WO2019029620A1 - Atx抑制剂及其制备方法和应用 - Google Patents

Atx抑制剂及其制备方法和应用 Download PDF

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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
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substituted
group
alkyl
unsubstituted
methyl
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French (fr)
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张健存
邹晴安
林财
陈延维
张礼军
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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
    • 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.

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Abstract

提供了具有ATX抑制活性的式I化合物以及在制备治疗与ATX相关疾病的药物中的用途。

Description

ATX抑制剂及其制备方法和应用
本申请要求于2017年8月9日递交的中国专利申请CN201710676599.4的优先权，并在此将其全部内容以引用方式并入本文。
技术领域
本发明涉及药物化学技术领域，特别是涉及一种ATX抑制剂及其制备方法和应用。
背景技术
Autotaxin(ATX)于1992年首次从A2058黑素瘤细胞中被分离出来，被称作“自分泌动力因子”，是一个分泌型糖蛋白。ATX具有磷酸二酯酶(PDE)的活性，是胞外焦磷酸酶/磷酸二酯酶(ENPP)家族的一员。ATX还具有溶血磷脂酶D(lysoPLD)活性，能够以溶血磷脂酰胆碱(lysophosphatidylcholine,LPC)为底物催化生成溶血磷脂酸(lysophosphatidic acid,LPA)。LPA不但是磷脂合成的前体，而且能通过各种信号传导途径引起广泛的生物学效应。LPA一旦生成，能够通过六个细胞表面特异的受体蛋白(LPA1-6)，即G蛋白偶联受体(GPCR)介导发挥作用。根据内皮细胞分化基因(Edg)和心室区基因命名，LPA1-6分别为LPA1/Edg-2/VZG-1、LPA2/Edg-4、LPA3/Edg-7、LPA4/p2y9/GPR23、LPA5/GPR92和LPA6/p2Y5，每个受体均通过Gα蛋白(Gs Gi、Gq和G12/13)介导，进而引发一系列的细胞信号级联作用。其中，主要的通路包括磷脂酰肌醇二磷酸酯(PIP2)的水解，进而引发细胞内的钙离子释放和蛋白激酶C(PKC)激活；抑制腺苷酸环化酶(cAMP)信号通路；激活Ras-MAPK、MERK、ERK通路，调控细胞增殖活动；激活磷酸肌醇PI3K-AKT通路，调控细胞存活和凋亡活动；以及，激活Rho通路调控细胞骨架重塑、形状改变和细胞迁移活动。在很多病理条件下，尤其是在肿瘤细胞中，ATX处于高表达状态，导致LPA浓度过高。在肿瘤细胞中，LPA浓度能升高至10μmol/L，远高于100nmol/L的正常水平。过多的LPA增加血管内皮生长因子(VEGF)的生成，促进血管生成；降低抑癌因子p53的表达，增加肿瘤细胞的存活和转移。ATX-LPA信号通路涉及到很多生理和病理过程，从而与很多严重疾病有着重要联系，主要包括心血管疾病、自身免疫性疾病、癌症、纤维化疾病、炎症、神经***疾病、疼痛等。LPA在肿瘤生成中具有多重功能，促进肿瘤细胞的生长、血管生成、转移和出现耐药性。所以，降低LPA的浓度水平，有利于肿瘤的治疗与控制。相对应的，抑制ATX的活性，阻断LPA的生成途径，是治疗多种严重疾病的研究热点。
随着对ATX的研究不断深入，促使很多以其为靶点的新型抑制剂的出现，其中，研究最集中的是癌症和纤维化疾病。纤维化疾病主要是特发性肺纤维化(IPF)和肝纤维化。IPF是一种表现为弥漫性肺泡炎和肺泡结构紊乱，并导致肺间质性纤维化进行性发展的一种致死性疾病，预后较差，平均生存时间为2到5年。IPF可能是与ATX-LPA通路联系最紧密的疾病，因为在肺部组织中，ATX的表达最高集中在支气管上皮细胞和肺泡巨噬细胞，而这些细胞可以并置成纤维细胞灶。
目前，GLPG-1690，作为Autotaxin抑制剂，已经进入临床II期试验阶段，用于特发性肺纤维化的治疗；血清中ATX浓度与肝纤维化和肝硬度值紧密相关，是预测肝硬化最好的指标之一。此外，ATX在许多肿瘤组织中高度表达，包括黑色素瘤、非小细胞肺癌、肝癌、肾癌、乳腺癌、甲状腺癌、卵巢癌和霍奇金淋巴瘤。LPA/ATX在肿瘤细胞生长过程中，能促使细胞侵袭和转移。所以，能够阻断ATX-LPA信号传导通路的ATX抑制剂为临床治疗癌症和纤维化疾病提供了一条新途径。
与传统激酶抑制剂相比，ATX抑制剂抑制ATX活性的同时影响多条与细胞增殖、生长和凋亡等相关的信号通路，对一些耐药型肿瘤产生较好的抑制效果，而且与多个器官的纤维化发生紧密相关，是研究与开发新型纤维化疾病药物的重要靶标。
发明内容
基于此，本发明的目的在于提供一种ATX抑制剂，其能够与ATX结合并抑制ATX的活性。
为实现上述目的，本发明采取以下技术方案：
一方面，本发明提供一种式I所示的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药：
Figure PCTCN2018099622-appb-000001
其中，在式I中：
Ar 1为取代或未取代的苯基，取代或未取代的萘基，或取代或未取代的5-10个原子组成的单环或双环杂芳基；当Ar 1被取代时，可被选自卤素、C 1-C 4烷基、C 1-C 4烷氧基、C 2-C 4烯基、氰基、-CF 3、-C(C＝O)CH 3、-C(C＝O)CF 3、-C(C＝O)OCH 3、-C(C＝O)NH 2和-NH(C＝O)CH 3中的一个或多个取代基在任意位置取代；
Ar 2为取代或未取代的五元或六元杂芳基；当Ar 2被取代时，可被选自卤素、氰基、C 1-C 4烷基、-C(C＝O)NH 2和-NH(C＝O)CH 3中的一个或多个取代基在任意位置取代；
R 1为H，C 1-C 4烷基或C 3-C 6环烷基；
R 2为H，取代或未取代的C 1-C 4烷基，取代或未取代的C 3-C 7环烷基，或取代或未取代的3-7个原子组成的杂环烷基；
R 3为H，卤素，氰基，C 1-C 3烷基，C 1-C 4烷氧基，C 2-C 4烯基，或C 2-C 4炔基；
A和M各自独立地为N或CR 6；其中R 6为氢，卤素或C 1-C 3烷基；
Cy为取代或未取代的7-11个原子组成的螺杂环、取代或未取代6-11个原子组成的稠合杂环，或取代或未取代7-11个原子组成的桥杂环；当Cy被取代时，可被1-2个选自氧，卤素，氰基，甲基，甲氧基和三氟甲基的基团取代。
R 4为氢，卤素或C 1-C 3烷基；
X为-O-，-C(＝O)-，-C(＝O)O-，-OC(＝O)-，-NR 7-，-SO 2-，-NR 7SO 2-，-SO 2NR 7-，-C(＝O)NR 7-，或-NR 7C(＝O)-；其中，R 7为氢或C 1-C 4烷基；
L为取代或未取代的C 1-C 6烷基，取代或未取代的C 3-C 7环烷基，取代或未取代的4-7个原子组成的杂环烷基，取代或未取代的C 5-C 6环烷基，取代或未取代的5-6个原子组成的杂环烷基；当L被取代时，可被选自卤素、C 1-C 4烷基、三氟甲基、氰基、羟基、氨基和C 1-C 4烷氧基的基团取代；
R 5为氢，取代或未取代的C 1-C 4烷基，羟基，氰基，或-N(R 8) 2；其中，R 8为氢或C 1-C 4烷基；
a为0、1、2、3、4或5；
b为0或1；
c为0或1；
其中，当a，b或c为0时，相应基团为化学键，例如a为0时，C(R 4) 2为化学键，b为0时，X为化学键，c为0时，L为化学键。
在一些实施方案中，本发明的式I的化合物为式II(a)或II(b)的化合物：
Figure PCTCN2018099622-appb-000002
Figure PCTCN2018099622-appb-000003
上述式II(a)或II(b)中，R 9为卤素，C 1-C 4烷基，C 1-C 4烷氧基，氰基或三氟甲基；
R 10为氢，卤素，氰基或三氟甲基；
R 11为氢，卤素或氰基；
W为S或O；
M为N或CR 6，其中R 6为氢；
R 1、R 2、R 3、R 4、R 5、Cy、X、L、a、b、c如式I所定义。
在一些实施方案中，本发明的式I或式II(a)或II(b)的化合物中：
R 1为C 1-C 4烷基，优选地为C 1-C 2烷基，更优选地为甲基；
在一些实施方案中，本发明的式I或式II(a)或II(b)的化合物中：
R 2为取代或未取代的C 1-C 4烷基，优选地为未取代的C 1-C 4烷基，更优选地为乙基；
在一些实施方案中，本发明的式I或式II(a)或II(b)的化合物中：
R 3为H，卤素，氰基或C 1-C 3烷基，优选地为H，卤素或C 1-C 3烷基，更优选地为H，氟或甲基；
在另一些实施方案中，本发明的式I或式II(a)或II(b)的化合物中：
A和M各自独立地为N或CR 6，其中R 6为氢；优选地，A和M均为CR 6，其中R 6为氢；更优选地，A为CR 6，其中R 6为氢，M为N。
在一些实施方案中，本发明的式I或式II(a)或II(b)的化合物中：
R 4为氢或C 1-C 3烷基；优选地，R 4为氢；
在一些实施方案中，本发明的式I或式II(a)或II(b)的化合物中：
X为-C(＝O)-，-C(＝O)NR 7-，或-SO 2-；其中，R 7为甲基；
在一些实施方案中，本发明的式I或式II(a)或II(b)的化合物中：
L为取代或未取代的C 1-C 4烷基，取代或未取代的4-5个原子组成的杂环烷基，当L被取代时，可被选自卤素或羟基的基团取代；优选地L为未取代或被羟基取代的
Figure PCTCN2018099622-appb-000004
未取代或被卤素或羟基取代的C 1-C 4的烷基；
在一些实施方案中，本发明的式I或式II(a)或II(b)的化合物中：
R 5为氢，羟基，未取代的C 1-C 4烷基，或-N(R 8) 2，其中，R 8为氢或C 1-C 4烷基；
在一些实施方案中，本发明的式I或式II(a)或II(b)的化合物中：
a为0或1；
在一些实施方案中，本发明的式I或式II(a)或II(b)的化合物中：
b为1；
在一些实施方案中，本发明的式I或式II(a)或II(b)的化合物中：
c为0或1。
在一些实施方案中，本发明的式I或式II(a)或II(b)的化合物中：Cy选自以下基团：
Figure PCTCN2018099622-appb-000005
其中，d为0，1，2；
e为1，2，3；
f为0，1，2；
g为1，2，3；且在螺杂环中，d、e、g和f之和不小于4并不大于8；在稠合杂环中，d、e、g和f之和不小于2并不大于7；在桥杂环中，d、e、g和f之和不小于2并不大于6。
在另一些实施方案中，本发明的式I或式II(a)或II(b)的化合物中，Cy选自以下基团：
Figure PCTCN2018099622-appb-000006
Figure PCTCN2018099622-appb-000007
在一些实施方案中，本发明的式II(a)的化合物中，
R 9为卤素，R 10为氢，R 11为氰基，W为S，R 1为C 1-C 4烷基(例如甲基)，R 2为C 1-C 4烷基(例如乙基)，R 3为氢或卤素(例如F)或C 1-C 3烷基(例如甲基)，M为N。
Cy选自以下基团：
Figure PCTCN2018099622-appb-000008
R 4为氢，
X为-C(＝O)-，-C(＝O)NR 7-，或-SO 2-；其中，R 7为甲基；
L为取代或未取代的C 1-C 4烷基，取代或未取代的4-5个原子组成的杂环烷基，当L被取代时，可被选自卤素或羟基的基团取代；优选地L为未取代或被羟基取代的
Figure PCTCN2018099622-appb-000009
未取代或被卤素或羟基取代的C 1-C 4的烷基；
R 5为氢，羟基，未取代的C 1-C 4烷基，或-N(R 8) 2，其中，R 8为氢或C 1-C 4烷基；
a为0或1；
b为1；
c为0或1。
在一些实施方案中，本发明的式II(b)的化合物中，
R 9为卤素，R 10为氢，R 11为氰基，W为S，R 1为C 1-C 4烷基(例如甲基)，R 2为C 1-C 4烷基(例如乙基)，R 3为氢或卤素(例如F)或C 1-C 3烷基(例如甲基)，Cy选自以下基团：
Figure PCTCN2018099622-appb-000010
R 4为氢，
X为-C(＝O)-，-C(＝O)NR 7-，或-SO 2-；其中，R 7为甲基；
L为取代或未取代的C 1-C 4烷基，取代或未取代的4-5个原子组成的杂环烷基，当L被取代时，可被选自卤素或羟基的基团取代；优选地L为未取代或被羟基取代的
Figure PCTCN2018099622-appb-000011
未取代或被卤素或羟基取代的C 1-C 4的烷基；
R 5为氢，羟基，未取代的C 1-C 4烷基，或-N(R 8) 2，其中，R 8为氢或C 1-C 4烷基；
a为0或1；
b为1；
c为0或1。
在一些实施方案中，本发明的式I、式II(a)或式II(b)的化合物为选自式III至式XXI的化合物：
Figure PCTCN2018099622-appb-000012
Figure PCTCN2018099622-appb-000013
Figure PCTCN2018099622-appb-000014
Figure PCTCN2018099622-appb-000015
Figure PCTCN2018099622-appb-000016
Figure PCTCN2018099622-appb-000017
其中，R 9为卤素，C 1-C 4烷基或三氟甲基；
R 10为氢，卤素或氰基；
R 11为氢或氰基；
R 1为C 1-C 4烷基；
R 2为C 1-C 4烷基；
R 3为氢，卤素或C 1-C 3烷基；
X为-C(＝O)-，-C(＝O)NR 7-，或-SO 2-；其中，R 7为氢或C 1-C 4烷基；
L为取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 7环烷基、取代或未取代的4-7个原子组成的杂环烷基，取代或未取代的C 5-C 6环烷基、取代或未取代的5-6个原子组成的杂环烷基；所述L被取代时，可被选自卤素，甲基和三氟甲基的取代基取代；
R 5为氢，取代或未取代的C 1-C 4烷基，羟基，氰基，或-N(R 8) 2；其中，R 8为氢或C 1-C 4烷基；
a为0、1、2或3；
b为0或1；
c为0或1。
优选地，在一些实施方案中，本发明的式III至式XXI的化合物中，
R 9为卤素；更优选地为F；
R 10为氢；
R 11为氰基；
R 1为甲基；
R 2为乙基；
R 3为F或甲基；
X为-C(＝O)-，-C(＝O)NR 7-，或-SO 2-；其中，R 7为甲基；
L为取代或未取代的C 1-C 4烷基，取代或未取代的4-5个原子组成的杂环烷基，当L被取代时，可被选自卤素和羟基的基团取代；更优选地L为未取代或被羟基取代的
Figure PCTCN2018099622-appb-000018
未取代或被卤素或羟基取代的C 1-C 4的烷基；
R 5为氢，羟基，未取代的C 1-C 4烷基，或-N(R 8) 2，其中，R 8为氢或C 1-C 4烷基；；a为0或1；
b为1；
c为0或1。
在一些实施方案中，本发明的式I所示的化合物为选自下列的化合物：
Figure PCTCN2018099622-appb-000019
Figure PCTCN2018099622-appb-000020
Figure PCTCN2018099622-appb-000021
Figure PCTCN2018099622-appb-000022
另一方面，本发明还提供了本发明的化合物的制备方法，包括以下合成路线：
Figure PCTCN2018099622-appb-000023
步骤1：中间体I与相应的醛和1,1,3,3-四甲基丁基异腈在氯化镁催化以及加热的条件下反应生成中间体II；
步骤2：中间体II在甲酸中经加热脱去保护基可得到中间体III；
步骤3：中间体III与相应卤代烃经亲核取代反应可得到中间体IV；步骤4：中间体IV经水解反应可得中间体V；
步骤5：中间体V与中间体VI在碱性条件下经加热发生亲核反应或金属催化的偶联反应得到中间体VII；
步骤6：中间体VII与中间体VIII经Buchward偶联反应得到中间体IX；
步骤7：中间体IX在酸性条件下脱去保护基得到中间体X；
步骤8：中间体X与中间体XI经亲核取代反应得到式I的化合物，
其中Ar 1、Ar 2、A、M、R 1、R 2、R 3、R 4、R 5、Cy、X、L、a、b、c如式I所定义，L 1为卤素。
再一方面，本发明还提供了本发明的化合物或其药学上可接受的盐、立体异构体、 溶剂化物或前药在制备用于预防或治疗具有ATX表达增加的病理学特征的疾病的药物中的用途。
在一些实施方案中，所述具有ATX表达增加的病理学特征的疾病包括：癌症，纤维化疾病、代谢疾病、骨髓增生异常综合征、心血管疾病、自身免疫性疾病、炎症、神经***疾病或疼痛；优选地，所述具有ATX表达增加的病理学特征的疾病为肺纤维化或肝纤维化。
又一方面，本发明还提供了一种药物组合物，所述药物组合物包含本发明的化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，以及药学上可以接受的辅料或载体。
再又一方面，本发明提供一种用于治疗和/或预防具有ATX表达增加的病理学特征的疾病的方法，所述方法包括给有此需要的受试者施用本发明的化合物或者其药学上可接受的盐、立体异构体、溶剂化物或前药或者本发明的药物组合物。
在一些实施方案中，所述具有ATX表达增加的病理学特征的疾病包括：癌症，纤维化疾病、代谢疾病、骨髓增生异常综合征、心血管疾病、自身免疫性疾病、炎症、神经***疾病或疼痛；优选地，所述具有ATX表达增加的病理学特征的疾病为肺纤维化或肝纤维化。
除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。
“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
“非对映异构体”是指有两个或多个手性中性并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994。
许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时，使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号，其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体，这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或过程中没有立体选择性或立体特异性时，可出现这种情况。
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对应异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。
术语“取代”是指用指定取代基的基团置换特定结构中的氢基。本发明中烷基或环烷基上的取代，如没有指明发生在特定的碳原子上，则表示可以发生在任何取代基个数尚未达到饱和的碳原子上。多个取代基从同一系列中选择时，它们可以相同，也可以不同。本发明中苯环、芳杂环或者杂环上的取代，如没有指明发生在特定的原子上，则表示可以发生在任何未被除氢与外的其它原子取代的位置。多个取代基从同一系列中选择时，它们可以相同，也可以不同。本发明所述的取代基包括，但不限于卤素、C 1-C 4烷基、C 1-C 4烷氧基、C 2-C 4烯基、氰基、-CF 3、-C(C＝O)CH 3、-C(C＝O)CF 3、-C(C＝O)OCH 3、-C(C＝O)NH 2和-NH(C＝O)CH 3、-O-，-C(＝O)-，-C(＝O)O-，-OC(＝O)-，-NR 7-，-SO 2-，-NR 7SO 2-，-SO 2NR 7-，-C(＝O)NR 7-，或-NR 7C(＝O)-，其中R 7为本文所定义。
术语“未取代的”，表示指定基团不带有取代基。
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C1-6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。
在本发明的各部分，描述了连接取代基。当所述结构清楚地需要连接基团时，针对所述基团所列举的马库什变量应理解为连接基团。例如，如果所述结构需要连接基团并且针对所述变量的马库什基团定义列举了“烷基”或“芳基”，则应理解，所述“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp 2双键，其包括“顺”和“反”的定位，或者“E”和“Z”的定位。在一实施方案中，烯基基团包含2-8个碳原子；在另一实施方案中，烯基基团包含2-6个碳原子；在又一实施方案中，烯基基团包含2-4个碳原子。烯基基团的实例包括，但并不限于，乙烯基(-CH＝CH 2)、烯丙基(-CH 2CH＝CH 2)等等。
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp三键。在一实施方案中，炔基基团包含2-8个碳原子；在另一实施方案中，炔基基团包含2-6个碳原子；在又一实施方案中，炔基基团包含2-4个碳原子。炔基基团的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH 2C≡CH)、1-丙炔基(-C≡C-CH 3)等等。
本文所用术语“烷基”是指饱和链状烷基，“链状烷基”是指直链或支链的烷基，如C 1-C 4烷基是指具有1至4个碳原子的饱和直链或支链的烷基，其中直链烷基的示例包括但不限于乙基，正丙基等，支链烷基的示例包括但不限于异丙基，叔丁基等；“环烷基”是指具有环状结构的烷基，如C 3-C 4环烷基指具有3至4个碳原子的具有环状结构的烷基，示例包括但不限于环丙基，环丁基、甲基取代环丙基等。“烯基”是指不饱和链状烷基，如C 2～C 4烯基表示碳原子数为2个到4个的具有一个双键的直链或支链烯基，示例包括但不限于乙烯基、丙烯基、丁烯基、异丁烯基等。
术语“烷氧基”表示末端含有一个氧原子的直链或支链烷基，示例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基等。
术语“环烷基”是指具有环状结构的烷基，如C 3-C 7环状烷基指具有3至7个碳原子的饱和或不饱和的具有环状结构的烷基，其中饱和环状烷基的示例包括但不限于环丙基，环戊基、环己基等，不饱和环状烷基的示例包括但不限于环戊烯等。
术语“杂环烷基”代表由碳原子以及选自氮、氧、硫等杂原子组成的饱和或部分不饱和(包含1或者2个双键)的非芳香环状基团。杂环烷基的示例包括但不限于：吡咯烷-2-基、哌啶-4-基、哌嗪-1-基、吗啉-4-基等。
术语“杂芳基”是指至少有一个环上的碳原子被选自氮、氧或硫的杂原子置换所形成的芳香环基团，可为5-7元单环杂芳基或7-12元双环杂芳基。示例包括但不限于吡啶基、嘧啶基、哒嗪基、吡嗪基、呋喃基、噻吩基、噻唑基、噁唑基、异噁唑基、异噻唑基、咪唑基、吡唑基、三氮唑基、四氮唑基等。
术语“螺杂环”是指至少含有一个选自氮、氧或硫的杂原子的两个环共用一个碳原子而形成的环状体系。螺杂环的示例包括但不限于：
Figure PCTCN2018099622-appb-000024
Figure PCTCN2018099622-appb-000025
等。
术语“稠合杂环”是指至少含有一个选自氮、氧或硫的杂原子的两个环共用两个碳原子而形成的环状体系。稠合杂环的示例包括但不限于：
Figure PCTCN2018099622-appb-000026
Figure PCTCN2018099622-appb-000027
等。
术语“桥杂环”是指至少含有一个选自氮、氧或硫的杂原子的两个环共用三个或三个以上碳原子而形成的环状体系。示例包括但不限于：
Figure PCTCN2018099622-appb-000028
Figure PCTCN2018099622-appb-000029
等。
术语“磺酰基”，无论是单独使用还是和其他的术语如“烷基磺酰基”连用，分别表示二价的基团-SO 2-。术语“烷基磺酰基”是指烷基取代的磺酰基基团，形成烷基磺酰基(-SO 2烷基，如-SO 2CH 3)。
术语“羧基”，无论是单独使用还是和其他术语连用，如“羧烷基”，表示-CO 2H。
术语“羰基”，无论是单独使用还是和其他术语连用，如“氨基羰基”或“酰氧基”，表示-(C＝O)-。
术语“羧基烷氧基”表示烷氧基基团被一个或多个羧基基团所取代，其中烷氧基和羧基基团具有如本发明所述的定义，这样的实例包括，但并不限于羧基甲氧基，羧基乙氧基等。
术语“烷硫基”包括C 1-10直链或支链的烷基连接到二价的硫原子上。其中一些实施方案是，烷硫基是较低级的C 1-3烷硫基，这样的实例包括，但并不限于甲硫基(CH 3S-)。
术语“卤代烷硫基”包括C 1-10的卤代烷基连接到二价硫原子上。其中一些实施方案是，卤代烷硫基是较低级的C 1-3卤代烷硫基，这样的实例包括，但并不限于三氟甲硫基。
在本发明中所使用的术语“不饱和的”表示基团中含有一个或多个不饱和度。
术语“杂原子”是指O、S、N、P和Si，包括N、S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3,4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR)。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
如本发明所描述的，环体系中有两个连接点与分子其余部分相连，如式(a1)或(a2)所示，表示既可以是E端也可以是E’端与分子其余部分相连，即两端的连接方式可以互换。
Figure PCTCN2018099622-appb-000030
本发明所使用的术语“前药”，代表一个化合物在体内转化为式I-XXI所示的化合物。 这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。
术语“溶剂化物”在文中用来描述包含本发明化合物和化学计量的一种或多种药学上可接受的溶剂分子(如乙醇)的分子络合物。当所述溶剂是水时采用术语“水合物”。
本发明包括式I-XXI化合物的游离形式，也包括其药学上可接受的盐及立体异构体及溶剂化物和前药。可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常，通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的，通过和适当的无机或有机碱反应形成酸性化合物的盐。
因此，本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如，常规的无毒盐包括自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等制备的盐，也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2－乙酰氧基－苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
如果本发明化合物为酸性的，则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐。由无机碱制备的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。由药学上可接受的有机无毒碱制备的盐，所述药学上可接受的有机无毒碱包括伯胺、仲胺、叔胺和取代的胺等，其中取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'－二苄基乙二胺、二乙胺、2－二乙基氨基乙醇、2－二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N－乙基吗啉、N－乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪,哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
如本文中所用的，术语“药物组合物”涉及适用于给患者(优选人患者)施用的组合物。本发明的特别优选的药物组合物包含一种或多种优选地治疗有效量的本发明的化合物。优选地，药学组合物包含一种或多种(药学上可接受的)载体、稳定剂、赋形剂、稀释剂、增溶剂、表面活性剂、乳化剂、防腐剂和/或佐剂的合适制剂。组合物可接受的组成成分优选在所用剂量和浓度下对接受体无毒性。本发明的药物组合物包括但不限于液体、冷冻和冻干组合物。
某些实施方案提供药物组合物，其包含本发明的化合物和一种或多种赋形剂，比如在本章节和本文中其它地方示例性描述的赋形剂。在此方面，本发明中可使用赋形剂达 成多种目的，比如调节制剂的物理、化学或生物学性质，比如调节粘度，和/或用于本发明的方法中以改进有效性和/或使此类制剂和方法针对由于例如应力引起的降解和损坏稳定化，此类应力在制造、装运、储存、使用前准备、施用和随后过程期间发生。
在某些实施方案中，药物组合物可含有用于修饰、维持或保持例如组合物的pH、容积摩尔渗透浓度(osmolarity)、粘度、澄清度、颜色、等渗性、气味、无菌性、稳定性、溶解或释放速率、吸收或渗透的制剂材料。
药学上可以接受的辅料或载体可以为赋形剂或缓释剂等。本发明的药物组合物可以是多种形式，如片剂、胶囊剂、散剂、糖浆剂、溶液剂、混悬剂和气雾剂等，并可以存在于适宜的固体或液体载体或稀释液中。本发明的药物组合物也可以储存在适宜的注射或滴注的消毒器具中。此外，本发明的药物组合物中还可包含气味剂、香味剂等。
本文中所描述的化合物在有此需要的患者中治疗、改善和/或预防如本文中所描述的病理性医学病情中是有用的。术语“治疗”既是指治疗性治疗，也是指预防或防止性措施。治疗包括将制剂应用于或施用于来自患有疾病/障碍、具有疾病/障碍的症状或具有对疾病/障碍的倾向的患者的机体、分离的组织或细胞，其目的是治愈、治疗、缓解、减轻、改变、补救、改善、增进或影响疾病、该疾病的症状或罹患该疾病的倾向。
如本文中所用的术语“改善”是指通过向有此需要的受试者施用根据本发明的化合物或组合物，具有如本文中所指定的肿瘤或癌症类型之一的患者的疾病状态的任何增进。这种改善也可以被看作是患者的(转移性)肿瘤或癌症进展的减慢或停止。如本文中所用的术语“预防”意为通过向有此需要的受试者施用根据本发明的化合物或组合物，避免具有如本文中所指定的(转移性)肿瘤或癌症类型之一的患者的发生或再发生。
术语“疾病”是指能够从用本文中所描述的化合物或药物组合物的治疗中获益的任何病况。除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
本发明的化合物通常经设计以特别在某些生物利用度和持续性范围内用于特定施用途径和方法、特定施用剂量和施用频率、特定疾病的特定治疗。组合物的材料优选以施用位点可接受的浓度存在。
因此本发明的化合物和组合物可通过任何合适施用途径递送。在本发明的上下文中，施用途径包括但不限于：局部途径(比如表皮、吸入、鼻、眼、耳/听觉、***、粘膜)；肠内途径(比如口、胃肠、舌下、唇下、颊(buccal)、直肠)；和胃肠外途径 (比如静脉内、动脉内、骨内、肌肉内、脑内、脑室内、硬膜外、囊内、皮下、腹膜内、羊膜腔(extra-amniotic)、关节内、心脏内、皮肤内、病灶内、子宫内、膀胱内、玻璃体内、透皮、鼻内、穿粘膜、滑膜内、管腔内)。
具体实施方式
以下实施例中所用缩写释义如下：
Boc：            叔丁氧羰基
Pd 2(dba) 3：      三(二亚苄基丙酮)二钯
JohnPhos：       2-(二叔丁基膦)联苯
除在文献中已知的或在实验程序中例证的标准方法外，可采用如下实施例中的方法制备本发明化合物。结合下述的实施例，能够对本发明的化合物以及合成方法进行更好的理解。实施例中的所有参数及相关说明，除另加说明外，都是以质量为依据的。柱层析分离所用填料若未说明均为硅胶。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。以下实施例描述了可以用于制备本发明中所述的化合物的方法，所述的方法仅仅是为说明目的的说明性方案描述，并不构成对本发明所具有的范围的限制。
实施例1
2-{[2-乙基-8-甲基-6-(7-(甲磺酰基)-2,7-二氮杂螺[3.5]壬烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
按照以下路线进行制备：
Figure PCTCN2018099622-appb-000031
(1)2-氨基-4-(4-氟苯基)噻唑-5-甲腈的制备。
将3-(4-氟苯基)-3-氧代丙腈(2.0g，12.26mmol)溶于乙醇(25mL)中，70℃搅拌15分钟。待反应液冷至室温，滴加硫脲(1.87g，24.5mmol)和碘(3.0g，12.26mmol)的乙醇溶液(15mL)，加完后继续反应2小时。将反应液倒入1M Na2S2O3(20mL)中，搅拌15分钟后，再加入水(45mL)，过滤，滤饼经水洗涤，真空干燥得白色固体1.48g，收率：55％。
(2)2-氯-4-(4-氟苯基)噻唑-5-甲腈的制备。
将氯化铜(1.36g,10.1mmol)悬浮于乙腈(30mL)中，加入亚硝酸叔丁酯(1.61mL,13.5mmol)，室温搅拌15分钟后，再分批加入2-氨基-4-(4-氟苯基)噻唑-5-甲腈 (1.48g,6.75mmol)。过滤，旋干，柱层析纯化(石油醚：乙酸乙酯＝25:1)得淡黄色固体1.5g，收率：93％。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.14(m,2H),7.23(m,2H)。
(3)6-溴-2-乙基-8-甲基-N-(2,4,4-三甲基戊烷-2-基)咪唑并[1,2-a]吡啶-3-胺的制备。
将5-溴-3-甲基吡啶-2-胺(4.49g,24mmol)、丙醛(4.32mL,60mmol)、1,1,3,3-四甲基丁基异氰(5mL,28.8mmol)和氯化镁(115mg,1.2mmol)溶于正丁醇(50mL)中，加热回流反应3小时。待反应液冷至室温，旋干，柱层析纯化(石油醚：乙酸乙酯＝20:1)得黄色油状物8.5g，收率：96％。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.15(d,J＝1.6Hz,1H),6.97(m,1H),2.79(m,3H),2.58(s,3H),1.69(s,2H),1.36(t,J＝7.6Hz,3H),1.18(s,6H),1.12(s,9H)。
(4)N-(6-溴-2-乙基-8-甲基咪唑并[1,2-a]吡啶-3-基)甲酰胺的制备。
将6-溴-2-乙基-8-甲基-N-(2,4,4-三甲基戊烷-2-基)咪唑并[1,2-a]吡啶-3-胺(8.5g,23.1mmol)溶于甲酸(100mL)，回流反应3小时。待反应液冷却，旋干，加水，用饱和碳酸氢钠溶液调pH至8左右，再用乙酸乙酯萃取(100mLx3)，无水硫酸钠干燥，旋干，经石油醚打浆得淡黄色固体5.8g，收率：89％。
(5)6-溴-2-乙基-N,8-二甲基咪唑并[1,2-a]吡啶-3-胺的制备。
将N-(6-溴-2-乙基-8-甲基咪唑并[1,2-a]吡啶-3-基)甲酰胺(5.8g,20.6mmol)溶于四氢呋喃(100mL)，加入硼烷四氢呋喃溶液(35mL,35mmol)，50℃反应过夜。待反应液冷却，加入甲醇(15mL)淬灭反应，旋干，柱层析纯化(石油醚：乙酸乙酯＝3:1)得淡黄色固体4.0g，收率：72％。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.02(s,1H),6.97(s,1H),2.81(m,6H),2.57(s,3H),1.35(t,J＝7.6Hz,3H)。
(6)2-{[6-溴-2-乙基-8-甲基咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
将6-溴-2-乙基-N,8-二甲基咪唑并[1,2-a]吡啶-3-胺(2.0g,7.43mmol)溶于四氢呋喃(40mL)，氮气保护，冷至0℃，加入钠氢(0.9g,22.3mmol)，回流反应半小时。待反应液冷至室温，加入2-氯-4-(4-氟苯基)噻唑-5-甲腈(3.1g，12.99mmo)的四氢呋喃溶液(20mL)，继续回流反应过夜。将反应液冷至0℃，滴加水淬灭反应，旋干 溶剂，加水，用乙酸乙酯萃取(80mLx3)，有机层经饱和食盐水洗涤，无水硫酸钠干燥，旋干得棕黑色稠状物。加入甲基叔丁基醚(50mL)和石油醚(50mL)，超声，过滤，烘干得棕色固体2.75g，收率79％。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.17(m,2H),7.80(s,1H),7.22-7.18(m,3H),3.64(s,3H),2.79(q,J＝7.6Hz,2H),2.66(s,3H),1.37(t,J＝7.6Hz,3H)。
(7)2-{3-[(5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基]-2-乙基-8-甲基咪唑并[1,2-a]吡啶-6-基}-2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯的制备。
将2-{[6-溴-2-乙基-8-甲基咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(472mg,1.0mmol)、2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐(395mg,1.5mmol)、Pd2(dba)3(46mg,0.05mmol)、JohnPhos(30mg,0.1mmol)和叔丁醇钠(192mg,2.0mmol)悬浮于甲苯(15mL)中，加热回流反应36小时。待反应液冷却，硅藻土过滤，旋干，柱层析纯化(石油醚：乙酸乙酯＝1:1)得棕色泡沫状物205mg，收率：33％。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.18(m,2H),7.19(m,2H),6.66(m,1H),6.58(m,1H),3.61(m,7H),3.40(m,4H),2.76(q,J＝7.6Hz,2H),2.61(s,3H),1.80(m,4H),1.47(s,9H),1.35(t,J＝7.6Hz,3H)。
(8)2-{[2-乙基-8-甲基-6-(2,7-二氮杂螺[3.5]壬烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
将2-{3-[(5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基]-2-乙基-8-甲基咪唑并[1,2-a]吡啶-6-基}-2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯(205mg,0.33mmol)溶于二氯甲烷(10mL)，加入三氟乙酸(1mL)，室温反应1小时。用饱和碳酸氢钠溶液调pH至8左右，水层用二氯甲烷萃取(20mLx3)，有机层经无水硫酸钠干燥，过滤，旋干，得棕色稠状物165mg，直接用于下一步反应。
(9)2-{[2-乙基-8-甲基-6-(7-(甲磺酰基)-2,7-二氮杂螺[3.5]壬烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
将2-{[2-乙基-8-甲基-6-(2,7-二氮杂螺[3.5]壬烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(40mg,0.078mol)溶于二氯甲烷(2mL)，加入三乙胺(22μL,0.16mmol)和甲磺酰氯(10μL,0.12mmol)。室温反应1小时后，旋干，经厚制备板纯化得淡黄色固体35mg，收率：76％。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.19(m,2H),7.20(m,2H),6.66(m,1H), 6.57(s,1H),3.62(m,7H),3.24(m,4H),2.79-2.74(m,5H),2.62(s,3H),1.98(m,4H),1.35(t,J＝7.6Hz,3H)。
实施例2
2-{2-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-2-乙基-8-甲基咪唑并[1,2-a]吡啶-6-基]-2,7-二氮杂螺[3.5]壬烷-7-基}-N,N-二甲基乙酰胺的制备。
Figure PCTCN2018099622-appb-000032
将2-{[2-乙基-8-甲基-6-(2,7-二氮杂螺[3.5]壬烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(40mg,0.078mmol)溶于二氯甲烷(2mL)，加入三乙胺(22μL,0.16mmol)和2-氯-N,N-二甲基乙酰胺(14mg,0.156mmol)，室温反应48小时。旋干，经厚制备板纯化(二氯甲烷：甲醇＝15:1)得棕色固体38mg，收率：80％。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.19(m,2H),7.20(m,2H),6.65(m,1H),6.58(s,1H),3.61(s,3H),3.58(s,4H),3.18(s,2H),3.08(s,3H),2.96(s,3H),2.76(q,J＝7.6Hz,2H),2.61(s,3H),2.52(m,4H),1.88(m,4H),1.35(t,J＝7.6Hz,3H)。
实施例3
2-{[2-乙基-6-(7-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,7-二氮杂螺[3.5]壬烷-2-基)-8-甲基咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
将2-{[2-乙基-8-甲基-6-(2,7-二氮杂螺[3.5]壬烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(80mg,0.16mmol)溶于乙腈(2mL)，加入碳酸钾(44mg,0.32mmol)和2-氯-1-(3-羟基氮杂环丁-1-基)乙酮(24mg,0.16mmol)，室温反应24小时。旋干，经厚制备板纯化(二氯甲烷：甲醇＝15:1)得棕色固体40mg，收率：41％。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.19(m,2H),7.19(m,2H),6.64(m,1H),6.57(s,1H),4.69(m,1H),4.44(m,1H),4.28(m,1H),4.10(m,1H),3.89(m,1H),3.61(s,3H),3.57(s,4H),3.02(m,2H),2.75(q,J＝7.6Hz,2H),2.60(s,3H),2.48(m,4H),1.87(m,4H),1.34(t,J＝7.6Hz,3H)。
实施例4
2-{[2-乙基-8-甲基-6-(5-(甲磺酰基)六氢吡咯并[3,4-c]吡咯-2-(1H)-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参考实施例1，用2-Boc-六氢吡咯并[3,4-c]吡咯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{[2-乙基-8-甲基-6-(5-(甲磺酰基)六氢吡咯并[3,4-c]吡咯-2-(1H)-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.19(m,2H),7.20(m,2H),6.83(m,1H),6.77(m,1H),3.63-3.48(m,5H),3.48-3.40(m,2H),3.29(m,2H),3.24-3.14(m,4H),2.88(s,3H),2.77(t,J＝7.6Hz,2H),2.64(s,3H),1.36(t,J＝7.6Hz,3H)。
实施例5
2-{5-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-2-乙基-8-甲基咪唑并[1,2-a]吡啶-6-基]六氢吡咯并[3,4-c]吡咯-2-(1H)-基}-N,N-二甲基乙酰胺的制备。
参照实施例2，用2-Boc-六氢吡咯并[3,4-c]吡咯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{5-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-2-乙基-8-甲基咪唑并[1,2-a]吡啶-6-基]六氢吡咯并[3,4-c]吡咯-2-(1H)-基}-N,N-二甲基乙酰胺。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.20(m,2H),7.20(m,2H),6.88(m,1H),6.78(m,1H),3.62(s,3H),3.37(m,2H),3.31(s,2H),3.07-3.03(m,5H),2.99-2.94(m,5H),2.86(m,2H),2.77(t,J＝7.6Hz,2H),2.62(m,5H),1.35(t,J＝7.6Hz,3H)。
实施例6
2-{[2-乙基-6-(5-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)六氢吡咯并[3,4-c]吡咯-2-(1H)-基-8-甲基咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例3，用2-Boc-六氢吡咯并[3,4-c]吡咯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{[2-乙基-6-(5-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)六氢吡咯并[3,4-c]吡咯-2-(1H)-基-8-甲基咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为：1H NMR(400MHz,CDCl3)δ:1H NMR(400MHz,CDCl3)δ:8.18(m,2H),7.19(m,2H),6.89(m,1H),6.78(m,1H),4.63(m,1H),4.35(m,1H),4.24(m,1H),4.03(m,1H),3.87(m,1H),3.62(s,3H),3.33(m,2H),3.13(m 2H),3.08(m,2H),2.97(m,2H),2.84(m,2H),2.76(t,J＝7.6Hz,2H),2.61(s,3H),2.56(m,2H),1.34(t,J＝7.6Hz,3H)。
实施例7
2-{[2-乙基-8-甲基-6-(6-(甲磺酰基)-2,6-二氮杂螺[3.3]庚烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例1，用2,6-二氮杂螺[3.3]庚烷-2-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{[2-乙基-8-甲基-6-(6-(甲磺酰基)-2,6-二氮杂螺[3.3]庚烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.19(m,2H),7.20(m,2H),6.68(m,1H),6.56(m,1H),4.12(s,4H),3.97(s,4H),3.59(s,3H),2.89(s,3H),2.76(t,J＝7.6Hz,2H),2.62(s,3H),1.35(t,J＝7.6Hz,3H)。
实施例8
2-{2-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-2-乙基-8-甲基咪唑并[1,2-a]吡啶-6-基]-2,6-二氮杂螺[3.3]庚烷-2-基}-N,N-二甲基乙酰胺的制备。
参照实施例2，用2,6-二氮杂螺[3.3]庚烷-2-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{2-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-2-乙基-8-甲基咪唑并[1,2-a]吡啶-6-基]-2,6-二氮杂螺[3.3]庚烷-2-基}-N,N-二甲基乙酰胺。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.19(m,2H),7.20(m,2H),6.66(m,1H),6.56(m,1H),3.93(s,4H),3.61(s,3H),3.59(s,4H),3.32(s,2H),2.98(s,3H),2.94(s,3H),2.76(t,J＝7.6Hz,2H),2.61(s,3H),1.34(t,J＝7.6Hz,3H)。
实施例9
2-{[2-乙基-6-(7-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,6-二氮杂螺[3.3]庚烷-2-基)-8-甲基咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例3，用2,6-二氮杂螺[3.3]庚烷-2-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{[2-乙基-6-(7-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,6-二氮杂螺[3.3]庚烷-2-基)-8-甲基咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.19(m,2H),7.20(m,2H),6.65(m,1H),6.55(m,1H),4.69(m,1H),4.36(m,1H),4.26(m,1H),4.02(m,1H),3.91(m,5H),3.61(s,3H),3.54(s,4H),3.11(s,2H),2.75(t,J＝7.6Hz,2H),2.61(s,3H),1.34(t,J＝7.6Hz,3H)。
实施例10
2-{[2-乙基-8-甲基-6-(6-(甲磺酰基)-2,6-二氮杂螺[3.4]辛烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例1，用2,6-二氮杂螺[3.4]辛烷-6-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{[2-乙基-8-甲基-6-(6-(甲磺酰基)-2,6-二氮杂螺[3.4]辛烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.19(m,2H),7.20(m,2H),6.68(m,1H),6.57(m,1H),3.86-3.77(m,4H),3.62(s,3H),3.57(m,2H),3.46(t,J＝7.2Hz,2H),2.89(s,3H),2.77(t,J＝7.6Hz,2H),2.63(s,3H),2.25(t,J＝7.2Hz,2H),1.35(t,J＝7.6Hz,3H)。
实施例11
2-{2-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-2-乙基-8-甲基咪唑并[1,2-a]吡啶-6-基]-2,6-二氮杂螺[3.4]辛烷-2-基}-N,N-二甲基乙酰胺的制备。
参照实施例2，用2,6-二氮杂螺[3.4]辛烷-6-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{2-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-2-乙基-8-甲基咪唑并[1,2-a]吡啶-6-基]-2,6-二氮杂螺[3.4]辛烷-2-基}-N,N-二甲基乙酰胺。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.19(m,2H),7.20(m,2H),6.66(m,1H),6.57(m,1H),3.82(m,2H),3.75(m,2H),3.61(s,3H),3.36(s,2H),3.05(s,3H),2.96(s,5H),2.78-2.73(m,4H),2.61(s,3H),2.15(t,J＝7.2Hz,2H),1.35(t,J＝7.6Hz,3H)。
实施例12
2-{[2-乙基-6-(7-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,6-二氮杂螺[3.4]辛烷-2-基)-8-甲基咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例3，用2,6-二氮杂螺[3.4]辛烷-6-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{[2-乙基-6-(7-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,6-二氮杂螺[3.4]辛烷-2-基)-8-甲基咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.19(m,2H),7.20(m,2H),6.66(m,1H),6.57(m,1H),4.70(m,1H),4.42(m,1H),4.29(m,1H),4.06(m,1H),3.90(m,1H),3.82(m,2H),3.74(m,2H),3.61(s,3H),3.19(m,2H),2.92(s,2H),2.79-2.71(m,4H),2.61(s,3H),2.14(t,J＝7.2Hz,2H),1.35(t,J＝7.6Hz,3H)。
实施例13
2-{[2-乙基-8-甲基-6-(2-(甲磺酰基)-2,7-二氮杂螺[3.5]壬烷-7-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例1，用2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷 -7-甲酸叔丁酯盐酸盐制备得到2-{[2-乙基-8-甲基-6-(6-(甲磺酰基)-2,7-二氮杂螺[3.5]壬烷-7-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.19(m,2H),7.20(m,2H),7.00(m,2H),6.57(m,1H),3.73(s,4H),3.63(s,3H),2.98(m,4H),2.88(s,3H),2.77(q,J＝7.6Hz,2H),2.62(s,3H),1.98(m,4H),1.35(t,J＝7.6Hz,3H)。
实施例14
2-{2-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-2-乙基-8-甲基咪唑并[1,2-a]吡啶-6-基]-2,7-二氮杂螺[3.5]壬烷-7-基}-N,N-二甲基乙酰胺的制备。
参照实施例2，用2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{2-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-2-乙基-8-甲基咪唑并[1,2-a]吡啶-6-基]-2,7-二氮杂螺[3.5]壬烷-7-基}-N,N-二甲基乙酰胺。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.19(m,2H),7.20(m,2H),7.00(m,2H),3.63(s,3H),3.38(s,2H),3.26(s,4H),2.99-2.93(m,10H),2.76(q,J＝7.6Hz,2H),2.61(s,3H),1.95(m,4H),1.35(t,J＝7.6Hz,3H)。
实施例15
2-{[2-乙基-6-(2-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,7-二氮杂螺[3.5]壬烷-7-基)-8-甲基咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例3，用2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{[2-乙基-6-(7-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,7-二氮杂螺[3.5]壬烷-2-基)-8-甲基咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.20(m,2H),7.20(m,2H),6.99(m,2H),6.57(m,1H),4.66(m,1H),4.38(m,1H),4.25(m,1H),4.04(m,1H),3.86(m,1H),3.63(s,3H),3.22-3.13(m,6H),2.95(m,4H),2.76(q,J＝7.6Hz,2H),2.61(s,3H),1.93(m,4H),1.34(t,J＝7.6Hz,3H)
实施例16
2-{[2-乙基-8-氟-6-(7-(甲磺酰基)-2,7-二氮杂螺[3.5]壬烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
Figure PCTCN2018099622-appb-000033
(1)5-溴-3-氟吡啶-2-胺的制备。
将3-氟吡啶-2-胺(5.01g,44.7mmol)溶于乙腈(200mL)，冷却至0℃，加入NBS(8.03g,45.1mmol)，继续0℃反应半小时。旋干溶剂，加水(200mL)，用二氯甲烷萃取(100mLx3)，有机层经1N氢氧化钠溶液洗涤、饱和食盐水洗涤以及无水硫酸钠干燥，旋干，得8.1g淡黄色固体，直接进行下一步反应。
(2)6-溴-2-乙基-8-氟-N-(2,4,4-三甲基戊烷-2-基)咪唑并[1,2-a]吡啶-3-胺的制备。
将5-溴-3-氟吡啶-2-胺(3.07g,15.7mmol)、丙醛(4.94mL,68.5mmol)、1,1,3,3-四甲基丁基异氰(5mL,28.8mmol)和氯化镁(130mg,1.37mmol)溶于正丁醇(30mL)中，加热回流反应3小时。待反应液冷至室温，旋干，柱层析纯化(石油醚：乙酸乙酯＝20:1)得黄色油状物5.8g，收率：98％。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.12(d,J＝1.6Hz,1H),6.93(dd,J＝1.6Hz,9.6Hz,1H),2.85(s,1H),2.78(q,J＝7.6Hz,2H),1.69(s,2H),1.38(t,J＝7.6Hz,3H),1.18(s,6H),1.13(s,9H)。
(3)N-(6-溴-2-乙基-8-氟咪唑并[1,2-a]吡啶-3-基)甲酰胺的制备。
将6-溴-2-乙基-8-氟-N-(2,4,4-三甲基戊烷-2-基)咪唑并[1,2-a]吡啶-3-胺(6g,16.2mmol)溶于甲酸(60mL)，回流反应3小时。待反应液冷却，旋干，加水，用饱和碳酸氢钠溶液调pH至8左右，再用乙酸乙酯萃取(100mLx3)，无水硫酸钠干燥，旋干，经石油醚打浆得淡黄色固体4.5g，收率：98％。直接进行下一步反应。
(4)6-溴-2-乙基-8-氟-N-甲基咪唑并[1,2-a]吡啶-3-胺的制备。
将N-(6-溴-2-乙基-8-氟咪唑并[1,2-a]吡啶-3-基)甲酰胺(2.86g,10.0mmol)溶于四氢呋喃(50mL)，加入硼烷四氢呋喃溶液(15mL,15mmol)，50℃反应过夜。待反应液冷却，加入甲醇(5mL)淬灭反应，旋干，柱层析纯化(石油醚：乙酸乙酯＝8:1)得淡黄色固体1.5g，收率：55％。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.00(d,J＝1.6Hz,1H),6.93(dd,J＝1.6Hz,9.6Hz,1H),2.83-2.77(m,6H),1.36(t,J＝7.6Hz,3H)。
(5)2-{[6-溴-2-乙基-8-氟咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
将6-溴-2-乙基-8-氟-N-甲基咪唑并[1,2-a]吡啶-3-胺(0.98g,3.60mmol)溶于四氢呋喃(25mL)，氮气保护，冷至0℃，加入钠氢(0.43g,10.8mmol)，回流反应半小时。待反应液冷至室温，加入2-氯-4-(4-氟苯基)噻唑-5-甲腈(1.30g，5.40mmo)的四氢呋喃溶液(10mL)，继续回流反应过夜。将反应液冷至0℃，滴加水淬灭反应，旋干溶剂，加水，用乙酸乙酯萃取(50mLx3)，有机层经饱和食盐水洗涤，无水硫酸钠干燥，旋干，经柱层析纯化(二氯甲烷：甲醇＝50：1)得棕色固体1.3g，收率76％。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.16(m,2H),7.79(m,1H),7.22-7.17(m,3H),3.67(s,3H),2.79(q,J＝7.6Hz,2H),1.39(t,J＝7.6Hz,3H)。
(6)2-{3-[(5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基]-2-乙基-8-氟咪唑并[1,2-a]吡啶-6-基}-2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯的制备。
将2-{[6-溴-2-乙基-8-氟咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(350mg,0.74mmol)、2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐(292mg,1.11mmol)、Pd2(dba)3(34mg,0.037mmol)、JohnPhos(22mg,0.074mmol)和叔丁醇钠(142mg,1.48mmol)悬浮于甲苯(10mL)中，加热回流反应36小时。待反应液冷却，硅藻土过滤，旋干，柱层析纯化(石油醚：乙酸乙酯＝2:1)得棕色泡沫状物150mg，收率：33％。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.18(m,2H),7.20(m,2H),6.61(d,J＝1.6Hz,1H),6.50(dd,J＝1.6Hz,11.2Hz,1H),3.62(m,7H),3.41(m,4H),2.75(q,J＝7.6Hz,2H),1.80(m,4H),1.40(s,9H),1.37(t,J＝7.6Hz,3H)。
(7)2-{[2-乙基-8-氟-6-(2,7-二氮杂螺[3.5]壬烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
将2-{3-[(5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基]-2-乙基-8-氟咪唑并[1,2-a]吡啶-6-基}-2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯(150mg,0.24mmol)溶于二氯甲烷(10mL)，加入三氟乙酸(1mL)，室温反应1小时。用饱和碳酸氢钠溶液调pH至8左右，水层用二氯甲烷萃取(20mLx3)，有机层经无水硫酸钠干燥，过滤，旋干，得棕色稠状物120mg，直接用于下一步反应。
(8)2-{[2-乙基-8-氟-6-(7-(甲磺酰基)-2,7-二氮杂螺[3.5]壬烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
将2-{[2-乙基-8-氟-6-(2,7-二氮杂螺[3.5]壬烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(40mg,0.077mol)溶于二氯甲烷(2mL)，加入三乙胺(22μL,0.16mmol)和甲磺酰氯(10μL,0.12mmol)。室温反应1小时后，旋干，经厚制备板纯化得淡黄色固体20mg，收率：44％。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.18(m,2H),7.20(m,2H),6.61(d,J＝2.0Hz,1H),6.50(dd,J＝2.0Hz,11.2Hz,1H),3.63(m,7H),3.24(m,4H),2.80-2.73(m,5H),1.99(m,4H),1.37(t,J＝7.2Hz,3H)。
实施例17
2-{2-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-2-乙基-8-氟咪唑并[1,2-a]吡啶-6-基]-2,7-二氮杂螺[3.5]壬烷-2-基}-N,N-二甲基乙酰胺的制备。
将2-{[2-乙基-8-氟-6-(2,7-二氮杂螺[3.5]壬烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(40mg,0.077mmol)溶于二氯甲烷(2mL)，加入三乙胺(22μL,0.16mmol)和2-氯-N,N-二甲基乙酰胺(14mg,0.156mmol)，室温反应48小时。旋干，经厚制备板纯化(二氯甲烷：甲醇＝15:1)得棕色固体25mg，收率：53％。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.19(m,2H),7.20(m,2H),6.59(d,J＝1.6Hz,1H),6.50(dd,J＝11.2Hz,1.6Hz,1H),3.62(s,3H),3.58(s,4H),3.19(s,2H),3.07(s,3H),2.96(s,3H),2.75(q,J＝7.2Hz,2H),2.53(m,4H),1.88(m,4H),1.36(t,J＝7.2Hz, 3H)。
实施例18
2-{[2-乙基-6-(7-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,7-二氮杂螺[3.5]壬烷-2-基)-8-氟咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
将2-{[2-乙基-8-氟-6-(2,7-二氮杂螺[3.5]壬烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(40mg,0.077mmol)溶于乙腈(2mL)，加入碳酸钾(22mg,0.16mmol)和2-氯-1-(3-羟基氮杂环丁-1-基)乙酮(12mg,0.08mmol)，室温反应24小时。旋干，经厚制备板纯化(二氯甲烷：甲醇＝15:1)得棕色固体15mg，收率：33％。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.19(m,2H),7.20(m,2H),6.59(d,J＝1.6Hz,1H),6.50(dd,J＝11.2Hz,1.6Hz,1H),4.69(m,1H),4.45(m,1H),4.29(m,1H),4.09(m,1H),3.90(m,1H),3.62(s,3H),3.58(s,4H),3.03(m,2H),2.74(q,J＝7.6Hz,2H),2.50(m,4H),1.88(m,4H),1.36(t,J＝7.6Hz,3H)。
实施例19
2-{[2-乙基-8-氟-6-(7-(甲磺酰基)-2,7-二氮杂螺[4.4]壬烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例16，用2,7-二氮杂螺[4.4]壬烷-2-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{[2-乙基-8-氟-6-(7-(甲磺酰基)-2,7-二氮杂螺[4.4]壬烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.19(m,2H),7.20(m,2H),6.71(m,1H),6.64(m,1H),3.64(m,3H),3.53-3.47(m,3H),3.42-3.36(m,3H),3.29-3.25(m,1H),3.22-3.16(m,1H),2.89(m,3H),2.76(q,J＝7.2Hz,2H),2.16-2.02(m,4H),1.37(t,J＝7.2Hz,3H)。
实施例20
2-{2-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-2-乙基-8-氟咪唑并[1,2-a]吡啶-6-基]-2,7-二氮杂螺[4.4]壬烷-2-基}-N,N-二甲基乙酰胺的制备。
参照实施例17，用2,7-二氮杂螺[4.4]壬烷-2-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{2-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-2-乙基-8-氟咪唑并[1,2-a]吡啶-6-基]-2,7-二氮杂螺[4.4]壬烷-2-基}-N,N-二甲基乙酰 胺。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.19(m,2H),7.20(m,2H),6.70(m,1H),6.61(m,1H),3.63(s,3H),3.35-3.25(m,5H),3.04(m,3H),2.95(m,3H),2.83(m,1H),2.74(m,4H),2.60(m,1H),2.05(m,2H),1.91(m,2H),1.37(t,J＝7.6Hz,3H)。
实施例21
2-{[2-乙基-8-氟-6-(7-(甲磺酰基)-2,6-二氮杂螺[3.3]庚烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例16，用2,6-二氮杂螺[3.3]庚烷-2-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{[2-乙基-8-氟-6-(7-(甲磺酰基)-2,6-二氮杂螺[3.3]庚烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.18(m,2H),7.20(m,2H),6.63(d,J＝1.2Hz,1H),6.49(dd,J＝1.2Hz,11.2Hz,1H),4.13(s,4H),3.99(s,4H),3.63(s,3H),2.89(s,3H),2.75(t,J＝7.6Hz,2H),1.37(t,J＝7.6Hz,3H)。
实施例22
2-{2-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-2-乙基-8-氟咪唑并[1,2-a]吡啶-6-基]-2,6-二氮杂螺[3.3]庚烷-2-基}-N,N-二甲基乙酰胺的制备。
参照实施例17，用2,6-二氮杂螺[3.3]庚烷-2-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{2-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-2-乙基-8-氟咪唑并[1,2-a]吡啶-6-基]-2,6-二氮杂螺[3.3]庚烷-2-基}-N,N-二甲基乙酰胺。
表征数据为：1H NMR(500MHz,CDCl3)δ:8.19(m,2H),7.21(m,2H),6.61(d,J＝1.5Hz,1H),6.49(dd,J＝1.5Hz,11.0Hz,1H),3.95(s,4H),3.62(s,3H),3.59(s,4H),3.32(s,2H),2.98(s,3H),2.95(s,3H),2.75(t,J＝7.5Hz,2H),1.37(t,J＝7.5Hz,3H)。
实施例23
2-{[2-乙基-6-(7-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,6-二氮杂螺[3.3]庚烷-2-基)-8-氟咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例18，用2,6-二氮杂螺[3.3]庚烷-2-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{[2-乙基-6-(7-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙 基)-2,6-二氮杂螺[3.3]庚烷-2-基)-8-氟咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.18(m,2H),7.20(m,2H),6.60(d,J＝1.6Hz,1H),6.48(dd,J＝1.6Hz,11.2Hz,1H),4.68(m,1H),4.35(m,1H),4.26(m,1H),4.02(m,1H),3.93(s,4H),3.87(m,1H),3.61(s,3H),3.57(s,4H),3.12(m,2H),2.74(t,J＝7.6Hz,2H),1.36(t,J＝7.6Hz,3H)。
实施例24
2-{[2-乙基-8-氟-6-(5-(甲磺酰基)六氢吡咯并[3,4-c]吡咯-2-(1H)-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例16，用2-Boc-六氢吡咯并[3,4-c]吡咯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{[2-乙基-8-氟-6-(5-(甲磺酰基)六氢吡咯并[3,4-c]吡咯-2-(1H)-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.19(m,2H),7.20(m,2H),6.76(dd,J＝2.0Hz,12.0Hz,1H),6.71(d,J＝1.6Hz,1H),3.64(s,3H),3.60(m,2H),3.51-3.43(m,2H),3.34-3.30(m,2H),3.23-3.16(m,4H),2.89(s,3H),2.76(q,J＝7.2Hz,2H),1.38(t,J＝7.2Hz,3H)。
实施例25
2-{5-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-2-乙基-8-氟咪唑并[1,2-a]吡啶-6-基]六氢吡咯并[3,4-c]吡咯-2-(1H)-基}-N,N-二甲基乙酰胺的制备。
参照实施例17，用2-Boc-六氢吡咯并[3,4-c]吡咯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{5-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-2-乙基-8-氟咪唑并[1,2-a]吡啶-6-基]六氢吡咯并[3,4-c]吡咯-2-(1H)-基}-N,N-二甲基乙酰胺。
表征数据为：1H NMR(500MHz,CDCl3)δ:8.19(m,2H),7.20(m,2H),6.81(dd,J＝1.5Hz,12.0Hz,1H),6.72(d,J＝1.5Hz,1H),3.63(s,3H),3.40(m,2H),3.32(s,2H),3.07(m,2H),3.03-3.01(m,5H),2.84(m,2H),2.76(q,J＝7.0Hz,2H),2.66(m,2H),1.38(t,J＝7.0Hz,3H)。
实施例26
2-{[2-乙基-6-(5-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)六氢吡咯并[3,4-c]吡咯-2-(1H)-基-8-氟咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例18，用2-Boc-六氢吡咯并[3,4-c]吡咯代替2,7-二氮杂螺[3.5]壬烷-7-甲 酸叔丁酯盐酸盐制备得到2-{[2-乙基-6-(5-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)六氢吡咯并[3,4-c]吡咯-2-(1H)-基-8-氟咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.18(m,2H),7.20(m,2H),6.82(m,1H),6.72(m,1H),4.65(m,1H),4.36(m,1H),4.26(m,1H),4.02(m,1H),3.87(m,1H),3.63(s,3H),3.37(m,2H),3.14(m,2H),3.08(m,2H),2.99(m,2H),2.82(m,2H),2.75(q,J＝7.6Hz,2H),2.61(m,2H),1.36(t,J＝7.0Hz,3H)。
实施例27
2-{[8-甲基-2-乙基-6-(2-(甲磺酰基)-2,7-二氮杂螺[3.5]壬烷-7-基)咪唑并[1,2-a]吡嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例13，用5-溴-吡嗪-2-胺代替5-溴-3-甲基吡啶-2-胺制备得到2-{[8-甲基-2-乙基-6-(2-(甲磺酰基)-2,7-二氮杂螺[3.5]壬烷-7-基)咪唑并[1,2-a]吡嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为： 1H NMR(400MHz,CDCl 3)δ:8.85(m,1H),8.18(m,2H),7.20(m,2H),6.94(m,1H),3.74(s,4H),3.64(s,3H),3.32(m,4H),2.89(s,3H),2.76(q,J＝7.6Hz,2H),2.62(s,3H),1.98(m,4H),1.38(t,J＝7.6Hz,3H)。
实施例28
2-{[8-甲-2-乙基-6-(7-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,7-二氮杂螺[3.5]壬烷-7-基)咪唑并[1,2-a]吡嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例15，用5-溴-吡嗪-2-胺代替5-溴-3-甲基吡啶-2-胺制备得到2-{[8-甲-2-乙基-6-(7-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,7-二氮杂螺[3.5]壬烷-7-基)咪唑并[1,2-a]吡嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为： 1H NMR(400MHz,CDCl 3)δ:8.83(m,1H),8.17(m,2H),7.20(m,2H),6.92(m,1H),4.66(m,1H),4.39(m,1H),4.25(m,1H),4.06(m,1H),3.88(m,1H),3.64(s,3H),3.51(m,2H),3.28(m,8H),2.77(q,J＝7.6Hz,2H),1.93(m,4H),1.38(t,J＝7.6Hz,3H)。
实施例29
2-{[8-甲基-2-乙基-6-(2-(甲磺酰基)-2,7-二氮杂螺[3.5]壬烷-7-基)咪唑并[1,2-b]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例13，用5-溴-哒嗪-2-胺代替5-溴-3-甲基吡啶-2-胺制备得到2-{[8-甲基-2-乙基-6-(2-(甲磺酰基)-2,7-二氮杂螺[3.5]壬烷-7-基)咪唑并[1,2-b]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为： 1H NMR(500MHz,CDCl 3)δ:8.18(m,2H),7.73(d,J＝10.0Hz,1H),7.19(m,2H),6.92(d,J＝10.0Hz,1H),3.73(s,4H),3.64(s,3H),3.44(m,4H),2.88(s,3H),2.76(q,J＝7.5Hz,2H),1.90(m,4H),1.37(t,J＝7.5Hz,3H)。
实施例30
2-{7-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-2-乙基-8-甲基咪唑并[1,2-b]哒嗪-6-基]-2,7-二氮杂螺[3.5]壬烷-7-基}-N,N-二甲基乙酰胺的制备。
参照实施例14，用5-溴-哒嗪-2-胺代替5-溴-3-甲基吡啶-2-胺制备得到2-{7-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-2-乙基-8-甲基咪唑并[1,2-b]哒嗪-6-基]-2,7-二氮杂螺[3.5]壬烷-7-基}-N,N-二甲基乙酰胺。
表征数据为： 1H NMR(500MHz,CDCl 3)δ:8.18(m,2H),7.73(d,J＝9.5Hz,1H),7.19(m,2H),6.91(d,J＝9.5Hz,1H),3.63(s,3H),3.54(s,2H),3.50(s,4H),3.41(m,4H),2.99(s,3H),2.95(s,3H),2.76(q,J＝7.5Hz,2H),1.93(m,4H),1.36(t,J＝7.5Hz,3H)。
实施例31
2-{[2-乙基-6-(2-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,7-二氮杂螺[3.5]壬烷-7-基)-8-甲基咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例15，用5-溴-哒嗪-2-胺代替5-溴-3-甲基吡啶-2-胺制备得到2-{[2-乙基-6-(2-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,7-二氮杂螺[3.5]壬烷-7-基)-8-甲基咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为： 1H NMR(500MHz,CDCl 3)δ:8.18(m,2H),7.69(d,J＝10.0Hz,1H),7.19(m,2H),6.91(d,J＝10.0Hz,1H),4.67(m,1H),4.39(m,1H),4.26(m,1H),4.05(m,1H),3.87(m,1H),3.63(s,3H),3.40(m,4H),3.22-3.17(m,6H),2.76(q,J＝7.5Hz,2H),1.84(m,4H),1.37(t,J＝7.6Hz,3H)。
实施例32
(S)-2-{[8-甲基-2-乙基-6-(2-(2-羟基丙酰基)-2,7-二氮杂螺[3.5]壬烷-7-基)咪唑并[1,2-a] 吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
将2-{[8-甲基-2-乙基-6-(2,7-二氮杂螺[3.5]壬烷-7-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(52mg,0.10mol)溶于二氯甲烷(3mL)，加入L-乳酸(14mg，0.15mmol)，三乙胺(28μL,0.20mmol)和HATU(57mg,0.15mmol)。室温反应1小时后，旋干，经厚制备板纯化(乙酸乙酯：石油醚＝2:1)得淡黄色固体35mg，收率：60％。
表征数据为： 1H NMR(500MHz,CDCl 3)δ:8.18(m,2H),7.30-7.26(m,4H),4.28(m,1H),4.09(m,2H),3.76(m,2H),3.67(s,3H),3.07(m,4H),2.76(q,J＝7.5Hz,2H),2.58(s,3H),1.95(m,4H),1.35(m,6H)。
实施例33
2-{[2-乙基-6-(2-乙酰基-2,7-二氮杂螺[3.5]壬烷-7-基)-8-甲基咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
将2-{[8-甲基-2-乙基-6-(2,7-二氮杂螺[3.5]壬烷-7-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(52mg,0.10mol)溶于二氯甲烷(3mL)，加入三乙胺(28μL,0.20mmol)和乙酰氯(12mg,0.15mmol)。室温反应1小时后，旋干，经厚制备板纯化(乙酸乙酯：石油醚＝2:1)得淡黄色固体30mg，收率：54％。
表征数据为： 1H NMR(400MHz,CDCl 3)δ:8.17(m,2H),7.18(m,2H),6.99(m,2H),3.85(s,2H),3.74(s,2H),3.62(s,3H),2.98(m,4H),2.75(q,J＝7.6Hz,2H),2.60(s,3H),1.93(m,4H),1.88(s,3H),1.33(t,J＝7.6Hz,3H)。
实施例34
2-{[2-乙基-6-(2-((二甲胺基)丙基)磺酰基-2,7-二氮杂螺[3.5]壬烷-7-基)-8-甲基咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
(1)2-{[2-乙基-6-(2-(氯丙基)磺酰基-2,7-二氮杂螺[3.5]壬烷-7-基)-8-甲基咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
将2-{[8-甲基-2-乙基-6-(2,7-二氮杂螺[3.5]壬烷-7-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(104mg,0.20mol)溶于二氯甲烷(5mL)，加入三乙胺(56μL,0.40mmol)和乙酰氯(12mg,0.15mmol)。室温反应1小时后，旋干，柱层析(二氯甲烷：甲醇＝40:1)得棕色稠状物80mg，收率：61％。
(2)2-{[2-乙基-6-(2-((二甲胺基)丙基)磺酰基-2,7-二氮杂螺[3.5]壬烷-7-基)-8-甲基咪 唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
将2-{[2-乙基-6-(2-(氯丙基)磺酰基-2,7-二氮杂螺[3.5]壬烷-7-基)-8-甲基咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(80mg,0.12mol)溶于乙腈(3mL)，加入二甲胺四氢呋喃溶液(300μL,0.60mmol)和碳酸钾(30mg,0.24mmol)。加热密封回流24小时后，冷却，旋干，经厚制备板纯化(二氯甲烷：甲醇＝30:1)得棕色固物60mg，收率：75％。
表征数据为： 1H NMR(400MHz,CDCl 3)δ:8.17(m,2H),7.18(m,2H),6.98(m,2H),3.73(s,4H),3.61(s,3H),3.08(m,2H),2.96(m,4H),2.75(q,J＝7.6Hz,2H),2.60(m,5H),2.37(s,6H),2.07(m,2H),1.96(m,4H),1.33(t,J＝7.6Hz,3H)。
实施例35
2-{[8-甲基-2-乙基-6-(2-甲磺酰基)-2,8-二氮杂螺[4.5]癸烷-8-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
(1)2-(1-苄基哌啶-4-基亚甲基)乙酸甲酯的制备。
将4-苄基哌啶酮(3.79g,20mmol)和甲氧甲酰基亚甲基三苯基膦(8.03g，24mmol)溶于甲苯(50mL)中，加热回流反应过夜。待反应液冷却，旋干，柱层析纯化(石油醚：乙酸乙酯＝10:1)得淡黄色油状物3.18g，收率：65％。
表征数据为： 1H NMR(400MHz,CDCl 3)δ: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)。
(2)2-(1-苄基-4-(硝基甲基)哌啶-4-基)乙酸甲酯的制备。
将2-(1-苄基哌啶-4-基亚甲基)乙酸乙酯(3.18g,13.0mmol)溶于THF(60mL)，加入硝基甲烷(1.41mL,26.0mmol)和1M四丁基氟化铵的四氢呋喃溶液(13mL)，加热回流反应过夜。待反应液冷至室温，旋干，经柱层析纯化(石油醚:乙酸乙酯＝5:1)得无色油状物3.6g，收率：91％。
表征数据为： 1H NMR(400MHz,CDCl 3)δ: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)。
(3)8-苄基-2,8-二氮杂螺[4.5]癸烷-3-酮的制备。
将2-(1-苄基-4-(硝基甲基)哌啶-4-基)乙酸甲酯(3.6g,11.7mmol)溶于THF(50mL)和水(20mL)中，加入铁粉(6.5g,117mmol)和氯化铵(1.26g,23.5mol)，75℃反应6小时。待反应液冷至室温，硅藻土过滤，乙酸乙酯(100mLx3)萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，旋干，经石油醚打浆得1.6g白色固体，收率：56％。
表征数据为： 1H NMR(400MHz,CDCl 3)δ: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)。
(4)8-苄基-2,8-二氮杂螺[4.5]癸烷的制备。
将四氢锂铝(0.56g,14.7mmol)悬浮于THF(15mL)中，冷却至0℃，滴加8-苄基-2,8-二氮杂螺[4.5]癸烷-3-酮(1.3g,4.1mmol)的THF(15mL)溶液，于60℃加热反应6小时。待反应液冷至室温，滴加水(0.6mL)淬灭反应，再滴加15％NaOH(0.6mL)，搅拌10分钟后，加入无水硫酸钠(10g)，继续搅拌15分钟后，硅藻土过滤，旋干得淡黄色油状物1.2g，不纯化直接进行下一步反应。
(5)8-苄基-2,8-二氮杂螺[4.5]癸烷-2-甲酸叔丁酯的制备
将8-苄基-2,8-二氮杂螺[4.5]癸烷(1.2g,5mmol)溶于二氯甲烷(30mL)，加入Boc酸酐(1.64g,7.5mmol)，室温反应过夜。旋干，柱层析纯化(石油醚:乙酸乙酯＝5:1)得淡黄色油状物1.5g，收率：90％。
表征数据为： 1H NMR(400MHz,CDCl 3)δ: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)。
(6)2,8-二氮杂螺[4.5]癸烷-2-甲酸叔丁酯的制备。
将8-苄基-2,8-二氮杂螺[4.5]癸烷-2-甲酸叔丁酯(1.5g,4.54mmol)溶于甲醇(30mL)中，加入10％Pd/C(0.3g)，通入氢气，室温反应过夜。硅藻土过滤，旋干，得淡黄色油状物1.1g，收率：100％。
表征数据为：m/z:241.2[M+1]
(7)2-{[8-甲基-2-乙基-6-(2-甲磺酰基)-2,8-二氮杂螺[4.5]癸烷-8-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例1，用2,8-二氮杂螺[4.5]癸烷-2-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{[8-甲基-2-乙基-6-(2-甲磺酰基)-2,8-二氮杂螺[4.5]癸烷-8-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为： 1H NMR(500MHz,CDCl 3)δ:8.20(m,2H),7.20(m,2H),7.02(m,2H),3.64(s,3H),3.45(t,J＝7.0Hz,2H),3.25(m,2H),3.12(m,2H),2.96(m,2H),2.87(s,3H),2.78(q,J＝7.5Hz,2H),2.63(s,3H),1.89(m,2H),1.80(m,4H),1.36(t,J＝7.5Hz,3H)。
实施例36
2-{[8-甲基-2-乙基-6-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,8-二氮杂螺[4.5]癸烷-8-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例3，用2,8-二氮杂螺[4.5]癸烷-2-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{[8-甲基-2-乙基-6-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,8-二氮杂螺[4.5]癸烷-8-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为： 1H NMR(500MHz,CDCl 3)δ:8.19(m,2H),7.19(m,2H),7.01(m,2H),4.67(m,1H),4.41(m,1H),4.26(m,1H),4.07(m,1H),3.88(m,1H),3.63(s,3H),3.16(m,2H),3.00(m,4H),2.78-2.72(m,4H),2.61-2.52(m,5H),1.76-1.69(m,6H),1.35(t,J＝7.5Hz,3H)。
实施例37
2-{8-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-2-乙基-8-甲基咪唑并[1,2-a]吡啶-6-基]-2,8-二氮杂螺[4.5]癸烷-2-基}-N,N-二甲基乙酰胺的制备。
参照实施例2，用2,8-二氮杂螺[4.5]癸烷-2-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{8-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-2-乙基-8-甲基咪唑并[1,2-a]吡啶-6-基]-2,8-二氮杂螺[4.5]癸烷-2-基}-N,N-二甲基乙酰胺。
表征数据为： 1H NMR(400MHz,CDCl 3)δ:8.17(m,2H),7.17(m,2H),6.99(m,2H),3.61(s,3H),3.32(s,2H),3.04-2.93(m,10H),2.77-2.72(m,4H),2.59(m,5H),1.76-1.69(m,6H),1.33(t,J＝7.6Hz,3H)。
实施例38
(S)-2-{[8-甲基-2-乙基-6-(2-(2-羟基丙酰基)-2,8-二氮杂螺[4.5]癸烷-8-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例32，用2,8-二氮杂螺[4.5]癸烷-2-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯制备得到(S)-2-{[8-甲基-2-乙基-6-(2-(2-羟基丙酰基)-2,8-二氮杂螺[4.5]癸烷-8-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为： 1H NMR(500MHz,CD 3OD)δ:8.17(m,2H),7.30-7.25(m,4H),4.43(m,1H),3.73(m,0.65H),3.67(s,3H),3.62-3.49(m,2.32H),3.40(m,1H),3.18(m,2H),3.07(m,2H),2.76(q,J＝7.5Hz,2H),2.58(s,3H),1.93(m,1H),1.84(m,1H),1.76(m,4H),1.36-1.31(m,6H)。
实施例39
2-{[8-甲基-2-乙基-6-(2-乙酰基)-2,8-二氮杂螺[4.5]癸烷-8-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例33，用2,8-二氮杂螺[4.5]癸烷-2-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯制备得到2-{[8-甲基-2-乙基-6-(2-乙酰基)-2,8-二氮杂螺[4.5]癸烷-8-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为： 1H NMR(500MHz,CDCl 3)δ:8.19(m,2H),7.20(m,2H),7.02(m,2H),3.64(s,3H),3.59-3.53(m,2H),3.41-3.32(m,2H),3.19-2.89(m,4H),2.78(q,J＝7.5Hz,2H), 2.62(s,3H),2.07(s,3H),1.92-1.82(m,2H),1.79-1.75(m,4H),1.36(t,J＝7.5Hz,3H)。
实施例40
2-{[2-乙基-6-(6-((3-氯丙基)磺酰基)-2,6-二氮杂螺[3.4]辛烷-2-基)-8-甲基咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例34，用2,6-二氮杂螺[3.4]辛烷-6-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯制备得到2-{[2-乙基-6-(6-((3-氯丙基)磺酰基)-2,6-二氮杂螺[3.4]辛烷-2-基)-8-甲基咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为： 1H NMR(400MHz,CDCl 3)δ:8.17(m,2H),7.18(m,2H),6.67(m,1H),6.56(m,1H),3.84-3.75(m,4H),3.69(t,J＝6.4Hz,2H),3.60(m,4H),3.47(m,3H),3.16(t,J＝7.2Hz,2H),2.75(q,J＝7.6Hz,2H),2.60(s,3H),2.32-2.21(m,4H),1.33(t,J＝7.6Hz,3H)。
实施例41
2-{[2-乙基-6-(6-((3-(二甲胺基)丙基)磺酰基)-2,6-二氮杂螺[3.4]辛烷-2-基)-8-甲基咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例34，用2,6-二氮杂螺[3.4]辛烷-6-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯制备得到2-{[2-乙基-6-(6-((3-(二甲胺基)丙基)磺酰基)-2,6-二氮杂螺[3.4]辛烷-2-基)-8-甲基咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为： 1H NMR(400MHz,CDCl 3)δ:8.17(m,2H),7.17(m,2H),6.68(m,1H),6.56(m,1H),3.83-3.74(m,4H),3.58(m,5H),3.46(m,2H),3.09(m,2H),2.74(q,J＝7.6Hz,2H),2.60(s,3H),2.55(m,2H),2.32(m,6H),2.21(m,2H),2.06(m,2H),1.33(t,J＝7.6Hz,3H)。
实施例42
2-{[8-甲基-2-乙基-6-((1S,4S)-5-((3-氯丙基)磺酰基)-2,5-二氮杂二环[2.2.1]庚烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例34，用(1S,4S)-2-BOC-2,5-二氮双环[2.2.1]庚烷代替2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯制备得到2-{[8-甲基-2-乙基-6-((1S,4S)-5-((3-氯丙基)磺酰基)-2,5-二氮杂二环[2.2.1]庚烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为： 1H NMR(400MHz,CDCl 3)δ:8.17(m,2H),7.18(m,2H),6.67(m,1H),6.56(m,1H),3.84-3.75(m,4H),3.69(t,J＝6.4Hz,2H),3.60(m,4H),3.47(m,3H),3.16(t,J＝ 7.2Hz,2H),2.75(q,J＝7.6Hz,2H),2.60(s,3H),2.32-2.21(m,4H),1.33(t,J＝7.6Hz,3H)。
实施例43
2-{[8-甲基-2-乙基-6-((1S,4S)-5-((3-(二甲胺基)丙基)磺酰基)-2,5-二氮杂二环[2.2.1]庚烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例34，用(1S,4S)-2-BOC-2,5-二氮双环[2.2.1]庚烷代替2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯制备得到2-{[8-甲基-2-乙基-6-((1S,4S)-5-((3-(二甲胺基)丙基)磺酰基)-2,5-二氮杂二环[2.2.1]庚烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为： 1H NMR(400MHz,CDCl 3)δ:8.17(m,2H),7.17(m,2H),6.68(m,1H),6.56(m,1H),3.83-3.74(m,4H),3.58(m,5H),3.46(m,2H),3.09(m,2H),2.74(q,J＝7.6Hz,2H),2.60(s,3H),2.55(m,2H),2.32(m,6H),2.21(m,2H),2.06(m,2H),1.33(t,J＝7.6Hz,3H)。
实施例44
(S)-2-{[2-乙基-6-(6-(2-羟基丙酰基)-2,6-二氮杂螺[3.4]辛烷-2-基)-8-甲基咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例32，用2,6-二氮杂螺[3.4]辛烷-6-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯制备得到(S)-2-{[2-乙基-6-(6-(2-羟基丙酰基)-2,6-二氮杂螺[3.4]辛烷-2-基)-8-甲基咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为： 1H NMR(400MHz,CDCl 3)δ:8.15(m,2H),7.24(m,2H),7.00(m,1H),6.80(m,1H),4.40(m,1H),3.81(m,4H),3.72-3.47(m,7H),2.72(q,J＝7.6Hz,2H),2.55(s,3H),2.24(m,1H),2.14(m,1H),1.32-1.28(m,6H)。
实施例45
2-{[8-甲基-2-乙基-6-((1S,4S)-5-((S)-2-羟基丙酰基)-2,5-二氮杂二环[2.2.1]庚烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例32，用(1S,4S)-2-BOC-2,5-二氮双环[2.2.1]庚烷代替2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯制备得到2-{[8-甲基-2-乙基-6-((1S,4S)-5-((S)-2-羟基丙酰基)-2,5-二氮杂二环[2.2.1]庚烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为： 1H NMR(400MHz,CDCl 3)δ: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)。
实施例46
2-{(1S,4S)-5-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-2-乙基-8-甲基咪唑并[1,2-a]吡啶-6-基]-2,5-二氮杂二环[2.2.1]庚烷-2-基}-N,N-二甲基乙酰胺的制备。
参照实施例2，用(1S,4S)-2-BOC-2,5-二氮双环[2.2.1]庚烷代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{(1S,4S)-5-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)-2-乙基-8-甲基咪唑并[1,2-a]吡啶-6-基]-2,5-二氮杂二环[2.2.1]庚烷-2-基}-N,N-二甲基乙酰胺。
表征数据为： 1H NMR(500MHz,CDCl 3)δ:8.19(m,2H),7.20(m,2H),6.76(s,1H),6.73(s,1H),4.17(m,1H),3.71(m,1H),3.62(m,3H),3.39(m,3H),3.24-3.14(m,2H),3.05(m,3H),2.94(m,3H),2.76(m,3H),2.63(s,3H),2.04(m,2H),1.35(t,J＝7.5Hz,3H)。
实施例47
2-{[8-甲基-2-乙基-6-((1S,4S)-5-(甲磺酰基)-2,5-二氮杂二环[2.2.1]庚烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例1，用(1S,4S)-2-BOC-2,5-二氮双环[2.2.1]庚烷代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{[8-甲基-2-乙基-6-((1S,4S)-5-(甲磺酰基)-2,5-二氮杂二环[2.2.1]庚烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为： 1H NMR(500MHz,CDCl 3)δ:8.19(m,2H),7.20(m,2H),6.76(m,2H),4.58(m,1H),4.45(m,1H),3.63(m,3H),3.57-3.45(m,3H),3.30(m,1H),2.89(m,3H),2.77(q,J＝7.5Hz,2H),2.65(s,3H),2.12(m,1H),1.99(m,1H),1.36(t,J＝7.5Hz,3H)。
实施例48
2-{[8-甲基-2-乙基-6-((1S,4S)-5-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,5-二氮杂二环[2.2.1]庚烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例3，用(1S,4S)-2-BOC-2,5-二氮双环[2.2.1]庚烷代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{[8-甲基-2-乙基-6-((1S,4S)-5-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,5-二氮杂二环[2.2.1]庚烷-2-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为： 1H NMR(400MHz,CDCl 3)δ:8.19(m,2H),7.20(m,2H),6.75(m,1H),6.71(m,1H),4.67(m,1H),4.40-4.26(m,2H),4.18(m,1H),4.05(m,1H),3.98(m,1H),3.87(m,1H),3.64(m,3.5H),3.39(m,1H),3.19(m,2H),3.10(m,1H),2.99(m,0.5H),2.77(m,2H),2.70(m,1H),2.63(s,3H),2.04-1.91(m,2H),1.35(t,J＝7.5Hz,3H)。
实施例49
2-{8-甲基-2-乙基-9-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)咪唑并[1,2-a]吡啶-6-基]-3,9-二氮杂螺[5.5]十一烷-3-基}-N,N-二甲基乙酰胺的制备。
参照实施例2，用3,9-二氮杂螺[5.5]十一烷-3-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{8-甲基-2-乙基-9-[3-((5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基)咪唑并[1,2-a]吡啶-6-基]-3,9-二氮杂螺[5.5]十一烷-3-基}-N,N-二甲基乙酰胺。
表征数据为： 1H NMR(400MHz,CDCl 3)δ:8.17(m,2H),7.18(m,2H),7.00(m,1H),6.98(m,1H),3.61(m,3H),3.23(s,2H),3.06(s,3H),2.99(m,4H),2.94(s,3H),2.75(q,J＝7.6Hz,2H),2.59(m,7H),1.65(m,4H),1.58(m,4H),1.33(t,J＝7.6Hz,3H)。
实施例50
2-{[8-甲-2-乙基-6-(9-(甲磺酰基)-3,9-二氮杂螺[5.5]十一烷-3-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例1，用3,9-二氮杂螺[5.5]十一烷-3-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{[8-甲-2-乙基-6-(9-(甲磺酰基)-3,9-二氮杂螺[5.5]十一烷-3-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为： 1H NMR(400MHz,CDCl 3)δ:8.17(m,2H),7.19(m,2H),6.99(m,2H),3.61(m,3H),3.23(m,4H),3.02(m,4H),2.78(s,3H),2.74(q,J＝7.6Hz,2H),2.60(s,3H),1.68(m,8H),1.33(t,J＝7.6Hz,3H)。
实施例51
2-{[8-甲-2-乙基-6-(9-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-3,9-二氮杂螺[5.5]十一烷-3-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例3，用3,9-二氮杂螺[5.5]十一烷-3-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯盐酸盐制备得到2-{[8-甲-2-乙基-6-(9-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-3,9-二氮杂螺[5.5]十一烷-3-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻 唑-5-甲腈。
表征数据为： 1H NMR(400MHz,CDCl 3)δ:8.17(m,2H),7.19(m,2H),7.00(m,1H),6.98(m,1H),4.66(m,1H),4.44(m,1H),4.26(m,1H),4.08(m,1H),3.88(m,1H),3.61(s,3H),3.06(m,2H),2.99(m,4H),2.75(q,J＝7.6Hz,2H),2.59(s,3H),2.52(m,4H),1.64(m,4H),1.57(m,4H),1.33(t,J＝7.6Hz,3H)。
实施例52
(S)-2-{[8-甲-2-乙基-6-(9-(2-羟基丙酰基)-3,9-二氮杂螺[5.5]十一烷-3-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例32，用3,9-二氮杂螺[5.5]十一烷-3-甲酸叔丁酯代替2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯制备得到(S)-2-{[8-甲-2-乙基-6-(9-(2-羟基丙酰基)-3,9-二氮杂螺[5.5]十一烷-3-基)咪唑并[1,2-a]吡啶-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为： 1H NMR(400MHz,CDCl 3)δ:8.17(m,2H),7.18(m,2H),6.99(m,2H),4.44(m,1H),3.88(br,1H),3.68(m,1H),3.61(m,4H),3.36(m,2H),3.03(m,4H),2.75(q,J＝7.6Hz,2H),2.60(s,3H),1.71(m,4H),1.55(m,4H),1.35-1.30(m,6H)。
实施例53
2-{[2-乙基-8-甲基-6-(6-(甲磺酰基)-2,6-二氮杂螺[3.4]辛烷-2-基)咪唑并[1,2-b]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
(1)6-溴-2-乙基-8-甲基-N-(2,4,4-三甲基戊烷-2-基)咪唑并[1,2-b]哒嗪-3-胺的制备。
将6-溴-4-甲基哒嗪-3-胺(1.25g,8.74mmol)、丙醛(1.58mL,21.8mmol)、1,1,3,3-四甲基丁基异氰(1.45g,10.5mmol)和氯化镁(115mg,1.2mmol)溶于正丁醇(15mL)中，加热回流反应3小时。待反应液冷至室温，旋干，柱层析纯化(石油醚：乙酸乙酯＝20:1)得黄色油状物1.45g，收率：59％。
表征数据为：1H NMR(400MHz,CDCl3)δ:6.74(s,1H),3.25(s,1H),2.83(q,J＝7.6Hz,2H),2.80(s,3H),1.69(s,2H),1.35(t,J＝7.6Hz,3H),1.18(s,6H),1.11(s,9H)。
(2)N-(6-溴-2-乙基-8-甲基咪唑并[1,2-b]哒嗪-3-基)甲酰胺的制备。
将6-溴-2-乙基-8-甲基-N-(2,4,4-三甲基戊烷-2-基)咪唑并[1,2-b]哒嗪-3-胺(1.45g,4.50mmol)溶于甲酸(30mL)，回流反应1.5小时。待反应液冷却，旋干，加水，用饱和碳酸氢钠溶液调pH至8左右，再用乙酸乙酯萃取(100mLx3)，无水硫酸钠干燥，旋干，经石油醚打浆得淡黄色固体0.75g，收率：70％。
表征数据为：MS(m/z)：283.1[M+1]，285.1[M+1]。
(3)N-(6-溴-2-乙基-8-甲基咪唑并[1,2-b]哒嗪-3-基)-N-甲基甲酰胺的制备。
将N-(6-溴-2-乙基-8-甲基咪唑并[1,2-b]哒嗪-3-基)甲酰胺(2.51g,10.5mmol)溶于丙酮(80mL)，加入碳酸钾(4.35g,31.5mmol)和碘甲烷(1.64mL,26.3mmol)，加热回流反应5小时。冷却，旋干，加入二氯甲烷和水，分层，水层用二氯甲烷萃取，合并有机层，无水硫酸钠干燥，旋干，经石油醚打浆得淡黄色固体2.3g，收率：86％。
表征数据为：MS(m/z)：297.1[M+1]，299.1[M+1]。
(4)6-溴-2-乙基-N,8-二甲基咪唑并[1,2-b]哒嗪-3-胺的制备。
将N-(6-溴-2-乙基-8-甲基咪唑并[1,2-b]哒嗪-3-基)-N-甲基甲酰胺(2.3g,9.12mmol)溶于甲醇(30mL)，加入4N HCl的二氧六环溶液(10mL)，室温反应过夜。旋干，加水，用饱和碳酸氢钠溶液调pH至8左右，用二氯甲烷(50mLx2)萃取，无水硫酸钠干燥，旋干，柱层析纯化(石油醚：乙酸乙酯＝5:1)得黄色油状物1.8g，收率：88％。
表征数据为：MS(m/z)：269.0[M+1]，271.0[M+1]。
(5)2-{[6-溴-2-乙基-8-甲基咪唑并[1,2-b]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
将6-溴-2-乙基-N,8-二甲基咪唑并[1,2-b]哒嗪-3-胺(1.8g,8.0mmol)溶于四氢呋喃(30mL)，氮气保护，冷至0℃，加入钠氢(0.9g,22.3mmol)，回流反应15分钟。待反应液冷至室温，加入2-氯-4-(4-氟苯基)噻唑-5-甲腈(2.48g，10.4mmo)，加热回流反应1小时。将反应液冷至0℃，滴加水淬灭反应，旋干溶剂，加水，用乙酸乙酯萃取(50mLx2)，有机层经饱和食盐水洗涤，无水硫酸钠干燥，旋干，经柱层析纯化(石油醚：乙酸乙酯＝5:1)得淡黄色固体2.78g，收率82％。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.13(m,2H),7.16(m,2H),6.99(m,1H),3.64(s,3H),2.81(q,J＝7.6Hz,2H),2.69(s,3H),1.36(t,J＝7.6Hz,3H)。
(6)2-{3-[(5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基]-2-乙基-8-甲基咪唑并[1,2-b]哒嗪-6-基}-2,6-二氮杂螺[3.4]辛烷-6-甲酸叔丁酯的制备。
将2-{[6-溴-2-乙基-8-甲基咪唑并[1,2-b]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(300mg,0.70mmol)和2,6-二氮杂螺[3.4]辛烷-6-甲酸叔丁酯(239mg,1.13mmol)溶于正丁醇(5mL)中，加入DIPEA(230μL,1.40mmol)，于封管中140℃反应48小时。冷至室温，旋干，经柱层析纯化(石油醚：乙酸乙酯＝1:1)得淡黄色固体280mg，收率：66％。
表征数据为：MS(m/z)：603.4[M+1]。
(7)2-{[2-乙基-8-甲基-6-(2,6-二氮杂螺[3.4]辛烷-2-基)咪唑并[1,2-b]哒嗪-3-基] (甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
将2-{3-[(5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基]-2-乙基-8-甲基咪唑并[1,2-b]哒嗪-6-基}-2,6-二氮杂螺[3.4]辛烷-6-甲酸叔丁酯(280mg,0.47mmol)溶于二氯甲烷(5mL)，加入三氟乙酸(1mL)，室温反应4小时。旋干，加入二氯甲烷，用饱和碳酸氢钠溶液调pH至8左右，用二氯甲烷(15mLx3)萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干得泡沫状固体210mg，收率：90％。
表征数据为：MS(m/z)：503.3[M+1]。
(8)2-{[2-乙基-8-甲基-6-(6-(甲磺酰基)-2,6-二氮杂螺[3.4]辛烷-2-基)咪唑并[1,2-b]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
将2-{[2-乙基-8-甲基-6-(2,6-二氮杂螺[3.4]辛烷-2-基)咪唑并[1,2-b]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(40mg,0.08mol)溶于二氯甲烷(2mL)，加入三乙胺(22μL,0.16mmol)和甲磺酰氯(13μL,0.16mmol)。室温反应1小时后，旋干，经厚制备板纯化得淡黄色固体30mg，收率：65％。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.16(m,2H),7.16(m,2H),6.27(m,1H),4.01-3.93(m,4H),3.59(s,3H),3.54(s,2H),3.44(m,2H),2.86(s,3H),2.75(q,J＝7.6Hz,2H),2.59(s,3H),2.22(m,2H),1.32(t,J＝7.6Hz,3H)。
实施例54
2-{[2-乙基-6-(2-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,6-二氮杂螺[3.4]辛烷-2-基)-8-甲基咪唑并[1,2-a]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
将2-{[2-乙基-8-甲基-6-(2,6-二氮杂螺[3.4]辛烷-2-基)咪唑并[1,2-b]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(60mg,0.12mmol)溶于乙腈(2mL)，加入碳酸钾(33mg,0.24mmol)和2-氯-1-(3-羟基氮杂环丁-1-基)乙酮(26mg,0.18mmol)，70℃加热反应1小时。旋干，经厚制备板纯化(二氯甲烷：甲醇＝10:1)得白色固体50mg，收率：67％。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.15(m,2H),7.16(m,2H),6.25(m,1H),4.66(m,1H),4.37(m,1H),4.25(m,1H),4.04(m,1H),3.97-3.85(m,5H),3.59(s,3H),3.14(m,2H),2.88(m,2H),2.77-2.68(m,4H),2.57(s,3H),2.11(m,2H),1.31(t,J＝7.6Hz,3H)。
实施例55
2-{[2-乙基-8-甲基-6-(2-(甲磺酰基)-2,7-二氮杂螺[3.5]壬烷-7-基)咪唑并[1,2-b]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例53，用2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯代替2,6-二氮杂螺[3.4]辛烷-6-甲酸叔丁酯制备得到2-{[2-乙基-8-甲基-6-(2-(甲磺酰基)-2,7-二氮杂螺[3.5]壬烷-7-基)咪唑并[1,2-b]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.18(m,2H),7.17(m,2H),6.71(m,1H),3.70(m,4H),3.61(s,3H),3.39(m,4H),2.86(s,3H),2.76(q,J＝7.6Hz,2H),2.60(s,3H),1.86(m,4H),1.33(t,J＝7.6Hz,3H)。
实施例56
2-{[2-乙基-6-(2-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,7-二氮杂螺[3.5]壬烷-7-基)-8-甲基咪唑并[1,2-a]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例54，用2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯代替2,6-二氮杂螺[3.4]辛烷-6-甲酸叔丁酯制备得到2-{[2-乙基-6-(2-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,7-二氮杂螺[3.5]壬烷-7-基)-8-甲基咪唑并[1,2-a]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.15(m,2H),7.16(m,2H),6.70(m,1H),4.64(m,1H),4.36(m,1H),4.23(m,1H),4.02(m,1H),3.84(m,1H),3.60(s,3H),3.36(m,4H),3.20-3.11(m,6H),2.75(q,J＝7.6Hz,2H),2.58(s,3H),1.81(m,4H),1.31(t,J＝7.6Hz,3H)。
实施例57
2-{[8-甲基-2-乙基-6-((1S,4S)-5-(甲磺酰基)-2,5-二氮杂二环[2.2.1]庚烷-2-基)咪唑并[1,2-b]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例53，用(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯代替2,6-二氮杂螺[3.4]辛烷-6-甲酸叔丁酯制备得到2-{[8-甲基-2-乙基-6-((1S,4S)-5-(甲磺酰基)-2,5-二氮杂二环[2.2.1]庚烷-2-基)咪唑并[1,2-b]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.16(m,2H),7.16(m,2H),6.39(m,1H),4.74(m,1H),4.57(m,1H),3.60(m,6H),3.36(m,2H),2.87(s,3H),2.76(q,J＝7.6Hz,2H),2.61(s,3H),2.04(m,1H),1.94(m,1H),1.33(t,J＝7.6Hz,3H)。
实施例58
2-{[8-甲基-2-乙基-6-((1S,4S)-5-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,5-二氮杂二环[2.2.1]庚烷-2-基)咪唑并[1,2-b]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例54，用(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯代替2,6-二氮杂螺[3.4]辛烷-6-甲酸叔丁酯制备得到2-{[8-甲基-2-乙基-6-((1S,4S)-5-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,5-二氮杂二环[2.2.1]庚烷-2-基)咪唑并[1,2-b]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为：1H NMR(400MHz,CDCl3)δ: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)。
实施例59
2-{[2-乙基-8-甲基-6-(6-(甲磺酰基)-2,6-二氮杂螺[3.3]庚烷-2-基)咪唑并[1,2-b]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例53，用2,6-二氮杂螺[3.3]庚烷-2-甲酸叔丁酯半草酸盐代替2,6-二氮杂螺[3.4]辛烷-6-甲酸叔丁酯制备得到2-{[2-乙基-8-甲基-6-(6-(甲磺酰基)-2,6-二氮杂螺[3.3]庚烷-2-基)咪唑并[1,2-b]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.16(m,2H),7.16(m,2H),6.26(m,1H),4.14(s,4H),4.10(s,4H),3.59(s,3H),2.86(s,3H),2.75(q,J＝7.6Hz,2H),2.59(s,3H),1.32(t,J＝7.6Hz,3H)。
实施例60
2-{[2-乙基-6-(7-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,6-二氮杂螺[3.3]庚烷-2-基)-8-甲基咪唑并[1,2-b]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例54，用2,6-二氮杂螺[3.3]庚烷-2-甲酸叔丁酯半草酸盐代替2,6-二氮杂螺[3.4]辛烷-6-甲酸叔丁酯制备得到2-{[2-乙基-6-(7-(2-(3-羟基氮杂环丁-1-基)-2-氧代乙基)-2,6-二氮杂螺[3.3]庚烷-2-基)-8-甲基咪唑并[1,2-b]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为：1H NMR(400MHz,CDCl3)δ:8.15(m,2H),7.16(m,2H),6.24(m,1H),4.65(m,1H),4.32(m,1H),4.23(m,1H),4.08(s,4H),3.98(m,1H),3.85(m,1H),3.58(s,3H),3.53(s,4H),3.09(m,2H),2.74(q,J＝7.6Hz,2H),2.57(s,3H),1.31(t,J＝7.6Hz,3H)。
实施例61
7-{3-[(5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基]2-乙基-8-甲基咪唑并[1,2-b]哒嗪-6-基}-2,7-二氮杂螺[3.5]壬烷-2-磺酰胺的制备。
(1)2-{[2-乙基-8-甲基-6-(2,7-二氮杂螺[3.5]壬烷-7-基)咪唑并[1,2-b]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈的制备。
参照实施例53，用2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯代替2,6-二氮杂螺[3.4]辛烷-6-甲酸叔丁酯制备得到2-{[2-乙基-8-甲基-6-(2,7-二氮杂螺[3.5]壬烷-7-基)咪唑并[1,2-b]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈。
表征数据为：MS(m/z)：517.3[M+1]。
(2)7-{3-[(5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基]2-乙基-8-甲基咪唑并[1,2-b]哒嗪-6-基}-2,7-二氮杂螺[3.5]壬烷-2-磺酰胺的制备。
将2-{[2-乙基-8-甲基-6-(2,7-二氮杂螺[3.5]壬烷-7-基)咪唑并[1,2-b]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(30mg,0.06mmol)溶于二氯甲烷(2mL)中，加入三乙胺(11μL,0.07mmol)，冷却至0℃。在另一反应瓶中，加入二氯甲烷(2mL)，冷却至0℃，再加入氯磺酰异氰酸酯(99mg,0.7mmol)和叔丁醇(52mg,0.7mmol)，搅拌50分钟后，将此反应液(1mL)加入至上述反应液中，于0℃继续搅拌6小时，旋干溶剂，经厚制备板纯化得白色固体20mg。将所得白色固体溶于二氯甲烷(4mL)，加入三氟乙酸(1mL)，室温反应2小时，旋干溶剂，用饱和碳酸氢钠调节pH至8左右，用二氯甲烷(10mLx3)萃取，无水硫酸钠干燥，旋干，经厚制备板纯化(二氯甲烷:甲醇＝20:1)得产物11mg，收率：32％。
表征数据为：1H NMR(400MHz,CDCl3)δ: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)。
实施例62
7-{3-[(5-氰基-4-(4-氟苯基)噻唑-2-基)(甲基)氨基]-2-乙基-8-甲基咪唑并[1,2-b]哒嗪-6-基}-2,7-二氮杂螺[3.5]壬烷-2-甲酰胺的制备。
将2-{[2-乙基-8-甲基-6-(2,7-二氮杂螺[3.5]壬烷-7-基)咪唑并[1,2-b]哒嗪-3-基](甲基)氨基}-4-(4-氟苯基)噻唑-5-甲腈(35mg,0.07mmol)溶于二氯甲烷(2mL)，加入三乙胺(41μL,0.28mmol)，氮气保护，加入三甲基硅基异氰酸酯(23mg,0.21mmol)，于室温反应3小时。加入水(0.5mL)，搅拌20分钟，旋干溶剂，经厚制备板纯化(二氯甲烷:甲醇＝20:1)得白色固体20mg。收率：50％。
表征数据为：1H NMR(400MHz,CDCl3)δ: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)。
实施例63 以FS-3为底物酶活性筛选
原理：利用lysoPLD酶活性能够将底物溶血磷脂胆碱(lysophosphatidylcholine,LPC)及其类似物进行水解。本实验所用的底物FS-3是用荧光素和荧光淬灭素同时标记的LPC类似物。当ATX作用该底物时，将其水解并释放出荧光素，从而进行检测。
试剂与仪器：ATX酶，底物FS-3及其相应试剂均购买自Echelon Biosciences Inc.公司(Salt Lake City,UT,USA)，DMSO(Sigma公司)。Envision2104荧光测定仪(美国Perkin Elmer公司)，加样器(Eppendorf公司)，微孔板(corning公司)。
具体实验步骤：首先加2ml的去离子水到底物FS-3中配置10μM的储存液，同时按照说明加适量的去离子水配制缓冲液C和D。加20μl包括缓冲液C和D和适量ATX酶的酶缓冲液到384微孔板中，每个孔然后加2.5μl的系列浓度梯度的化合物和相应的对照，室温孵育10分钟，然后每孔加2.5μl的FS-3底物，用微孔板读板仪进行动态读板一个小时，发射光和激发光的波长分别为485nM和528nM。根据荧光比值计算化合物对酶反应的抑制率，用GraphPad软件进行分析计算出化合物的IC 50值。
化合物的平均IC50值归纳为三个等级，分别为：A：IC 50<10nM；B:10nM<IC 50<50nM；C:IC 50>50nM。
实验结果如下表1所示。
表1 目标化合物对Autotaxin的抑制活性
实施例编号 IC 50值(nM) IC 50等级 实施例编号 IC 50值 IC 50等级
实施例1 3.92 A 实施例2 3.65 A
实施例3 1.77 A 实施例4 2.27 A
实施例5 4.45 A 实施例6 2.69 A
实施例7 12 B 实施例8 12 B
实施例9 4.87 A 实施例10 2.38 A
实施例11 2.71 A 实施例12 4.21 A
实施例13 1.37 A 实施例14 1.43 A
实施例15 1.50 A 实施例16 1.99 B
实施例17 2.22 A 实施例18 16.7 B
实施例19 10.2 B 实施例20 1.96 A
实施例21 0.83 A 实施例22 10.2 B
实施例23 2.87 A 实施例24 1.09 A
实施例25 2.77 A 实施例26 1.79 A
实施例27 36.2 B 实施例28 30.8 B
实施例29 60.2 C 实施例30 101 C
实施例31 53.1 C 实施例32 2.28 A
实施例33 8.73 A 实施例34 3.26 A
实施例35 1.28 A 实施例36 1.98 A
实施例37 2.01 A 实施例38 3.22 A
实施例39 10.6 B 实施例40 3.66 A
实施例41 1.96 A 实施例42 8.62 A
实施例43 3.69 A 实施例44 2.63 A
实施例45 2.84 A 实施例46 12.5 A
实施例47 9.6 A 实施例48 5.27 A
实施例49 20.2 B 实施例50 36.2 B
实施例51 10.4 B 实施例52 24.3 B
从上述结果中可以看出，本发明的化合物对Autotaxin有较好的抑制作用，特别是其中部分化合物，对Autotaxin抑制的IC50达到10nM以下，显示出了非常好的Autotaxin抑制活性。
实施例64 以LPC为底物酶活性筛选
原理：利用lysoPLD酶活性能够将底物溶血磷脂胆(lysophosphatidylcholine,LPC)进行水解，生成溶血磷脂酸(LPA)和胆碱，胆碱在胆碱氧化酶的作用下氧化生成H 2O 2，存在辣根过氧化物酶(HRP)时，Amplex Red试剂与H 2O 2以1:1的化学定量比反应，形成强荧光产物进行荧光定量检测。
实验步骤：受试化合物用DMSO溶解成10mM储备液，用DMSO进行3倍梯度稀释，起始浓度时10mM，10个浓度点。用反应缓冲溶液制备终浓度为2ng/μl ATX，2U/ml HRP和0.2U/ml choline oxidase的混合溶液1。向实验板中每孔加入20μl上述混合溶液1，按照10nl/孔，使用Echo550将DMSO稀释后的化合物转移进入实验板。用反应缓冲溶液中制备终浓度为60mM LPC和400uM Amplex Red的混合溶液2，实验板中每孔加入20ul的混合溶液2。加样后实验板在震板仪器上震荡30s，室温孵育30min。用Envision读取激发光530nm，发射光590nm的荧光信号。根据荧光比值计算化合物对酶反应的抑制率，用软件进行分析计算出化合物的IC 50值，见表2。
表2 本发明化合物以LPC为底物的ATX抑制活性分析
实施例编号 IC 50(μM) 实施例编号 IC 50(μM)
实施例3 0.639 实施例4 0.835
实施例6 1.092 实施例9 0.205
实施例10 0.661 实施例12 0.776
实施例13 0.404 实施例14 0.376
实施例15 0.199 实施例16 0.416
实施例21 0.058 实施例23 0.23
实施例24 0.30 实施例26 0.233
实施例28 2.182 实施例29 0.087
实施例31 0.038 实施例32 0.495
实施例33 0.575 实施例34 0.507
实施例35 0.80 实施例36 0.52
实施例38 0.488 实施例43 0.613
实施例44 0.462 实施例45 1.13
实施例47 0.597 实施例48 0.26
实施例51 0.506 实施例53 0.544
实施例54 0.678 实施例55 2.412
实施例56 0.421 实施例57 0.903
实施例58 0.286 实施例59 0.126
实施例60 0.28 实施例61 1.99
实施例62 0.099
由表2可知，本发明化合物具有较好的ATX抑制活性，从而可以抑制LPC被水解成LPA。
实施例65 人血浆LPA检测活性筛选
原理：以血浆中存在的LPC为底物，用LC/MS/MS定量分析检测生成的LPA18:2(以LPA17:0为内标)，在不同的受试化合物浓度点，剩余活性百分比由LPA18:2的生成量与不存在受试化合物时的生成量之比得出，计算IC 50值。
实验步骤：来源于至少6个个体人混合空白血浆，受试化合物从储备液起用稀释液3倍梯度稀释，配制8个系列浓度的工作溶液(含零点)。取10μL融化后的空白血浆样品，加入含内标(LPA17:0)的冰甲醇溶液直接进行蛋白沉淀，作为***对照样品。分别取2μL的系列浓度的工作溶液，加入198μL的人空白血浆，孵育浓度为0～10μM，将样品放入含5％CO 2的37℃孵育箱，孵育2个小时。孵育结束后，取10μL血浆样品，加入合适体积的含内标(LPA17:0)的冰甲醇溶液进行蛋白沉淀蛋白，离心后取上清液，通过LC/MS/MS，进行LPA18:2的检测，用软件进行分析计算出化合物的IC 50值，见表 2。
表3 本发明化合物的人全血分析IC 50
实施例编号 IC 50(μM) 实施例编号 IC 50(μM)
实施例9 0.147 实施例15 0.068
实施例21 0.164 实施例56 0.366
实施例59 0.147 实施例60 0.619
实施例62 0.224
由表3可知，本发明化合物能够抑制人血浆中的ATX，从而抑制LPC被水解成LPA。
实施例66 本发明化合物在SD大鼠经博莱霉素诱导的单侧肺纤维化模型中的预防 性治疗药效试验
BLM诱导的大鼠IPF模型：动物在SPF屏障内进行3-7天的适应性饲养后，根据动物体重随机分组，建立SD大鼠左侧肺肺纤维化模型：大鼠气管注射博莱霉素(3mg/kg)复制肺纤维化模型模型周期2周。造模当天开始口服给药(当天为试验第一天)，阳性药物每天两次，施用本发明化合物每天一次。连续给药14天。实验期间两天检测一次动物体重，监测试验周期内动物死亡率。
实验终点日(第15日)，动物安乐死时测量动物体重，对所有动物执行安乐死。动物经低温生理盐水全身灌注后，取全肺组织，再用10％***固定液进行肺组织离体灌流，灌流液10-15ml，再将肺组织固定于10％中性***固定液，固定液体积与肺组织体积比至少10:1，标本放于常温下固定至少72小时，采用Collagen-1、Ki67、a-SMA进行病理检测。
试验结果表明，本发明化合物可有效抑制SD大鼠肺纤维化，对肺纤维化疾病具有很好的预防和治疗作用。
实施例67 本发明化合物药代动力学试验
准确称取适量本发明化合物，加入适量溶媒，涡旋振荡后超声至澄清溶液，过滤后做为静脉给药制剂。准确称取适量本发明化合物，加入适量溶媒，涡旋振荡后超声至混合均匀的灌胃给药制剂。静脉、灌胃给药制剂均留样进行给药溶液分析。
实验前一天，大鼠禁食过夜(12h以上)，实验过程中可自由饮水。实验当天，称量体重后，计算每只大鼠的理论给药体积。给药制剂在实验当天现配现用，配制与给药间隔不超过2小时。SD大鼠给药4h后可恢复进食，实验过程中可自由饮水。
SD大鼠采用颈静脉取血方式，按规定时间点，从颈静脉采集0.2～0.4mL全血，置于含有EDTA-K2的抗凝管中颠倒数次充分混匀。收集到的血样在4℃，4000g条件下离 心5分钟取血浆。血浆样品置于-75±15℃冰箱保存直至分析。
建立测定SD大鼠血浆中本发明化合物的LC-MS/MS分析方法，测定生物样品中本发明化合物浓度。利用WinNonlin(PhoenixTM,)或其它类似软件进行药代动力学参数计算。
试验结果表明，本发明化合物在体内半衰期较长，毒性低，清除率理想，生物利用度高，具有优异的药代动力学性质。
上述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本
发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (11)

  1. 式I所示的化合物或者其药学上可接受的盐、立体异构体、溶剂化物或前药
    Figure PCTCN2018099622-appb-100001
    其中，在式I中：
    Ar 1为取代或未取代的苯基，取代或未取代的萘基，或取代或未取代的5-10个原子组成的单环或双环杂芳基；当Ar 1被取代时，可被选自卤素、C 1-C 4烷基、C 1-C 4烷氧基、C 2-C 4烯基、氰基、-CF 3、-C(C＝O)CH 3、-C(C＝O)CF 3、-C(C＝O)OCH 3、-C(C＝O)NH 2和-NH(C＝O)CH 3中的一个或多个取代基在任意位置取代；
    Ar 2为取代或未取代的五元或六元杂芳基；当Ar 2被取代时，可被选自卤素、氰基、C 1-C 4烷基、-C(C＝O)NH 2和-NH(C＝O)CH 3中的一个或多个取代基在任意位置取代；
    R 1为H，C 1-C 4烷基或C 3-C 6环烷基；
    R 2为H，取代或未取代的C 1-C 4烷基，取代或未取代的C 3-C 7环烷基，或取代或未取代的3-7个原子组成的杂环烷基；
    R 3为H，卤素，氰基，C 1-C 3烷基，C 1-C 4烷氧基，C 2-C 4烯基，或C 2-C 4炔基；
    A和M各自独立地为N或CR 6；其中R 6为氢，卤素，或C 1-C 3烷基；
    Cy为取代或未取代的7-11个原子组成的螺杂环，取代或未取代的6-11个原子组成的稠合杂环，或取代或未取代的7-11个原子组成的桥杂环；当Cy被取代时，可被1-2个选自氧，卤素，氰基，甲基，甲氧基和三氟甲基的基团取代；
    R 4为氢，卤素或C 1-C 3烷基；
    X为-O-，-C(＝O)-，-C(＝O)O-，-OC(＝O)-，-NR 7-，-SO 2-，-NR 7SO 2-，-SO 2NR 7-，-C(＝O)NR 7-，或-NR 7C(＝O)-；其中，R 7为氢或C 1-C 4烷基；
    L为取代或未取代的C 1-C 6烷基，取代或未取代的C 3-C 7环烷基，取代或未取代的4-7个原子组成的杂环烷基，取代或未取代的C 5-C 6环烷基，取代或未取代的5-6个原子组成的杂环烷基；当L被取代时，可被选自卤素，C 1-C 4烷基，三氟甲基，氰基， 羟基，氨基和C 1-C 4烷氧基的基团取代；
    R 5为氢，取代或未取代的C 1-C 4烷基，羟基，氰基，或-N(R 8) 2；其中，R 8为氢或C 1-C 4烷基；
    a为0、1、2、3、4或5；
    b为0或1；
    c为0或1；
    其中，当a，b或c为0时，相应基团为化学键。
  2. 根据权利要求1所述的化合物或者其药学上可接受的盐、立体异构体、溶剂化物或前药，其中，式I的化合物为式II(a)或II(b)的化合物
    Figure PCTCN2018099622-appb-100002
    其中，R 9为卤素，C 1-C 4烷基，C 1-C 4烷氧基，氰基或三氟甲基；
    R 10为氢，卤素，氰基或三氟甲基；
    R 11为氢，卤素或氰基；
    W为S或O；
    M为N或CR 6，其中R 6为氢；
    R 1、R 2、R 3、R 4、R 5、Cy、X、L、a、b、c如权利要求1所定义。
  3. 根据权利要求1或2所述的化合物或者其药学上可接受的盐、立体异构体、溶剂化物或前药，其中，在式I或式II(a)或II(b)中，
    R 1为C 1-C 4烷基，优选地为C 1-C 2烷基，更优选地为甲基；
    R 2为取代或未取代的C 1-C 4烷基，优选地为未取代的C 1-C 4烷基，更优选地为乙基；
    R 3为H，卤素，氰基或C 1-C 3烷基，优选地为H，卤素或C 1-C 3烷基，更优选地为H，氟或甲基；
    A和M各自独立地为N或CR 6，其中R 6为氢；优选地，A和M均为CR 6，其中R 6为氢；更优选地，A为CR 6，其中R 6为氢，M为N；
    R 4为氢或C 1-C 3烷基；优选地，R 4为氢；
    X为-C(＝O)-，-C(＝O)NR 7-，或-SO 2-；其中，R 7为甲基；
    L为取代或未取代的C 1-C 4烷基，取代或未取代的4-5个原子组成的杂环烷基，当L被取代时，可被选自卤素和羟基的基团取代；更优选地L为未取代或被羟基取代的
    Figure PCTCN2018099622-appb-100003
    未取代或被卤素或羟基取代的C 1-C 4的烷基；
    R 5为氢，羟基，未取代的C 1-C 4烷基，或-N(R 8) 2，其中，R 8为氢或C 1-C 4烷基；
    a为0或1；
    b为1；
    c为0或1。
  4. 根据权利要求1至3中任一项所述的化合物或者其药学上可接受的盐、立体异构体、溶剂化物或前药，其中，在式I或式II(a)或II(b)中，Cy为选自以下的基团：
    Figure PCTCN2018099622-appb-100004
    其中，d为0，1，2；
    e为1，2，3；
    f为0，1，2；
    g为1，2，3；且在螺杂环中，d、e、g和f之和不小于4并不大于8；在稠合杂环中，d、e、g和f之和不小于2并不大于7；在桥杂环中，d、e、g和f之和不小于2并不大于6；
    优选地，Cy为选自以下的基团：
    Figure PCTCN2018099622-appb-100005
  5. 根据权利要求1至4中任一项所述的化合物或者其药学上可接受的盐、立体异构体、溶剂化物或前药，其中，在式II(a)中，
    R 9为卤素，R 10为氢，R 11为氰基，W为S，R 1为C 1-C 4烷基，R 2为C 1-C 4烷基，
    R 3为氢或卤素或C 1-C 3烷基，M为N，
    Cy选自以下基团：
    Figure PCTCN2018099622-appb-100006
    R 4为氢，
    X为-C(＝O)-，-C(＝O)NR 7-，或-SO 2-；其中，R 7为甲基；
    L为取代或未取代的C 1-C 4烷基，取代或未取代的4-5个原子组成的杂环烷基，当L被取代时，可被选自卤素或羟基的基团取代；优选地L为未取代或被羟基取代的
    Figure PCTCN2018099622-appb-100007
    未取代或被卤素或羟基取代的C 1-C 4的烷基；
    R 5为氢，羟基，未取代的C 1-C 4烷基，或-N(R 8) 2，其中，R 8为氢或C 1-C 4烷基；
    a为0或1；
    b为1；
    c为0或1；
    其中，在式II(b)中，
    R 9为卤素，R 10为氢，R 11为氰基，W为S，R 1为C 1-C 4烷基(例如甲基)，R 2为C 1-C 4烷基(例如乙基)，R 3为氢或卤素(例如F)或C 1-C 3烷基(例如甲基)，Cy选自以下基团：
    Figure PCTCN2018099622-appb-100008
    R 4为氢，
    X为-C(＝O)-，-C(＝O)NR 7-，或-SO 2-；其中，R 7为甲基；
    L为取代或未取代的C 1-C 4烷基，取代或未取代的4-5个原子组成的杂环烷基，当L被取代时，可被选自卤素或羟基的基团取代；优选地L为未取代或被羟基取代的
    Figure PCTCN2018099622-appb-100009
    未取代或被卤素或羟基取代的C 1-C 4的烷基；
    R 5为氢，羟基，未取代的C 1-C 4烷基，或-N(R 8) 2，其中，R 8为氢或C 1-C 4烷基；
    a为0或1；
    b为1；
    c为0或1。
  6. 根据权利要求1至5中任一项所述的化合物或者其药学上可接受的盐、立体异构体、溶剂化物或前药，其中，式I的化合物为选自式III至XXI的化合物
    Figure PCTCN2018099622-appb-100010
    Figure PCTCN2018099622-appb-100011
    Figure PCTCN2018099622-appb-100012
    Figure PCTCN2018099622-appb-100013
    Figure PCTCN2018099622-appb-100014
    其中，R 9为卤素，C 1-C 4烷基或三氟甲基；
    R 10为氢，卤素或氰基；
    R 11为氢或氰基；
    R 1为C 1-C 4烷基，
    R 2为C 1-C 4烷基；
    R 3为氢，卤素或C 1-C 3烷基；
    X为-C(＝O)-，-C(＝O)NR 7-，或-SO 2-；其中，R 7为氢或C 1-C 4烷基；
    L为取代或未取代的C 1-C 6烷基，取代或未取代的C 3-C 7环烷基，取代或未取代的4-7个原子组成的杂环烷基，取代或未取代的C 5-C 6环烷基，取代或未取代的5-6个原子组成的杂环烷基；当L被取代时，可被选自卤素，甲基和三氟甲基的取代基取代；
    R 5为氢，取代或未取代的C 1-C 4烷基，羟基，氰基，或-N(R 8) 2；其中，R 8为氢或C 1-C 4烷基；
    a为0、1、2或3；
    b为0或1；
    c为0或1；
    优选地，
    R 9为卤素；更优选地为F；
    R 10为氢；
    R 11为氰基；
    R 1为甲基；
    R 2为乙基；
    R 3为氟或甲基；X为-C(＝O)-，-C(＝O)NR 7-，或-SO 2-；其中，R 7为甲基；
    L为取代或未取代的C 1-C 4烷基，取代或未取代的4-5个原子组成的杂环烷基，当 L被取代时，可被选自卤素和羟基的基团取代；更优选地L为未取代或被羟基取代的
    Figure PCTCN2018099622-appb-100015
    未取代或被卤素或羟基取代的C 1-C 4的烷基；
    R 5为氢，羟基，未取代的C 1-C 4烷基，或-N(R 8) 2，其中，R 8为氢或C 1-C 4烷基；
    a为0或1；
    b为1；
    c为0或1。
  7. 根据权利要求1-至6中任一项所述的化合物或者其药学上可接受的盐、立体异构体、溶剂化物或前药，其中，式I至XXI所示的化合物为选自下列的化合物：
    Figure PCTCN2018099622-appb-100016
    Figure PCTCN2018099622-appb-100017
    Figure PCTCN2018099622-appb-100018
    Figure PCTCN2018099622-appb-100019
  8. 根据权利要求1至7中任一项所述的化合物或者其药学上可接受的盐、立体异构体、溶剂化物或前药在制备用于预防和/或治疗具有ATX表达增加的病理学特征的疾病的药物中的用途。
  9. 根据权利要求8所述的用途，其中，所述具有ATX表达增加的病理学特征的疾病包括：癌症、纤维化疾病、代谢疾病、骨髓增生异常综合征、心血管疾病、自身免疫性疾病、炎症、神经***疾病或疼痛；
    优选地，所述具有ATX表达增加的病理学特征的疾病为肺纤维化或肝纤维化。
  10. 一种药物组合物，所述药物组合物包含权利要求1-7中任一项所述的化合物或者其药学上可接受的盐、立体异构体、溶剂化物或前药，以及药学上可以接受的辅料或载体。
  11. 一种用于治疗和/或预防具有ATX表达增加的病理学特征的疾病的方法，所述方法包括给有此需要的受试者施用权利要求1至7中任一项所述的化合物或者其药学上可接受的盐、立体异构体、溶剂化物或前药或者权利要求10所述的药物组合物。
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020244539A1 (zh) * 2019-06-04 2020-12-10 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
EP3805234A4 (en) * 2018-05-24 2022-03-09 Guangzhou Henovcom Bioscience Co., Ltd. AROMATIC HETEROCYCLIC COMPOUND, PHARMACEUTICAL COMPOSITION AND ITS USE
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
CN112778334B (zh) * 2019-11-07 2022-04-15 广州市恒诺康医药科技有限公司 芳杂环化合物、其药物组合物及其应用
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
WO2023093832A1 (zh) * 2021-11-25 2023-06-01 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 (en) * 2018-05-24 2022-03-09 Guangzhou Henovcom Bioscience Co., Ltd. AROMATIC HETEROCYCLIC COMPOUND, PHARMACEUTICAL COMPOSITION AND ITS USE
WO2020244539A1 (zh) * 2019-06-04 2020-12-10 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
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

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