WO2021088957A1 - 芳杂环化合物、其药物组合物及其应用 - Google Patents

芳杂环化合物、其药物组合物及其应用 Download PDF

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WO2021088957A1
WO2021088957A1 PCT/CN2020/126996 CN2020126996W WO2021088957A1 WO 2021088957 A1 WO2021088957 A1 WO 2021088957A1 CN 2020126996 W CN2020126996 W CN 2020126996W WO 2021088957 A1 WO2021088957 A1 WO 2021088957A1
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alkyl
compound
group
independently
alkoxy
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French (fr)
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张健存
邹晴安
陈延维
康宁
张礼军
胡洋
游华金
肖学兵
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广州市恒诺康医药科技有限公司
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    • C07D513/00—Heterocyclic 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
    • C07D513/02—Heterocyclic 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
    • C07D513/04—Ortho-condensed systems
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, ***e
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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    • C07D—HETEROCYCLIC COMPOUNDS
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Definitions

  • the present invention relates to the field of medicinal chemistry, in particular to a new class of aromatic heterocyclic compounds as ATX (Autotaxin) inhibitors, pharmaceutical compositions containing the compounds, and the use of the compounds or compositions in the treatment of ATX (Autotaxin) Application in diseases with increased expression of pathological features.
  • ATX Autotaxin
  • ATX Autotaxin
  • PDE phosphodiesterase
  • ENPP extracellular pyrophosphatase/phosphodiesterase
  • LPC lysophosphatidylcholine
  • LPA cell surface-specific receptor proteins
  • GPCR G protein-coupled receptors
  • the main pathways include the hydrolysis of phosphatidylinositol diphosphate (PIP2), which in turn triggers the release of intracellular calcium ions and the activation of protein kinase C (PKC); inhibits the adenylate cyclase (cAMP) signaling pathway; activates Ras-MAPK, MERK, and ERK pathways regulate cell proliferation; activate phosphoinositide PI3K-AKT pathway to regulate cell survival and apoptosis; finally, activate Rho pathway to regulate cytoskeleton remodeling, shape changes and cell migration activities.
  • PIP2 phosphatidylinositol diphosphate
  • PLC protein kinase C
  • cAMP adenylate cyclase
  • Rho pathway to regulate cytoskeleton remodeling, shape changes and cell migration activities.
  • ATX is in a high expression state, resulting in excessive LPA concentration.
  • the LPA concentration can be increased to 10 ⁇ mol/L, much higher than the normal level of 100nmol/L. Too much LPA increases the production of vascular endothelial growth factor (VEGF) and promotes angiogenesis; reduces the expression of tumor suppressor p53, and increases tumor cell survival and metastasis.
  • VEGF vascular endothelial growth factor
  • the ATX-LPA signaling pathway involves many physiological and pathological processes, and thus has important links with many serious diseases, including cardiovascular diseases, autoimmune diseases, cancer, fibrotic diseases, inflammation, neurological diseases, pain, etc. LPA has multiple functions in tumorigenesis, promoting tumor cell growth, angiogenesis, metastasis and the emergence of drug resistance. Therefore, reducing the concentration of LPA is conducive to the treatment and control of tumors.
  • inhibiting the activity of AXT and blocking the production pathway of LPA are research hotspots in the treatment of many serious diseases.
  • Fibrotic diseases are mainly idiopathic pulmonary fibrosis (IPF) and liver fibrosis.
  • IPF idiopathic pulmonary fibrosis
  • liver fibrosis fibrosis.
  • IPF is a fatal disease that manifests as diffuse alveolitis and alveolar structural disorders, and leads to the progressive development of pulmonary interstitial fibrosis.
  • the prognosis is poor, and the average survival time is 2 to 5 years.
  • IPF may be the disease most closely related to the ATX-LPA pathway, because in lung tissues, the highest expression of ATX is concentrated in bronchial epithelial cells and alveolar macrophages, and these cells can be juxtaposed to fibroblast foci.
  • GLPG-1690 as an Autotaxin inhibitor, has entered the phase II clinical trial for the treatment of idiopathic pulmonary fibrosis; serum ATX concentration is closely related to liver fibrosis and liver stiffness, which is the most predictive 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's lymphoma.
  • LPA/ATX can promote cell invasion and metastasis during the growth of tumor cells. Therefore, ATX inhibitors block the signal transduction pathway and provide a new way for the clinical treatment of cancer and fibrotic diseases.
  • ATX inhibitors Compared with traditional kinase inhibitors, ATX inhibitors inhibit ATX activity while affecting multiple signal pathways related to cell proliferation, growth and apoptosis, and have a better inhibitory effect on some drug-resistant tumors.
  • the occurrence of organ fibrosis is closely related and is an important target for the research and development of new fibrotic disease drugs.
  • the present invention provides a new type of aromatic heterocyclic compound, which has good inhibitory activity on ATX.
  • the compound of the present invention has excellent pharmacodynamics, pharmacokinetic properties and/or toxicological properties, and has better clinical application prospects.
  • the articles “a”, “an” and “said” used herein are intended to include “at least one” or “one or more.” Therefore, the articles used herein refer to articles of one or more than one (ie at least one) object.
  • a component refers to one or more components, that is, more than one component may be considered to be adopted or used in the embodiment of the described embodiment.
  • Stereoisomers refer to compounds that have the same chemical structure but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • tautomer or "tautomeric form” refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversion through the recombination of some bond-forming electrons.
  • keto-enol tautomerism are the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-ketone tautomerism.
  • a specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • substituted means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Unless otherwise indicated, a substituted group may have a substituent at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from specific groups, then the substituents can be substituted at each position with the same or different substitutions.
  • C 1-6 alkyl refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • alkyl or "alkyl group” used in the present invention means a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally Ground is substituted by one or more substituents described in this invention.
  • 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 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 in this invention.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), 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 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C(CH 3 ) 2
  • alkoxy means that the alkyl group is connected to the rest of the molecule through an oxygen atom, where the alkyl group has the definition as described in the present invention. Unless otherwise specified, the alkoxy group contains 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 another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described in this invention.
  • 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-but Oxygen (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, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-(
  • hydroxyalkyl as used in the present invention means that an alkyl group is substituted by one or more hydroxy groups, wherein the alkyl group has the definition as described in the present invention. Examples of this include, but are not limited to, hydroxy Ethyl, 2-hydroxypropyl, hydroxymethyl, etc.
  • heterocyclic group and “heterocyclic ring” are used interchangeably herein, unless otherwise specified, and refer to a monovalent monocyclic non-aromatic ring system and/or polycyclic ring system containing at least one non-aromatic ring;
  • One or more 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 of the ring atoms of the polycyclic system (in certain embodiments, 1, 2, 3, or 4) are independently selected from O, S(O ) The heteroatoms of 0-2 and N, and the remaining ring atoms are all carbon atoms.
  • the heterocyclic ring contains 1 or 2 heteroatoms, all of which are nitrogen atoms.
  • the heterocyclic 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 the aromatic ring and the other is in the non-aromatic ring.
  • the heterocyclyl group has 3-20, 3-15, 3-10, 3-8, 4-7, or 5-6 ring atoms.
  • the heterocyclic group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system.
  • the heterocyclyl group may be a bridged or unbridged, spirocyclic or non-spirocyclic, and/or fused or non-fused bicyclic group.
  • One or more nitrogen atoms 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 quaternized replace.
  • Some rings may be partially or fully saturated, or aromatic, provided that the heterocycle is not fully aromatic.
  • the monocyclic heterocycle and polycyclic heterocycle may be connected to the main structure at any heteroatom or carbon atom that results in a stable compound.
  • the polycyclic heterocyclic group can be connected to the main structure through any of its rings, including any aromatic or non-aromatic ring, regardless of whether the ring contains a heteroatom or not.
  • the heterocyclic group is "heterocycloalkyl", which is 1) a saturated or partially unsaturated (but non-aromatic) monovalent monocyclic group containing at least one ring heteroatom as described in the present invention , Or 2) A saturated or partially unsaturated (but not aromatic) monovalent bicyclic group or tricyclic group, in which at least one ring contains at least one heteroatom as described in the present invention.
  • heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolane Group, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothio
  • Examples in which the sulfur atom in the heterocyclic group is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl.
  • the heterocyclic group may be optionally substituted by one or more substituents described in the present invention.
  • the heterocyclic group is a heterocyclic group composed 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.
  • the sulfur atom of the ring can optionally be oxidized to S-oxide.
  • the nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound.
  • heterocyclic groups composed of 3-8 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrroline Group, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide Cyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine Group, dioxanyl, dithianyl, thiazinyl, homopiperazinyl, homopiperid
  • Examples in which the sulfur atom in the heterocyclic group is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl.
  • the heterocyclic group composed of 3-8 atoms can be optionally substituted by one or more substituents described in the present invention.
  • the heterocyclic group is a heterocyclic group composed 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.
  • the sulfur atom of the ring can optionally be oxidized to S-oxide.
  • the nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound.
  • the heterocyclic group composed of 3-6 atoms can be optionally substituted by one or more substituents described in the present invention.
  • the heterocyclic group is a heterocyclic 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.
  • the sulfur atom of the ring can optionally be oxidized to S-oxide.
  • the nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound.
  • heterocyclic groups composed of 5-6 atoms include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidine Group, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, 2-oxopyrrolidinyl, oxo-1,3 -Thiazolidine, sulfolane, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholine Group, piperazinyl, dioxanyl, dithianyl, thiazinyl, 2-piper
  • heterocyclylalkyl includes alkyl substituted with heterocyclyl
  • heterocyclylalkoxy includes alkoxy substituted with heterocyclyl, in which the oxygen atom is connected to the rest of the molecule
  • heterocyclic alkylamino includes heterocyclyl substituted alkylamino in which the nitrogen atom is connected to the rest of the molecule.
  • heterocyclic group, alkyl group, alkoxy group and alkylamino group all have the definition as described in the present invention, such examples include, but are not limited to, azetidine-1-ylmethyl, azetidine -1-ylethyl, azetidine-1-ylpropyl, pyrrol-1-ylmethyl, pyrrol-1-ylethyl, pyrrol-1-ylpropyl, morpholin-4-ylethyl Group, morpholin-4-ylethoxy, piperazin-4-ylethoxy, piperidin-4-ylethylamino, etc.
  • fused bicyclic ring refers to a saturated or unsaturated fused ring system, referring to a non-aromatic bicyclic ring system, as shown in formula (a1) , That is, ring B and ring B'share a bond. Such a system may contain independent or conjugated unsaturation, but its core structure does not contain aromatic or heteroaromatic rings (but aromatics can be used as substituents on it).
  • Each ring in the fused bicyclic ring is either carbocyclic or heteroalicyclic.
  • Examples of this include, but are not limited to, hexahydro-furo[3,2-b]furan, 2,3,3a,4 ,7,7a-hexahydro-1H-indene, 7-azabicyclo[2.3.0]heptane, fused bicyclo[3.3.0]octane, fused bicyclo[3.1.0]hexane, these all contain Within the fused bicyclic ring.
  • fused bicyclic group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, D, F, Cl, Br, I, N 3 , CN, NO 2 , OH, SH, NH 2 , Oxo, alkyl, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, alkoxy, haloalkoxy, or haloalkoxyalkyl, etc.
  • fused heterobicyclic group refers to a saturated or unsaturated fused ring system or bridged ring system, and refers to a non-aromatic bicyclic ring system or bridged ring system. Such a system may contain independent or conjugated unsaturation, but its core structure does not contain aromatic or heteroaromatic rings (but aromatics can be used as substituents on it).
  • each ring system contains one or more heteroatoms, wherein each ring system contains a 3-7 membered ring, that is, contains 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S , Where S or P is optionally substituted by one or more oxygen atoms to obtain groups such as SO, SO 2 , PO, PO 2 , such examples include, but are not limited to, hexahydro-furo [3, 2-b]furan, 7-azabicyclo[2.3.0]heptane, 2-azabicyclo[2.2.1]heptane, octahydropyrrole[3,2-b]pyrrole, octahydropyrrole[3, 4-c]pyrrole, octahydro-1H-pyrrole[3,2-b]pyridine and the like.
  • fused heterobicyclic group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, D, F, Cl, Br, I, N 3 , CN, NO 2 , OH, SH, NH 2.
  • substituent may be, but not limited to, D, F, Cl, Br, I, N 3 , CN, NO 2 , OH, SH, NH 2.
  • spirocyclyl indicates that one ring originates from a special cyclic carbon on another ring.
  • ring A and ring B share a carbon atom in two saturated ring systems and are called “spirocyclic rings”.
  • Each ring in the spiro ring is either carbocyclic or heteroalicyclic.
  • Examples of this include, but are not limited to, 2,7-diazaspiro[4.4]nonane-2-yl, 7-oxo-2-azaspiro[4.5]decane-2-yl, 4-azaspiro[4.4]nonane-2-yl Spiro[2.4]heptane-5-yl, 4-oxaspiro[2.4]heptane-5-yl, 5-azaspiro[2.4]heptane-5-yl, spiro[2.4]heptan-5-yl, spiro [4.4] Nonyl, 7-hydroxy-5-azaspiro[2.4]heptan-5-yl and the like.
  • the spiro bicyclic group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, D, F, Cl, Br, I, N 3 , CN, NO 2 , OH, SH, NH 2 , Oxo, alkyl, haloalkyl, cyano substituted alkyl, hydroxyalkyl, alkoxy, haloalkoxy, or haloalkoxyalkyl, etc.
  • spirobicyclylene means that the spirobicyclyl system has two points of attachment to the rest of the molecule, wherein the spirobicyclyl has the definition as described in the present invention.
  • spiroheterobicyclyl means that one ring originates from a special cyclic carbon on another ring. For example, as described above, ring A and ring B share a carbon atom in two saturated ring systems and are called "spirocyclic rings”.
  • each ring system contains one or more heteroatoms, wherein each ring system contains a 3-7 membered ring, that is, contains 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S
  • S or P is optionally substituted with one or more oxygen atoms to obtain groups such as SO, SO 2 , PO, PO 2 and such examples include, but are not limited to 4-azaspiro [2.4] Heptane-5-yl, 4-oxaspiro[2.4]heptane-5-yl, 5-azaspiro[2.4]heptane-5-yl, 7-hydroxy-5-azaspiro[2.4]heptan Alkyl-5-yl, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 1,6-diazaspiro[3.4]octane, 2, 7-diazaspiro[3.5]nonane, 1,7-diazaspiro
  • the spiro heterobicyclic group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, D, F, Cl, Br, I, N 3 , CN, NO 2 , OH, SH, NH 2 , Oxo, alkyl, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, alkoxy, haloalkoxy, or haloalkoxyalkyl, etc.
  • bridged ring group used in the present invention refers to a saturated or unsaturated bridged ring system, involving a non-aromatic bridged ring system, as shown in formula (a2), that is, ring A1 and ring A2 share an alkane chain or a heterocyclic ring system.
  • Alkyl chain where j is 1, 2, 3 or 4.
  • Such a system may contain independent or conjugated unsaturation, but its core structure does not contain aromatic or heteroaromatic rings (but aromatics can be used as substituents on it).
  • Each ring in the bridged ring is either carbocyclic or heteroalicyclic.
  • bicyclo[2.2.1]heptane 2-azabicyclo[2.2.1]heptane, 1,2,3,4,4a,5,8,8a-octahydronaphthalene, these are included in the fused bicyclic or bridged ring system.
  • the bridging ring group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, D, F, Cl, Br, I, N 3 , CN, NO 2 , OH, SH, NH 2 , Oxo, alkyl, haloalkyl, cyano substituted alkyl, hydroxyalkyl, alkoxy, haloalkoxy, or haloalkoxyalkyl, etc.
  • bridged heterocyclic group refers to a saturated or unsaturated bridged ring system, referring to a non-aromatic bridged ring system. Such a system may contain independent or conjugated unsaturation, but its core structure does not contain aromatic or heteroaromatic rings (but aromatics can be used as substituents on it).
  • each ring system contains one or more heteroatoms, wherein each ring system contains a 3-7 membered ring, that is, contains 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S , Where S or P is optionally substituted with one or more oxygen atoms to obtain groups such as SO, SO 2 , PO, PO 2 , such examples include, but are not limited to 2-azabicyclo [2.2. 1]Heptane, (1R,5S)-3,6-diazabicyclo[3.1.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, (1R,5S)-8 -Azabicyclo[3.2.1]octane and so on.
  • bridge heterocyclic group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, D, F, Cl, Br, I, N 3 , CN, NO 2 , OH, SH, NH 2 , Oxo, alkyl, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, alkoxy, haloalkoxy, or haloalkoxyalkyl, etc.
  • connection points in the ring system that are connected to the rest of the molecule, as shown in formula (a3) or (a4), which means that it can be either the E end or the E'end and the rest of the molecule. , That is, the connection methods at both ends can be interchanged.
  • n typically describes the number of ring atoms in a molecule, and the number of ring atoms in the molecule 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 any oxidation state of N, S and P; primary, secondary, tertiary amine and quaternary ammonium salt forms; or on the nitrogen atom in the heterocyclic ring
  • the form in which hydrogen is substituted for example, N (like the N in 3,4-dihydro-2H-pyrrolyl), NH (like the NH in the pyrrolidinyl group) or NR (like the N-substituted pyrrolidinyl group NR).
  • cyano substituted alkyl or "cyanoalkyl” includes C 1-10 straight or branched chain alkyl groups substituted with one or more cyano groups.
  • the cyano-substituted alkyl group is a C 1-6 "lower cyanoalkyl group” substituted with one or more cyano groups, and other examples are the cyano-substituted alkyl group.
  • Alkyl is C 1-4 "lower cyanoalkyl" substituted with one or more cyano groups. Examples of this include, but are not limited to, CNCH 2 -, CNCH 2 CH 2 -, CNCH 2 CH 2 CH 2 -, CNCH 2 CHCNCH 2 -, etc.
  • the ring system (shown in the figure below) formed by attaching a substituent to the central ring by drawing a bond represents that the substituent can be substituted at any substitutable position on any ring.
  • formula b represents any position on ring A or ring B that may be substituted, such as formula c, d, e, f, g, h, i, j, k, l, m, n, o, p, q, etc.
  • the "pharmaceutically acceptable salt” used in the present invention refers to the organic and inorganic salts of the compound of the present invention.
  • Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19.
  • Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods described in books and literature such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3 -Phenylpropylprop
  • Salts obtained by reaction with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1 -C 4 alkyl) 4 salts.
  • the present invention also contemplates the quaternary ammonium salt formed by any compound containing the N group.
  • Water-soluble or oil-soluble or dispersed 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 comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 Sulfonates and aromatic sulfonates.
  • suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 Sulfonates and aromatic sulfonates.
  • solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to the association formed by the solvent molecule being water.
  • the term "hydrate” may be used.
  • one compound molecule of the present invention may be combined with one water molecule, such as a monohydrate; in other embodiments, one compound molecule of the present invention may be combined with more than one water molecule, such as dihydrate In other embodiments, one compound molecule of the present invention can be combined with less than one water molecule, such as a hemihydrate. It should be noted that the hydrate of the present invention retains the bioavailability of the compound in its non-hydrated form.
  • treating any disease or condition as used in the present invention, in some embodiments refers to ameliorating the disease or condition (ie slowing down or preventing or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, “treatment” refers to the regulation of the disease or condition physically (e.g., stabilizing the perceptible symptoms) or physiologically (e.g., stabilizing the parameters of the body) or both. In other embodiments, “treating” refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.
  • the aromatic heterocyclic compound provided by the present invention can effectively inhibit the activity of ATX, and can be used to prepare and treat diseases with the pathological characteristics of increased ATX expression, such as cancer, fibrotic diseases (such as pulmonary fibrosis or liver fibrosis), and metabolic diseases , Myelodysplastic syndrome, cardiovascular disease, autoimmune disease, inflammation, neurological disease or pain medication.
  • diseases with the pathological characteristics of increased ATX expression such as cancer, fibrotic diseases (such as pulmonary fibrosis or liver fibrosis), and metabolic diseases , Myelodysplastic syndrome, cardiovascular disease, autoimmune disease, inflammation, neurological disease or pain medication.
  • the present invention provides a new aromatic heterocyclic compound, which has a structure represented by formula (I) or (II):
  • Cy 1 is C 5-12 spiro bicyclic group, C 5-12 spiro heterobicyclic group, C 5-12 fused bicyclic group, C 5-12 fused heterobicyclic group, C 5-12 bridged cyclic group, or C 5 -12 bridged heterocyclyl, wherein said Cy 1 is optionally substituted with 1, 2, 3 or 4 R 4 ;
  • Cy 2 is a heterocyclic group consisting of 3-8 atoms, wherein the Cy 2 is optionally substituted with 1, 2, 3, or 4 R 4 ;
  • Z is C 3-6 heterocyclyl C 1-4 alkyl, or
  • R 1a is H, C 1-4 alkyl, or halogenated C 1-4 alkyl
  • R 2 is H, -CN, -NO 2 , -OH, -NH 2 , F, Cl, Br, I, C 1-4 alkyl, halogenated C 1-4 alkyl, or C 1-4 hydroxy alkane base;
  • R 3 is H, -CN, -NO 2 , -OH, -NH 2 , F, Cl, Br, I, C 1-4 alkyl, halogenated C 1-4 alkyl, cyano substituted C 1- 4 alkyl group, or C 1-4 hydroxyalkyl group;
  • X 6 is N or CH 2 ;
  • X 7 is -O-, -S-, -NH-, -(CH 2 ) m4 -NH-(CH 2 ) m5 -, -(CH 2 ) m4 -O-(CH 2 ) 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;
  • t 0, 1, 2, 3 or 4;
  • the compound of the present invention has a structure represented by formula (Ia) or (IIa):
  • X 3 , X 4 and X 5 are each independently -O-, -S-, -NH-, -(CH 2 ) m1 -NH-(CH 2 ) m2 -, -(CH 2 ) m1 -O-( CH 2 ) m2 -, -(CH 2 ) m1 -S-(CH 2 ) m2 -, or -(CH 2 ) m3 -;
  • Each m1 is independently 1, 2, or 3;
  • Each m2 is independently 0, 1, 2, or 3;
  • Each m3 is independently 1, 2, or 3;
  • n1 0, 1, 2, 3, or 4.
  • Cy 2 is Among them, m3 is 1, 2, or 3, and n1 is 0, 1, 2, 3, or 4.
  • Cy 1 and Cy 2 are independently optionally substituted with 1, 2, 3 or 4 R 4 .
  • R 2 is H, -CN, -NO 2 , -OH, -NH 2 , F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, Hydroxymethyl, hydroxyethyl, trifluoromethyl, or trifluoroethyl.
  • the compound of the present invention is a compound 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, or tautomer thereof.
  • Body nitrogen oxides, metabolites, prodrugs, and pharmaceutically acceptable excipients, diluents or carriers.
  • the pharmaceutical composition of the present invention further comprises an additional therapeutic agent.
  • the additional therapeutic agent is related to fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, skin diseases
  • a therapeutic agent for diseases related to academic disorders and/or abnormal angiogenesis is related to 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, immunomodulators, analgesics, non-steroidal anti-inflammatory drugs, steroids, synthetic DMARDS, treatment of proliferative diseases Drugs, glucocorticoids, cell growth inhibitors, alkylating agents, antimetabolites, cytotoxic antibiotics, antibodies, etc.
  • additional therapeutic agent includes, but is not limited to, immunomodulators, analgesics, non-steroidal anti-inflammatory drugs, steroids, synthetic DMARDS, treatment of proliferative diseases Drugs, glucocorticoids, cell growth inhibitors, 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 characterized by pathological characteristics of increased ATX expression in mammals .
  • the disease with the pathological characteristics of increased ATX expression includes: cancer, fibrotic disease, metabolic disease, myelodysplastic syndrome, cardiovascular disease, autoimmune disease, inflammation, neurological disease, or pain.
  • the disease with the pathological characteristics of increased ATX expression is pulmonary fibrosis or liver fibrosis.
  • the compound of the present invention or a pharmaceutical composition thereof may be administered in combination with another therapeutic agent.
  • the use of the present invention includes administering to a mammal an amount of the compound or pharmaceutical composition of the present invention sufficient to achieve the treatment or prevention.
  • the compound of the present invention When used as a medicine, the compound of the present invention is usually administered in the form of a pharmaceutical composition.
  • the composition can be prepared in a manner well known in pharmaceutical technology and comprises at least one compound according to the invention according to formula I, Ia, II, or IIa.
  • the compound of the present invention is administered in a pharmaceutically effective amount.
  • the amount of the compound of the present invention actually administered will usually be determined by the physician according to the relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound of the present invention administered, the age, weight and response of the individual patient, and the patient’s symptoms. Severity, etc.
  • the pharmaceutical composition of the present invention can be administered by a variety of routes, including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal.
  • routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal.
  • the compounds of the 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 an inert diluent such as water or liquid paraffin can be used.
  • the compositions may also contain substances other than diluents, and in some embodiments, contain wetting agents, sweeteners or flavoring products.
  • composition for parenteral administration may be an emulsion or a sterile solution.
  • propylene glycol, polyethylene glycol, vegetable oils, particularly olive oil, or injectable organic esters may be used as a solvent or carrier, and in some embodiments, ethyl oleate may be used as a solvent or carrier.
  • These compositions may also contain adjuvants, especially wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers. Sterilization can be performed in several ways, in some embodiments, using a bacteriological filter, sterilization by radiation or by heating. They can also be prepared in the form of sterile solid compositions, which can be dissolved in sterile water or any other sterile injectable medium at the time of use.
  • the composition can also be an aerosol.
  • the composition may be a stable sterile solution or a solid composition dissolved in pyrogen-free sterile water, saline or any other pharmaceutically acceptable carrier during use.
  • the active ingredient is finely divided and combined with a water-soluble solid diluent or carrier, in certain embodiments, with 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 pharmaceutical field. In certain embodiments, suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, Glycerin monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene, ethylene glycol, water, ethanol, etc. Whether a particular excipient 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 the subject and the specific active ingredients in the dosage form. If necessary, the composition or single unit dosage form may also contain small 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 the compound of the present invention, which is used in medicine.
  • the present invention provides a compound of the present invention or a pharmaceutical composition containing the compound of the present invention, which is used for the prevention and/or treatment of fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, Cardiovascular diseases, neurodegenerative diseases, dermatological disorders and/or diseases related to abnormal angiogenesis.
  • the present invention provides a compound of the present invention or a pharmaceutical composition containing the compound of the present invention, which is used for the preparation for the prevention and/or treatment of fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases Drugs for diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders and/or diseases related to abnormal angiogenesis.
  • the invention provides pharmaceutical compositions comprising a compound of the invention and other therapeutic agents.
  • other therapeutic agents are diseases related to fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders 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 fibrotic diseases.
  • the fibrotic disease is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), cystic fibrosis, other diffuse parenchymal lung diseases of different etiology (including iatrogenic drug-induced fibrosis, occupational and / Or environment-induced fibrosis), granulomatous disease (sarcoidosis, allergic pneumonia), collagen vascular disease, alveolar protein deposition, Langerhans cell granuloma, lymphangiomyotysis, genetic disease (Hermans Kipdrack syndrome, tuberous sclerosis, neurofibroma, metabolic accumulation disorder, familial interstitial lung disease), radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, Bolai Mycin-induced pulmonary fibro
  • IPF idi
  • the present invention provides a compound of the present invention or a pharmaceutical composition containing the compound of the present invention, which is used to prepare 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 different etiology (including iatrogenic drug-induced fibrosis, occupational And/or environment-induced fibrosis), granulomatous disease (sarcoidosis, allergic pneumonia), collagen vascular disease, alveolar protein deposition, Langerhans cell granuloma, lymphangiomyotysis, genetic disease (Herman Sky-Pudlak syndrome, tuberous sclerosis, neurofibroma, metabolic accumulation disorder, familial interstitial lung disease), radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, Bleomycin-induced
  • PPF idiopathic
  • the present invention provides a method of preventing and/or treating a mammal suffering from fibrotic diseases, the method comprising administering an effective amount of one of the compounds or pharmaceutical compositions of the present invention Or more to treat or prevent the condition.
  • the fibrotic disease is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), cystic fibrosis, other diffuse parenchymal lung diseases of different etiology (including iatrogenic drug-induced fibrosis, occupational and / Or environment-induced fibrosis), granulomatous disease (sarcoidosis, allergic pneumonia), collagen vascular disease, alveolar protein deposition, Langerhans cell granuloma, lymphangiomyotysis, genetic disease (Hermans Chi-Pudlak syndrome, tuberous sclerosis, neurofibroma, metabolic accumulation disorder, familial interstitial lung disease), radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD
  • a particular aspect of the method of the present invention includes administering an effective amount of the compound of the present invention of formula I, Ia, II, or IIa to an individual suffering from a fibrotic disease for a period of time sufficient to reduce the level of fibrosis in the individual, and preferably Stop the process that causes the fibrosis.
  • a specific embodiment of the method includes administering an effective amount of the compound of the invention of formula I, Ia, II, or IIa to an individual patient suffering from developing idiopathic pulmonary fibrosis for a period of time sufficient to reduce or prevent The patient has idiopathic pulmonary fibrosis, and preferably the process that causes the idiopathic pulmonary fibrosis is terminated.
  • co-administration includes any means of delivering two or more therapeutic agents to the patient as part of the same treatment regimen.
  • two or more active agents can be administered simultaneously in a single formulation (ie, as a single pharmaceutical composition), this is not necessary.
  • the active agent can also be administered at different times in different formulations.
  • the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the definition of the substituents is as shown in formula I, Ia, II, or IIa.
  • the following reaction schemes and examples are used to further illustrate the content of the present invention.
  • Anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained by refluxing and drying with sodium metal.
  • Anhydrous dichloromethane and chloroform are obtained by refluxing and drying with calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide are dried in advance with anhydrous sodium sulfate.
  • reaction flask is plugged with a suitable rubber stopper, and the substrate is injected through a syringe.
  • the glassware is all dried.
  • the chromatographic column is a silica gel column.
  • Silica gel 300-400 mesh was purchased from Qingdao Ocean Chemical Plant.
  • 1 H NMR spectra were recorded using a Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer.
  • the 1 H NMR spectrum uses CDC1 3 , DMSO-d 6 , CD 3 OD or acetone-d 6 as the solvent (in ppm), and uses TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard.
  • TMS 0. ppm
  • chloroform 7.26 ppm
  • the measurement conditions for low-resolution mass spectrometry (MS) data are: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1x 30mm, 3.5 microns, 6min, flow rate 0.6mL/min.
  • Mobile phase 5 %-95% (the ratio of (CH 3 CN containing 0.1% formic acid) in (H 2 O containing 0.1% formic acid)), using electrospray ionization (ESI), and detecting with UV at 210nm/254nm.
  • Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50/80mm DAC) are used for UV detection at 210nm/254nm.
  • E 1 and E 2 are each independently selected from Cl, Br or I; 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 Group or 2,4,4-trimethylpent-2-yl; Cy has the definition of Cy 1 and Cy 2 of the present invention; Y has the definition of Y 1 and Y 2 of the present invention; R 1a , R 2 , R 3 , R 6 , Z and t all have the definitions described in the present invention.
  • Intermediate 1-1, Pr 2 NC and aldehyde R 2 CHO are catalyzed by Lewis acid to produce intermediate 1-2 through a three-component reaction; Intermediate 1-2 is reacted in formic acid under heating conditions to obtain intermediate Body 1-3; Intermediate 1-3 and Intermediate 2-2 are obtained through nucleophilic substitution reaction under alkaline and heating conditions to obtain Intermediate 1-4; Intermediate 1-4 is first reacted with strong base, Carry out nucleophilic substitution reaction with intermediate 1-5, and then react with substituted alkyl R 1a E 4 to obtain intermediate 1-6; intermediate 1-6 can be hydrogenated under acidic conditions or palladium-catalyzed or with trimethyl Iodosilane reaction removes the protective group Pr 1 to obtain Intermediate 1-7; Intermediate 1-7 and Intermediate 2-7 undergo nucleophilic substitution reaction under alkaline and heating conditions to obtain the compound represented by formula I or II .
  • Step 2) N-(2-Bromo-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)carboxamide
  • N-(2-bromo-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)carboxamide 525mg, 1.91mmol
  • 60% sodium hydrogen (229 mg, 5.73 mmol)
  • a tetrahydrofuran solution (3 mL) of 2-chloro-4-(4-fluorophenyl)thiazole-5-carbonitrile (454 mg, 1.91 mmol) was added dropwise.
  • Step 4) 4- ⁇ 5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)amino]-6-ethylimidazo[2,1-b][1,3 ,4]thiadiazol-2-yl ⁇ -1,4-diazepan-1-carboxylic acid tert-butyl ester
  • Step 1) (R)- ⁇ 1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-ethylimidazo[2 ,1-b][1,3,4]thiadiazol-2-yl]pyrrolidin-3-yl ⁇ carboxylic acid tert-butyl ester
  • Step 2) (R)-2- ⁇ [2-(3-Aminopyrrolidin-1-yl)-6-ethylimidazo[2,1-b][1,3,4]thiadiazole-5 -Yl](methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile
  • Step 1) (R)-2- ⁇ [2-(3-((2-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-2- (Oxoethyl)amino)pyrrolidin-1-yl)-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino ⁇ - 4-(4-fluorophenyl)thiazole-5-carbonitrile
  • Step 2) Step 1) (R)-2- ⁇ [2-(3-((2-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl) -2-oxoethyl)amino)pyrrolidin-1-yl)-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl) Amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile
  • Step 1) cis-3- ⁇ [(benzyloxy)carbonyl]amino ⁇ -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
  • Step 2) Benzyl cis-(4-fluoropyrrolidin-3-yl)carbamate
  • Step 4) cis- ⁇ 1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-ethylimidazo[2, 1-b][1,3,4]thiadiazol-2-yl]-4-fluoropyrrolidin-3-yl ⁇ (methyl)benzyl carbamate
  • Step 5 cis-2- ⁇ [6-ethyl-2-(3-fluoro-4-(methylamino)pyrrolidin-1-yl)imidazo[2,1-b][1,3, 4]Thiadiazol-5-yl](methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile
  • Step 6) cis-2-((6-ethyl-2-(3-fluoro-4-((2-(3-hydroxyazetidin-1-yl)-2-oxoethyl) (Methyl)amino)pyrrolidin-1-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino)-4-(4-fluoro (Phenyl)thiazole-5-carbonitrile
  • Step 1) (R)-2- ⁇ [2-(3-Aminopyrrolidin-1-yl)-6-ethylimidazo[2,1-b][1,3,4]thiadiazole-5 -Yl](methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile
  • reaction solution was poured into water (15mL), extracted with ethyl acetate (15mL x 2), the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a white solid, and purified by beating with petroleum ether to obtain the target Compound (150 mg, 98%).
  • lysoPLD hydrolyze the substrate lysophosphatidylcholine (LPC) to produce lysophosphatidylcholine (LPA) and choline.
  • LPC lysophosphatidylcholine
  • LPA lysophosphatidylcholine
  • Choline is oxidized under the action of choline oxidase to generate H 2 O 2 .
  • HRP horseradish peroxidase
  • Amplex Red reagent reacts with H 2 O 2 at a chemical quantitative ratio of 1:1 to form a strong fluorescent product for fluorescent quantitative detection.
  • test compound was dissolved in DMSO into a 10 mM stock solution, and a 3-fold gradient dilution was performed 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. Add 20 ⁇ l of the above mixed solution 1 to each well of the experiment plate, and use Echo550 to transfer the compound diluted in DMSO into the experiment plate at 10 nl/well.
  • Test compound LPC-IC 50 Test compound LPC-IC 50 Example 1 ++++ Example 2 ++++ Example 3 +++ Example 4 ++++ Example 5 +++ Example 6 ++++ Example 7 ++++ Example 8 +++ Example 9 ++++ Example 10 +++ Example 11 ++++ Example 13 ++++ Example 14 +++ Example 15 + Example 16 +++ Example 17 ++++ Example 18 ++++ To To
  • test compound was diluted 3-fold with the diluent from the stock solution to prepare 8 series of working solutions (including zero point). Take 10 ⁇ L of melted blank plasma sample, add ice methanol solution containing internal standard (LPA17:0) for protein precipitation directly, as system control sample. Take 2 ⁇ L of the working solution of series concentration, add 198 ⁇ L of human blank plasma, and incubate the concentration of 0-10 ⁇ M, put the sample into the 37°C incubator containing 5% CO 2 and incubate for 2 hours.
  • LPA17:0 internal standard
  • Test compound Plasma activity IC 50 Test compound Plasma activity IC 50 Example 1 +++ Example 2 ++++ Example 3 ND Example 4 ++++ Example 5 +++ Example 6 ++++ Example 7 ++++ Example 8 ND
  • Example 9 ND Example 10 ND Example 11 ++++ Example 12 ND Example 13 ++++ Example 14 ND Example 15 ND Example 16 ND Example 17 ++++ Example 18 ++++
  • the compound of the present invention can also effectively inhibit ATX in human plasma, thereby inhibiting the hydrolysis of LPC into LPA, and the IC 50 value of the compound is basically lower than 100 nM.
  • mice Male SD rats were selected as test animals.
  • the LC/MS/MS method was used to quantitatively determine the plasma drug concentration of the test compound of the present invention administered intravenously and orally to the rats at different time points, so as to evaluate the SD of the test compound. Pharmacokinetic characteristics in mice.
  • the clear solution of the test compound of the present invention was injected into SD rats via foot vein (free diet, 6-8 weeks of age), and the suspension solution of the test compound was intragastrically administered to SD rats (free diet, 6-8 Zhou age).
  • 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 the administration.
  • the blood volume was 0.15 mL each time. All the whole blood samples collected were placed in the caudal vein.
  • the compound of the present invention has good inhibitory activity on ATX, has excellent in vivo and in vitro pharmacodynamics, pharmacokinetic properties, and has better clinical application prospects.

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Abstract

作为ATX(Autotaxin)抑制剂的一类新的芳杂环化合物，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)或(II)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 2、R 3、R 6、Cy 1、Cy 2、Y 1、Y 2、Z和t均具有本公开所述定义。

Description

芳杂环化合物、其药物组合物及其应用 发明领域
本发明涉及药物化学领域，尤其涉及作为ATX(Autotaxin)抑制剂的一类新的芳杂环化合物，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应用。
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***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芳杂环类化合物，其对ATX具有很好的抑制活性。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。
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。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。
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、F、Cl、Br、I、N 3、CN、NO 2、OH、SH、NH 2、氧代(C＝O)、烷基、卤代烷基、氰基取代的烷基、羟基烷基、烷氧基、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“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。
本发明使用的术语“羟基烷基”表示烷基基团被一个或多个羟基基团所取代，其中烷基基团具有如本发明所述的定义，这样的实例包括，但并不限于羟乙基，2-羟基丙基，羟甲基等。
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 PCTCN2020126996-appb-000001
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 PCTCN2020126996-appb-000002
基，二氮杂
Figure PCTCN2020126996-appb-000003
基，硫氮杂
Figure PCTCN2020126996-appb-000004
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 PCTCN2020126996-appb-000005
基，二氮杂
Figure PCTCN2020126996-appb-000006
基，硫氮杂
Figure PCTCN2020126996-appb-000007
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“杂环基烷基”包括杂环基取代的烷基；术语“杂环基烷氧基”包括杂环基取代的烷氧基，其中氧原子与分子的其余部分相连；术语“杂环基烷氨基”包括杂环基取代的烷氨基，其中氮原子与分子的其余部分相连。其中杂环基、烷基、烷氧基和烷氨基均具有如本发明所述定义，这样的实例包括，但并不限于，氮杂环丁烷-1-基甲基、氮杂环丁烷-1-基乙基、氮杂环丁烷-1-基丙基、吡咯-1-基甲基，吡咯-1-基乙基、吡咯-1-基丙基、吗啉-4-基乙基、吗啉-4-基乙氧基、哌嗪-4-基乙氧基、哌啶-4-基乙基氨基等。
术语“稠合双环”，“稠环”，“稠合双环基”，“稠环基”表示饱和或不饱和的稠环体系体系，涉及非芳香族的双环体系，如式(a1)所示，即环B与环B’共有一个键。这样的体系可以包含独立的或共轭的不饱和状态，但其核心结构不包含芳香环或芳杂环(但是芳香族可以作为其上的取代基)。稠合双环中的每一个环要么是碳环要么是杂脂环族，这样的实例包括，但并不限于，六氢-呋喃并[3,2-b]呋喃，2,3,3a,4,7,7a-六氢-1H-茚，7-氮杂双环[2.3.0]庚烷，稠合双环[3.3.0]辛烷，稠合双环[3.1.0]己烷，这些都包含在稠合双环之内。并且所述稠合双环基可以是取代或未取代的，其中取代基可以是，但并不限于，D、F、Cl、Br、I、N 3、CN、NO 2、OH、SH、NH 2、氧代、烷基、卤代烷基、氰基取代的烷基、羟基烷基、烷氧基、卤代烷氧基、或卤代烷氧基烷基等等。
Figure PCTCN2020126996-appb-000008
术语“稠合杂双环基”表示饱和或不饱和的稠环体系或桥环体系，涉及非芳香族的双环体系或桥环体系。这样的体系可以包含独立的或共轭的不饱和状态，但其核心结构不包含芳香环或芳杂环(但是芳香族可以作为其上的取代基)。且至少一个环体系包含一个或多个杂原子，其中每一个环体系包含3-7元环，即包含1-6个碳原子和选自N，O，P，S的1-3个杂原子,在此S或P任选地被一个或多个氧原子所取代得到例如SO，SO 2，PO，PO 2的基团，这样的实例包括，但并不限于六氢-呋喃并[3,2-b]呋喃，7-氮杂双环[2.3.0]庚烷，2-氮杂双环[2.2.1]庚烷，八氢吡咯[3,2-b]吡咯，八氢吡咯[3,4-c]吡咯，八氢-1H-吡咯[3,2-b]吡啶等。并且所述稠合杂双环基可以是取代或未取代的，其中取代基可以是，但并不限于，D、F、Cl、Br、I、N 3、CN、NO 2、OH、SH、NH 2、氧代、烷基、卤代烷基、氰基取代的烷基、羟基烷基、烷氧基、卤代烷氧基、或卤代烷氧基烷基等等。
术语“螺环基”，“螺环”，“螺双环基”，“螺双环”表示一个环起源于另一个环上特殊的环状碳。例如，环A和环B在两个饱和的环体系中共享一个碳原子，则被称为“螺环”。螺环里面的每一个环要么是碳环要么是杂脂环族。这样的实例包括，但并不限于2,7-二氮杂螺[4.4]壬烷-2-基，7-氧-2-氮杂螺[4.5]癸烷-2-基，4-氮杂螺[2.4]庚烷-5-基，4-氧杂螺[2.4]庚烷-5-基，5-氮杂螺[2.4]庚烷-5-基，螺[2.4]庚烷基，螺[4.4]壬烷基，7-羟基-5-氮杂螺[2.4]庚烷-5-基等。并且所述螺双环基可以是取代或未取代的，其中取代基可以是，但并不限于，D、F、Cl、Br、I、N 3、CN、NO 2、OH、SH、NH 2、氧代、烷基、卤代烷基、氰基取代的烷基、羟基烷基、烷氧基、卤代烷氧基、或卤代烷氧基烷基等等。
Figure PCTCN2020126996-appb-000009
术语“亚螺双环基”表示螺双环基体系具有两个连接点与分子其余部分相连，其中螺双环基具有如本发明所述的定义。
术语“螺杂双环基”表示一个环起源于另一个环上特殊的环状碳。例如，如上面所描述的，环A和环B在两个饱和的环体系中共享一个碳原子，则被称为“螺环”。且至少一个环体系包含一个或多个杂原子，其中每一个环体系包含3-7元环，即包含1-6个碳原子和选自N，O，P，S的1-3个杂原子,在此S或P任选地被一个或多个氧原子所取代得到例如SO，SO 2，PO，PO 2的基团，这样的实例包括，但并不限于4-氮杂螺[2.4]庚烷-5-基，4-氧杂螺[2.4]庚烷-5-基，5-氮杂螺[2.4]庚烷-5-基，7-羟基-5-氮杂螺[2.4]庚烷-5-基，2,6-二氮杂螺[3.3]庚烷，2,6-二氮杂螺[3.4]辛烷，1,6-二氮杂螺[3.4]辛烷，2,7-二氮杂螺[3.5]壬烷，1,7-二氮杂螺[3.5]壬烷，3,9-二氮杂螺[5.5]十一烷等。并且所述螺杂双环基可以是取代或未取代的，其中取代基可以是，但并不限于，D、F、Cl、Br、I、N 3、CN、NO 2、OH、SH、NH 2、氧代、烷基、卤代烷基、氰基取代的烷基、羟基烷基、烷氧基、卤代烷氧基、或卤代烷氧基烷基等等。
本发明使用的术语“桥环基”表示饱和或不饱和的桥环体系，涉及非芳香族的桥环体系，如式(a2)所示，即环A1与环A2共有一个烷链或一个杂烷链，其中j为1，2，3或4。这样的体系可以包含独立的或共轭的不饱和状态，但其核心结构不包含芳香环或芳杂环(但是芳香族可以作为其上的取代基)。桥接环中的每一个环要么是碳环要么是杂脂环族，这样的实例包括，但并不限于，双环[2.2.1]庚烷，2-氮杂双环[2.2.1]庚烷，1,2,3,4,4a,5,8,8a-八氢萘，这些都包含在稠合双环或桥环的体系之内。并且所述桥环基可以是取代或未取代的，其中取代基可以是，但并不限于，D、F、Cl、Br、I、N 3、CN、NO 2、OH、SH、NH 2、氧代、烷基、卤代烷基、氰基取代的烷基、羟基烷基、烷氧基、卤代烷氧基、或卤代烷氧基烷基等等。
Figure PCTCN2020126996-appb-000010
术语“桥杂环基”表示饱和或不饱和的桥环体系，涉及非芳香族的桥环体系。这样的体系可以包含独立的或共轭的不饱和状态，但其核心结构不包含芳香环或芳杂环(但是芳香族可以作为其上的取代基)。且至少一个环体系包含一个或多个杂原子，其中每一个环体系包含3-7元环，即包含1-6个碳原子和选自N，O，P，S的1-3个杂原子,在此S或P任选地被一个或多个氧原子所取代得到例如 SO，SO 2，PO，PO 2的基团，这样的实例包括，但并不限于2-氮杂双环[2.2.1]庚烷，(1R,5S)-3,6-二氮杂双环[3.1.1]庚烷，2,5-二氮杂双环[2.2.1]庚烷，(1R,5S)-8-氮杂双环[3.2.1]辛烷等。并且所述桥杂环基可以是取代或未取代的，其中取代基可以是，但并不限于，D、F、Cl、Br、I、N 3、CN、NO 2、OH、SH、NH 2、氧代、烷基、卤代烷基、氰基取代的烷基、羟基烷基、烷氧基、卤代烷氧基、或卤代烷氧基烷基等等。
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(a3)或(a4)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 PCTCN2020126996-appb-000011
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 PCTCN2020126996-appb-000012
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐如盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯 磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过与适当的碱反应得到的盐包括碱金属，碱土金属，铵和N +(C 1-C 4烷基) 4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-8磺酸化物和芳香磺酸化物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
当所述溶剂为水时，可以使用术语“水合物”。在一些实施例中，一个本发明化合物分子可以与一个水分子相结合，比如一水合物；在另外一些实施例中，一个本发明化合物分子可以与多于一个的水分子相结合，比如二水合物，还有一些实施例中，一个本发明化合物分子可以与少于一个的水分子相结合，比如半水合物。应注意，本发明所述的水合物保留有非水合形式的所述化合物的生物有效性。
如本发明所使用的术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
发明内容
本发明提供的芳杂环化合物，能有效抑制ATX活性，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***疾病或疼痛的药物。
一方面，本发明提供了一种新的芳杂环化合物，其具有式(I)、或(II)所示结构：
Figure PCTCN2020126996-appb-000013
其中，
Cy 1是C 5-12螺双环基、C 5-12螺杂双环基、C 5-12稠合双环基、C 5-12稠合杂双环基、C 5-12桥环基、或C 5-12桥杂环基，其中所述Cy 1任选地被1、2、3或4个R 4取代；
Cy 2是3-8个原子组成的杂环基，其中所述Cy 2任选地被1、2、3或4个R 4取代；
Y 1是-C(＝O)-、或-S(＝O) 1-2-；
Y 2是-(CH 2) 1-2-O-、-C(＝O)-CH 2-O-、-NHC(＝O)-CH 2-、-C(＝O)-(CH 2) 1-2-、-C(＝O)-CH 2-N(R 1b)-、或-NHC(＝O)NH-；
Z是C 3-6杂环基C 1-4烷基、或
Figure PCTCN2020126996-appb-000014
R 1a是H、C 1-4烷基、或卤代C 1-4烷基；
R 1b是C 1-4烷基-C(＝O)-、C 1-4烷基-S(＝O) 1-2-、(C 1-4烷基) 2N-C(＝O)-、或C 2-7杂环基-C(＝O)-C 1-4烷基-，所述R 1b任选地被1、2、3或4个R 7取代；
R 2为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、C 1-4烷基、卤代C 1-4烷基、或C 1-4羟基烷基；
R 3为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、C 1-4烷基、卤代C 1-4烷基、氰基取代的C 1-4烷基、或C 1-4羟基烷基；
各R 4分别独立地为H、D、氧代(C＝O)、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、C 1-4烷基、卤代C 1-4烷基、氰基取代的C 1-4烷基、C 1-4羟基烷基、C 1-4烷氧基、卤代C 1-4烷氧基、或卤代C 1-4烷氧基C 1-4烷基；
各R 5分别独立地为H、D、氧代(C＝O)、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、C 1-4烷基、卤代C 1-4烷基、氰基取代的C 1-4烷基、C 1-4羟基烷基、C 1-4烷氧基、卤代C 1-4烷氧基、或卤代C 1-4烷氧基C 1-4烷基；
各R 6分别独立地为H、D、氧代(C＝O)、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、C 1-4烷基、卤代C 1-4烷基、氰基取代的C 1-4烷基、C 1-4羟基烷基、C 1-4烷氧基、卤代C 1-4烷氧基、或卤代C 1-4烷氧基C 1-4烷基；
各R 7分别独立地为H、D、氧代(C＝O)、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、C 1-4烷基、卤代C 1-4烷基、氰基取代的C 1-4烷基、C 1-4羟基烷基、C 1-4烷氧基、卤代C 1-4烷氧基、或卤代C 1-4烷氧基C 1-4烷基；
X 6为N、或CH 2；
X 7为-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；
n2为0、1、2、3或4；和
t为0、1、2、3或4；
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，本发明所述化合物具有式(Ia)、或(IIa)所示结构：
Figure PCTCN2020126996-appb-000015
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，其中Cy 1是
Figure PCTCN2020126996-appb-000016
Cy 2是
Figure PCTCN2020126996-appb-000017
其中，
X 3、X 4和X 5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-、或-(CH 2) m3-；
各m1分别独立地为1、2、或3；
各m2分别独立地为0、1、2、或3；
各m3分别独立地为1、2、或3；和
n1是0、1、2、3或4。
在一些实施方案，其中Cy 2是
Figure PCTCN2020126996-appb-000018
其中，m3是1、2、或3，n1是0、1、2、3或4。
在一些实施方案，其中Cy 1是
Figure PCTCN2020126996-appb-000019
Cy 2是
Figure PCTCN2020126996-appb-000020
其中，所述Cy 1和Cy 2独立任选地被1、2、3或4个R 4取代。
在一些实施方案，其中，Z是
Figure PCTCN2020126996-appb-000021
Figure PCTCN2020126996-appb-000022
在一些实施方案，其中，R 2是H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、甲基、乙基、丙基、异丙基、丁基、羟甲基、羟乙基、三氟甲基、或三氟乙基。
在一些实施方案，其中，R 1b是CH 3-C(＝O)-、CH 3CH 2-C(＝O)-、CH 3-S(＝O) 1-2-、CH 3CH 2-S(＝O) 1-2-、(CH 3) 2N-C(＝O)-、或氮杂环丁基-C(＝O)-CH 2-，所述R 1b任选地被1、2、3或4个R 7取代；和
各R 7分别独立地为H、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、-CF 3、-CH 2CF 3、-CH 2CH 2CN、-CH 2CH 2OH、或CHF 2-O-CH 2-。
在一些实施方案，其中，各R 4、R 5、和R 6分别独立地为H、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、-CF 3、-CH 2CF 3、-CH 2CH 2CN、CHF 2-O-CH 2-、CF 3-O-CH 2-、或-CH 2CH 2OH。
在一些实施方案，本发明所述化合物为具有以下结构之一的化合物：
Figure PCTCN2020126996-appb-000023
Figure PCTCN2020126996-appb-000024
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***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、Ia、II、或IIa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、***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、***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、***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、Ia、II、或IIa所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。
所属领域的专业人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company，使用时都没有经过进一步纯化，除非其他方面表明。一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，天津市福晨化学试剂厂，武汉鑫华远科技发展有限公司，青岛腾龙化学试剂有限公司，和青岛海洋化工厂购买得到。
无水四氢呋喃，二氧六环，甲苯，***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 1260 pre-HPLC或Calesep pump 250 pre-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 PCTCN2020126996-appb-000025
其中，E 1和E 2各自独立地选自Cl、Br或I；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；Cy具有本发明Cy 1和Cy 2所述定义；Y具有本发明Y 1和Y 2所述定义；R 1a、R 2、R 3、R 6、Z和t均具有本发明所述定义。
将中间体1-1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1-2；将中间体1-2在甲酸中加热的条件下反应得到中间体1-3；所得中间体1-3和中间体2-2在碱性以及加热条件下，通过亲核取代反应得到中间体1-4；中间体1-4先与强碱反应后，再与中间体1-5进行亲核取代反应，随后再与取代的烷基R 1aE 4反应得到中间体1-6；中间体1-6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1-7；中间体1-7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I或II所示的化合物。
实施例
实施例1
2-{[6-乙基-2-(3-((2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)-1,4-二氮杂环庚烷-1-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备
Figure PCTCN2020126996-appb-000026
步骤1)2-溴-6-乙基-N-(2,4,5-三甲基戊烷-2-基)咪唑并[2,1-b][1,3,4]噻二唑-5-胺
向2-氨基-5-溴-1,3,4-噻二唑(2.0g，11.2mmol)的正丁醇(20mL)混合物中加入1,1,3,3-四甲基丁基异腈(1.56g，11.2mmol)、正丙醛(1.6g，28mmol)和无水氯化镁(0.5g，5.6mmol)，所得混合物于 120℃下反应4小时，减压浓缩除去溶剂。所得残余物经柱层析纯化(乙酸乙酯:石油醚＝1:5)得到标题化合物为棕色油状物(3.5g，88％)。MS(m/z)：359.1[M+1]，361.1[M+1]。
步骤2)：N-(2-溴-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-5-基)甲酰胺
将2-溴-6-乙基-N-(2,4,5-三甲基戊烷-2-基)咪唑并[2,1-b][1,3,4]噻二唑-5-胺(3.5g，9.75mmol)的甲酸(20mL)溶液于80℃下反应3小时，减压浓缩，然后向残余物中加入石油醚进行打浆，过滤，干燥，得到产品2.3g，收率：74％。MS(m/z)：275.0[M+1]，277.0[M+1]。
步骤3)2-{[2-溴-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈
冰浴冷却下，向N-(2-溴-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-5-基)甲酰胺(525mg，1.91mmol)的THF(8mL)混合物中加入60％钠氢(229mg，5.73mmol)。将所得混合物搅拌15分钟后，滴加2-氯-4-(4-氟苯基)噻唑-5-甲腈(454mg，1.91mmol)的四氢呋喃溶液(3mL)。升至室温反应30分钟，经薄层板监控反应完全，向反应混合物中加入碘甲烷(542mg，3.82mmol)，继续于室温下反应2小时。经LC-MS检测反应完全，向混合物中滴加水淬灭反应，加入水(20mL)，然后用乙酸乙酯(15mL x 3)萃取，合并有机层，经饱和食盐水洗，经无水硫酸钠干燥，减压浓缩，所得残余物经柱层析(石油醚:乙酸乙酯＝2:1)纯化得到标题化合物为白色固体(603mg，68％)。
步骤4)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][1,3,4]噻二唑-2-基}-1,4-二氮杂环庚烷-1-甲酸叔丁酯
向1,4-二氮杂环庚烷-1-甲酸叔丁酯(217mg，1.08mmol)的DMF(6mL)溶液中加入碳酸钾(450mg，3.26mmol)和2-{[2-溴-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(500mg，1.08mmol)。反应混合物加热至70℃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(20mL 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，所得残余物经柱层析(石油醚:乙酸乙酯＝1:1)纯化得淡黄色固体561mg，收率：89％。
步骤5)2-{[2-(1,4-二氮杂环庚烷-1-基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈
在0-5℃下，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][1,3,4]噻二唑-2-基}-1,4-二氮杂环庚烷-1-甲酸叔丁酯(561mg，0.96mmol)的DCM(10mL)搅拌溶液中滴加CF 3COOH(1mL)，10分钟后升至室温反应1小时，经LC-MS检测反应完全。混合物减压浓缩，用MeOH(20mL)溶解所得残余物，加入NaHCO 3(2g)搅拌中和30分钟，减压浓缩，向残余物中加入DCM(20mL)使其溶解，过滤，减压浓缩得到标题化合物为淡黄色固体(456mg，98％)。
步骤6)2-{[6-乙基-2-(3-((2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)-1,4-二氮杂环庚烷-1-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈
向2-{[2-(1,4-二氮杂环庚烷-1-基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(80mg，0.17mmol)的乙腈(5mL)溶液中依次加入K 2CO 3(70mg，0.51mmol)和KI(14mg，0.8mmol)，将混合物搅拌5分钟后，加入2-氯-1-(3-羟基氮杂环丁-1-基)乙酮(25mg，0.17mmol)。将混合物加热至75℃反应2小时，过滤，减压浓缩，所得残余物经柱层析纯化(二氯甲烷:甲醇＝15:1)得到标题化合物为白色固体(45mg，46％)。 1H NMR(400MHz,CDCl 3)δ:8.14(m,2H),7.16(m,2H),4.64(m,1H),4.35(m,1H),4.25(m,1H),4.01(m,1H),3.87(m,1H),3.66(m,2H),3.59-3.56(m,5H),3.22(m,2H),2.93(m,2H),2.82(m,2H),2.58(q,J＝7.6Hz,2H),2.02(m,2H),1.27(m,3H)。MS(m/z)：596.4[M+1]。
实施例2
(R)-N-{1-[5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-2-基]吡咯烷-3-基}-N-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)乙酰胺的制备
Figure PCTCN2020126996-appb-000027
步骤1)(R)-{1-[5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-2-基]吡咯烷-3-基}甲酸叔丁酯
向(R)-3-叔丁氧基酰胺基吡咯烷(0.98g，5.23mmol)的DMF(15mL)溶液中加入碳酸钾(1.97g，14.3mmol)和2-{[2-溴-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(2.2g，4.76mmol)。将混合物加热至65℃反应3小时，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，所得残余物经柱层析(石油醚:乙酸乙酯＝1.5:1)纯化得到标题化合物为白色固体(2.61g，97％)。
步骤2)(R)-2-{[2-(3-氨基吡咯烷-1-基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈
在0-5℃下，向(R)-{1-[5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-2-基]吡咯烷-3-基}甲酸叔丁酯(2.61g，4.59mmol)的DCM(10mL)搅拌溶液中滴加CF 3COOH(1mL)，10分钟后升至室温反应1小时，经LC-MS检测反应完全。混合物减压浓缩，然后用MeOH(20mL)溶解所得残余物，加入NaHCO 3(3g)搅拌中和30分钟，减压浓缩，向残余物中加入DCM(20mL)溶解，过滤，减压浓缩得到标题化合物为白色固体(1.89g，88％)。
步骤3)(R)-2-{[6-乙基-2-(3-((2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)氨基)四氢吡咯烷-1-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈
向(R)-2-{[2-(3-氨基吡咯烷-1-基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(1.5g，3.2mmol)的乙腈(28mL)溶液中依次加入K 2CO 3(1.32g，9.6mmol)和KI(0.27g，1.6mmol)，所得混合物搅拌5分钟后，加入2-氯-1-(3-羟基氮杂环丁-1-基)乙酮(0.58g，3.85mmol)。将混合物加热至65℃反应2小时，过滤，减压浓缩，所得残余物经柱层析纯化(二氯甲烷:甲醇＝25:1)得到标题化合物为白色固体(1.27g，67％)。 1H NMR(400MHz,CDCl 3)δ:8.15(m,2H),7.18(m,2H),4.70(m,1H),4.30(m,2H),3.99(m,1H),3.91(m,1H),3.64-3.46(m,7H),3.33-3.16(m,3H),2.60(q,J＝7.6Hz,2H),2.22(m,1H),1.99(m,2H),1.28(m,3H)。MS(m/z)：582.2[M+1]。
步骤4)(R)-N-{1-[5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-2-基]吡咯烷-3-基}-N-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)乙酰胺
0℃下，向(R)-2-{[6-乙基-2-(3-((2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)氨基)四氢吡咯烷-1-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(70mg，0.12mmol)的二氯甲烷(5mL)溶液中滴加AcCl(28mg，0.36mmol)，混合物保持在此温度下搅拌5分钟后，缓慢滴加Et 3N(37mg，0.36mmol)。将混合物升至室温反应过夜，减压浓缩，向残余物中加入THF(2mL)和水(2mL)，再加入K 2CO 3(83mg，0.6mmol)，加热至60℃反应过夜，过滤，减压浓缩，所得残余物经厚制备板纯化(二氯甲烷:甲醇＝15:1，)得到标题化合物为白色固体(35mg，47％)。 1H NMR(400MHz,CDCl 3)δ:8.15(m,2H),7.16(m,2H),4.69(m,1H),4.47(m,1H),4.28(m,1H),4.14(m,1H),3.98-3.40(m,12H),2.60(m,2H),2.39(m,1H),2.39-2.22(m,4H),1.28(m,3H)。MS(m/z)：624.2[M+1]。
实施例3
(R)-2-{[-2-(3-(二(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)氨基)吡咯烷-1-基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备
Figure PCTCN2020126996-appb-000028
向(R)-2-{[6-乙基-2-(3-((2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)氨基)四氢吡咯烷-1-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(1.08g，1.86mmol)的MeCN(20mL)溶液中依次加入K 2CO 3(0.77g，5.57mmol)、KI(0.15g，0.93mmol)和2-氯-1-(3-羟基氮杂环丁-1-基)乙酮 (0.33g，2.23mmol)，将混合物升温至90℃反应过夜。反应液冷却至室温，过滤，减压浓缩，所得残余物经柱层析纯化(二氯甲烷:甲醇＝20:1)得到标题化合物为白色固体(320mg，25％)。 1H NMR(400MHz,CDCl 3)δ:8.15(m,2H),7.16(m,2H),4.61(m,1H),4.53(m,1H),4.43-4.35(m,2H),4.25-4.20(m,3H),4.13(m,1H),3.89-3.78(m,2H),3.68-3.58(m,5H),3.49-3.28(m,4H),3.17(m,1H),2.60(q,J＝7.6Hz,2H),2.25(m,1H),2.02(m,4H),1.28(m,3H)。MS(m/z)：695.1[M+1]。
实施例4
(R)-N-{1-[5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-2-基]吡咯烷-3-基}-N-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)甲磺酰胺的制备
Figure PCTCN2020126996-appb-000029
在0℃下，向(R)-2-{[6-乙基-2-(3-((2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)氨基)四氢吡咯烷-1-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(70mg，0.12mmol)的DCM(5mL)溶液中滴加TMSCl(39mg，0.36mmol)，混合物保持在此温度下搅拌5分钟后，缓慢滴加Et 3N(74mg，0.72mmol)，然后保持0℃反应1小时。将反应混合物降温至-20℃后缓慢加入MsCl(11mg，0.10mmol)，保持在-20℃下反应2小时。经LC-MS检测反应完全，加入甲醇淬灭反应，过滤，减压浓缩，所得残余物经厚制备板纯化(二氯甲烷:甲醇＝15:1)得到标题化合物为白色固体(35mg，44％)。 1H NMR(400MHz,CDCl 3)δ:8.14(m,2H),7.16(m,2H),4.68(m,1H),4.59(m,1H),4.33(m,1H),4.25(m,1H),4.07-3.86(m,3H),3.79-3.58(m,5H),3.45(m,2H),3.12(s,3H),2.61(m,2H),2.39(m,1H),2.20(m,1H),2.00(m,1H),1.26(m,3H)。MS(m/z)：660.4[M+1]。
实施例5
(R)-1-{1-[5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-2-基]吡咯烷-3-基}-3-(3-羟基环丁烷)脲的制备
Figure PCTCN2020126996-appb-000030
在0℃、氩气保护下，向三光气(19mg，0.064mmol)的DCM(2mL)混合物中滴加(R)-2-{[2-(3-氨基吡咯烷-1-基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(60mg，0.128mmol)和三乙胺(53μL，0.38mmol)的DCM(1mL)溶液。加完后，混合物于0℃下搅拌30分钟，再加入3-氨基环丁醇盐酸盐(47mg，0.38mmol)和三乙胺(73μL，0.53mmol)的DMF(1mL)溶液。混合物于室温下反应过夜，将反应液倒入水(10mL)中，用DCM(15mL x 3)萃取，合并有机层，有机层经饱和食盐水洗(20mL x 3)，无水硫酸钠干燥，减压浓缩，所得残余物经厚制备板纯化(二氯甲烷:甲醇＝15:1)得到标题化合物为白色固体(42mg，57％)。 1H NMR(400MHz,CDCl 3)δ:8.13-8.05(m,2H),7.16-7.05(m,2H),5.57(m,0.5H),5.24(m,0.5H),4.88(m,1H),4.54(m,1.5H),4.34(m,0.5H),4.08(m,1H),3.86-3.52(m,6H),3.39-3.28(m,2H),2.81(m,1H),2.58(m,2H),2.37-2.17(m,3H),1.99(m,1H),1.81(m,1H),1.28(m,3H)。MS(m/z)：582.2[M+1]。
实施例6
(S)-1-{1-[5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-2-基]吡咯烷-3-基}-3-(3-羟基环丁烷)脲的制备
Figure PCTCN2020126996-appb-000031
参照实施例5，用(S)-3-叔丁氧基酰胺基四氢吡咯烷代替(R)-3-叔丁氧基酰胺基四氢吡咯烷制备得到(S)-1-{1-[5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-2-基]吡咯烷-3-基}-3-(3-羟基环丁烷)脲。 1H NMR(400MHz,CDCl 3)δ:8.13-8.06(m,2H),7.16-7.06(m,2H),5.57(m,0.5H),5.26(m,0.5H),4.96(m,1H),4.54(m,1H),4.08(m,1H),3.83-3.52(m,7H),3.41-3.28(m,2H),2.81(m,1H),2.57(m,2H),2.35-2.22(m,3H),2.00(m,1H),1.81(m,1H),1.28(m,3H)。MS(m/z)：582.2[M+1]。
实施例7
(R)-N-{1-[5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-2-基]吡咯烷-3-基}-1-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)-3,3-二甲基脲的制备
Figure PCTCN2020126996-appb-000032
步骤1)(R)-2-{[2-(3-((2-(3-((叔丁基二甲基硅基)氧基)氮杂环丁烷-1-基)-2-氧代乙基)氨基)吡咯烷-1-基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈
向(R)-2-{[2-(3-氨基吡咯烷-1-基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(280mg，0.60mmol)，1-(3–((叔丁基二甲基硅烷基)氧基)氮杂环丁烷-1-基)-2-氯乙酮(210mg，0.78mmol)的乙腈(10mL)混合物中加入碳酸钾(165mg，1.2mmol)和碘化钾(50mg，0.30mmol)，将所得混合物加热回流反应4小时，冷却，过滤，减压浓缩，所得残余物经柱层析纯化(二氯甲烷:甲醇＝30:1)得到标题化合物为黄色泡沫状固体(300mg，72％)。LC-MS(m/z):696.3[M+1]。
步骤2)步骤1)(R)-2-{[2-(3-((2-(3-((叔丁基二甲基硅基)氧基)氮杂环丁烷-1-基)-2-氧代乙基)氨基)吡咯烷-1-基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈
向(R)-2-{[2-(3-((2-(3-((叔丁基二甲基硅基)氧基)氮杂环丁烷-1-基)-2-氧代乙基)氨基)吡咯烷-1-基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(100mg，0.14mmol)的乙腈溶液中加入三乙胺(40μL，0.28mmol)和二甲氨基甲酰氯(16μL，0.17mmol)，将所得混合物加热回流反应4小时。冷却至室温，向反应混合物中加入1.0N盐酸(1.0mL)，搅拌30分钟，减压浓缩。然后向残余物中加入水(10mL)，用二氯甲烷(15mL x 3)萃取，合并有机层，经无水硫酸钠干燥，减压浓缩，所得残余物经厚制备板纯化(二氯甲烷:甲醇＝16:1)得到标题化合物为白色固体(20mg)。 1H NMR(400MHz,CDCl 3)δ:8.17(m,2H),7.18(m,2H),4.72-4.63(m,1H),4.48-4.37(m,2H),4.30-4.22(m,1H),4.09-4.01(m,1H),3.94-3.86(m,1H),3.80-3.74(m,1H),3.72-3.66(m,2H),3.66-3.61(m,1H),3.60(s,3H),3.49-3.41(m,2H),2.87(s,6H),2.64-2.58(m,2H),2.39-2.31(m,1H),2.26-2.19(m,1H),1.32-1.28(m,3H)。MS(m/z):653.1[M+1]。
实施例8
顺式-2-{[6-乙基-2-(3-氟-4-((2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)(甲基)氨基)吡咯烷-1-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备
Figure PCTCN2020126996-appb-000033
步骤1)顺式-3-{[(苄氧基)羰基]氨基}-4-氟吡咯烷-1-羧酸叔丁酯
向顺式-3-氨基-4-氟吡咯烷-1-羧酸叔丁酯(0.3g，1.47mmol)的二氯甲烷(5mL)溶液中加入三乙胺(0.3mL，2.14mmol)，然后在氮气保护，冷却至0℃，滴加氯甲酸苄酯(0.25mL，1.76mmol)。将混合物缓慢升至室温并搅拌2小时，LC-MS显示反应完全后，将反应液倒入水(15mL)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，所得残余物经柱层析纯化(石油醚:乙酸乙酯＝1:1)得到标题化合物为淡黄色油状物(0.41g，81％)。MS(m/z):339.2[M+1]。
步骤2)顺式-(4-氟吡咯烷-3-基)氨基甲酸苄酯
向顺式-3-{[(苄氧基)羰基]氨基}-4-氟吡咯烷-1-羧酸叔丁酯(0.41g，1.21mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL，6mmol)。所得混合物在室温下搅拌2小时，LC-MS显示反应完全后，减压浓缩得到粗品0.28g，其不经纯化直接用于下一步反应。MS(m/z)：239.2[M+1]。
步骤3)顺式-[1-(5-乙酰氨基-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-2-基)-4-氟吡咯烷-3-基]氨基甲酸苄酯
向顺式-(4-氟吡咯烷-3-基)氨基甲酸苄酯(0.28g，1.17mmol)的DMF(5mL)溶液中加入N-(2-溴-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-5-基)甲酰胺(0.32g，1.17mmol)和碳酸钾(0.48g，3.47mmol)，将混合物加热至90℃反应过夜。待反应液冷却至室温，将反应液倒入水(15mL)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(20mL x 3)，无水硫酸钠干燥，减压浓缩，所得残余物经柱层析纯化(二氯甲烷:甲醇＝50:1)得到目标产物(85mg，16％)。MS(m/z)：432.2[M+1]。
步骤4)顺式-{1-[5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-2-基]-4-氟吡咯烷-3-基}(甲基)氨基甲酸苄酯
在0℃、氮气保护下，向顺式-[1-(5-乙酰氨基-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-2-基)-4-氟吡咯烷-3-基]氨基甲酸苄酯(80mg，0.18mmol)的THF(5mL)溶液中，加入60％钠氢(14.8mg，0.36mmol)，混合物搅拌10分钟后，滴加2-氯-4-(4-氟苯基)噻唑-5-甲腈(42.3mg，0.18mmol)的四氢呋喃溶液(3mL)。将混合物升至室温反应20分钟，经薄层板监控反应完全，加入碘甲烷(55mg，0.39mmol)，继续于室温反应2小时。经LC-MS检测反应完全，滴加水淬灭反应，向混合物中加入水(15mL)，用乙酸乙酯(15mL x 2)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，所得残余物经柱层析纯化(石油醚:乙酸乙酯＝2:1)得产物(90mg，79％)。MS(m/z)：635.2[M+1]。
步骤5)顺式-2-{[6-乙基-2-(3-氟-4-(甲基氨基)吡咯烷-1-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈
在0℃、氮气保护下，向顺式-{1-[5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-2-基]-4-氟吡咯烷-3-基}(甲基)氨基甲酸苄酯(90mg，0.14mmol)的二氯甲烷(4mL)溶液中滴加三甲基碘硅烷(59μL，0.42mmol)。混合物于室温搅拌1小时后，加水淬灭反应，减压浓缩，向残余物中加入水(15mL)和甲基叔丁醚(15mL)，分层，水相用碳酸氢钠调pH至8左右后，用乙酸乙酯(15mL x 2)萃取，合并的有机相用饱和食盐水洗，无水硫酸钠干燥，旋干得目标产物(60mg，84％)。MS(m/z)：501.1[M+1]。
步骤6)顺式-2-{[6-乙基-2-(3-氟-4-((2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙基)(甲基)氨基)吡咯烷-1-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈
向顺式-2-{[6-乙基-2-(3-氟-4-(甲基氨基)吡咯烷-1-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(60mg，0.12mmol)的乙腈(3mL)混合物中加入2-氯-1-(3-羟基氮杂环丁-1-基)乙酮(17.6mg，0.12mmol)、碳酸钾(33mg，0.24mmol)和碘化钾(10mg，0.06mmol)，将混合物加热至80℃反应2小时。待反应液冷至室温，过滤，减压浓缩，所得残余物经厚制备板纯化(二氯甲烷:甲醇＝20:1)得到标题化合物为淡黄色固体(30mg，41％)。MS(m/z)：614.2[M+1]。
实施例9
2-{[6-乙基-2-(3-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙氧基)吡咯烷-1-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备
Figure PCTCN2020126996-appb-000034
步骤1)(R)-2-{[2-(3-氨基吡咯烷-1-基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈
向2-{[2-溴-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(150mg，0.32mmol)的N,N-二甲基甲酰胺(3.0mL)溶液中加入3-吡咯烷醇(33mg，0.39mmol)和碳酸钾(89mg，0.65mmol)，混合物于室温反应5小时。将反应液倒入水(15mL)中，用乙酸乙酯(15mL x 2)萃取，合并的有机层经饱和盐水洗，无水硫酸钠干燥，减压浓缩得白色固体，石油醚打浆纯化得到目标化合物(150mg，98％)。
步骤1)2-{[6-乙基-2-(3-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙氧基)吡咯烷-1-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈
向(R)-2-{[2-(3-氨基吡咯烷-1-基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(47mg，0.10mmol)的四氢呋喃(3.0mL)溶液中，加入60％氢化钠(20mg，0.50mmol)，混合物于室温搅拌15分钟，然后加入1-(3–((叔丁基二甲基硅烷基)氧基)氮杂环丁烷-1-基)-2-氯乙酮(33mg，0.12mmol)，升温至55℃下加热反应5h。将反应混合物冷却至0℃后，滴加水淬灭反应，再加入1.0N盐酸(5.0mL)并升至室温搅拌30分钟。混合物减压浓缩，加水(15mL)，然后用二氯甲烷(15mL x 3)萃取，合并的有机层经无水硫酸钠干燥，减压浓缩，所得残余物经厚制备板纯化(二氯甲烷:甲醇＝30:1)得到标题化合物为白色固体(18mg，31％)。 1H-NMR(400MHz,CDCl 3)δ:8.17(m,2H),7.18(m,2H),4.72-4.65(m,1H),4.47-4.39(m,1H),4.33-4.26(m,2H),4.11-4.03(m,3H),3.95-3.88(m,1H),3.64-3.60(m,5H),3.60-3.51(m,2H),2.64-2.59(m,2H),2.32-2.24(m,1H),2.21-2.11(m,1H),1.32-1.28(m,3H)。LC-MS(m/z):583.2[M+1]。
实施例10
(R)-2-{[6-乙基-2-(3-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙氧基)吡咯烷-1-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备
Figure PCTCN2020126996-appb-000035
参照实施例9，用(R)-3-吡咯烷醇代替3-吡咯烷醇制备得到(R)-2-{[6-乙基-2-(3-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙氧基)吡咯烷-1-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。 1H-NMR(500MHz,CDCl 3)δ:8.17(m,2H),7.18(m,2H),4.73-4.66(m,1H),4.47-4.40(m,1H),4.34-4.27(m,2H),4.12-4.08(m,1H),4.07(m,2H),3.95-3.88(m,1H),3.64-3.60(m,5H),3.60-3.52(m,2H),2.64-2.59(m,2H),2.32-2.25(m,1H),2.20-2.11(m,1H),1.32-1.29(m,3H)。LC-MS(m/z):583.3[M+1]。
实施例11
(S)-2-{[6-乙基-2-(3-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙氧基)吡咯烷-1-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备
Figure PCTCN2020126996-appb-000036
参照实施例9，用(S)-3-吡咯烷醇代替3-吡咯烷醇制备得到(S)-2-{[6-乙基-2-(3-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙氧基)吡咯烷-1-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。 1H-NMR(500MHz,CDCl 3)δ:8.17(m,2H),7.18(m,2H),4.71-4.66(m,1H),4.46-4.39(m,1H),4.33-4.27(m,2H),4.12-4.03(m,3H),3.95-3.88(m,1H),3.63-3.60(m,5H),3.60-3.52(m,2H),2.64-2.59(m,2H),2.32-2.24(m,1H),2.20-2.12(m,1H),1.31-1.28(m,3H)。LC-MS(m/z):583.3[M+1]。
实施例12
(R)-2-{[6-乙基-2-(3-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙氧基)哌啶-1-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备
Figure PCTCN2020126996-appb-000037
参照实施例9，用(R)-3-哌啶醇代替3-吡咯烷醇制备得到(R)-2-{[6-乙基-2-(3-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙氧基)哌啶-1-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。 1H-NMR(500MHz,CDCl 3)δ:8.17(m,2H),7.18(m,2H),4.68-4.57(m,1H),4.46-4.37(m,1H),4.31-4.24(m,1H),4.12-4.03(m,3H),3.92-3.84(m,1H),3.66-3.60(m,2H),3.60(m,3H),3.54-3.46(m,1H),3.42(m,2H),2.63-2.59(m,2H),2.00-1.91(m,2H),1.83-1.77(m,1H),1.69-1.65(m,1H),1.32-1.29(m,3H)。LC-MS(m/z):597.2[M+1]。
实施例13
(S)-2-{[6-乙基-2-(3-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙氧基)哌啶-1-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备
Figure PCTCN2020126996-appb-000038
参照实施例9，用(S)-3-哌啶醇代替3-吡咯烷醇制备得到(S)-2-{[6-乙基-2-(3-(2-(3-羟基氮杂环丁烷-1-基)-2-氧代乙氧基)哌啶-1-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。 1H-NMR(500MHz,CDCl 3)δ:8.17(m,2H),7.18(m,2H),4.68-4.58(m,1H),4.46-4.37(m,1H),4.31-4.25(m,1H),4.12-4.04(m,3H),3.92-3.85(m,1H),3.67-3.61(m,2H),3.61(m,3H),3.55-3.47(m,1H),3.42(m,2H),2.63-2.59(m,2H),1.99-1.91(m,2H),1.83-1.77(m,1H),1.68-1.63(m,1H),1.32-1.29(m,3H)。LC-MS(m/z):597.2[M+1]。
实施例14
2-{[6-乙基-2-(6-(3-羟基氮杂环丁烷-1-羰基)-3-氮杂双环[3.1.0]己烷-3-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备
Figure PCTCN2020126996-appb-000039
步骤1)6-(3-羟基氮杂环丁烷-1-羰基)-3-氮杂双环[3.1.0]己烷-3-甲酸叔丁酯
向3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-羧酸(30mg，0.132mmol)的二氯甲烷(10mL)溶液中加入HATU(75mg，0.198mmol)、氮杂环丁烷-3-醇盐酸盐(17mg，0.158mmol)和N,N-二异丙基乙胺(41mg，0.317mmol)。混合物于室温反应6小时，TLC监测反应完全。向反应液中加入二氯甲烷(5mL)和水(10mL)，搅拌5分钟后分液，有机相再用0.5M HCl(10mL)洗和饱和食盐水(10mL)洗，无水硫酸钠干燥，过滤，减压浓缩得到43mg白色固体，粗品不经纯化直接用于下一步反应。LC-MS(m/z):283.2[M+1]。
步骤2)3-氮杂双环[3.1.0]己-6-基(3-氮杂环丁烷-1-基)甲酮盐酸盐
冰浴下，向上一步所得6-(3-羟基氮杂环丁烷-1-羰基)-3-氮杂双环[3.1.0]己烷-3-甲酸叔丁酯粗品的二氯甲烷(10mL)溶液中滴加35％的盐酸乙醇溶液(1mL)，混合物于室温反应过夜。将反应液浓缩得到无色油状物51mg，直接用于下一步反应。LC-MS(m/z):183.1[M+1]。
步骤3)2-{[6-乙基-2-(6-(3-羟基氮杂环丁烷-1-羰基)-3-氮杂双环[3.1.0]己烷-3-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈
向3-氮杂双环[3.1.0]己-6-基(3-氮杂环丁烷-1-基)甲酮盐酸盐(51mg，0.24mmol)的DMF(10mL)溶液中加入碳酸钾(46mg，0.33mmol)和2-{[2-溴-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(61mg，0.13mmol)，混合物于70℃下反应过夜。过滤，滤液在油泵减压下浓缩至干，残留物用厚制备板纯化(二氯甲烷:甲醇＝15:1)得到标题化合物为浅黄色固体(27mg，36％)。 1H NMR(400MHz,CDCl 3)δ8.15(m,2H),7.16(m,2H),4.71(m,1H),4.44(m,1H),4.25(m,1H),4.08(m,1H),3.86(m,1H),3.64(m,4H),3.57(s,3H),2.59(q,J＝7.6Hz,2H),2.26(m,2H),1.30(t,J＝7.6Hz,3H),0.77(m,2H)。MS(m/z)：565.1[M+1]。
实施例15
2-{[6-乙基-2-(3-(3-羟基氮杂环丁烷-1-羰基)-8-氮杂双环[3.2.1]辛烷-8-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备
Figure PCTCN2020126996-appb-000040
参照实施例14，用8-(叔丁氧羰基)-8-氮杂双环[3.2.1]辛烷-3-羧酸代替3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-羧酸制备得到2-{[6-乙基-2-(3-(3-羟基氮杂环丁烷-1-羰基)-8-氮杂双环[3.2.1]辛烷-8-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。 1H NMR(500MHz,CDCl 3)δ8.14(m,2H),7.16(m,2H),4.68(m,1H),4.41-4.25(m,2H),4.24-4.09(m,2H),4.02(m,1H),3.83(m,1H),3.58(s,3H),2.78(m,1H),2.59(q,J＝7.5Hz,2H),2.15(m,4H),1.80(m,2H),1.66(m,2H),1.30(t,J＝7.5Hz,3H)。MS(m/z)：593.2[M+1]。
实施例16
2-{[6-乙基-2-(6-(3-羟基氮杂环丁烷-1-羰基)-2-氮杂螺环[3.3]庚烷-2-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备
Figure PCTCN2020126996-appb-000041
参照实施例14，用2-(叔丁氧羰基)-2-氮杂螺环[3.3]庚烷-6-羧酸代替3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-羧酸制备得到2-{[6-乙基-2-(6-(3-羟基氮杂环丁烷-1-羰基)-2-氮杂螺环[3.3]庚烷-2-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。 1H NMR(500MHz,CDCl 3)δ8.14(m,2H),7.16(m,2H),4.67(m,1H),4.33-4.19(m,2H),4.09(m,4H),3.92(m,1H),3.85(m,1H),3.56(s,3H),2.91(m,1H),2.63-2.49(m,4H),2.42(m,2H),1.29(t,J＝7.5Hz,3H)。MS(m/z)：579.1[M+1]。
实施例17
2-{1-[5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-2-基]吡咯烷-3-基}-N-(3-羟基环丁基)乙酰胺的制备
Figure PCTCN2020126996-appb-000042
参照实施例14，用2-(1-(叔丁氧羰基)吡咯烷-3-基)乙酸代替3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-羧酸以及用3-氨基环丁醇盐酸盐代替氮杂环丁烷-3-醇盐酸盐制备得到2-{1-[5-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-6-乙基咪唑并[2,1-b][1,3,4]噻二唑-2-基]吡咯烷-3-基}-N-(3-羟基环丁基)乙酰胺。 1H NMR(400MHz,CDCl 3)δ8.16(m,2H),7.17(m,2H),5.69(m,1H),4.49(m,1H),3.95(m,1H),3.74(m,1H),3.60-3-43(m,5H),3.15(m,1H),2.82(m,2H),2.61(q,J＝7.6Hz,2H),2.37-2.22(m,5H),1.84-1.76(m,3H),1.30(t,J＝7.6Hz,3H)。MS(m/z)：581.3[M+1]。
实施例18
2-{[6-乙基-2-(3-(3-(3-羟基氮杂环丁烷-1-基)-3-氧代丙基)吡咯烷-1-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备
Figure PCTCN2020126996-appb-000043
参照实施例14，用3-[1-(叔丁氧羰基)吡咯烷-3-基]丙酸代替3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-羧酸制备得到2-{[6-乙基-2-(3-(3-(3-羟基氮杂环丁烷-1-基)-3-氧代丙基)吡咯烷-1-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。 1H NMR(400MHz,CDCl 3)δ8.16(m,2H),7.18(m,2H),4.70(m,1H),4.34(m,1H),4.26(m,1H),4.00(m,1H),3.88(m,1H),3.66-3-52(m,5H),3.44(m,1H),3.09(m,1H),2.61(q,J＝7.6Hz,2H),2.53(m,1H),2.41(m,1H),2.25-2.15(m,3H),1.85-1.72(m,3H),1.30(t,J＝7.6Hz,3H)。MS(m/z)：581.3[M+1]。
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：受试化合物用DMSO溶解成10mM储备液，用DMSO进行3倍梯度稀释，起始浓度时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。用反应缓冲溶液中制备终浓度为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13 ++++
实施例14 +++ 实施例15 +
实施例16 +++ 实施例17 ++++
实施例18 ++++    
注：ND：未进行测试
由表1可知，本发明化合物具有很好的ATX抑制活性，大部分化合物的IC 50值均低于100nM。
体外分析：人血浆LPA检测活性筛选
原理：以血浆中存在的LPC为底物，用LC/MS/MS定量分析检测生成的LPA18:2(以LPA17:0为内标)，在不同的受试化合物浓度点，剩余活性百分比由LPA18:2的生成量与不存在受试化合物时的生成量之比得出，计算IC 50值。
实验步骤：来源于至少6个个体人混合空白血浆，受试化合物从储备液起用稀释液3倍梯度稀释，配制8个系列浓度的工作溶液(含零点)。取10μL融化后的空白血浆样品，加入含内标(LPA17:0)的冰甲醇溶液直接进行蛋白沉淀，作为***对照样品。分别取2μL的系列浓度的工作溶液，加入198μL的人空白血浆，孵育浓度为0～10μM，将样品放入含5％CO 2的37℃孵育箱，孵育2个小时。孵育结束后，取10μL血浆样品，加入合适体积的含内标(LPA17:0)的冰甲醇溶液进行蛋白沉淀蛋白，离心后取上清液，通过LC/MS/MS，进行LPA18:2的检测，用软件进行分析计算出化合物的IC 50值，见表2。
表2本发明化合物的人全血分析IC 50
+：≥1000nM；++：500-1000nM；+++：100-500nM；++++：0.01-100nM
受试化合物 血浆活性IC 50 受试化合物 血浆活性IC 50
实施例1 +++ 实施例2 ++++
实施例3 ND 实施例4 ++++
实施例5 +++ 实施例6 ++++
实施例7 ++++ 实施例8 ND
实施例9 ND 实施例10 ND
实施例11 ++++ 实施例12 ND
实施例13 ++++ 实施例14 ND
实施例15 ND 实施例16 ND
实施例17 ++++ 实施例18 ++++
注：ND：未进行测试
由表2可知，本发明化合物亦能有效抑制人血浆中的ATX，从而抑制LPC被水解成LPA，化合物的IC 50值基本都低于100nM。
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本发明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。
将本发明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。
药代动力学研究表明，本发明化合物在体内具有较佳的半衰期和暴露量，具有很好的生物利用度。
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 (15)

  1. 化合物，其具有式(I)、或(II)所示结构：
    Figure PCTCN2020126996-appb-100001
    其中，
    Cy 1是C 5-12螺双环基、C 5-12螺杂双环基、C 5-12稠合双环基、C 5-12稠合杂双环基、C 5-12桥环基、或C 5-12桥杂环基，其中所述Cy 1任选地被1、2、3或4个R 4取代；
    Cy 2是3-8个原子组成的杂环基，其中所述Cy 2任选地被1、2、3或4个R 4取代；
    Y 1是-C(＝O)-、或-S(＝O) 1-2-；
    Y 2是-(CH 2) 1-2-O-、-C(＝O)-CH 2-O-、-NHC(＝O)-CH 2-、-C(＝O)-(CH 2) 1-2-、-C(＝O)-CH 2-N(R 1b)-、或-NHC(＝O)NH-；
    Z是C 3-6杂环基C 1-4烷基、或
    Figure PCTCN2020126996-appb-100002
    R 1a是H、C 1-4烷基、或卤代C 1-4烷基；
    R 1b是C 1-4烷基-C(＝O)-、C 1-4烷基-S(＝O) 1-2-、(C 1-4烷基) 2N-C(＝O)-、或C 2-7杂环基-C(＝O)-C 1-4烷基-，所述
    R 1b任选地被1、2、3或4个R 7取代；
    R 2为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、C 1-4烷基、卤代C 1-4烷基、或C 1-4羟基烷基；
    R 3为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、C 1-4烷基、卤代C 1-4烷基、氰基取代的C 1-4烷基、或C 1-4羟基烷基；
    各R 4分别独立地为H、D、氧代(C＝O)、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、C 1-4烷基、卤代C 1-4烷基、氰基取代的C 1-4烷基、C 1-4羟基烷基、C 1-4烷氧基、卤代C 1-4烷氧基、或卤代C 1-4烷氧基C 1-4烷基；
    各R 5分别独立地为H、D、氧代(C＝O)、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、C 1-4烷基、卤代C 1-4烷基、氰基取代的C 1-4烷基、C 1-4羟基烷基、C 1-4烷氧基、卤代C 1-4烷氧基、或卤代C 1-4烷氧基C 1-4烷基；
    各R 6分别独立地为H、氧代(C＝O)、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、C 1-4烷基、卤代C 1-4烷基、氰基取代的C 1-4烷基、C 1-4羟基烷基、C 1-4烷氧基、卤代C 1-4烷氧基、或卤代C 1-4烷氧基C 1-4烷基；
    各R 7分别独立地为H、氧代(C＝O)、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、C 1-4烷基、卤代C 1-4烷基、氰基取代的C 1-4烷基、C 1-4羟基烷基、C 1-4烷氧基、卤代C 1-4烷氧基、或卤代C 1-4烷氧基C 1-4烷基；
    X 6为N、或CH 2；
    X 7为-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；
    n2为0、1、2、3或4；和
    t为0、1、2、3或4；
    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。
  2. 根据权利要求1所述的化合物，其具有式(Ia)、或(IIa)所示结构：
    Figure PCTCN2020126996-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Cy 1是
    Figure PCTCN2020126996-appb-100004
    Cy 2是
    Figure PCTCN2020126996-appb-100005
    其中，
    X 3、X 4和X 5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-、或-(CH 2) m3-；
    各m1分别独立地为1、2、或3；
    各m2分别独立地为0、1、2、或3；
    各m3分别独立地为1、2、或3；和
    n1是0、1、2、3或4。
  4. 根据权利要求1或2所述的化合物，其中Cy 2是
    Figure PCTCN2020126996-appb-100006
    其中，m3是1、2、或3，n1是0、1、2、3或4，其中所述Cy 2任选地被1、2、3或4个R 4取代。
  5. 根据权利要求1或2所述的化合物，其中Cy 1是
    Figure PCTCN2020126996-appb-100007
    Figure PCTCN2020126996-appb-100008
    其中，所述Cy 1和Cy 2独立任选地被1、2、3或4个R 4取代。
  6. 根据权利要求1或2所述的化合物，其中，Z是
    Figure PCTCN2020126996-appb-100009
    Figure PCTCN2020126996-appb-100010
  7. 根据权利要求1所述的化合物，其中，R 2是H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、甲基、乙基、丙基、异丙基、丁基、羟甲基、羟乙基、三氟甲基、或三氟乙基。
  8. 根据权利要求1或2所述的化合物，其中，R 1b是CH 3-C(＝O)-、CH 3CH 2-C(＝O)-、CH 3-S(＝O) 1-2-、CH 3CH 2-S(＝O) 1-2-、(CH 3) 2N-C(＝O)-、或氮杂环丁基-C(＝O)-CH 2-，所述R 1b任选地被1、2、3或4个R 7取代；和
    各R 7分别独立地为H、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、-CF 3、-CH 2CF 3、-CH 2CH 2CN、-CH 2CH 2OH、或CHF 2-O-CH 2-。
  9. 根据权利要求1所述的化合物，其中，各R 4、R 5、和R 6分别独立地为H、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、-CF 3、-CH 2CF 3、-CH 2CH 2CN、CHF 2-O-CH 2-、CF 3-O-CH 2-、或-CH 2CH 2OH。
  10. 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 PCTCN2020126996-appb-100011
    Figure PCTCN2020126996-appb-100012
    Figure PCTCN2020126996-appb-100013
    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。
  11. 药物组合物，所述药物组合物包含权利要求1-10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。
  12. 根据权利要求11所述的药物组合物，其进一步包含附加治疗剂。
  13. 使用根据权利要求1-10任一项所述的化合物或权利要求11-12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。
  14. 根据权利要求13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***疾病或疼痛。
  15. 根据权利要求13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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