warmed to room temperature and reacted for 30 minutes, and the reaction was completed by TLC monitoring.
  • Step 2) 2-(4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1 -b]thiazol-2-yl)piperidin-1-yl)acetic acid
  • Step 1) 4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)amino)-6-ethylimidazo[2,1-b]thiazole-2- yl)piperidine-1-carboxylate tert-butyl ester
  • Step 2) 4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(cyclopropyl)amino)-6-ethylimidazo[2,1-b ]Thiazol-2-yl)piperidine-1-carboxylate tert-butyl ester
  • Step 1) 4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(isopropyl)amino)-6-ethylimidazo[2,1-b ]Thiazol-2-yl)piperidine-1-carboxylate tert-butyl ester
  • Step 2) 2-((6-ethyl-2-(piperidin-4-yl)imidazo[2,1-b]thiazol-5-yl)(isopropyl)amino)-4-(4- Fluorophenyl)thiazole-5-carbonitrile
  • Comparative Example 1 can be synthesized with reference to compound 7 in Table III of PCT patent application WO 2014139882A1.
  • the lysoPLD enzyme activity can hydrolyze the substrate lysophosphatidylcholine (LPC) to generate lysophosphatidic acid (LPA) and choline, and choline is oxidized to H 2 O 2 under the action of choline oxidase.
  • LPC lysophosphatidylcholine
  • LPA lysophosphatidic acid
  • choline is oxidized to H 2 O 2 under the action of choline oxidase.
  • HRP horseradish peroxidase
  • Amplex Red reagent reacts with H 2 O 2 in a 1:1 stoichiometric ratio to form a strong fluorescent product for fluorescence quantitative detection.
  • test compound of the present invention and Comparative Example 1 were respectively dissolved in DMSO into a 10 mM stock solution, and 3-fold gradient dilution was carried out with DMSO, the initial concentration was 10 mM, and there were 10 concentration points.
  • a mixed solution 1 with a final concentration of 2ng/ ⁇ l ATX, 2U/ml HRP and 0.2U/ml choline oxidase was prepared with the reaction buffer solution.
  • a mixed solution 2 with a final concentration of 60 mM LPC and 400 uM Amplex Red was prepared with the reaction buffer solution, and 20 ⁇ l of the mixed solution 2 was added to each well of the experimental plate. After adding the sample, the experimental plate was shaken for 30 s on a shock plate apparatus, and incubated at room temperature for 30 min. Excitation light 530nm, emission light 590nm fluorescence signal was read with Envision. Calculate the inhibition rate of the compound to the enzymatic reaction according to the fluorescence ratio, and use the software to analyze and calculate the IC 50 value of the compound, as shown in Table 1.
  • Example 1 ++++ Example 2 ++++ Example 3 +++ Example 4 ++++ Example 5 ++++ Example 6 ++++ Example 7 ++++ Example 8 ++++ Example 9 ++++ Example 10 ++++ Example 11 ++++ Example 12 ++++ Example 13 +++ Example 14 ++++ Example 15 +++ Example 16 ++++ Example 17 +++ Example 18 +++ Example 19 ++++ Example 20 ++++ Example 21 ++++ Example 22 ++++ Example 23 ++++ Example 24 +++ Example 25 ++++ Example 26 ++++ Example 27 ++++ Comparative Example 1 +++++
  • the clear solution of the test compound was injected into SD rats (ad libitum, 6-8 weeks old) via the foot vein, and the suspension solution of the test compound was administered by gavage to SD rats (ad libitum, 6-8 weeks old). ).
  • the animals were all collected blood samples from the tail vein at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 10 and 24 hours after administration, with a blood volume of 0.15 mL each time.
  • In the centrifuge tube of EDTA-K2 invert the centrifuge tube upside down to fully mix the anticoagulant and blood, centrifuge at 4°C and 1500g for 10min within 30min to separate the plasma, transfer the plasma sample to a new centrifuge tube, and store it at -90 ⁇ -60°C conditions to analysis.
  • Adopt LC-MS/MS to measure the blood concentration of the test compound of the present invention, adopt the non-compartmental model in Pharsight Phoenix 8.0 software to calculate the pharmacokinetic parameters, and calculate the absolute bioavailability
  • the compounds of the present invention have higher exposure and bioavailability.
  • the compounds of the present invention have good inhibitory activity against ATX, excellent in vitro and in vivo efficacy and pharmacokinetic properties, and have good clinical application prospects.

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Abstract

本发明提供了作为ATX(Autotaxin)抑制剂的一类新的咪唑并噻唑类化合物,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治疗哺乳动物具有ATX(Autotaxin)表达增加的病理学特征的疾病,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、氮氧化物、代谢物、前药、或混合物,其中,R 1a、R 1c、R 2、R 3、R 6、Cy、Y、Z和t均具有本发明所述定义。

Description

咪唑并噻唑类化合物、其药物组合物及其用途 发明领域
本发明涉及药物化学领域,尤其涉及作为ATX(Autotaxin)抑制剂的一类新的咪唑并噻唑类化合物,包含所述化合物的药物组合物,以及使用所述化合物或组合物在治疗具有ATX(Autotaxin)表达增加的病理学特征的疾病中的用途。
发明背景
Autotaxin(ATX)于1992年首次从A2058黑素瘤细胞中被分离出来,被称作“自分泌动力因子”,是一个分泌型糖蛋白。ATX具有磷酸二酯酶(PDE)的活性,是胞外焦磷酸酶/磷酸二酯酶(ENPP)家族的一员。ATX还具有溶血磷脂酶D(lysoPLD)活性,能够以溶血磷脂酰胆碱(lysophosphatidylcholine,LPC)为底物催化生成溶血磷脂酸(lysophosphatidic acid,LPA)。LPA不但是磷脂合成的前体,而且能通过各种信号传导途径引起广泛的生物学效应。LPA一旦生成,能够通过六个细胞表面特异的受体蛋白(LPA1-6),即G蛋白偶联受体(GPCR)介导发挥作用。根据内皮细胞分化基因(Edg)和心室区基因命名,LPA1-6分别为LPA1/Edg-2/VZG-1,LPA2/Edg-4,LPA3/Edg-7,LPA4/p2y9/GPR23,LPA5/GPR92和LPA6/p2Y5,每个受体均通过Gα蛋白(Gs、Gi、Gq、和G12/13)介导,进而引发一系列的细胞信号级联作用。其中,主要的通路包括磷脂酰肌醇二磷酸酯(PIP2)的水解,进而引发细胞内的钙离子释放和蛋白激酶C(PKC)激活;抑制腺苷酸环化酶(cAMP)信号通路;激活Ras-MAPK,MERK,ERK通路,调控细胞增殖活动;激活磷酸肌醇PI3K-AKT通路,调控细胞存活和凋亡活动;最后,激活Rho通路调控细胞骨架重塑、形状改变和细胞迁移活动。在很多病理条件下,尤其是在肿瘤细胞中,ATX处于高表达状态,导致LPA浓度过高。在肿瘤细胞中,LPA浓度能升高至10μmol/L,远高于100nmol/L的正常水平。过多的LPA将增加血管内皮生长因子(VEGF)的生成,促进血管生成;降低抑癌因子p53的表达,增加肿瘤细胞的存活和转移。ATX-LPA信号通路涉及到很多生理和病理过程,从而与很多严重疾病有着重要联系,主要包括心血管疾病、自身免疫性疾病、癌症、纤维化疾病、炎症、神经系统疾病、疼痛等。LPA在肿瘤生成中具有多重功能,促进肿瘤细胞的生长、血管生成、转移和出现耐药性。所以,降低LPA的浓度水平,有利于肿瘤的治疗与控制。相对应的,抑制AXT的活性,阻断LPA的生成途径,是治疗多种严重疾病的研究热点。
随着对ATX的研究不断深入,促使很多以其为靶点的新型抑制剂的出现,其中,研究最集中的是癌症和纤维化疾病。纤维化疾病主要是特发性肺纤维化(IPF)和肝纤维化。IPF是一种表现为弥漫性肺泡炎和肺泡结构紊乱,并导致肺间质性纤维化进行性发展的一种致死性疾病,预后较差,平均生存时间为2到5年。IPF可能是与ATX-LPA通路联系最紧密的疾病,因为在肺部组织中,ATX的表达最高集中在支气管上皮细胞和肺泡巨噬细胞,而这些细胞可以并置成纤维细胞灶。
目前,GLPG-1690,作为Autotaxin抑制剂,已经进入临床II期试验阶段,用于特发性肺纤维化的治疗;血清中ATX浓度与肝纤维化和肝硬度值紧密相关,是预测肝硬化最好的指标之一。此外,ATX在许多肿瘤组织中高度表达,包括黑色素瘤、非小细胞肺癌、肝癌、肾癌、乳腺癌、甲状腺癌、卵巢癌和霍奇金淋巴瘤。LPA/ATX在肿瘤细胞生长过程中,能促使细胞侵袭和转移。所以,ATX抑制剂,阻断信号传导通路,为临床治疗癌症和纤维化疾病提供了一条新途径。
与传统激酶抑制剂相比,ATX抑制剂抑制ATX活性的同时影响多条与细胞增殖、生长和凋亡等相关的信号通路,对一些耐药型肿瘤产生较好的抑制效果,而且与多个器官的纤维化发生紧密相关,是研究与开发新型纤维化疾病药物的重要靶标。
本发明提供了一类新的咪唑并噻唑类化合物,其对ATX具有很好的抑制活性,对于体外酶活性,很多甚至优于对比例1。此外,从药代动力学测试结果可看出,本发明化合物具有较高的暴露量和生物利用度。总之,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发明。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咪唑并噻唑类化合物,其对ATX具有非常好的抑制活性,并在大鼠体内具有较高的暴露量和生物利用度,可用于制备治疗具有ATX表达增加的病理学特征的疾病,譬如,癌症、纤维化疾病(如肺纤维化或肝纤维化)、代谢疾病、骨髓增生异常综合征、心血管疾病、自身免疫性疾病、炎症、神经系统疾病或疼痛的药物。本发明也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并噻唑类化合物,其具有式(I)所示结构:
Figure PCTCN2021130584-appb-000001
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、氮氧化物、代谢物、前药、或混合物;
其中,
Cy是
Figure PCTCN2021130584-appb-000002
Y是-C(=O)-、-N(R 1b)C(=O)-、-S(=O) 1-2-、-(CH 2) t1-、-C(=O)-(CH 2) t1-、-N(R 1b)C(=O)-(CH 2) t1-、-(CH 2) t2-N(R 1b)C(=O)-(CH 2) t1-、-C(=O)-CH 2-N(R 1b)-、或-NHC(=O)NH-;
Z是H、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氰基烷基、C 3-8环烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 3-8环烷基C 1-6烷基、C 6-10芳基、或C 1-9杂芳基;其中所述Z任选地被一个或多个R 5取代;
X 1、X 2和X 3各自独立地为-O-、-S-、-NH-、-(CH 2) m1-NH-(CH 2) m2-、-(CH 2) m1-O-(CH 2) m2-、-(CH 2) m1-S-(CH 2) m2-、-C(=O)-、-C(=O)NR 8-、-S(=O) 1-2-、或-(CH 2) m3-;
R 1a是H、C 2-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-6环烷基、或C 3-6环烷基C 1-6烷基;其中所述C 2-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-6环烷基和C 3-6环烷基C 1-6烷基任选地被1、2、3、4或5个独立地选自H、D、氧代(C=O)、-CN、-NO 2、-OH、-NH 2、-N 3、F、Cl、Br和I的取代基取代;
R 1b是H、C 1-4烷基、C 3-6环烷基、或C 3-6环烷基C 1-4烷基;其中所述R 1b任选地被1、2、3或4个R 7取代;
R 1c是H、F、Cl、Br、I、-CN、-C(=O)NHR 8、-CF 2H、-CF 3、-C(=O)OR 8、-NO 2、-S(=O) 1-2OR 8、C 1-3烷基、C 1-3烯基、或C 1-3炔基;
R 2为H、-CN、-NO 2、-OH、-NH 2、-N 3、F、Cl、Br、I、C 1-4烷基、C 1-4卤代烷基、或C 1-4羟基烷基;
R 3为H、-CN、-NO 2、-OH、-NH 2、-N 3、F、Cl、Br、I、C 1-6烷基、C 1-6烯基、C 1-6炔基、C 1-6卤代烷基、C 1-6氰基烷基、或C 1-6羟基烷基;
R 4、R 5、R 6、R 7和R 8,在每次出现时,各自独立地为H、D、氧代(C=O)、-CN、-NO 2、-OH、-NH 2、-N 3、F、Cl、Br、I、C 1-6烷基、C 1-6卤代烷基、C 1-6氰基烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6卤代烷氧基、或C 1-6卤代烷氧基C 1-6烷基;
m1在每次出现时,各自独立地为1、2、或3;
m2在每次出现时,各自独立地为0、1、2、或3;
m3在每次出现时,各自独立地为1、2、或3;
n1是0、1、2、3或4;
t为0、1、2、3或4;和
t1和t2分别独立地为1、2、3或4。
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、水合物、溶剂化物、立体异构体、互变异构体、氮氧化物、代谢物、前药,以及药学上可接受的辅料、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。
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或治疗哺乳动物具有ATX表达增加的病理学特征的疾病的药物中的用途。
在一些实施方案,其中所述具有ATX表达增加的病理学特征的疾病包括:癌症、纤维化疾病、代谢疾病、骨髓增生异常综合征、心血管疾病、自身免疫性疾病、炎症、神经系统疾病或疼痛。
在一些实施方案,其中所述具有ATX表达增加的病理学特征的疾病为肺纤维化或肝纤维化。
本发明详细说明
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。
除非另外说明,应当应用本文所使用得下列定义。出于本发明的目的,化学元素与元素周期表CAS版,和《化学和物理手册》,第75版,1994一致。此外,有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述,其全部内容通过引用并入本文。
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。
“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。
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、D、氧代(C=O)、-CN、-NO 2、-OH、-NH 2、-N 3、F、Cl、Br、I、烷基、卤代烷基、氰基烷基、羟基烷基、氨基烷基、烷氧基、烷氨基、卤代烷氧基、或卤代烷氧基烷基等等。
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。
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“氘代烷基”或“氘代乙基”是指烷基基团或乙基基团被1、2、3、4、5或6个D原子取代,其中烷基基团具有本发明所述定义。氘代烷基或氘代乙基的实例包括,但不限于-CD 3、-CH 2D、-CHD 2、-CD 2CD 3、-CH 2CD 3、-CD 2CH 3等等。
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(如F、Cl、Br、或I)所取代,这样的实例包含,但不限于,三氟甲基、三氟乙基、2,2,3,3-四氟丙基、三氟甲氧基等。
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,此类实例包括,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
Figure PCTCN2021130584-appb-000003
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
Figure PCTCN2021130584-appb-000004
基,二氮杂
Figure PCTCN2021130584-appb-000005
基,硫氮杂
Figure PCTCN2021130584-appb-000006
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。
在一实施方案中,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
Figure PCTCN2021130584-appb-000007
基,二氮杂
Figure PCTCN2021130584-appb-000008
基,硫氮杂
Figure PCTCN2021130584-appb-000009
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。
在一实施方案中,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。
在另一实施方案中,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。
如本发明所描述的,环体系中有两个连接点与分子其余部分相连,如式(a1)或(a2)所示,表示既可以是E端也可以是E’端与分子其余部分相连,即两端的连接方式可以互换。
Figure PCTCN2021130584-appb-000010
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“杂原子”是指O、S、N、P和Si,包括N、S和P任何氧化态的形式;伯、仲、叔胺和季铵盐的形式;或者杂环中氮原子上的氢被取代的形式,例如,N(像3,4-二氢-2H-吡咯基中的N),NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR)。
术语“氰基取代烷基”或“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。
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(如下图所示)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。
Figure PCTCN2021130584-appb-000011
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。
发明内容
本发明提供的咪唑并噻唑类化合物,能有效抑制ATX活性,对于体外酶活性,很多优于对比例1,并在大鼠体内具有较高的暴露量和生物利用度,可用于制备治疗具有ATX表达增加的病理学特征的疾病,譬如,癌症、纤维化疾病(如肺纤维化或肝纤维化)、代谢疾病、骨髓增生异常综合征、心血管疾病、自身免疫性疾病、炎症、神经系统疾病或疼痛的药物。
一方面,本发明提供了一种新的咪唑并噻唑类化合物,其具有式(I)所示结构:
Figure PCTCN2021130584-appb-000012
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、氮氧化物、代谢物、前药、或混合物;
其中,
Figure PCTCN2021130584-appb-000013
Y是-C(=O)-、-N(R 1b)C(=O)-、-S(=O) 1-2-、-(CH 2) t1-、-C(=O)-(CH 2) t1-、-N(R 1b)C(=O)-(CH 2) t1-、-(CH 2) t2-N(R 1b)C(=O)-(CH 2) t1-、-C(=O)-CH 2-N(R 1b)-、或-NHC(=O)NH-;
Z是H、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氰基烷基、C 3-8环烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 3-8环烷基C 1-6烷基、C 6-10芳基、或C 1-9杂芳基;其中所述Z任选地被一个或多个R 5取代;
X 1、X 2和X 3各自独立地为-O-、-S-、-NH-、-(CH 2) m1-NH-(CH 2) m2-、-(CH 2) m1-O-(CH 2) m2-、-(CH 2) m1-S-(CH 2) m2-、-C(=O)-、-C(=O)NR 8-、-S(=O) 1-2-、或-(CH 2) m3-;
R 1a是H、C 2-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-6环烷基、或C 3-6环烷基C 1-6烷基;其中所述C 2-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-6环烷基和C 3-6环烷基C 1-6烷基任选地被1、2、3、4或5个独立地选自H、D、氧代(C=O)、-CN、-NO 2、-OH、-NH 2、-N 3、F、Cl、Br和I的取代基取代;
R 1b是H、C 1-4烷基、C 3-6环烷基、或C 3-6环烷基C 1-4烷基;其中所述R 1b任选地被1、2、3或4个R 7取代;
R 1c是H、F、Cl、Br、I、-CN、-C(=O)NHR 8、-CF 2H、-CF 3、-C(=O)OR 8、-NO 2、-S(=O) 1-2OR 8、C 1-3烷基、C 1-3烯基、或C 1-3炔基;
R 2为H、-CN、-NO 2、-OH、-NH 2、-N 3、F、Cl、Br、I、C 1-4烷基、C 1-4卤代烷基、或C 1-4羟基烷基;
R 3为H、-CN、-NO 2、-OH、-NH 2、-N 3、F、Cl、Br、I、C 1-6烷基、C 1-6烯基、C 1-6炔基、C 1-6卤代烷基、C 1-6氰基烷基、或C 1-6羟基烷基;
R 4、R 5、R 6、R 7和R 8,在每次出现时,各自独立地为H、D、氧代(C=O)、-CN、-NO 2、-OH、-NH 2、-N 3、F、Cl、Br、I、C 1-6烷基、C 1-6卤代烷基、C 1-6氰基烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6卤代烷氧基、或C 1-6卤代烷氧基C 1-6烷基;
m1在每次出现时,各自独立地为1、2、或3;
m2在每次出现时,各自独立地为0、1、2、或3;
m3在每次出现时,各自独立地为1、2、或3;
n1是0、1、2、3或4;
t为0、1、2、3或4;和
t1和t2分别独立地为1、2、3或4。
在一些实施方案,本发明化合物具有式(II)所示结构:
Figure PCTCN2021130584-appb-000014
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、氮氧化物、代谢物、前药、或混合物。
在一些实施方案,R 1a是H、C 2-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 3-6环烷基、或C 3-6环烷基C 1-4烷基;其中所述C 2-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 3-6环烷基和C 3-6环烷基C 1-4烷基任选地被1、2、3、4或5个独立地选自H、D、氧代(C=O)、-CN、-NO 2、-OH、-NH 2、-N 3、F、Cl、Br和I的取代基取代。
在一些实施方案,R 1a是H、乙基、氘代乙基、异丙基、三氟乙基、三氟甲基、羟乙基、环丙基、或环丙基甲基。
在一些实施方案,Cy是
Figure PCTCN2021130584-appb-000015
其中,X 3是-NH-、或-(CH 2) 1-2-;m3是1、2、或3;和n1是0、1、2、3或4。
在一些实施方案,其中Cy是
Figure PCTCN2021130584-appb-000016
Figure PCTCN2021130584-appb-000017
在一些实施方案,其中R 1b是H、甲基、或乙基。
在一些实施方案,其中Z是C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氰基烷基、C 3-6杂环基C 1-4烷基、或C 3-6环烷基C 1-4烷基,其中所述C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氰基烷基、C 3-6杂环基C 1-4烷基和C 3-6环烷基C 1-4烷基任选地被一个或多个R 5取代;或Z是
Figure PCTCN2021130584-appb-000018
其中
X 4是N、或-CH 2-;
X 5是-O-、-S-、-NH-、-(CH 2) m4-NH-(CH 2) m5-、-(CH 2) m4-O-(CH 2) m5-、-(CH 2) m4-S-(CH 2) m5-、或-(CH 2) m6-;
各m4分别独立地为1、2、3或4;
各m5分别独立地为0、1、2、3或4;
各m6分别独立地为1、2、3或4;和
n2是0、1、2、3或4。
在一些实施方案,其中Z是-CH 2CH 2OH,-CH 2C(CH 3) 2OH,-CH 2C(CH 3) 2CH 2OH,-CH 2CH 2CN,-CH 2CHF 2,-CH(CH 3)CH 2OH,-C(CH 3) 2CH 2OH,-CH 2C(CH 3) 3
Figure PCTCN2021130584-appb-000019
Figure PCTCN2021130584-appb-000020
在一些实施方案,其中,R 4、R 5、R 6、R 7和R 8,在每次出现时,各自独立地为H、D、氧代(C=O)、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、甲基、乙基、丙基、异丙基、叔丁基、甲氧基、乙氧基、-OCH 2CF 3、-OCH 2CH 2F、-CF 3、-CH 2F、-CH 2CF 3、-CH 2CH 2F、-CH 2CH 2CN、CHF 2-O-CH 2-、CF 3-O-CH 2-、-CH 2OH、或-CH 2CH 2OH。
在一些实施方案,本发明化合物为具有以下结构之一的化合物:
Figure PCTCN2021130584-appb-000021
Figure PCTCN2021130584-appb-000022
Figure PCTCN2021130584-appb-000023
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、氮氧化物、代谢物、前药、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、水合物、溶剂化物、立体异构体、互变异构体、氮氧化物、代谢物、前药,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,本发明所述组合物中,其中所述附加治疗剂是与纤维变性疾病、增殖性疾病、炎性疾病、自身免疫疾病、呼吸疾病、心血管疾病、神经变性疾病、皮肤病学障碍和/或异常血管生成相关疾病治疗剂。
在一些实施方案,本发明所述的药物组合物,其中所述附加治疗剂包括但不限于,免疫调节剂、镇痛剂、非甾体抗炎药、类固醇、合成DMARDS、治疗增殖性疾病的药物、糖皮质激素、细胞生长抑制剂、烷化剂、抗代谢剂、细胞毒抗生素、抗体类等。
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或治疗哺乳动物具有ATX表达增加的病理学特征的疾病的药物中的用途。
在一些实施方案,其中所述具有ATX表达增加的病理学特征的疾病包括:癌症、纤维化疾病、代谢疾病、骨髓增生异常综合征、心血管疾病、自身免疫性疾病、炎症、神经系统疾病或疼痛。
在一些实施方案,其中所述具有ATX表达增加的病理学特征的疾病为肺纤维化或肝纤维化。
在一些实施方案,本发明化合物或其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、或II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。
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/或治疗纤维变性疾病、增殖性疾病、炎性疾病、自身免疫疾病、呼吸疾病、心血管疾病、神经变性疾病、皮肤病学障碍和/或异常血管生成相关疾病。
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,其用于制备用于预 防和/或治疗纤维变性疾病、增殖性疾病、炎性疾病、自身免疫疾病、呼吸疾病、心血管疾病、神经变性疾病、皮肤病学障碍和/或异常血管生成相关疾病的药物。
在一些实施方案,本发明提供了包含本发明化合物和其它治疗剂的药物组合物。在具体实施方案中,其它治疗剂是与纤维变性疾病、增殖性疾病、炎性疾病、自身免疫疾病、呼吸疾病、心血管疾病、神经变性疾病、皮肤病学障碍和/或异常血管生成相关疾病治疗剂。
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,其用于预防和/或治疗纤维变性疾病。在具体实施方案中,纤维变性疾病选自特发性肺纤维变性(IPF)、囊性纤维变性、不同病因学的其它弥漫性实质性肺疾病(包括医原性药物诱导的纤维变性、职业和/或环境诱导的纤维变性)、肉芽肿疾病(结节病、过敏性肺炎)、胶原血管病、肺泡蛋白沉积、朗格汉斯细胞肉芽肿、淋巴管平滑肌增多症、遗传疾病(赫曼斯基普德拉克综合征、结节性硬化症、神经纤维瘤、代谢蓄积障碍、家族性的问质性肺病)、辐射诱导的纤维变性、慢性阻塞性肺病(COPD)、硬皮病、博来霉素诱导的肺纤维变性、慢性哮喘、硅肺病、石棉诱导的肺纤维变性、急性呼吸窘迫综合征(ARDS)、肾纤维变性、肾小管间质纤维变性、肾小球肾炎、局部区段性肾小球硬化、IgA肾病变、高血压、奥尔波特病(Alport)、肠纤维变性、肝纤维变性、硬化、醇诱导的肝纤维变性、毒素/药物诱导的肝纤维变性、血色素沉着症、非醇脂肪性肝炎(NASH)、胆管损伤、原发性胆汁性肝硬化、感染诱导的肝纤维变性、病毒诱导的肝纤维变性和自身免疫肝炎、角膜瘢痕、肥厚性瘢痕、迪皮特朗病、瘢痕疙瘩、皮肤纤维变性、皮肤硬皮病、全身性硬化症、脊髓损伤/纤维变性、骨髓纤维变性、血管再狭窄、动脉粥样硬化、动脉硬化、韦格纳肉芽肿、佩罗尼病或慢性淋巴细胞性。更特别的是,纤维变性疾病是特发性肺纤维变性(IPF)。
在另一些实施方案,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,其用于制备用于预防和/或治疗纤维变性疾病的药物。在特别的实施方案中,纤维变性疾病选自特发性肺纤维变性(IPF)、囊性纤维变性、不同病因学的其它弥漫性实质性肺疾病(包括医原性药物诱导的纤维变性、职业和/或环境诱导的纤维变性)、肉芽肿疾病(结节病、过敏性肺炎)、胶原血管病、肺泡蛋白沉积、朗格汉斯细胞肉芽肿、淋巴管平滑肌增多症、遗传疾病(赫曼斯基一普德拉克综合征、结节性硬化症、神经纤维瘤、代谢蓄积障碍、家族性的问质性肺病)、辐射诱导的纤维变性、慢性阻塞性肺病(COPD)、硬皮病、博来霉素诱导的肺纤维变性、慢性哮喘、硅肺病、石棉诱导的肺纤维变性、急性呼吸窘迫综合征(ARDS)、肾纤维变性、肾小管问质纤维变性、肾小球肾炎、局部区段性肾小球硬化、IgA肾病变、高血压、奥尔波特病(Alport)、肠纤维变性、肝纤维变性、硬化、醇诱导的肝纤维变性、毒素/药物诱导的肝纤维变性、血色素沉着症、非醇脂肪性肝炎(NASH)、胆管损伤、原发性胆汁性肝硬化、感染诱导的肝纤维变性、病毒诱导的肝纤维变性和自身免疫肝炎、角膜癫痕、肥厚性癫痕、迪皮特朗病、癫痕疙瘩、皮肤纤维变性、皮肤硬皮病、全身性硬化症、脊髓损伤/纤维变性、骨髓纤维变性、血管再狭窄、动脉粥样硬化、动脉硬化、韦格纳肉芽肿、佩罗尼病或慢性淋巴细胞性。更特别的是,纤维变性疾病是特发性肺纤维变性(IPF)。
在治疗方面的另外的方法中,本发明提供了预防和/或治疗患有纤维变性疾病的哺乳动物的方法,所述方法包括施用有效量的本发明所述的化合物或药物组合物中的一个或多个以用于治疗或预防所述病症。在具体实施方案中,纤维变性疾病选自特发性肺纤维变性(IPF)、囊性纤维变性、不同病因学的其它弥漫性实质性肺疾病(包括医原性药物诱导的纤维变性、职业和/或环境诱导的纤维变性)、肉芽肿疾病(结节病、过敏性肺炎)、胶原血管病、肺泡蛋白沉积、朗格汉斯细胞肉芽肿、淋巴管平滑肌增多症、遗传疾病(赫曼斯基一普德拉克综合征、结节性硬化症、神经纤维瘤、代谢蓄积障碍、家族性的间质性肺病)、辐射诱导的纤维变性、慢性阻塞性肺病(COPD)、硬皮病、博来霉素诱导的肺纤维变性、慢性哮喘、硅肺病、石棉诱导的肺纤维变性、急性呼吸窘迫综合征(ARDS)、肾纤维变性、肾小管间质纤维变性、肾小球肾炎、局部区段性肾小球硬化、IgA肾病变、高血压、奥尔波特病(Alport)、肠纤维变性、肝纤维变性、硬化、醇诱导的肝纤维变性、毒素/药物诱导的肝纤维变性、血色素沉着症、非醇脂肪性肝炎(NASH)、胆管损伤、原发性胆汁性肝硬化、感染诱导的肝纤维变性、病毒诱导的肝纤维变性和自身免疫肝炎、角膜瘢痕、肥厚性瘢痕、迪皮特朗病、瘢痕疙瘩、皮肤纤维变性、皮肤硬皮病、全身性硬化症、脊髓损伤/纤维变性、骨髓纤维变性、血管再狭窄、动脉粥样硬化、动脉硬化、韦格纳肉芽肿、佩罗尼病或慢性淋巴细胞性。更特别的是,纤维变性疾病是特发性肺纤维变性(IPF)。
本发明方法的特别方案包括向患有纤维变性疾病的个体施用有效量的式I、Ia、II、或IIa的本发明化合 物持续一段时期,所述时间段足以降低个体中纤维变性水平,并且优选终止造成所述纤维变性的过程。所述方法的具体实施方案包括给患有发展特发性肺纤维变性的个体患者施用有效量的式I、Ia、II、或IIa的本发明化合物持续一段时间,所述时间段足以减少或预防所述患者的特发性肺纤维变性,并且优选终止造成所述特发性肺纤维变性的过程。
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。
具体实施方式
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、或II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,安耐吉化学公司(Energy-chemical Company),上海韶远(Shanghai Shaoyuan Company),J&K Chemical Company,阿拉丁化学公司(Aladdin Chemical Company),Meryer Chemical Company,TCI Chemical Company,Xiya Reagent Company,Bidepharm Company,Macklin Company和Alfa Chemical Company,使用时均未经过进一步纯化,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-C18,2.1x 30mm,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下面的合成方案1所示。
合成方案1:
Figure PCTCN2021130584-appb-000024
其中,E 1选自Cl、Br或I;E 2选自Cl、Br、I或B(OH) 2;E 3选自Cl、Br、I、OMs、OTs或OTf;Pr 1选自Boc、Cbz或PMB;Pr 2选自叔丁基或2,4,4-三甲基戊-2-基;R 1a、R 2、R 3、R 6、Y、Z、Cy和t均具有本发明所述定义。
中间体1-1与NBS或者苯基三甲基溴化铵反应得到中间体1-2;中间体1-2与硫脲发生关环反应得到中间体1-3;中间体1-3与Pr 2NC和醛R 2CHO在路易斯酸催化作用下,通过三组分反应生成中间体1-4;中间体1-4在加热条件下与乙酸反应,所得中间体再与Boc酸酐或者CbzCl反应得到中间体1-5;中间体1-5先与强碱反应后,再与中间体1-6进行亲核取代反应,随后再与取代的烷基R 1aE 2反应得到中间体1-7;中间体1-7可在酸性条件下或钯催化氢化或与三甲基碘硅烷反应脱去保护基Pr 1从而得到中间体1-8;中间体1-8和中间体2-7在碱性以及加热条件下,通过亲核取代反应得到式1-9所示的化合物。
实施例
实施例1
2-(乙基(6-乙基-2-(1-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)哌啶-4-基)咪唑并[2,1-b]噻唑-5-基)氨基)-4-(4-氟苯基)噻唑-5-甲腈的制备
Figure PCTCN2021130584-appb-000025
步骤1)4-(羟基乙基)哌啶-1-甲酸苄酯
向2-(哌啶-4-基)乙醇(0.5g,3.88mmol)的二氯甲烷(10mL)溶液中加入三乙胺(1.08mL,7.76mmol),将混合物冷却至0℃,滴加氯甲酸苄酯(0.6mL,4.26mmol)。反应混合物于0℃下搅拌2小时后,减压浓缩除去溶剂,加入水(20mL),用乙酸乙酯萃取(20mL x 3),合并有机相,有机相经饱和食盐水洗,无水硫酸钠干燥,减压浓缩得粗品0.8g,直接用于下一步反应。
步骤2)4-(氧代乙基)哌啶-1-甲酸苄酯
在氮气保护、-70℃下,向草酰氯(0.48mL,5.67mmol)的二氯甲烷(5mL)溶液中滴加二甲亚砜(0.8mL,11.2mmol),混合物搅拌30分钟后,滴加4-(羟基乙基)哌啶-1-甲酸苄酯(0.8g,3.04mmol)的二氯甲烷(8mL)溶液,再滴加三乙胺(2.3mL,16.6mmol)。搅拌1小时后,将混合物减压浓缩除去溶剂,加入水(20mL),用乙酸乙酯萃取(20mL x 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(石油醚:乙酸乙酯=10:1)得到标题化合物为淡黄色油状物(0.57g,72%)。LCMS[M+1] +:262.1。
步骤3)4-(1-溴-2-氧代乙基)哌啶-1-甲酸苄酯
在0℃下,向4-(氧代乙基)哌啶-1-甲酸苄酯(0.57g,2.18mmol)的四氢呋喃(5mL)溶液中加入三甲基苯基三溴化铵(0.94g,2.5mmol),所得混合物在此温度下搅拌50分钟。减压浓缩,向残余物中加入水(15mL),用乙酸乙酯(15mL x 3)萃取,合并有机层,有机层经饱和食盐水洗,无水硫酸钠干燥,减压浓缩得到标题化合物为淡黄色油状物(714mg),直接用于下一步反应。
步骤4)4-(2-氨基噻唑-5-基)哌啶-1-甲酸苄酯
向4-(1-溴-2-氧代乙基)哌啶-1-甲酸苄酯(710mg,2.09mmol)的无水乙醇(12mL)溶液中加入硫脲(0.33g,4.4mmol)。所得混合物于80℃反应2小时。停止反应,待反应液冷却至室温,减压浓缩,加入水(30mL),用乙酸乙酯(20mL x 3)萃取,合并有机层,有机层经饱和碳酸氢钠溶液洗,无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化(石油醚:乙酸乙酯=2:1)得到产物(0.54g,81%)。LCMS[M+1] +:318.1。
步骤5)4-(5-(叔丁基氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-甲酸苄酯
在0℃下,向4-(2-氨基噻唑-5-基)哌啶-1-甲酸苄酯(0.54g,1.7mmol)的乙二醇二甲醚(15mL)溶液中,依次加入叔丁基异氰(0.17g,2mmol)、正丙醛(0.1g,3.4mmol)和氯化镁(10mg,0.08mmol)。混合物搅拌10分钟后升至室温搅拌2小时。过滤,反应液减压浓缩得粗品(0.5g)。LCMS[M+1] +:441.2。
步骤6)4-(5-乙酰胺基-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-甲酸叔丁酯
向4-(5-(叔丁基氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-甲酸苄酯(0.5g,1.14mmol)的乙酸(5mL)溶液中加入对甲苯磺酸(0.22g,1.14mmol),混合物于100℃下反应过夜。待反应液冷却,减压浓缩,加入乙酸乙酯(15mL)和水(15mL),分离出水相,往水相中加入二氧六环(10mL)、三乙胺(0.79mL,5.7mmol)和二碳酸二叔丁酯(0.39mL,1.71mmol),室温搅拌3小时。减压浓缩,向残余物中加入水(20mL),用乙酸乙酯(15mL x 3)萃取,合并有机层,有机层经饱和食盐水洗,无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化(石油醚:乙酸乙酯=1:1)得产物(0.2g,45%)。LCMS[M+1] +:393.2。
步骤7)4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-甲酸叔丁酯
在冰水浴、氮气保护下,向4-(5-乙酰胺基-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-甲酸叔丁酯(150mg,0.38mmol)的四氢呋喃(6mL)溶液中加入60%NaH(46mg,1.14mmol),混合物搅拌15分钟后,缓慢滴加2-氯-4-(4-氟苯基)噻唑-5-甲腈(91mg,0.38mmol)的四氢呋喃溶液(3mL)。将混合物升至室温反应30分钟,经薄层板监控反应完全,加入碘甲烷(89mg,0.57mmol),继续反应3小时,经LC-MS检测反应完全。将反应液倒入水(20mL)中,用乙酸乙酯(15mL x 3)萃取,合并有机层,有机层经饱 和食盐水洗,无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化(石油醚:乙酸乙酯=3:1)得到标题化合物为白色固体(137mg,62%)。LCMS[M+1] +:581.2。
步骤8)2-((6-乙基-2-(哌啶-4-基)咪唑并[2,1-b]噻唑-5-基)(乙基)氨基)-4-(4-氟苯基)噻唑-5-甲腈
向4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-甲酸苄酯(137mg,0.24mmol)的二氯甲烷溶液(3mL)中,加入三氟乙酸(0.5mL),混合物于室温搅拌反应3小时后,经LC-MS检测反应完全,减压浓缩,残余物用甲醇(6mL)溶解,加入NaHCO 3(50mg)搅拌中和30分钟,减压浓缩,向残余物中加入二氯甲烷(10mL)使其溶解,过滤,减压浓缩得到标题化合物为白色固体(112mg,98%)。MS(m/z):481.2[M+1]。
步骤9)2-(乙基(6-乙基-2-(1-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)哌啶-4-基)咪唑并[2,1-b]噻唑-5-基)氨基)-4-(4-氟苯基)噻唑-5-甲腈
向2-((6-乙基-2-(哌啶-4-基)咪唑并[2,1-b]噻唑-5-基)(乙基)氨基)-4-(4-氟苯基)噻唑-5-甲腈(112mg,0.23mmol)的乙腈溶液(3mL)中,加入K 2CO 3(96mg,0.70mmol)、KI(19mg,0.12mmol)和2-氯-1-(3-羟基氮杂环丁-1-基)乙酮(35mg,0.23mmol)。将所得混合物升温至65℃反应5小时,经LC-MS检测反应完全。过滤,减压浓缩,残余物经厚制备板纯化(二氯甲烷:甲醇=20:1)得到标题化合物为白色固体(66mg,48%)。 1H NMR(400MHz,CDCl 3)δ:8.13(m,2H),7.16(m,2H),6.94(m,1H),4.68(m,1H),4.44(m,1H),4.28(m,1H),4.11(m,2H),3.94(m,2H),3.21(m,4H),2.76(m,1H),2.60(m,2H),2.47(m,2H),2.04(m,2H),1.31(m,6H),1.25(s,3H)。LCMS[M+1] +:594.2。
实施例2
2-(环丙基甲基(6-乙基-2-(1-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)哌啶-4-基)咪唑并[2,1-b]噻唑-5-基)氨基)-4-(4-氟苯基)噻唑-5-甲腈的制备
Figure PCTCN2021130584-appb-000026
2-(环丙基甲基(6-乙基-2-(1-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)哌啶-4-基)咪唑并[2,1-b]噻唑-5-基)氨基)-4-(4-氟苯基)噻唑-5-甲腈的合成步骤参照实施例1,除了用溴甲基环丙烷代替碘乙烷,得到标题化合物为白色固体(51mg,34%)。 1H NMR(400MHz,CDCl 3)δ:8.12(m,2H),7.16(m,2H),7.00(m,1H),4.68(m,1H),4.44(m,1H),4.27(m,1H),4.12(m,1H),3.98(m,1H),3.90(m,1H),3.69(m,1H),3.20(m,4H),2.78(m,1H),2.64-2.53(m,4H),2.04(m,2H),1.31(m,3H),1.25(s,3H),1.14(m,1H),0.54(m,2H),0.33(m,1H),0.23(m,1H)。LCMS[M+1] +:620.2。
实施例3
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(2-羟基乙基)乙酰胺的制备
Figure PCTCN2021130584-appb-000027
步骤1)2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)乙酸乙酯
向2-((6-乙基-2-(哌啶-4-基)咪唑并[2,1-b]噻唑-5-基)(乙基)氨基)-4-(4-氟苯基)噻唑-5-甲腈(2.8g,5.83mmol)的乙腈(25mL)溶液中加入碳酸钾(2.42g,17.5mmol)。混合物经冰水浴冷却后加入溴乙酸乙酯(1.16g,6.95mmol),搅拌2小时后经LC-MS检测反应完全。将反应液倒入水(30mL)中,用乙酸乙酯(30mL x 3)萃取,合并有机层,经饱和食盐水洗,无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化 (石油醚:乙酸乙酯=1:2)得到标题化合物为白色固体(2.31g,70%)。LCMS[M+1] +:567.2。
步骤2)2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)乙酸
向2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)乙酸乙酯(2.31g,4.08mmol)的四氢呋喃(10mL)和水(10mL)的溶液中加入氢氧化锂一水合物(514mg,12.2mmol)。混合物于室温反应3小时,经LC-MS检测反应完全。减压浓缩,向残余物中加入水(50mL),用1N HCl调pH至5左右,过滤,滤饼经水洗,烘干得到标题化合物为白色固体(1.98g,90%)。LCMS[M+1] +:539.2。
步骤3)2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(2-羟基乙基)乙酰胺
向2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)乙酸(50mg,0.093mmol)的二氯甲烷(3mL)溶液中依次加入HATU(46mg,0.12mmol)、DIPEA(36mg,0.28mmol)和乙醇胺(11mg,0.18mmol)。所得混合物于室温搅拌2小时后,减压浓缩,残余物经厚制备板纯化(DCM:MeOH=15:1)得到标题化合物为白色固体(50mg,93%)。 1H NMR(400MHz,CD 3OD)δ:8.12(m,2H),7.52(m,1H),7.25(m,2H),4.17(m,1H),4.01(m,1H),3.73(m,2H),3.61(m,2H),3.35(m,2H),3.24(m,2H),3.11(m,2H),3.03(m,1H),2.88(m,1H),2.60(m,2H),2.37(m,1H),2.03(m,2H),1.88(m,2H),1.30(m,6H)。LCMS[M+1] +:582.3。
实施例4
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(2-羟基乙基)-N-甲基乙酰胺的制备
Figure PCTCN2021130584-appb-000028
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(2-羟基乙基)-N-甲基乙酰胺的合成步骤参照实施例3,除了用N-甲基-2-羟基乙胺代替乙醇胺,得到标题化合物为白色固体(43mg,78%)。 1H NMR(400MHz,CD 3OD)δ:8.13(m,2H),7.54(m,1H),7.25(m,2H),4.17(m,1H),4.01(m,1H),3.71(m,2H),3.52(m,4H),3.35(m,2H),3.22-3.12(m,3H),2.96(m,2H),2.94(m,1H),2.87(m,1H),2.61(m,2H),2.47(m,1H),2.09(m,2H),1.87(m,2H),1.30(m,6H)。LCMS[M+1] +:596.1。
实施例5
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(3-羟基环丁基)乙酰胺的制备
Figure PCTCN2021130584-appb-000029
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(3-羟基环丁基)乙酰胺的合成步骤参照实施例3,除了用3-氨基环丁醇盐酸盐代替乙醇胺,得到标题化合物为白色固体(41mg,73%)。 1H NMR(400MHz,CD 3OD)δ:8.13(m,2H),7.53(m,1H),7.25(m,2H),4.17(m,1H),4.00(m,2H),3.87(m,1H),3.73(m,1H),3.24(m,2H),3.12(m,2H),3.03(m,2H),2.88(m,1H),2.68(m,1H),2.61(m,2H),2.39(m,2H),2.28(m,2H),2.06(m,2H),1.86(m,3H),1.30(m,6H)。LCMS[M+1] +:608.4。
实施例6
2-((6-乙基-2-(1-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)哌啶-4-基)咪唑并[2,1-b]噻唑-5-基)(2,2,2-三氟乙基)氨基)-4-(4-氟苯基)噻唑-5-甲腈的制备
Figure PCTCN2021130584-appb-000030
2-((6-乙基-2-(1-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)哌啶-4-基)咪唑并[2,1-b]噻唑-5-基)(2,2,2-三氟乙基)氨基)-4-(4-氟苯基)噻唑-5-甲腈的合成步骤参照实施例1,除了用2,2,2-三氟乙基三氟甲烷磺酸酯代替碘乙烷,得到标题化合物为白色固体(96mg,87%)。 1H NMR(400MHz,CD 3OD)δ:8.15(m,2H),7.51(m,1H),7.27(m,2H),4.88(m,1H),4.75(m,1H),4.51(m,1H),4.47(m,1H),4.21(m,1H),4.05(m,1H),3.78(m,1H),3.14(m,2H),3.02(m,2H),2.84(m,1H),2.61(m,2H),2.26(m,2H),2.03(m,2H),1.82(m,2H),1.30(m,3H)。LCMS[M+1] +:648.1。
实施例7
2-((乙基-d 5)(6-乙基-2-(1-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)哌啶-4-基)咪唑并[2,1-b]噻唑-5-基)氨基)-4-(4-氟苯基)噻唑-5-甲腈的制备
Figure PCTCN2021130584-appb-000031
2-((乙基-d 5)(6-乙基-2-(1-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)哌啶-4-基)咪唑并[2,1-b]噻唑-5-基)氨基)-4-(4-氟苯基)噻唑-5-甲腈的合成步骤参照实施例1,除了用碘乙烷-d 5代替碘乙烷,得到标题化合物为白色固体(76mg,76%)。 1H NMR(400MHz,CD 3OD)δ:8.13(m,2H),7.52(m,1H),7.24(m,2H),4.57(m,1H),4.47(m,1H),4.21(m,1H),4.05(m,1H),3.77(m,1H),3.10(m,6H),3.01(m,1H),2.83(m,1H),2.60(m,2H),2.27(m,2H),2.03(m,2H),1.82(m,2H),1.30(m,3H)。LCMS[M+1] +:599.2。
实施例8
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(2-羟基-2-甲基丙基)乙酰胺的制备
Figure PCTCN2021130584-appb-000032
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(2-羟基-2-甲基丙基)乙酰胺的合成步骤参照实施例3,除了用2羟基-2-甲基丙胺代替乙醇胺,得到标题化合物为白色固体(44mg,78%)。 1H NMR(400MHz,CD 3OD)δ:8.13(m,2H),7.53(m,1H),7.25(m,2H),4.17(m,1H),4.01(m,1H),3.73(m,2H),3.23(m,4H),3.08(m,2H),2.91(m,1H),2.61(m,2H),2.46(m,2H),2.09(m,2H),1.88(m,2H),1.31(m,6H),1.18(m,6H)。LCMS[M+1] +:610.3。
实施例9
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(3-羟基-2,2-二甲基丙基)乙酰胺的制备
Figure PCTCN2021130584-appb-000033
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(3-羟基-2,2-二甲基丙基)乙酰胺的合成步骤参照实施例3,除了用3-羟基-2,2-二甲基丙胺代替乙醇胺,得到标题化合物为白色固体(44mg,76%)。 1H NMR(400MHz,CD 3OD)δ:8.13(m,2H),7.53(m,1H),7.25(m,2H),4.18(m,1H),4.00(m,1H),3.73(m,2H),3.27-3.21(m,4H),3.16(m,3H),3.05(m,2H),2.89(m,1H),2.61(m,2H),2.43(m,1H),2.07(m,2H),1.88(m,2H),1.31(m,6H),0.88(s,6H)。LCMS[M+1] +:624.2。
实施例10
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(2-氰基乙基)-N-甲基乙酰胺的制备
Figure PCTCN2021130584-appb-000034
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(2-氰基乙基)-N-甲基乙酰胺的合成步骤参照实施例3,除了用3-甲氨基丙腈代替乙醇胺,得到标题化合物为白色固体(45mg,80%)。 1H NMR(400MHz,CD 3OD)δ:8.13(m,2H),7.55(m,1H),7.25(m,2H),4.18(m,1H),4.00(m,1H),3.77-3.66(m,4H),3.61(m,1H),3.24(m,3H),3.15(m,2H),2.98(m,2H),2.85(m,1H),2.74(m,1H),2.61(m,2H),2.12(m,2H),1.90(m,2H),1.31(m,6H)。LCMS[M+1] +:605.4。
实施例11
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(2,2-二氟乙基)乙酰胺的制备
Figure PCTCN2021130584-appb-000035
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(2,2-二氟乙基)乙酰胺的合成步骤参照实施例3,除了用2,2-二氟乙胺代替乙醇胺,得到标题化合物为白色固体(38mg,68%)。 1H NMR(400MHz,CD 3OD)δ:8.13(m,2H),7.54(m,1H),7.26(m,2H),5.93(m,1H),4.19(m,1H),4.03(m,1H),3.63(m,2H),3.14(m,2H),3.02(m,2H),2.91(m,1H),2.83(m,1H),2.63(m,1H),2.36(m,2H),2.03(m,2H),1.89(m,2H),1.32(m,6H)。LCMS[M+1] +:602.2。
实施例12
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(1-(羟基甲基)环丙基)乙酰胺的制备
Figure PCTCN2021130584-appb-000036
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(1-(羟 基甲基)环丙基)乙酰胺的合成步骤参照实施例3,除了用1-(氨基环丙基)甲醇代替乙醇胺,得到标题化合物为白色固体(47mg,83%)。 1H NMR(400MHz,CD 3OD)δ:8.14(m,2H),7.52(m,1H),7.25(m,2H),4.17(m,1H),4.01(m,1H),3.73(m,1H),3.59(s,2H),3.22(m,1H),3.06(s,2H),2.97(m,2H),2.85(m,1H),2.60(m,2H),2.32(m,2H),2.04(m,2H),1.85(m,2H),1.31(m,6H),0.80(m,4H)。LCMS[M+1] +:608.3。
实施例13
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(1-羟基丙烷-2-基)乙酰胺的制备
Figure PCTCN2021130584-appb-000037
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(1-羟基丙烷-2-基)乙酰胺的合成步骤参照实施例3,除了用DL-氨基丙醇代替乙醇胺,得到标题化合物为白色固体(45mg,81%)。 1H NMR(400MHz,CD 3OD)δ:8.13(m,2H),7.54(m,1H),7.24(m,2H),4.17(m,1H),4.01(m,1H),3.73(m,2H),3.52(m,2H),3.24(m,2H),3.18(m,1H),3.08(m,2H),2.91(m,1H),2.61(m,2H),2.45(m,1H),2.08(m,2H),1.88(m,2H),1.30(m,6H),1.15(m,3H)。LCMS[M+1] +:565.2。
实施例14
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(1-羟基-2-甲基丙烷-2-基)乙酰胺的制备
Figure PCTCN2021130584-appb-000038
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(1-羟基-2-甲基丙烷-2-基)乙酰胺的合成步骤参照实施例3,得到标题化合物为白色固体(41mg,72%),除了用2-氨基-2-甲基-1-丙醇代替乙醇胺。 1H NMR(400MHz,CD 3OD)δ:8.13(m,2H),7.53(m,1H),7.24(m,2H),4.19(m,1H),4.01(m,1H),3.73(m,1H),3.54(m,2H),3.22(m,1H),3.04(m,4H),2.88(m,1H),2.61(m,2H),2.40(m,2H),2.08(m,2H),1.84(m,2H),1.30(m,12H)。LCMS[M+1] +:610.2。
实施例15
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-((1-羟基环丙基)甲基)乙酰胺的制备
Figure PCTCN2021130584-appb-000039
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-((1-羟基环丙基)甲基)乙酰胺的合成步骤参照实施例3,除了用1-(氨基甲基)环丙醇代替乙醇胺,得到标题化合物为白色固体(38mg,67%)。 1H NMR(400MHz,CD 3OD)δ:8.13(m,2H),7.54(m,1H),7.25(m,2H),4.17(m,1H),4.01(m,1H),3.73(m,2H),3.37(s,2H),3.24-3.19(m,4H),3.10(m,2H),2.91(m,1H),2.61(m,2H),2.45(m,2H),2.09(m,2H),1.89(m,2H),1.31(m,6H),0.70(m,2H),0.60(m,2H)。LCMS[M+1] +:608.2。
实施例16
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-((1-羟基环 丁基)甲基)乙酰胺的制备
Figure PCTCN2021130584-appb-000040
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-((1-羟基环丁基)甲基)乙酰胺的合成步骤参照实施例3,除了用1-(氨基甲基)环丁醇代替乙醇胺,得到标题化合物为白色固体(41mg,71%)。 1H NMR(400MHz,CD 3OD)δ:8.13(m,2H),7.51(m,1H),7.25(m,2H),4.17(m,1H),4.01(m,1H),3.39(s,2H),3.09(m,2H),2.97(m,2H),2.87-2.81(m,2H),2.61(m,2H),2.32(m,2H),2.03(m,6H),1.84(m,2H),1.75(m,2H),1.61(m,1H),1.31(m,6H)。LCMS[M+1] +:622.2。
实施例17
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(3,3-二氟环丁基)乙酰胺的制备
Figure PCTCN2021130584-appb-000041
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(3,3-二氟环丁基)乙酰胺的的合成步骤参照实施例3,得到标题化合物为白色固体(43mg,74%),除了用3,3-二氟环丁胺代替乙醇胺。 1H NMR(400MHz,CD 3OD)δ:8.13(m,2H),7.51(m,1H),7.25(m,2H),4.17(m,2H),4.01(m,1H),3.03(s,2H),2.96-2.81(m,5H),2.67-2.56(m,4H),2.87-2.81(m,2H),2.28(m,2H),2.02(m,2H),1.86(m,2H),1.31(m,6H)。LCMS[M+1] +:627.1。
实施例18
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(环丙基甲基)乙酰胺的制备
Figure PCTCN2021130584-appb-000042
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(环丙基甲基)乙酰胺的合成步骤参照实施例3,除了用环丙基甲胺代替乙醇胺,得到标题化合物为白色固体(38mg,69%)。 1H NMR(400MHz,CD 3OD)δ:8.13(m,2H),7.52(m,1H),7.25(m,2H),4.17(m,1H),4.01(m,1H),3.10(m,2H),3.04(m,2H),2.99(m,4H),2.86(m,1H),2.61(m,2H),2.32(m,2H),2.04(m,2H),1.86(m,2H),1.31(m,6H),0.49(m,2H),0.22(m,2H)。LCMS[M+1] +:592.1。
实施例19
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(环丁基甲基)乙酰胺的制备
Figure PCTCN2021130584-appb-000043
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(环丁基甲基)乙酰胺的合成步骤参照实施例3,除了用环丁基甲胺代替乙醇胺,得到标题化合物为白色固体(40mg,71%)。 1H NMR(400MHz,CD 3OD)δ:8.13(m,2H),7.51(m,1H),7.24(m,2H),4.17(m,1H),4.01(m,1H),3.24(m,2H),3.22(m,1H),3.02(m,2H),2.98(m,6H),2.94(m,1H),2.81(m,1H),2.63-2.50(m,2H),2.29(m,2H),2.03(m,2H),1.87(m,2H),1.74(m,2H),1.31(m,2H)。LCMS[M+1] +:606.2。
实施例20
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-特戊基乙酰胺的制备
Figure PCTCN2021130584-appb-000044
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-特戊基乙酰胺的合成步骤参照实施例3,除了用特戊胺代替乙醇胺,得到标题化合物为白色固体(37mg,66%)。 1H NMR(400MHz,CD 3OD)δ:8.13(m,2H),7.53(m,1H),7.25(m,2H),4.19(m,1H),4.01(m,1H),3.06(m,3H),2.99(m,2H),2.91-2.81(m,3H),2.61(m,2H),2.33(m,2H),2.06-1.81(m,2H),1.31(m,6H),0.92(s,9H)。LCMS[M+1] +:608.2。
实施例21
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(3-氧杂环丁基)乙酰胺的制备
Figure PCTCN2021130584-appb-000045
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(3-氧杂环丁基)乙酰胺的合成步骤参照实施例3,除了用3-氧杂环丁胺代替乙醇胺,得到标题化合物为白色固体(39mg,71%)。 1H NMR(400MHz,CD 3OD)δ:8.13(m,2H),7.52(m,1H),7.25(m,2H),4.96(m,1H),4.87(m,1H),4.60(m,2H),4.17(m,1H),4.02(m,2H),3.06(s,2H),2.98(m,2H),2.82(m,2H),2.61(m,2H),2.29(m,2H),2.03(m,2H),1.88(m,2H),1.31(m,6H)。LCMS[M+1] +:594.1。
实施例22
2-(乙基(6-乙基-2-(1-(2-吗啡啉基-2-氧代乙基)哌啶-4-基)咪唑并[2,1-b]噻唑-5-基)氨基)-4-(4-氟苯基)噻唑-5-甲腈的制备
Figure PCTCN2021130584-appb-000046
2-(乙基(6-乙基-2-(1-(2-吗啡啉基-2-氧代乙基)哌啶-4-基)咪唑并[2,1-b]噻唑-5-基)氨基)-4-(4-氟苯基)噻唑-5-甲腈的合成步骤参照实施例3,除了用吗啡啉代替乙醇胺,得到标题化合物为白色固体(41mg,73%)。 1H NMR(400MHz,CD 3OD)δ:8.13(m,2H),7.52(m,1H),7.25(m,2H),4.17(m,1H),4.00(m,1H),3.65(m,5H),3.58(m,2H),3.03-3.96(m,5H),2.87(m,1H),2.61(m,2H),2.25(m,2H),2.04(m,2H),1.78(m,2H),1.30(m,6H)。LCMS[M+1] +:608.1。
实施例23
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(四氢-2H-吡喃-4-基)乙酰胺的制备
Figure PCTCN2021130584-appb-000047
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(乙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(四氢-2H-吡喃-4-基)乙酰胺的合成步骤参照实施例3,除了用4-氨基四氢吡喃代替乙醇胺,得到标题化合物为白色固体(45mg,78%)。 1H NMR(500MHz,CDCl 3)δ:8.15(m,2H),7.19(m,2H),7.02(m,1H),6.96(m,1H),4.12(m,1H),4.05-3.96(m,4H),3.51(m,2H),3.04(m,2H),2.96(m,2H),2.76(m,1H),2.62(m,2H),2.31(m,2H),2.06(m,2H),1.90(m,2H),1.77(m,2H),1.52(m,2H),1.34(m,6H)。LCMS[M+1] +:622.3。
实施例24
2-(环丙基(6-乙基-2-(1-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)哌啶-4-基)咪唑并[2,1-b]噻唑-5-基)氨基)-4-(4-氟苯基)噻唑-5-甲腈的制备
Figure PCTCN2021130584-appb-000048
步骤1)4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-甲酸叔丁酯
在0℃下,向4-(5-乙酰胺基-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-甲酸叔丁酯(1g,2.55mmol)的四氢呋喃(15mL)溶液中分批加入钠氢(306mg,7.65mmol),混合物搅拌10分钟后,滴加2-氯-4-(4-氟苯基)噻唑-5-甲腈(596mg,2.50mmol)的四氢呋喃溶液(5mL)。混合物升至室温反应,经LCMS检测反应完全后,将反应液倒入水中,用乙酸乙酯(15mL x 3)萃取,合并的有机层经饱和食盐水洗,无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化(石油醚:乙酸乙酯=4:1至1.5:1)得到标题化合物为黄色泡沫状固体(980mg,70%)。LCMS[M+1] +:553.3。
步骤2)4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(环丙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-甲酸叔丁酯
向4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-甲酸叔丁酯(330mg,0.60mmol)的1,2-二氯乙烷(10mL)溶液中加入环丙基硼酸(156mg,1.8mmol)、醋酸铜(108mg,0.60mmol)、2,2'-联吡啶(96mg,0.60mmol)和碳酸钠(192mg,1.8mmol),混合物在氧气条件下(气 球),于75℃反应过夜。硅藻土过滤,减压浓缩,残余物经柱层析纯化(石油醚:乙酸乙酯=5:1至3:1)得到标题化合物为淡黄色泡沫状固体(287mg,71%)。LCMS[M+1] +:593.3。
步骤3)2-(环丙基(6-乙基-2-(哌啶-4-基)咪唑并[2,1-b]噻唑-5-基]氨基}-4-(4-氟苯基)噻唑-5-甲腈
向4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(环丙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-甲酸叔丁酯(287mg,0.48mmol)的二氯甲烷(3mL)溶液中加入三氟乙酸(0.5mL)。混合物于室温反应2小时后,减压浓缩,向残余物中加入水(15mL)和二氯甲烷(15mL),用碳酸氢钠溶液调pH至8左右,用二氯甲烷(15mL x 2)萃取,合并有机层,无水硫酸钠干燥,减压浓缩,得到标题化合物为淡黄色泡沫状固体(230mg,96%)。LCMS[M+1] +:493.3。
步骤4)2-(环丙基(6-乙基-2-(1-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)哌啶-4-基)咪唑并[2,1-b]噻唑-5-基)氨基)-4-(4-氟苯基)噻唑-5-甲腈
向2-(环丙基(6-乙基-2-(哌啶-4-基)咪唑并[2,1-b]噻唑-5-基]氨基}-4-(4-氟苯基)噻唑-5-甲腈(50mg,0.1mmol)的乙腈(3mL)溶液中加入2-氯-1-(3-羟基氮杂环丁-1-基)乙酮(15mg,0.1mmol)、碳酸钾(27mg,0.2mmol)和碘化钾(8.3mg,0.050mmol),混合物于70℃反应2小时。减压浓缩,所得残余物经厚制备板纯化(二氯甲烷:异丙醇=12:1)得到标题化合物为白色固体(40mg,66%)。 1H NMR(500MHz,CDCl 3)δ:8.09(m,2H),7.15(m,2H),6.89(m,1H),4.93(m,1H),4.68(m,1H),4.45(m,1H),4.30(m,1H),4.10(m,1H),3.99(m,1H),3.07-2.95(m,3H),2.70(m,1H),2.54(m,2H),2.21(m,2H),2.01(m,2H),1.81(m,2H),1.27(m,3H),0.95(m,2H),0.73(m,2H)。LCMS[M+1] +:606.3。
实施例25
2-((6-乙基-2-(1-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)哌啶-4-基)咪唑并[2,1-b]噻唑-5-基)(异丙基)氨基)-4-(4-氟苯基)噻唑-5-甲腈的制备
Figure PCTCN2021130584-appb-000049
步骤1)4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(异丙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-甲酸叔丁酯
向4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-甲酸叔丁酯(330mg,0.60mmol)的DMF(9mL)溶液中加入钠氢(72mg,1.8mmol)。混合物于室温搅拌5分钟后,再加入2-溴丙烷(282μL,3.0mmol)。反应混合物于85℃下反应,待TLC显示反应完全后,将反应液冷却至0℃,滴加水淬灭反应,加水(15mL),用乙酸乙酯萃取(15mL x 3),合并有机层,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(石油醚:乙酸乙酯=4:1至3:1)得到标题化合物为淡黄色泡沫状固体(365mg,89%)。LCMS[M+1] +:595.3。
步骤2)2-((6-乙基-2-(哌啶-4-基)咪唑并[2,1-b]噻唑-5-基)(异丙基)氨基)-4-(4-氟苯基)噻唑-5-甲腈
向4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(异丙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-甲酸叔丁酯(365mg,0.61mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(0.45mL)。混合物于室温反应2小时后,减压浓缩,加入水(15mL)和二氯甲烷(15mL),用碳酸氢钠溶液调pH至8左右,用二氯甲烷(15mL x 2)萃取,合并有机层,无水硫酸钠干燥,减压浓缩,得到标题化合物为淡黄色泡沫状固体(290mg,96%)。LCMS[M+1] +:495.3。
步骤3)2-((6-乙基-2-(1-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)哌啶-4-基)咪唑并[2,1-b]噻唑-5-基)(异丙基)氨基)-4-(4-氟苯基)噻唑-5-甲腈
向2-((6-乙基-2-(哌啶-4-基)咪唑并[2,1-b]噻唑-5-基)(异丙基)氨基)-4-(4-氟苯基)噻唑-5-甲腈(50mg,0.1mmol)的乙腈(3mL)溶液中加入2-氯-1-(3-羟基氮杂环丁-1-基)乙酮(15mg,0.1mmol)、碳酸氢钠(21mg,0.25mmol)和碘化钾(8.3mg,0.050mmol)。混合物于70℃反应3小时,过滤,减压浓缩,所得残余物经厚制备板纯化(二氯甲烷:异丙醇=12:1)得到标题化合物为白色固体(35mg,57%)。 1H NMR(500 MHz,CDCl 3)δ:8.15(m,2H),7.18(m,2H),6.94(m,1H),5.11(m,1H),4.71(m,1H),4.47(m,1H),4.30(m,1H),4.12(m,1H),3.92(m,1H),3.11-3.05(m,4H),2.73(m,1H),2.60(m,3H),2.30(m,2H),2.03(m,2H),1.86(m,2H),1.33(m,6H),1.27(m,3H)。LCMS[M+1] +:608.3。
实施例26
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(异丙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(四氢-2H-吡喃-4-基)乙酰胺的制备
Figure PCTCN2021130584-appb-000050
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(异丙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(四氢-2H-吡喃-4-基)乙酰胺的合成步骤参照实施例25,除了用2-氯-N-(四氢-2H-吡喃-4-基)乙酰胺代替2-氯-1-(3-羟基氮杂环丁-1-基)乙酮,得到标题化合物为白色固体(50mg,72%)。 1H-NMR(400MHz,CDCl 3)δ:8.15(m,2H),7.19(m,2H),7.05-6.98(m,1H),6.96(s,1H),5.12(m,1H),4.08-4.00(m,1H),4.00-3.94(m,2H),3.54-3.48(m,2H),3.03(s,2H),2.98-2.92(m,2H),2.76(m,1H),2.63-2.59(m,2H),2.30(m,2H),2.07-2.04(m,2H),1.92-1.88(m,2H),1.82-1.72(m,2H),1.56-1.48(m,2H),1.37-1.32(m,6H),1.29-1.26(m,3H)。LCMS[M+1] +:636.3。
实施例27
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(异丙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(氧杂环丁烷-3-基)乙酰胺的制备
Figure PCTCN2021130584-appb-000051
2-(4-(5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(异丙基)氨基)-6-乙基咪唑并[2,1-b]噻唑-2-基)哌啶-1-基)-N-(氧杂环丁烷-3-基)乙酰胺的合成步骤参照实施例25,除了用2-氯-N-(氧杂环丁烷-3-基)乙酰胺代替2-氯-1-(3-羟基氮杂环丁-1-基)乙酮,得到标题化合物为白色固体(48mg,72%)。 1H-NMR(400MHz,CDCl 3)δ:8.15(m,2H),7.71-7.60(m,1H),7.19(m,2H),6.98(s,1H),5.16-5.07(m,2H),4.98(m,2H),4.54(m,2H),3.06(s,2H),3.00-2.95(m,2H),2.81-2.73(m,1H),2.63-2.59(m,2H),2.39-2.28(m,2H),2.09-2.07(m,2H),1.87-1.77(m,2H),1.37-1.32(m,6H),1.29-1.26(m,3H)。LCMS[M+1] +:608.3。
对比例1 2-(4-(2-乙基-3-((4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-8-甲基咪唑并[1,2a]吡啶-6-基)哌嗪-1-基)-1-(3-羟基氮杂环丁烷-1-基)乙酮
Figure PCTCN2021130584-appb-000052
对比例1可参照PCT专利申请WO 2014139882A1表III中化合物7合成得到。
生物试验
体外分析:以LPC为底物酶活性筛选
原理:利用lysoPLD酶活性能够将底物溶血磷脂胆(lysophosphatidylcholine,LPC)进行水解,生成溶血磷脂酸(LPA)和胆碱,胆碱在胆碱氧化酶的作用下氧化生成H 2O 2,存在辣根过氧化物酶(HRP)时,Amplex Red试剂与H 2O 2以1:1的化学定量比反应,形成强荧光产物进行荧光定量检测。
实验步骤:本发明受试化合物和对比例1分别用DMSO溶解成10mM储备液,用DMSO进行3倍梯度稀释,起始浓度是10mM,10个浓度点。用反应缓冲溶液制备终浓度为2ng/μl ATX,2U/ml HRP和0.2U/ml胆碱氧化酶(choline oxidase)的混合溶液1。向实验板中每孔加入20μl上述混合溶液1,按照10nl/孔,使用Echo550将DMSO稀释后的化合物转移进入实验板。用反应缓冲溶液制备终浓度为60mM LPC和400uM Amplex Red的混合溶液2,实验板中每孔加入20μl的混合溶液2。加样后,实验板在震板仪器上震荡30s,室温孵育30min。用Envision读取激发光530nm,发射光590nm的荧光信号。根据荧光比值计算化合物对酶反应的抑制率,用软件进行分析计算出化合物的IC 50值,见表1。
表1本发明化合物以LPC为底物的ATX抑制活性分析
+:>1000nM;++:500-1000nM;+++:100-500nM;++++:0.01-100nM
受试化合物 LPC-IC 50 受试化合物 LPC-IC 50
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 ++++ 对比例1 +++
由表1可知,本发明化合物具有非常好的ATX抑制活性,绝大部分化合物的IC 50值均低于100nM且明显优于对比例1。
大鼠药代动力学试验
本研究选用雄性SD大鼠受试动物,用LC/MS/MS法定量测定了大鼠分别静脉注射和口服给予受试化合物不同时间点的血浆药物浓度,从而评估受试化合物在SD大鼠体内的药代动力学特征。
将受试化合物的澄清溶液经足静脉注射到SD大鼠体内(自由饮食,6-8周龄),将受试化合物的混悬溶液灌胃给予SD大鼠(自由饮食,6-8周龄)。动物均于给药后0.083、0.25、0.5、1、2、4、6、8、10和24小时于尾静脉采集血样,每次采血量为0.15mL,所有采集的全血样品均置于含EDTA-K2的离心管中,上下颠倒离心管使抗凝剂与血液充分混合,在30min内于4℃、1500g条件下离心10min分离血浆,转移血浆样品至新的离心管中,保存在-90~-60℃条件至分析。采用LC-MS/MS测定本发明受试化合物血药浓 度,采用Pharsight Phoenix 8.0软件中的非房室模型计算药代动力学参数,并计算绝对生物利用度,见表2。
表2本发明化合物药代动力学测试结果
Figure PCTCN2021130584-appb-000053
从表2可以看出,本发明化合物具有较高的暴露量和生物利用度。
总之,本发明化合物对ATX具有很好的抑制活性,具有优异的体内外药效、药代性质,具备较佳的临床应用前景。
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 (16)

  1. 化合物,其具有式(I)所示结构:
    Figure PCTCN2021130584-appb-100001
    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、氮氧化物、代谢物、前药、或混合物;
    其中,
    Cy是
    Figure PCTCN2021130584-appb-100002
    Y是-C(=O)-、-N(R 1b)C(=O)-、-S(=O) 1-2-、-(CH 2) t1-、-C(=O)-(CH 2) t1-、-N(R 1b)C(=O)-(CH 2) t1-、-(CH 2) t2-N(R 1b)C(=O)-(CH 2) t1-、-C(=O)-CH 2-N(R 1b)-、或-NHC(=O)NH-;
    Z是H、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氰基烷基、C 3-8环烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 3-8环烷基C 1-6烷基、C 6-10芳基、或C 1-9杂芳基;其中所述Z任选地被一个或多个R 5取代;
    X 1、X 2和X 3各自独立地为-O-、-S-、-NH-、-(CH 2) m1-NH-(CH 2) m2-、-(CH 2) m1-O-(CH 2) m2-、-(CH 2) m1-S-(CH 2) m2-、-C(=O)-、-C(=O)NR 8-、-S(=O) 1-2-、或-(CH 2) m3-;
    R 1a是H、C 2-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-6环烷基、或C 3-6环烷基C 1-6烷基;其中所述C 2-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-6环烷基和C 3-6环烷基C 1-6烷基任选地被1、2、3、4或5个独立地选自H、D、氧代(C=O)、-CN、-NO 2、-OH、-NH 2、-N 3、F、Cl、Br和I的取代基取代;
    R 1b是H、C 1-4烷基、C 3-6环烷基、或C 3-6环烷基C 1-4烷基;其中所述R 1b任选地被1、2、3或4个R 7取代;
    R 1c是H、F、Cl、Br、I、-CN、-C(=O)NHR 8、-CF 2H、-CF 3、-C(=O)OR 8、-NO 2、-S(=O) 1-2OR 8、C 1-3烷基、C 1-3烯基、或C 1-3炔基;
    R 2为H、-CN、-NO 2、-OH、-NH 2、-N 3、F、Cl、Br、I、C 1-4烷基、C 1-4卤代烷基、或C 1-4羟基烷基;
    R 3为H、-CN、-NO 2、-OH、-NH 2、-N 3、F、Cl、Br、I、C 1-6烷基、C 1-6烯基、C 1-6炔基、C 1-6卤代烷基、C 1-6氰基烷基、或C 1-6羟基烷基;
    R 4、R 5、R 6、R 7和R 8,在每次出现时,各自独立地为H、D、氧代(C=O)、-CN、-NO 2、-OH、-NH 2、-N 3、F、Cl、Br、I、C 1-6烷基、C 1-6卤代烷基、C 1-6氰基烷基、C 1-6羟基烷基、C 1-6烷氧基、C 1-6卤代烷氧基、或C 1-6卤代烷氧基C 1-6烷基;
    m1在每次出现时,各自独立地为1、2、或3;
    m2在每次出现时,各自独立地为0、1、2、或3;
    m3在每次出现时,各自独立地为1、2、或3;
    n1是0、1、2、3或4;
    t为0、1、2、3或4;和
    t1和t2分别独立地为1、2、3或4。
  2. 根据权利要求1所述的化合物,其具有式(II)所示结构:
    Figure PCTCN2021130584-appb-100003
    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、氮氧化物、代谢物、前药、或混合物。
  3. 根据权利要求1或2所述的化合物,其中R 1a是H、C 2-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 3-6环烷基、或C 3-6环烷基C 1-4烷基;其中所述C 2-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 3-6环烷基和C 3-6环烷基C 1-4烷基任选地被1、2、3、4或5个独立地选自H、D、氧代(C=O)、-CN、-NO 2、-OH、-NH 2、-N 3、F、Cl、Br和I的取代基取代。
  4. 根据权利要求1或2所述的化合物,其中R 1a是H、乙基、氘代乙基、异丙基、三氟甲基、三氟乙基、羟乙基、环丙基、或环丙基甲基。
  5. 根据权利要求1或2所述的化合物,其中Cy是
    Figure PCTCN2021130584-appb-100004
    其中,X 3是-NH-、或-(CH 2) 1-2-;m3是1、2、或3;和n1是0、1、2、3或4。
  6. 根据权利要求1或2所述的化合物,其中Cy是
    Figure PCTCN2021130584-appb-100005
    Figure PCTCN2021130584-appb-100006
  7. 根据权利要求1或2所述的化合物,其中R 1b是H、甲基、或乙基。
  8. 根据权利要求1或2所述的化合物,其中Z是C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氰基烷基、C 3-6杂环基C 1-4烷基、或C 3-6环烷基C 1-4烷基,其中所述C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氰 基烷基、C 3-6杂环基C 1-4烷基和C 3-6环烷基C 1-4烷基任选地被一个或多个R 5取代;或Z是
    Figure PCTCN2021130584-appb-100007
    其中
    X 4是N、或-CH 2-;
    X 5是-O-、-S-、-NH-、-(CH 2) m4-NH-(CH 2) m5-、-(CH 2) m4-O-(CH 2) m5-、-(CH 2) m4-S-(CH 2) m5-、或-(CH 2) m6-;
    各m4分别独立地为1、2、3或4;
    各m5分别独立地为0、1、2、3或4;
    各m6分别独立地为1、2、3或4;和
    n2是0、1、2、3或4。
  9. 根据权利要求1或2所述的化合物,其中Z是-CH 2CH 2OH,-CH 2C(CH 3) 2OH,-CH 2C(CH 3) 2CH 2OH,-CH 2CH 2CN,-CH 2CHF 2,-CH(CH 3)CH 2OH,-C(CH 3) 2CH 2OH,-CH 2C(CH 3) 3
    Figure PCTCN2021130584-appb-100008
    Figure PCTCN2021130584-appb-100009
  10. 根据权利要求1或2所述的化合物,其中,R 4、R 5、R 6、R 7和R 8,在每次出现时,各自独立地为H、D、氧代(C=O)、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、甲基、乙基、丙基、异丙基、叔丁基、甲氧基、乙氧基、-OCH 2CF 3、-OCH 2CH 2F、-CF 3、-CH 2F、-CH 2CF 3、-CH 2CH 2F、-CH 2CH 2CN、CHF 2-O-CH 2-、CF 3-O-CH 2-、-CH 2OH、或-CH 2CH 2OH。
  11. 根据权利要求1所述的化合物,其为具有以下结构之一的化合物:
    Figure PCTCN2021130584-appb-100010
    Figure PCTCN2021130584-appb-100011
    Figure PCTCN2021130584-appb-100012
    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、氮氧化物、代谢物、前药、或混合物。
  12. 药物组合物,所述药物组合物包含权利要求1-11中任一项所述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、氮氧化物、代谢物、前药,以及药学上可以接受的辅料、稀释剂或载体。
  13. 根据权利要求12所述的药物组合物,其进一步包含附加治疗剂。
  14. 使用根据权利要求1-11任一项所述的化合物或权利要求12-13任一项所述的药物组合物在制备用于预防或治疗哺乳动物具有ATX表达增加的病理学特征的疾病的药物中的用途。
  15. 根据权利要求14所述的用途,其中,所述具有ATX表达增加的病理学特征的疾病包括:癌症、纤维化疾病、代谢疾病、骨髓增生异常综合征、心血管疾病、自身免疫性疾病、炎症、神经系统疾病或疼痛。
  16. 根据权利要求14所述的用途,其中,所述具有ATX表达增加的病理学特征的疾病为肺纤维化或肝纤维化。
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