WO2021088957A1 - Composé hétérocyclique aromatique, composition pharmaceutique et son application - Google Patents

Composé hétérocyclique aromatique, composition pharmaceutique et son application 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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Chinese (zh)
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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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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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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    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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

L'invention concerne un nouveau composé hétérocyclique aromatique en tant qu'inhibiteur d'ATX (Autotaxine), une composition pharmaceutique contenant le composé, et une utilisation du composé et de la composition dans le traitement d'une maladie présentant une caractéristique pathologique d'expression accrue de l'ATX chez un mammifère, le composé répondant à la structure représentée par la formule (I) ou (II), ou un sel, un hydrate, un solvate, un stéréoisomère, un tautomère, un oxyde d'azote, un métabolite, un promédicament ou un mélange pharmaceutiquement acceptable de ceux-ci : où R 1a, R 2, R 3, R 6, Cy 1, Cy 2, Y 1, Y 2, Z et t sont tous définis comme décrits dans la présente invention.
PCT/CN2020/126996 2019-11-07 2020-11-06 Composé hétérocyclique aromatique, composition pharmaceutique et son application WO2021088957A1 (fr)

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