WO2019029620A1 - Inhibiteur d'atx, son procédé de préparation et son utilisation - Google Patents

Inhibiteur d'atx, son procédé de préparation et son utilisation Download PDF

Info

Publication number
WO2019029620A1
WO2019029620A1 PCT/CN2018/099622 CN2018099622W WO2019029620A1 WO 2019029620 A1 WO2019029620 A1 WO 2019029620A1 CN 2018099622 W CN2018099622 W CN 2018099622W WO 2019029620 A1 WO2019029620 A1 WO 2019029620A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
group
alkyl
unsubstituted
methyl
Prior art date
Application number
PCT/CN2018/099622
Other languages
English (en)
Chinese (zh)
Inventor
张健存
邹晴安
林财
陈延维
张礼军
Original Assignee
广州市恒诺康医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 广州市恒诺康医药科技有限公司 filed Critical 广州市恒诺康医药科技有限公司
Publication of WO2019029620A1 publication Critical patent/WO2019029620A1/fr

Links

Classifications

    • 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
    • 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
    • A61K31/4353—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
    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring 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
    • A61K31/495—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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring 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
    • A61K31/495—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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring 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
    • A61K31/495—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to the technical field of medicinal chemistry, in particular to an ATX inhibitor and a preparation method and application thereof.
  • ATX Autotaxin
  • PDE phosphodiesterase
  • ENPP extracellular pyrophosphatase/phosphodiesterase
  • LPA lysophosphatidyl acid
  • LPC lysophosphatidylcholine
  • LPA is not only a precursor of phospholipid synthesis, but also causes a wide range of biological effects through various signaling pathways.
  • LPA is mediated through six cell surface-specific receptor proteins (LPA1-6), the G protein-coupled receptor (GPCR).
  • LPA1-6 is LPA1/Edg-2/VZG-1, LPA2/Edg-4, LPA3/Edg-7, LPA4/p2y9/GPR23, LPA5/GPR92, respectively.
  • Edg endothelial cell differentiation gene
  • LPA6/p2Y5 each receptor is mediated by G ⁇ proteins (Gs Gi, Gq, and G12/13), which in turn triggers a cascade of cellular signaling cascades.
  • the main pathway includes hydrolysis of phosphatidylinositol diphosphate (PIP2), which triggers intracellular calcium release and protein kinase C (PKC) activation; inhibition of adenylate cyclase (cAMP) signaling pathway; activation Ras-MAPK, MERK, ERK pathway, regulate cell proliferation activities; activate phosphoinositide PI3K-AKT pathway, regulate cell survival and apoptosis; and activate Rho pathway to regulate cytoskeletal remodeling, shape change and cell migration.
  • PIP2 phosphatidylinositol diphosphate
  • PDC protein kinase C
  • cAMP adenylate cyclase
  • the concentration of LPA can be increased to 10 ⁇ mol/L, well above the normal level of 100 nmol/L.
  • Excessive LPA increases the production of vascular endothelial growth factor (VEGF), promotes angiogenesis, decreases 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, nervous system diseases, and pain.
  • LPA has multiple functions in tumorigenesis, promoting tumor cell growth, angiogenesis, metastasis and drug resistance. Therefore, reducing the concentration level of LPA is conducive to the treatment and control of tumors.
  • inhibiting the activity of ATX and blocking the production of LPA are hotspots for the treatment of various serious diseases.
  • Fibrotic diseases are mainly idiopathic pulmonary fibrosis (IPF) and liver fibrosis.
  • IPF idiopathic pulmonary fibrosis
  • IPF liver fibrosis.
  • IPF is a fatal disease characterized by diffuse alveolitis and alveolar structural disorders, and leads to the progressive development of interstitial fibrosis.
  • the prognosis is poor, with an average survival time of 2 to 5 years.
  • IPF may be the most closely associated disease with the ATX-LPA pathway, because in lung tissue, ATX expression is most concentrated in bronchial epithelial cells and alveolar macrophages, and these cells can be juxtaposed into fibroblasts.
  • GLPG-1690 as an Autotaxin inhibitor, has entered the phase II clinical trial for the treatment of idiopathic pulmonary fibrosis; the serum ATX concentration is closely related to liver fibrosis and liver stiffness, which is the most predictive of 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 tumor cell growth. Therefore, ATX inhibitors that block the ATX-LPA signaling pathway provide a new way to clinically treat cancer and fibrotic diseases.
  • ATX inhibitors Compared with traditional kinase inhibitors, ATX inhibitors inhibit ATX activity and affect multiple signaling pathways related to cell proliferation, growth and apoptosis, and have a good inhibitory effect on some drug-resistant tumors.
  • the fibrosis of organs is closely related and is an important target for research and development of new fibrotic diseases.
  • an object of the present invention to provide an ATX inhibitor which is capable of binding to ATX and inhibiting the activity of ATX.
  • the present invention adopts the following technical solutions:
  • the invention provides a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • R 1 is H, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl
  • R 2 is H, a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted C 3 -C 7 cycloalkyl group, or a substituted or unsubstituted heterocycloalkyl group of 3-7 atoms;
  • R 3 is H, halogen, cyano, C 1 -C 3 alkyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl;
  • a and M are each independently N or CR 6 ; wherein R 6 is hydrogen, halogen or C 1 -C 3 alkyl;
  • Cy is a substituted or unsubstituted spiro heterocyclic ring of 7 to 11 atoms, a substituted or unsubstituted 6-11 atomic fused heterocyclic ring, or a substituted or unsubstituted 7-11 atomic bridged heterocyclic ring; When Cy is substituted, it may be substituted with 1-2 groups selected from the group consisting of oxygen, halogen, cyano, methyl, methoxy and trifluoromethyl.
  • R 4 is hydrogen, halogen or C 1 -C 3 alkyl
  • L is a substituted or unsubstituted C 1 -C 6 alkyl group, a substituted or unsubstituted C 3 -C 7 cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group of 4-7 atoms, substituted or unsubstituted a C 5 -C 6 cycloalkyl group, a substituted or unsubstituted heterocyclic alkyl group of 5-6 atoms; when L is substituted, it may be selected from halogen, C 1 -C 4 alkyl, trifluoromethyl a group substituted with a cyano group, a cyano group, a hydroxyl group, an amino group, and a C 1 -C 4 alkoxy group;
  • R 5 is hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, hydroxy, cyano, or -N(R 8 ) 2 ; wherein R 8 is hydrogen or C 1 -C 4 alkyl;
  • a 0, 1, 2, 3, 4 or 5;
  • b is 0 or 1;
  • c is 0 or 1;
  • the corresponding group is a chemical bond, for example, when a is 0, C(R 4 ) 2 is a chemical bond, when b is 0, X is a chemical bond, and when c is 0, L is a chemical bond.
  • the compound of Formula I of the invention is a compound of Formula II (a) or II (b):
  • R 9 is halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyano or trifluoromethyl;
  • R 10 is hydrogen, halogen, cyano or trifluoromethyl
  • R 11 is hydrogen, halogen or cyano
  • W is S or O
  • M is N or CR 6 , wherein R 6 is hydrogen
  • R 1 , R 2 , R 3 , R 4 , R 5 , Cy, X, L, a, b, c are as defined in formula I.
  • R 1 is C 1 -C 4 alkyl, preferably C 1 -C 2 alkyl, more preferably methyl;
  • R 2 is a substituted or unsubstituted C 1 -C 4 alkyl group, preferably an unsubstituted C 1 -C 4 alkyl group, more preferably an ethyl group;
  • R 3 is H, halogen, cyano or C 1 -C 3 alkyl, preferably H, halogen or C 1 -C 3 alkyl, more preferably H, fluoro or methyl;
  • a and M are each independently N or CR 6 , wherein R 6 is hydrogen; preferably, both A and M are CR 6 , wherein R 6 is hydrogen; more preferably, A is CR 6 , wherein R 6 is hydrogen, M is N.
  • R 4 is hydrogen or C 1 -C 3 alkyl; preferably, R 4 is hydrogen;
  • L is a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted heterocycloalkyl group of 4 to 5 atoms, and when L is substituted, may be substituted with a group selected from a halogen or a hydroxyl group;
  • L is unsubstituted or substituted by hydroxy a C 1 -C 4 alkyl group which is unsubstituted or substituted by a halogen or a hydroxy group;
  • R 5 is hydrogen, hydroxy, unsubstituted C 1 -C 4 alkyl, or -N(R 8 ) 2 , wherein R 8 is hydrogen or C 1 -C 4 alkyl;
  • a is 0 or 1
  • c 0 or 1.
  • Cy is selected from the group consisting of:
  • e 1, 2, 3;
  • f 0,1,2;
  • g is 1, 2, 3; and in the spiroheterocycle, the sum of d, e, g, and f is not less than 4 and not more than 8; in the fused heterocyclic ring, the sum of d, e, g, and f is not less than 2 is not more than 7; in the bridged heterocyclic ring, the sum of d, e, g, and f is not less than 2 and not more than 6.
  • Cy is selected from the group consisting of:
  • R 9 is halogen
  • R 10 is hydrogen
  • R 11 is cyano
  • W is S
  • R 1 is C 1 -C 4 alkyl (eg methyl)
  • R 2 is C 1 -C 4 alkyl (eg ethyl
  • R 3 is hydrogen or halogen (for example F) or C 1 -C 3 alkyl (for example methyl)
  • M is N.
  • Cy is selected from the following groups:
  • R 4 is hydrogen
  • L is a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted heterocycloalkyl group of 4 to 5 atoms, and when L is substituted, may be substituted with a group selected from a halogen or a hydroxyl group;
  • L is unsubstituted or substituted by hydroxy a C 1 -C 4 alkyl group which is unsubstituted or substituted by a halogen or a hydroxy group;
  • R 5 is hydrogen, hydroxy, unsubstituted C 1 -C 4 alkyl, or -N(R 8 ) 2 , wherein R 8 is hydrogen or C 1 -C 4 alkyl;
  • a is 0 or 1
  • c 0 or 1.
  • R 9 is halogen
  • R 10 is hydrogen
  • R 11 is cyano
  • W is S
  • R 1 is C 1 -C 4 alkyl (eg methyl)
  • R 2 is C 1 -C 4 alkyl (eg ethyl
  • R 3 is hydrogen or halogen (for example F) or C 1 -C 3 alkyl (for example methyl)
  • Cy is selected from the group consisting of:
  • R 4 is hydrogen
  • L is a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted heterocycloalkyl group of 4 to 5 atoms, and when L is substituted, may be substituted with a group selected from a halogen or a hydroxyl group;
  • L is unsubstituted or substituted by hydroxy a C 1 -C 4 alkyl group which is unsubstituted or substituted by a halogen or a hydroxy group;
  • R 5 is hydrogen, hydroxy, unsubstituted C 1 -C 4 alkyl, or -N(R 8 ) 2 , wherein R 8 is hydrogen or C 1 -C 4 alkyl;
  • a is 0 or 1
  • c 0 or 1.
  • the compound of Formula I, Formula II (a) or Formula II (b) of the invention is a compound selected from Formula III to Formula XXI:
  • R 9 is halogen, C 1 -C 4 alkyl or trifluoromethyl
  • R 10 is hydrogen, halogen or cyano
  • R 11 is hydrogen or cyano
  • R 1 is C 1 -C 4 alkyl
  • R 2 is C 1 -C 4 alkyl
  • R 3 is hydrogen, halogen or C 1 -C 3 alkyl
  • L is a substituted or unsubstituted C 1 -C 6 alkyl group, a substituted or unsubstituted C 3 -C 7 cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group of 4-7 atoms, substituted or unsubstituted a C 5 -C 6 cycloalkyl group, a substituted or unsubstituted heterocyclic alkyl group of 5-6 atoms; when the L is substituted, it may be selected from a substituent selected from a halogen, a methyl group and a trifluoromethyl group.
  • R 5 is hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, hydroxy, cyano, or -N(R 8 ) 2 ; wherein R 8 is hydrogen or C 1 -C 4 alkyl;
  • a 0, 1, 2 or 3;
  • b is 0 or 1;
  • c 0 or 1.
  • R 9 is halogen; more preferably F;
  • R 10 is hydrogen
  • R 11 is a cyano group
  • R 1 is a methyl group
  • R 2 is an ethyl group
  • R 3 is F or methyl
  • L is a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted heterocycloalkyl group of 4 to 5 atoms, and when L is substituted, may be substituted with a group selected from a halogen and a hydroxyl group; More preferably L is unsubstituted or substituted by a hydroxy group a C 1 -C 4 alkyl group which is unsubstituted or substituted by a halogen or a hydroxy group;
  • R 5 is hydrogen, hydroxy, unsubstituted C 1 -C 4 alkyl, or -N(R 8 ) 2 , wherein R 8 is hydrogen or C 1 -C 4 alkyl; a is 0 or 1;
  • c 0 or 1.
  • the compound of Formula I of the present invention is a compound selected from the group consisting of:
  • the invention also provides a process for the preparation of a compound of the invention, comprising the following synthetic route:
  • Step 1 Intermediate I is reacted with the corresponding aldehyde and 1,1,3,3-tetramethylbutyl isocyanide under magnesium chloride catalysis and heating to form intermediate II;
  • Step 2 Intermediate II is deprotected by heating in formic acid to obtain intermediate III;
  • Step 3 Intermediate III and the corresponding halogenated hydrocarbon are subjected to nucleophilic substitution reaction to obtain intermediate IV;
  • Step 4 Intermediate IV is hydrolyzed to obtain intermediate V;
  • Step 5 Intermediate V and intermediate VI are heated under basic conditions to undergo nucleophilic reaction or metal catalyzed coupling reaction to obtain intermediate VII;
  • Step 6 intermediate VII and intermediate VIII by Buchward coupling reaction to obtain intermediate IX;
  • Step 7 Intermediate IX is deprotected under acidic conditions to give intermediate X;
  • Step 8 nucleophilic substitution reaction of intermediate X with intermediate XI to give a compound of formula I,
  • Ar 1 , Ar 2 , A, M, R 1 , R 2 , R 3 , R 4 , R 5 , Cy, X, L, a, b, c are as defined in formula I, and L 1 is a halogen.
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, for use in the manufacture of a medicament for the prophylaxis or treatment of a pathological characteristic having increased ATX expression. Use in medicine.
  • the disease having an increased pathological profile of ATX expression comprises: cancer, fibrotic disease, metabolic disease, myelodysplastic syndrome, cardiovascular disease, autoimmune disease, inflammation, neurological disease or Pain; preferably, the disease having an increased pathological feature of ATX expression is pulmonary fibrosis or liver fibrosis.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and pharmaceutically acceptable Excipient or carrier.
  • the present invention provides a method for treating and/or preventing a disease having an increased pathological characteristic of ATX, the method comprising administering a compound of the present invention or a pharmaceutically thereof to a subject in need thereof An acceptable salt, stereoisomer, solvate or prodrug or pharmaceutical composition of the invention.
  • the disease having an increased pathological profile of ATX expression comprises: cancer, fibrotic disease, metabolic disease, myelodysplastic syndrome, cardiovascular disease, autoimmune disease, inflammation, neurological disease or Pain; preferably, the disease having an increased pathological feature of ATX expression is pulmonary fibrosis or liver fibrosis.
  • the articles used herein are used to refer to the articles of one or more than one (ie, at least one).
  • a component refers to one or more components, that is, there may be more than one component contemplated for use or use in embodiments of the embodiments.
  • Stereoisomer refers to a compound that has the same chemical structure but differs in the way the atoms or groups are spatially aligned. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotomers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • Enantiomer refers to two isomers of a compound that are not superimposable but are mirror images of each other.
  • Diastereomer refers to a stereoisomer that has two or more chiral neutralities and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. The mixture of diastereomers can be separated by high resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.
  • optically active compounds Many organic compounds exist in optically active forms, i.e., they have the ability to rotate a plane of plane polarized light.
  • the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers.
  • the prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light caused by the compound, wherein (-) or l indicates that the compound is left-handed.
  • Compounds prefixed with (+) or d are dextrorotatory.
  • a particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as a mixture of enantiomers.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as the (R)-, (S)- or (R, S)-configuration presence.
  • each asymmetric atom has at least 50% enantiomeric excess in the (R)- or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the compounds of the invention may be one of the possible isomers or mixtures thereof, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms) The form exists.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have a cis or trans configuration.
  • the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography, depending on the difference in physicochemical properties of the components. Method and / or step crystallization.
  • racemate of any of the resulting end products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art by known methods, for example, by obtaining the diastereomeric salts thereof. Separation. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • tautomer or "tautomeric form” refers to structural isomers having different energies that are interconvertible by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion of a pentane-2,4-dione and a 4-hydroxypent-3-en-2-one tautomer.
  • Another example of tautomerization is phenol-keto tautomerization.
  • a specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridine-4(1H)-one tautomers. All tautomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.
  • substituted refers to the replacement of a hydrogen group in a particular structure with a group of the specified substituent.
  • Substitution on an alkyl or cycloalkyl group in the present invention if not indicated to occur on a particular carbon atom, means that it can occur on a carbon atom whose number of substituents has not reached saturation. When a plurality of substituents are selected from the same series, they may be the same or different.
  • Substitutions on a benzene ring, an aromatic heterocycle or a heterocycle in the present invention if not indicated to occur on a particular atom, indicate that it can occur at any position that is not replaced by a hydrogen atom and other atoms.
  • C1-6 alkyl specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups.
  • linking substituents are described.
  • the Markush variable recited for the group is understood to be a linking group.
  • the definition of a Markush group for the variable recites “alkyl” or “aryl”, it will be understood that the “alkyl” or “aryl” are respectively Represents a linked alkylene group or an arylene group.
  • alkenyl denotes a straight or branched chain monovalent hydrocarbon radical containing from 2 to 12 carbon atoms, wherein at least one site of unsaturation, ie having a carbon-carbon sp 2 double bond, includes “shun” and "Anti-”location, or positioning of "E” and "Z".
  • the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group comprises 2 - 4 carbon atoms.
  • alkynyl means a straight or branched chain monovalent hydrocarbon radical containing from 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., has a carbon-carbon sp triple bond.
  • the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group comprises 2 - 4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), and the like. .
  • alkyl refers to a saturated chain alkyl group
  • chain alkyl refers to a straight or branched alkyl group, such as C 1 -C 4 alkyl means having from 1 to 4 carbon atoms.
  • alkyl means an alkyl group having a cyclic structure, such as C 3 -C 4 cycloalkyl refers to an alkyl group having a cyclic structure of 3 to 4 carbon atoms, and examples include, but are not limited to, cyclopropyl, cyclobutane A group, a methyl group, a cyclopropyl group or the like.
  • Alkenyl means an unsaturated chain alkyl group, such as a C 2 -C 4 alkenyl group, which represents a straight or branched alkenyl group having one double bond having from 2 to 4 carbon atoms, examples including but not limited to Vinyl, propenyl, butenyl, isobutenyl and the like.
  • alkoxy denotes a straight or branched alkyl group having an oxygen atom at the end, and examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and the like.
  • cycloalkyl refers to an alkyl group having a cyclic structure, such as a C 3 -C 7 cyclic alkyl group, which refers to a saturated or unsaturated alkyl group having a cyclic structure of from 3 to 7 carbon atoms, wherein the saturated Examples of the cyclic alkyl group include, but are not limited to, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group and the like, and examples of the unsaturated cyclic alkyl group include, but are not limited to, cyclopentene and the like.
  • heterocycloalkyl denotes a non-aromatic cyclic group consisting of a carbon atom and a saturated or partially unsaturated (containing 1 or 2 double bonds) consisting of a hetero atom selected from nitrogen, oxygen, sulfur, and the like.
  • heterocycloalkyl groups include, but are not limited to, pyrrolidin-2-yl, piperidin-4-yl, piperazin-1-yl, morpholin-4-yl and the like.
  • heteroaryl refers to an aromatic ring radical formed by the replacement of at least one carbon atom on the ring with a heteroatom selected from nitrogen, oxygen or sulfur, which may be a 5-7 membered monocyclic heteroaryl or 7- 12-membered bicyclic heteroaryl.
  • heteroatom selected from nitrogen, oxygen or sulfur
  • examples include, but are not limited to, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, trinitrogen Azolyl, tetrazolyl, and the like.
  • spiroheterocycle refers to a cyclic system formed by the fact that two rings containing at least one hetero atom selected from nitrogen, oxygen or sulfur share one carbon atom. Examples of spiroheterocycles include, but are not limited to: Wait.
  • fused heterocyclic ring refers to a cyclic system formed by the combination of two carbon atoms containing at least one hetero atom selected from nitrogen, oxygen or sulfur. Examples of fused heterocycles include, but are not limited to: Wait.
  • bridged heterocycle refers to a cyclic system formed by the combination of three or more carbon atoms of two rings containing at least one hetero atom selected from nitrogen, oxygen or sulfur. Examples include but are not limited to: Wait.
  • alkylsulfonyl refers to an alkyl-substituted sulfonyl group forming an alkylsulfonyl group (-SO 2 alkyl group such as -SO 2 CH 3 ).
  • carboxyalkoxy denotes that the alkoxy group is substituted by one or more carboxy groups, wherein the alkoxy and carboxy groups have the definitions as described herein, such examples include, but are not limited to, Carboxymethoxy, carboxyethoxy, and the like.
  • alkylthio includes a C1-10 straight or branched alkyl group attached to a divalent sulfur atom.
  • the alkylthio group is a lower C 1-3 alkylthio group, examples of which include, but are not limited to, methylthio (CH 3 S-).
  • haloalkylthio includes a C 1-10 haloalkyl group attached to a divalent sulfur atom.
  • the haloalkylthio group is a lower C 1-3 haloalkylthio group, examples of which include, but are not limited to, trifluoromethylthio.
  • unsaturated as used in the present invention means that the group contains one or more unsaturations.
  • heteroatom refers to O, S, N, P, and Si, including any form of oxidation states of N, S, and P; forms of primary, secondary, tertiary, and quaternary ammonium salts; or nitrogen atoms in heterocycles. a form in which hydrogen is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like in N-substituted pyrrolidinyl) NR).
  • halogen means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • two points of attachment in the ring system are attached to the rest of the molecule, as shown by formula (a1) or (a2), indicating that either the E-terminus or the E-terminus can be attached to the rest of the molecule. That is, the connection methods at both ends can be interchanged.
  • prodrug denotes a compound which is converted in vivo to a compound of formula I-XXI. Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue.
  • solvate is used herein to describe a molecular complex comprising a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, such as ethanol.
  • solvent molecules such as ethanol.
  • hydrate is used when the solvent is water.
  • the present invention includes free forms of the compounds of formula I-XXI, as well as pharmaceutically acceptable salts and stereoisomers thereof, and solvates and prodrugs thereof.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods. Generally, salts of basic compounds are prepared by ion exchange chromatography or by reaction of a free base with a stoichiometric or excess amount of an inorganic or organic acid in the desired salt form in a suitable solvent or combination of solvents. Similarly, a salt of an acidic compound is formed by reaction with a suitable inorganic or organic base.
  • pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention which are formed by the reaction of a basic compound of the invention with an inorganic or organic acid.
  • conventional non-toxic salts include those prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, and hard.
  • Fatty acid lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl A salt prepared from oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid or the like.
  • a suitable "pharmaceutically acceptable salt” refers to a salt prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts prepared from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, zinc salts, and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred.
  • a salt prepared from a pharmaceutically acceptable organic non-toxic base including a primary amine, a secondary amine, a tertiary amine, a substituted amine, and the like, wherein the substituted amine includes a naturally occurring substituted amine , cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- Dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxylamine, isopropylamine, lysine Acid, methyl glucosamine, morpholine, piperazine, piperidine, guanidine, polyamine resin, procaine, guanidine, theobromine, triethylamine, tri
  • the term "pharmaceutical composition” relates to a composition suitable for administration to a patient, preferably a human patient.
  • Particularly preferred pharmaceutical compositions of the invention comprise one or more, preferably a therapeutically effective amount of a compound of the invention.
  • the pharmaceutical composition comprises one or more (pharmaceutically acceptable) carriers, stabilizers, excipients, diluents, solubilizers, surfactants, emulsifiers, preservatives and/or adjuvants suitable preparation.
  • the acceptable composition of the composition is preferably non-toxic to the recipient at the dosages and concentrations employed.
  • Pharmaceutical compositions of the invention include, but are not limited to, liquid, frozen, and lyophilized compositions.
  • compositions comprising a compound of the invention and one or more excipients, such as the excipients exemplarily described in this section and elsewhere herein.
  • excipients can be used in the present invention for a variety of purposes, such as adjusting the physical, chemical or biological properties of the formulation, such as adjusting the viscosity, and/or being used in the methods of the invention to improve effectiveness and/or
  • Such formulations and methods are stabilized against degradation and damage due to, for example, stresses that occur during manufacturing, shipping, storage, pre-use preparation, administration, and subsequent processes.
  • the pharmaceutical composition may contain, for example, modify, maintain or maintain, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, Formulation material for stability, dissolution or release rate, absorption or penetration.
  • the pharmaceutically acceptable excipient or carrier may be an excipient or a sustained release agent or the like.
  • the pharmaceutical compositions of the present invention may be in a variety of forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and may be presented in a suitable solid or liquid carrier or diluent.
  • the pharmaceutical compositions of the invention may also be stored in a suitable injectable or drip sterilizing device. Further, an odorant, a fragrance, or the like may be contained in the pharmaceutical composition of the present invention.
  • treatment refers to both therapeutic treatment and prevention or prevention measures. Treatment includes applying or administering the formulation to a body, isolated tissue or cell from a patient having a disease/disorder, having a disease/disorder, or having a predisposition to the disease/disorder for the purpose of healing, treating, relieving, Alleviate, alter, remedy, improve, enhance or affect the disease, the symptoms of the disease, or the propensity to develop the disease.
  • the term “improving” as used herein refers to any of the disease states of a patient having one of the types of tumors or cancers as specified herein by administering a compound or composition according to the invention to a subject in need thereof. enhance. This improvement can also be seen as a slowing or cessation of the patient's (metastatic) tumor or cancer progression.
  • prevention means to avoid a patient having one of the (metastatic) tumors or cancer types as specified herein by administering a compound or composition according to the invention to a subject in need thereof. Occurs or reoccurs.
  • disease refers to any condition that is capable of benefiting from the treatment with a compound or pharmaceutical composition described herein. Unless otherwise stated, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art. All patents and publications related to the present invention are hereby incorporated by reference in their entirety.
  • the compounds of the invention are typically designed to be used in particular treatment routes and methods, specific administration doses and frequency of administration, specific treatments for a particular disease, particularly within certain bioavailability and persistence ranges.
  • the material of the composition is preferably present at a concentration that is acceptable for the site of administration.
  • routes of administration include, but are not limited to, topical routes (eg, epidermis, inhalation, nasal, ocular, ear/auditory, vaginal, mucosal); enteral routes (eg, oral, gastrointestinal, sublingual, sublingual) , buccal, rectal); and parenteral routes (eg intravenous, intraarterial, intraosseous, intramuscular, intracerebral, intraventricular, epidural, intracapsular, subcutaneous, intraperitoneal, amniotic (extra) -amniotic), intra-articular, intracardiac, intradermal, intralesional, intrauterine, intravesical, vitreous, transdermal, intranasal, transmucosal, intrasynovial, intraluminal).
  • topical routes eg, epidermis, inhalation, nasal, ocular, ear/auditory, vaginal, mucosal
  • enteral routes eg, oral, gastrointestinal, sublingual, sub
  • the compounds of the invention can be prepared by the methods of the following examples.
  • the compounds of the present invention and the synthetic methods can be better understood in conjunction with the following examples. All parameters and related descriptions in the examples are based on quality unless otherwise stated.
  • the filler used for column chromatography separation is silica gel unless otherwise stated.
  • the experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer.
  • the following examples are illustrative of the methods that can be used to prepare the compounds described in the present invention, which are merely illustrative of the illustrative examples and are not intended to limit the scope of the invention.
  • the characterization data is: 1H NMR (400 MHz, CDCl3) ⁇ : 8.14 (m, 2H), 7.23 (m, 2H).
  • 6-Bromo-2-ethyl-8-methyl-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine (8.5 g, 23.1 mmol) was dissolved in formic acid (100 mL) and refluxed for 3 hr. The reaction solution was cooled, vortexed, and added with water. The mixture was adjusted to pH 8 with saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate (100 mL ⁇ 3), dried over anhydrous sodium sulfate g, yield: 89%.
  • N-(6-Bromo-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl)carboxamide (5.8 g, 20.6 mmol) was dissolved in tetrahydrofuran (100 mL), boron was added A solution of the alkanetetrahydrofuran (35 mL, 35 mmol) was reacted at 50 ° C overnight. The reaction mixture was cooled, and the mixture was evaporated, evaporated, mjjjjjjjjj
  • 6-Bromo-2-ethyl-N,8-dimethylimidazo[1,2-a]pyridin-3-amine (2.0 g, 7.43 mmol) was dissolved in tetrahydrofuran (40 mL). At 0 ° C, sodium hydrogen (0.9 g, 22.3 mmol) was added and the reaction was refluxed for half an hour. After the reaction solution was cooled to room temperature, a solution of 2-chloro-4-(4-fluorophenyl)thiazole-5-carbonitrile (3.1 g, 12.99 mmol) in THF (20 mL) was evaporated. The reaction mixture was cooled to 0 ° C, and the mixture was evaporated to dryness. Things. Methyl tert-butyl ether (50 mL) and petroleum ether (50 mL) were added, and then filtered and evaporated to give a white solid.
  • 2-Boc-hexahydropyrrolo[3,4-c]pyrrole was used instead of 2,7-diazaspiro[3.5]decane-7-carboxylic acid tert-butyl ester hydrochloride to prepare 2- ⁇ [2-ethyl-8-methyl-6-(5-(methylsulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2-(1H)-yl)imidazo[1,2- a] Pyridin-3-yl](methyl)amino ⁇ -4-(4-fluorophenyl)thiazole-5-carbonitrile.
  • 2-Boc-hexahydropyrrolo[3,4-c]pyrrole was used instead of 2,7-diazaspiro[3.5]decane-7-carboxylic acid tert-butyl ester hydrochloride to prepare 2- ⁇ 5-[3-((5-Cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethyl-8-methylimidazo[1,2 -a] Pyridin-6-yl]hexahydropyrrolo[3,4-c]pyrrole-2-(1H)-yl ⁇ -N,N-dimethylacetamide.
  • 2-Boc-hexahydropyrrolo[3,4-c]pyrrole was used instead of 2,7-diazaspiro[3.5]decane-7-carboxylic acid tert-butyl ester hydrochloride to prepare 2- ⁇ [2-ethyl-6-(5-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)hexahydropyrrolo[3,4-c]pyrrole-2 -(1H)-yl-8-methylimidazo[1,2-a]pyridin-3-yl](methyl)amino ⁇ -4-(4-fluorophenyl)thiazole-5-carbonitrile.
  • 6-Bromo-2-ethyl-8-fluoro-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine (6 g, 16.2 mmol) was dissolved in formic acid (60 mL) and refluxed for 3 h. The reaction solution was cooled, vortexed, and added with water. The mixture was adjusted to pH 8 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate (100 mL ⁇ 3), dried over anhydrous sodium sulfate, dried, and then evaporated, g, yield: 98%. Go directly to the next step.
  • N-(6-Bromo-2-ethyl-8-fluoroimidazo[1,2-a]pyridin-3-yl)carboxamide (2.86 g, 10.0 mmol) was dissolved in tetrahydrofuran (50 mL) and borane was added. Tetrahydrofuran solution (15 mL, 15 mmol) was reacted at 50 ° C overnight. The reaction mixture was cooled, and then the mixture was evaporated. EtOAcjjjjjjjjjjj
  • 2-Boc-hexahydropyrrolo[3,4-c]pyrrole was used instead of 2,7-diazaspiro[3.5]decane-7-carboxylic acid tert-butyl ester hydrochloride to prepare 2- ⁇ [2-ethyl-8-fluoro-6-(5-(methylsulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2-(1H)-yl)imidazo[1,2-a Pyridin-3-yl](methyl)amino ⁇ -4-(4-fluorophenyl)thiazole-5-carbonitrile.
  • the characterization data are: 1 H NMR (400 MHz, CDCl 3 ) ⁇ : 7.35-7.28 (m, 5H), 5.66 (s, 1H), 3.70 (s, 3H), 3.54 (s, 2H), 3.01 (m, 2H) ), 2.54 (m, 4H), 2.35 (m, 2H).
  • the characterization data are: 1 H NMR (400 MHz, CDCl 3 ) ⁇ : 7.35-7.28 (m, 5H), 4.74 (s, 2H), 3.71 (s, 3H), 3.54 (s, 2H), 2.60 (s, 2H) ), 2.49 (m, 4H), 1.73 (m, 4H).
  • the characterization data are: 1 H NMR (400 MHz, CDCl 3 ) ⁇ : 7.32-7.26 (m, 5H), 6.11 (s, 1H), 3.51 (s, 2H), 3.19 (s, 2H), 2.42 (m, 4H) ), 2.21 (s, 2H), 1.69 (m, 4H).
  • Lithium tetrahydrogen aluminum (0.56 g, 14.7 mmol) was suspended in THF (15 mL), cooled to 0 ° C, and 8-benzyl-2,8-diazaspiro[4.5]nonan-3-one was added dropwise.
  • the reaction solution was cooled to room temperature, and water (0.6 mL) was added dropwise to quench the reaction, and then 15% NaOH (0.6 mL) was added dropwise.
  • anhydrous sodium sulfate (10 g) was added and stirring was continued for 15 minutes.
  • the mixture was filtered through EtOAc (EtOAc)EtOAc.
  • the characterization data are: 1 H NMR (400 MHz, CDCl 3 ) ⁇ : 7.33 - 7.25 (m, 5H), 3.51 (s, 2H), 3.37 (m, 2H), 3.16 (m, 2H), 2.50 (m, 2H) ), 2.33 (m, 2H), 1.70 (m, 2H), 1.58 (m, 4H), 1.47 (s, 9H).
  • tert-Butyl 8-benzyl-2,8-diazaspiro[4.5]decane-2-carboxylate (1.5 g, 4.54 mmol) was dissolved in methanol (30 mL) and 10% Pd/C (0.3 g) ), hydrogen gas was introduced, and the reaction was allowed to proceed overnight at room temperature. The mixture was filtered through celite, and evaporated to dryness.
  • the characterization data is: m/z: 241.2 [M+1]
  • Example 32 the preparation of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate was replaced by tert-butyl 2,7-diazaspiro[3.5]decane-2-carboxylate ( S)-2- ⁇ [8-Methyl-2-ethyl-6-(2-(2-hydroxypropionyl)-2,8-diazaspiro[4.5]decane-8-yl)imidazolium [1,2-a]pyridin-3-yl](methyl)amino ⁇ -4-(4-fluorophenyl)thiazole-5-carbonitrile.
  • the tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate was used instead of the tert-butyl 2,7-diazaspiro[3.5]decane-2-carboxylate.
  • the characterization data are: 1 H NMR (400 MHz, CDCl 3 ) ⁇ : 8.15 (m, 2H), 7.24 (m, 2H), 7.10-7.02 (m, 2H), 4.91 (m, 0.6H), 4.64 (m, 0.4H), 4.58 (m, 1H), 4.45 (m, 0.6H), 4.20 (m, 0.4H), 3.69-3.60 (m, 4H), 3.55 (m, 1H), 3.42 (m, 1H), 3.17 (m, 0.6H), 3.01 (m, 0.4H), 2.72 (m, 2H), 2.56 (s, 3H), 2.09 (m, 1H), 1.96 (m, 1H), 1.33-1.28 (m, 6H).
  • the tert-butyl 2,9-diazaspiro[5.5]undecane-3-carboxylate was used in place of the tert-butyl 2,7-diazaspiro[3.5]decane-7-carboxylate hydrochloride.
  • Preparation of the salt gives 2- ⁇ [8-methyl-2-ethyl-6-(9-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-3,9- Diazaspiro[5.5]undecano-3-yl)imidazo[1,2-a]pyridin-3-yl](methyl)amino ⁇ -4-(4-fluorophenyl)thiazole-5- Formonitrile.
  • 6-Bromo-2-ethyl-8-methyl-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-b]pyridazin-3-amine ( 1.45 g, 4.50 mmol) was dissolved in formic acid (30 mL) and refluxed for 1.5 h. The reaction solution was cooled, vortexed, and added with water. The mixture was adjusted to pH with a saturated sodium hydrogen carbonate solution, and then extracted with ethyl acetate (100 mL ⁇ 3), dried over anhydrous sodium sulfate, dried, and then evaporated, g, yield: 70%.
  • the characterization data is: MS (m/z): 283.1 [M+1], 285.1 [M+1].
  • N-(6-Bromo-2-ethyl-8-methylimidazo[1,2-b]pyridazin-3-yl)carboxamide (2.51 g, 10.5 mmol) was dissolved in acetone (80 mL). Potassium carbonate (4.35 g, 31.5 mmol) and methyl iodide (1.64 mL, 26.3 mmol) were heated and refluxed for 5 hours. After cooling, spin-drying, dichloromethane and water were added, the layers were separated, and the aqueous layer was extracted with methylene chloride. 86%.
  • Example 54 a 2,7-diazaspiro[3.5]decane-2-carboxylic acid tert-butyl ester was used instead of 2,6-diazaspiro[3.4]octane-6-carboxylic acid tert-butyl ester to obtain 2 - ⁇ [2-ethyl-6-(2-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-2,7-diazaspiro[3.5] ⁇ Alkan-7-yl)-8-methylimidazo[1,2-a]pyridazin-3-yl](methyl)amino ⁇ -4-(4-fluorophenyl)thiazole-5-carbonitrile.
  • the characterization data are: 1H NMR (400MHz, CDCl3) ⁇ : 8.17 (m, 2H), 7.16 (m, 2H), 6.41 (m, 1H), 4.63 (m, 1H), 4.43-4.19 (m, 3H), 3.99 (m, 1H), 3.85 (m, 1H), 3.60 (m, 5H), 3.35 (m, 1H), 3.17 (m, 2H), 3.06 (m, 0.6H), 2.90 (m, 0.4H) , 2.75 (m, 2H), 2.58 (m, 4H), 1.97 (m, 1H), 1.84 (m, 1H), 1.32 (m, 3H).
  • the characterization data are: 1H NMR (400MHz, CDCl3) ⁇ : 8.17-8.14 (m, 2H), 7.19-7.15 (t, 2H), 4.54 (S, 2H), 3.66 (s, 4H), 3.61 (S, 3H) ), 3.40-3.86 (m, 4H), 2.79-2.73 (m, 2H), 2.59 (s, 3H), 1.84-1.82 (m, 4H).
  • the characterization data are: 1H NMR (400MHz, CDCl3) ⁇ : 8.17-8.14 (m, 2H), 7.19-7.15 (t, 2H), 4.29 (s, 2H), 3.72 (s, 4H), 3.61 (S, 3H) ), 3.41-3.86 (m, 4H), 2.79-2.73 (m, 2H), 2.59 (s, 3H), 1.84-1.82 (m, 4H).
  • Example 63 Screening for FS-3 as a substrate for enzyme activity
  • the substrate lysophosphatidylcholine (LPC) and its analogs can be hydrolyzed by lysoPLD enzyme activity.
  • the substrate FS-3 used in this experiment is an LPC analog labeled with both fluorescein and fluorescence quencher. When ATX acts on the substrate, it is hydrolyzed and fluorescein is released for detection.
  • ATX enzyme, substrate FS-3 and its corresponding reagents were purchased from Echelon Biosciences Inc. (Salt Lake City, UT, USA), DMSO (Sigma). Envision 2104 Fluorometer (Perkin Elmer, USA), sampler (Eppendorf), microplate (corning).
  • the average IC50 values of the compounds were summarized into three grades: A: IC 50 ⁇ 10 nM; B: 10 nM ⁇ IC 50 ⁇ 50 nM; C: IC 50 >50 nM.
  • Example number IC 50 value (nM) IC 50 rating Example number IC 50 value IC 50 rating Example 1 3.92 A Example 2 3.65 A Example 3 1.77 A Example 4 2.27 A Example 5 4.45 A Example 6 2.69 A Example 7 12 B Example 8 12 B Example 9 4.87 A Example 10 2.38 A Example 11 2.71 A Example 12 4.21 A Example 13 1.37 A Example 14 1.43 A Example 15 1.50 A Example 16 1.99 B Example 17 2.22 A Example 18 16.7 B Example 19 10.2 B Example 20 1.96 A Example 21 0.83 A Example 22 10.2 B Example 23 2.87 A Example 24 1.09 A Example 25 2.77 A Example 26 1.79 A
  • Example 27 36.2 B Example 28 30.8 B Example 29 60.2 C Example 30 101 C Example 31 53.1 C Example 32 2.28 A Example 33 8.73 A Example 34 3.26 A Example 35 1.28 A Example 36 1.98 A Example 37 2.01 A Example 38 3.22 A Example 39 10.6 B Example 40 3.66 A Example 41 1.96 A Example 42 8.62 A Example 43 3.69 A Example 44 2.63 A Example 45 2.84 A Example 46 12.5 A Example 47 9.6 A Example 48 5.27 A Example 49 20.2 B Example 50 36.2 B Example 51 10.4 B Example 52 24.3 B
  • the compound of the present invention has a good inhibitory effect on Autotaxin, and in particular, some of the compounds have an IC50 of less than 10 nM against Autotaxin, showing a very good Autotaxin inhibitory activity.
  • the lysophosphatidylcholine can be hydrolyzed by lysophosphidylcholine (LPC) to form lysophosphatidic acid (LPA) and choline.
  • LPC lysophosphidylcholine
  • LPA lysophosphatidic acid
  • choline Under the action of choline oxidase, choline is oxidized to form H 2 O 2 .
  • HRP horseradish peroxidase
  • Amplex Red reagent reacts with H 2 O 2 in a stoichiometric ratio of 1:1 to form a strong fluorescent product for fluorescence quantitative detection.
  • test compound was dissolved in DMSO to a 10 mM stock solution, and subjected to a 3-fold gradient dilution with DMSO at a starting concentration of 10 mM at 10 concentration points.
  • a mixed solution of a final concentration of 2 ng/ ⁇ l ATX, 2 U/ml HRP and 0.2 U/ml choline oxidase was prepared using a reaction buffer solution. 20 ⁇ l of the above mixed solution 1 was added to each well of the experimental plate, and the diluted DMSO compound was transferred to the experimental plate using Echo 550 at 10 nl/well.
  • a mixed solution 2 of a final concentration of 60 mM LPC and 400 uM Amplex Red was prepared in the reaction buffer solution, and 20 ul of the mixed solution 2 was added to each well of the test plate. After the sample was loaded, the plate was shaken on the shock plate for 30 s and incubated at room temperature for 30 min. The excitation light was read at 530 nm with Envision to emit a fluorescent signal of 590 nm. The inhibition rate of the compound on the enzyme reaction was calculated based on the fluorescence ratio, and the IC 50 value of the compound was calculated by software analysis, as shown in Table 2.
  • the compound of the present invention has a good ATX inhibitory activity, thereby inhibiting the hydrolysis of LPC to LPA.
  • LPC18:2 (using LPA17:0 as internal standard) was detected by LC/MS/MS quantitative analysis using LPC in plasma as the substrate. At the concentration of different test compound, the remaining activity percentage was determined by LPA18. The ratio of the amount of 2: produced to the amount of production in the absence of the test compound was calculated, and the IC 50 value was calculated.
  • the blank plasma was mixed from at least 6 individuals, and the test compound was diluted 3 times from the stock solution with a dilution solution to prepare 8 series working solutions (including zero point).
  • 10 ⁇ L of the melted blank plasma sample was taken and directly subjected to protein precipitation by adding an internal standard (LPA17:0) in ice methanol solution as a system control sample.
  • an internal standard LPA17:0
  • ice methanol solution Take 2 ⁇ L of serial concentration of working solution, add 198 ⁇ L of human blank plasma, incubate at 0-10 ⁇ M, place the sample in a 37 ° C incubator containing 5% CO 2 and incubate for 2 hours.
  • Example number IC 50 ( ⁇ M) Example number IC 50 ( ⁇ M) Example 9 0.147 Example 15 0.068 Example 21 0.164 Example 56 0.366 Example 59 0.147 Example 60 0.619 Example 62 0.224
  • the compound of the present invention is capable of inhibiting ATX in human plasma, thereby inhibiting hydrolysis of LPC into LPA.
  • Example 66 Prevention of a compound of the present invention in a bleomycin-induced unilateral pulmonary fibrosis model in SD rats sexual therapy efficacy test
  • BLM-induced rat IPF model After 3-7 days of adaptive feeding in the SPF barrier, animals were randomly divided into groups to establish a model of left lung pulmonary fibrosis in SD rats: rat tracheal injection of bleomycin (3 mg/kg) replicated the pulmonary fibrosis model model for 2 weeks. Oral administration was started on the day of modeling (the first day of the test on the same day), and the positive drug was administered twice a day, and the compound of the present invention was administered once a day. Continuous administration for 14 days. Animal weight was measured two days during the experiment and animal mortality was monitored during the test period.
  • test results show that the compound of the present invention can effectively inhibit pulmonary fibrosis in SD rats, and has a good preventive and therapeutic effect on pulmonary fibrosis diseases.
  • An appropriate amount of the compound of the present invention is accurately weighed, an appropriate amount of a solvent is added, vortexed, and then ultrasonicated to a clear solution, and filtered to prepare an intravenous drug.
  • the intravenous and intragastric administration preparations were all sampled for analysis of the administration solution.
  • the rats were fasted overnight (12 h or more), and they were free to drink water during the experiment.
  • the theoretical dosing volume of each rat was calculated.
  • the preparation for administration was ready for use on the day of the experiment, and the preparation and administration interval was not more than 2 hours. SD rats can resume eating after 4 hours of administration, and they can drink water freely during the experiment.
  • the SD rats were subjected to jugular vein blood sampling. 0.2 to 0.4 mL of whole blood was collected from the jugular vein at a predetermined time point, and placed in an anticoagulation tube containing EDTA-K2 and mixed thoroughly several times. The collected blood samples were centrifuged for 5 minutes at 4 ° C and 4000 g to take plasma. Plasma samples were stored in a -75 ⁇ 15 ° C refrigerator until analysis.
  • test results show that the compound of the invention has long half-life in vivo, low toxicity, good clearance rate, high bioavailability and excellent pharmacokinetic properties.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Rheumatology (AREA)
  • Cardiology (AREA)
  • Pain & Pain Management (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Transplantation (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Fait l'objet de la présente invention un composé de formule I à activité inhibitrice d'ATX ainsi que son application dans la préparation d'un médicament pour le traitement ou la prévention de maladies associées à ATX.
PCT/CN2018/099622 2017-08-09 2018-08-09 Inhibiteur d'atx, son procédé de préparation et son utilisation WO2019029620A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710676599 2017-08-09
CN201710676599.4 2017-08-09

Publications (1)

Publication Number Publication Date
WO2019029620A1 true WO2019029620A1 (fr) 2019-02-14

Family

ID=65270903

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/099622 WO2019029620A1 (fr) 2017-08-09 2018-08-09 Inhibiteur d'atx, son procédé de préparation et son utilisation

Country Status (2)

Country Link
CN (1) CN109384803B (fr)
WO (1) WO2019029620A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020244539A1 (fr) * 2019-06-04 2020-12-10 江苏恒瑞医药股份有限公司 Dérivé de pyridone, son procédé de préparation et son application pharmaceutique
EP3805234A4 (fr) * 2018-05-24 2022-03-09 Guangzhou Henovcom Bioscience Co., Ltd. Composé hétérocyclique aromatique, composition pharmaceutique et utilisation associées
CN114507244A (zh) * 2020-11-16 2022-05-17 广州市恒诺康医药科技有限公司 咪唑并噻唑类化合物、其药物组合物及其用途
US11970493B2 (en) 2020-10-06 2024-04-30 Ildong Pharmaceutical Co., Ltd. Autotaxin inhibitor compounds

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021088957A1 (fr) * 2019-11-07 2021-05-14 广州市恒诺康医药科技有限公司 Composé hétérocyclique aromatique, composition pharmaceutique et son application
CN111187261B (zh) * 2020-01-15 2021-10-26 沈阳药科大学 基于吲哚母核的atx抑制剂及其制备方法和应用
CN113493453B (zh) * 2020-04-07 2023-06-16 江苏恒瑞医药股份有限公司 稠合芳香环类衍生物、其制备方法及其在医药上的应用
JP2023533294A (ja) * 2020-07-09 2023-08-02 スージョウ アーク バイオファーマシューティカル カンパニー リミテッド Ａｔｘ阻害剤及びその製造方法並びに使用
CN118317958A (zh) * 2021-11-25 2024-07-09 上海济煜医药科技有限公司 三并环衍生物及其制备方法和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105143221A (zh) * 2013-03-14 2015-12-09 加拉帕戈斯股份有限公司 用于治疗炎性障碍的化合物及其药物组合物
CN105339370A (zh) * 2013-06-19 2016-02-17 加拉帕戈斯股份有限公司 用于治疗炎症性疾病的新化合物和及其药物组合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105143221A (zh) * 2013-03-14 2015-12-09 加拉帕戈斯股份有限公司 用于治疗炎性障碍的化合物及其药物组合物
CN105339370A (zh) * 2013-06-19 2016-02-17 加拉帕戈斯股份有限公司 用于治疗炎症性疾病的新化合物和及其药物组合物

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3805234A4 (fr) * 2018-05-24 2022-03-09 Guangzhou Henovcom Bioscience Co., Ltd. Composé hétérocyclique aromatique, composition pharmaceutique et utilisation associées
WO2020244539A1 (fr) * 2019-06-04 2020-12-10 江苏恒瑞医药股份有限公司 Dérivé de pyridone, son procédé de préparation et son application pharmaceutique
CN113874354A (zh) * 2019-06-04 2021-12-31 江苏恒瑞医药股份有限公司 吡啶酮类衍生物、其制备方法及其在医药上的应用
CN113874354B (zh) * 2019-06-04 2024-02-20 江苏恒瑞医药股份有限公司 吡啶酮类衍生物、其制备方法及其在医药上的应用
US11970493B2 (en) 2020-10-06 2024-04-30 Ildong Pharmaceutical Co., Ltd. Autotaxin inhibitor compounds
CN114507244A (zh) * 2020-11-16 2022-05-17 广州市恒诺康医药科技有限公司 咪唑并噻唑类化合物、其药物组合物及其用途
CN114507244B (zh) * 2020-11-16 2023-10-27 广州市恒诺康医药科技有限公司 咪唑并噻唑类化合物、其药物组合物及其用途

Also Published As

Publication number Publication date
CN109384803A (zh) 2019-02-26
CN109384803B (zh) 2021-08-31

Similar Documents

Publication Publication Date Title
WO2019029620A1 (fr) Inhibiteur d'atx, son procédé de préparation et son utilisation
JP7505023B2 (ja) 疾患の治療用のホスホイノシチド３－キナーゼ（ｐｉ３ｋ）のアロステリッククロメノン阻害剤
CN112638917B (zh) 作为激酶抑制剂的杂环化合物、包括该杂环化合物的组合物、及其使用方法
JP2022527607A (ja) Ｇｌｐ－１ｒアゴニスト及びその使用
RU2632870C2 (ru) Трициклические гетероциклические соединения и ингибиторы jak
US8741910B2 (en) Soluble guanylate cyclase activators
WO2020259679A1 (fr) Dérivé hétérocyclique azoté à cinq chaînons de pyrimidine, son procédé de préparation et son utilisation pharmaceutique
ES2649144T3 (es) Compuestos heteroaromáticos y su uso como ligandos de dopamina D1
TWI829676B (zh) 噁二唑暫時受體電位通道抑制劑
US11319303B2 (en) Compound used as autophagy regulator, and preparation method therefor and uses thereof
JP2020525525A (ja) Ｒｈｏ−関連プロテインキナーゼ阻害剤、ｒｈｏ−関連プロテインキナーゼ阻害剤を含む医薬組成物、当該医薬組成物の調製方法及び使用
WO2021190417A1 (fr) Nouvel inhibiteur aminopyrimidine d'egfr
WO2017198149A1 (fr) Inhibiteur de fgfr4, procédé pour sa préparation et applications correspondantes
JP2003533524A (ja) ホスホジエステラーゼ阻害剤として有効な置換ピロロピリジノン誘導体
US20120165331A1 (en) Di/tri-aza-spiro-C9-C11alkanes
CN109071548A (zh) 可用于治疗尤其是癌症的吡咯并咪唑衍生物或其类似物
JP2019513792A (ja) テトラヒドロイソキノリン誘導体
WO2015058661A1 (fr) Inhibiteur de bcr-abl kinase et application correspondante
EP4358954A1 (fr) Inhibiteurs de cdk2 et leurs procédés d'utilisation
WO2021032004A9 (fr) Composé d'azahétéroaryle et son utilisation
CN113754635B (zh) 稠环类化合物及其制备方法和用途
JP6847942B2 (ja) 二環式複素環式誘導体
WO2023020209A1 (fr) Composé d'urée contenant une substitution du cycle 2-hétéroaromatique, son procédé de préparation et son utilisation
CN118184658A (zh) Usp1抑制剂
WO2023169170A1 (fr) Composé hétérocyclique utilisé en tant qu'inhibiteur de shp2, composition comprenant un composé hétérocyclique, et procédé l'utilisant

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18843432

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18843432

Country of ref document: EP

Kind code of ref document: A1