WO2019134680A1 - Inhibiteur de kinase-1 régulateur du signal apoptotique et utilisation associée - Google Patents

Inhibiteur de kinase-1 régulateur du signal apoptotique et utilisation associée Download PDF

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WO2019134680A1
WO2019134680A1 PCT/CN2019/070465 CN2019070465W WO2019134680A1 WO 2019134680 A1 WO2019134680 A1 WO 2019134680A1 CN 2019070465 W CN2019070465 W CN 2019070465W WO 2019134680 A1 WO2019134680 A1 WO 2019134680A1
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unsubstituted
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alkyl
independently selected
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张健存
邹晴安
陈延维
李斌
康宁
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Guangzhou Henovcom Bioscience Co Ltd
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Guangzhou Henovcom Bioscience Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to an apoptosis signal-regulating kinase-1 inhibitor and its use.
  • the mitogen-activated protein kinase (MAPK) pathway is a critical signaling pathway regulating cellular stress responses, including three classes of protein kinases, MAPK, MAPK kinase (MAP2K) and MAPK kinase kinase (MAP3K).
  • MAPK MAPK
  • MAPK MAPK kinase
  • MAPK3K MAPK kinase kinase kinase
  • MAP3K MAPK kinase kinase kinase
  • MAP3K MAPK kinase kinase kinase
  • Apoptosis Signaling Regulatory Kinase 1 also known as MAP3K5
  • MAP3K5 Apoptosis Signaling Regulatory Kinase 1
  • MAP2K3K5 Apoptosis Signaling Regulatory Kinase 1
  • MAP2K3K4 Apoptosis Signaling Regulatory Kinase 1
  • MAP2K6 Apoptosis Signaling Regulatory Kinase 1
  • JNK c-Jun N-terminal kinase
  • Apoptosis Signaling Regulatory Kinase-1 is a 1374 amino acid polypeptide with 9 alpha-helix regions and 11 beta-sheet regions with a serine/threonine as the central region of action for the kinase. There is a coiled-coil structure at the N-terminus and the C-terminus, respectively, and the catalytic region has 2 ⁇ -helices and 5 ⁇ -sheets.
  • ASK1 forms a stable homodimer through the coiled-coil structure at the C-terminus and then forms a heterologous complex with ASK2.
  • ASK1 acts as a stabilizing agent in the complex, and the two can activate each other.
  • ASK1 Under normal conditions, the N-terminus of ASK1 binds to reduced thioredoxin (Trx), which is used to block the activation of ASK1. Under oxidative stress, Trx detaches and the conformation of ASK1 changes, allowing the phosphorylation site to autophosphorylate or phosphorylate.
  • ASK1 has three autophosphorylation sites, Thr813, Thr838 and Thr842.
  • Thr813 is located in the loop region between ⁇ 8 and ⁇ 9, away from the substrate binding site, which phosphorylates and changes the surrounding conformation, indirectly affecting the catalytic function of ASK1.
  • Thr838 is located in the catalytic region, and this site is phosphorylated to stabilize the catalytic region. At the same time, Thr838 plays an important role in oxidative stress-induced ASK1 activation.
  • the third phosphorylation site Thr842 is near the catalytic region amino acid residue Asp803.
  • ASK1 is in an unactivated state under normal conditions and has no phosphorylation function and cannot regulate downstream pathways. However, once the body has immune stress, including oxidative stress, endoplasmic reticulum stress, calcium influx, DNA damage, viral infection, and some inflammatory factors (such as tumor necrosis factor alpha (TNF ⁇ ) and lipopolysaccharide (LPS) ), etc., ASK1 will respond. Activation of ASK1 is regulated by a number of proteins that are in contact with it, of which the role of reduced thioredoxin (Trx) is critical. Trx is a redox protein that changes its structure depending on the redox state of the cell.
  • Trx reduced thioredoxin
  • Trx[Trx-(SH)2] binds to the N-terminal coiled-coil structure of the ASK1 oligomer, inhibiting the activation of ASK1 by inhibiting the homophilic interaction under non-stimulated conditions.
  • Trx will be converted to an oxidized state (Trx-S2), detached from ASK1, causing the N-terminal coiled-coil structure to be closely oligomerized, forming The ASK1 signalling body will attract TNF receptor-associated factor 1 and (TRAF2 and 6) to form a complex, which triggers ASK1 autophosphorylation site and activates by autophosphorylation.
  • TRAF2 and 6 can also be directly used as activating factor of ASK1 to depolymerize Trx from ASK1.
  • calmodulin kinase CaMKII
  • Ang angiotensin II receptor type 1
  • TLR 4 Toll-like receptors TLR 4, 7 and 8
  • CaMKII calmodulin kinase
  • Ang angiotensin II receptor type 1
  • TLR 4 Toll-like receptors TLR 4, 7 and 8
  • TRAF2 and 6 will be reduced in Trx [Trx] -(SH)2]
  • Depolymerization from ASK1 triggers Thr838 phosphorylation to activate ASK1; or in the influx of calcium ions, CaMKII acts directly on ASK1 to activate it.
  • ASK1 protein phosphorylates downstream MKK4/7 or MKK3/6, which in turn activates the relevant JNK (JNK1, 2, and 3) pathways or the associated p38 (p38 ⁇ , ⁇ , ⁇ , and ⁇ ) pathways, triggering downstream A range of biological effects, such as apoptosis, immune response, secretion of cytokines, etc.
  • JNK1, 2, and 3 the relevant JNK
  • p38 ⁇ , ⁇ , ⁇ , and ⁇ p38 ⁇ , ⁇ , ⁇ , and ⁇
  • ASK1 Under oxidative stress, ASK1 is activated in a large amount, which increases the release of cytokines in mitochondria and decreases the consumption of caspase-9, which leads to mitochondria-dependent apoptosis.
  • ASK1 can also participate in the process of cytokine release and inflammation in vivo under the regulation of Toll-like receptor-4 (TLR4) signaling.
  • TLR4 Toll-like receptor-4
  • TLR4 specifically recognizes lipopolysaccharide on the surface of Gram-negative bacteria, and the resulting complex produces reactive oxygen species, triggers ASK1 activation, and activates p38 through the MAPK pathway, resulting in the release of a series of cytokines and inflammation. Therefore, the ASK1-MAPK pathway is closely related to the occurrence of many diseases.
  • the diseases involved in the ASK1-MAPK pathway are: (1) cardiovascular disease, including ischemia/reperfusion injury, cardiac remodeling, and endothelial dysfunction; (2) neurodegenerative diseases, including polyglutamine (PolyQ) Diseases (such as Huntington's disease, spinal cord muscle atrophy, certain types of spinal cerebellar ataxia), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), normal Intraocular pressure glaucoma, etc.; (3) inflammatory diseases, including multiple sclerosis (MS), rheumatoid arthritis (RA); (4) infectious diseases, including influenza virus, HIV-1, Japanese encephalitis virus (JEV) , sepsis, hepatitis C virus (HCV), etc.; (5) tumors, including skin cancer, colon cancer, stomach cancer, liver cancer, melanoma; (6) other diseases, including Fanconi anemia, asthma, hepatic steatosis (such as Nonalcoholic fatty liver disease (NAFLD
  • ASK1 protein activity can block the downstream pathway controlled by ASK1, thereby alleviating or curing related diseases. Therefore, it is of great scientific significance to find and discover highly effective ASK1 inhibitors. And good clinical application prospects.
  • the present invention provides a new class of fused ring compounds which bind to ASK1 and act as ASK1 inhibitors.
  • V 1 and V 6 are each independently selected from: N or C;
  • V 2 , V 3 , V 4 and V 5 are each independently selected from: O, S, N, -N(R 1 )-, -C(R 2 )- or none;
  • Each R 1 is independently selected from the group consisting of: H, D, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 -C 4 alkyne a substituted or unsubstituted C 3 -C 7 cycloalkyl group, or a substituted or unsubstituted heterocycloalkyl group of 3-7 atoms;
  • Each R 2 is independently selected from the group consisting of: H, D, oxo, thio, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted a C 2 -C 4 alkynyl group, a substituted or unsubstituted C 3 -C 7 cycloalkyl group, or a substituted or unsubstituted heterocycloalkyl group of 3-7 atoms;
  • R 4 and R 5 is independently selected from the group consisting of: H, D, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 a -C 6 alkenyl group, a substituted or unsubstituted C 2 -C 6 alkynyl group, a substituted or unsubstituted C 6 -C 10 aryl group, or a substituted or unsubstituted heteroaryl group of 5-10 atoms, or R 4 and R 5 together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring of 3 to 6 atoms;
  • a 1, 2 or 3;
  • R 7 and R 8 is independently selected from the group consisting of: H, D, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 a -C 6 alkenyl group, a substituted or unsubstituted C 2 -C 6 alkynyl group, a substituted or unsubstituted C 6 -C 10 aryl group, or a substituted or unsubstituted heteroaryl group of 5-10 atoms;
  • W 1 , W 2 and W 3 are each independently selected from: N or -C(R 11 )-;
  • Each R 11 is independently selected from the group consisting of: H, D, halogen, -CN, substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted ester, amide, amino, ether, sulfonamide, Or a phosphoramide group;
  • Each R 12 is independently selected from the group consisting of: H, D, substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkyne a group, or a C 3 -C 6 cycloalkyl group;
  • b is 1, 2, 3 or 4;
  • Ar 1 and Ar 2 are each independently selected from: 1 or more R 16 substituted or unsubstituted aryl groups of 6-10 atoms, or 1 or more R 16 substituted or unsubstituted 5-6 a heteroaryl group composed of atoms;
  • Each R 16 is independently selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, one or more R 17 substituted or unsubstituted C 1 -C 6 alkyl, one or more R 17 substituted or unsubstituted C 2 -C 4 alkenyl, 1 or more R 17 substituted or unsubstituted C 2 -C 4 alkynyl, 1 or more R 17 substituted or unsubstituted C 3 -C 6 cycloalkyl, 1 One or more R 17 substituted or unsubstituted C 2 -C 7 heterocycloalkyl groups, one or more R 17 substituted or unsubstituted C 1 -C 6 alkoxy groups, substituted by one or more R 17 Or an unsubstituted C 6 -C 10 aryl group, one or more R 17 substituted or unsubstituted heteroaryl groups of 5-10 atoms, or -COOR 18 ;
  • Each R 17 is independently selected from the group consisting of: H, halogen, hydroxy, or cyano;
  • R 18 is selected from the group consisting of: H, or a C 1 -C 4 alkyl group.
  • V 1 , V 2 , V 3 , V 4 , V 5 , and V 6 together comprise the following cyclic structure:
  • R 1 and R 2 are as described above.
  • the fused ring compound has the structure of Formula II:
  • V 3 and V 4 are each independently selected from -C(R 2 )- or N;
  • R 2 , X, Y, Z, W 1 , W 2 , W 3 , Ar 1 and Ar 2 are as described above.
  • the fused ring compound has the structure of Formula III:
  • V 3 is -C(R 2 )- and V 4 is N, or V 3 is N and V 4 is -C(R 2 )-;
  • W 2 is selected from: N or -C(R 11 )-;
  • B 1 , B 2 , B 3 and B 4 are each independently selected from: O, N, S, -C(R 15 )- or none;
  • E 1 and E 2 are each independently selected from: N or -C(R 15 )-;
  • R 13 is selected from the group consisting of: H, 1 or more R 17 -substituted C 1 -C 4 alkyl groups, or 1 or more R 17 -substituted or unsubstituted C 3 -C 6 cycloalkyl groups;
  • R 14 is selected from the group consisting of: H, D, 1 or more R 17 substituted or unsubstituted C 1 -C 4 alkyl, 1 or more R 17 substituted or unsubstituted C 2 -C 4 alkenyl, 1 One or more R 17 substituted or unsubstituted C 2 -C 4 alkynyl groups, or one or more R 17 substituted or unsubstituted C 3 -C 6 cycloalkyl groups; or, R 13 , R 14 and The linked N and C together form a heterocyclic group consisting of 5-8 atoms;
  • Each R 15 is independently selected from: H, D, 1 or more R 17 substituted or unsubstituted C 1 -C 4 alkyl, 1 or more R 17 substituted or unsubstituted C 2 -C 4 Alkenyl, 1 or more R 17 substituted or unsubstituted C 2 -C 4 alkynyl, or 1 or more R 17 substituted or unsubstituted C 3 -C 6 cycloalkyl;
  • R 2 , X, Y, Z, R 11 and R 17 are as defined in claim 1.
  • the fused ring compound has the structure of Formula IV:
  • V 3 , V 4 , X, Y, Z, W 2 and R 13 are as described above.
  • the fused ring compound has the structure of Formula V:
  • V 3 , V 4 , X, Y, Z, W 2 and R 13 are as described above.
  • X, Y, and Z are joined to form the following structure:
  • X, Y, and Z are joined to form the following structure:
  • each R 2 is independently selected from: C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, or C 3 -C 6 cycloalkyl.
  • each R 2 is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, or ring. Amyl.
  • each R 11 is independently selected from the group consisting of: H, halo, or C 1 -C 3 alkyl.
  • R 11 is selected from the group consisting of F, Cl, Br, I, methyl, ethyl, propyl, or isopropyl.
  • R 13 is selected from the group consisting of: H, C 1 -C 4 alkyl, hydroxy-substituted C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl.
  • R 13 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, or hydroxy-substituted isopropyl.
  • R 4 and R 5 are each independently selected from: H, C 1 -C 3 alkyl, or C 3 -C 6 cycloalkyl, or a carbon to which R 4 and R 5 are attached
  • R 4 and R 5 are each independently selected from the group consisting of: H, methyl, ethyl, or propyl.
  • the fused ring compound has the structure of Formula VI:
  • W 2 is selected from the group consisting of: N or -C(R 11 )-;
  • R 2 is selected from the group consisting of: C 3 -C 6 cycloalkyl
  • Each R 9 and R 10 are independently selected from: H, 1 or more R 16 substituted or unsubstituted C 2 -C 6 alkynyl groups, 1 or more R 16 substituted or unsubstituted C 1 -C a 6 alkyl group, one or more R 16 substituted or unsubstituted C 6 -C 10 aryl groups, one or more R 16 substituted or unsubstituted heteroaryl groups of 5-6 atoms, 1 or a plurality of R 16 substituted or unsubstituted C 3-7 heterocyclic groups, or one or more R 16 substituted or unsubstituted C 3 -C 6 cycloalkyl groups;
  • R 11 is selected from the group consisting of halogen
  • R 13 is selected from the group consisting of: C 1 -C 4 alkyl
  • Each R 16 is independently selected from the group consisting of: hydrogen, -CN, -OH, carboxyl, -COOMe, halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1-6 alkyl or halogen .
  • Each of R 9 and R 10 is independently selected from the group consisting of: H, ethynyl, C 1 -C 6 alkyl, phenyl, C 3 -C 6 cycloalkyl, heteroaryl of 5-6 atoms, naphthyl Or a C 3-7 heterocyclic group; wherein the C 1 -C 6 alkyl group, phenyl group, C 3 -C 6 cycloalkyl group, heteroaryl group composed of 5-6 atoms, naphthyl group and C 3-
  • the 7 heterocyclic group may be optionally selected from one or more independently selected from the group consisting of F, Cl, Br, I, CH 3 O-, CH 3 CH 2 O-, -CF 3 , -CH 2 CF 3 , C 1-4 Substituted by alkyl, -CN, -OH, C 1-4 haloalkyl, carboxy, and -COOMe substituents.
  • the fused ring compound is selected from the group consisting of:
  • the invention also provides the use of the above fused ring compounds.
  • the ASK1-mediated disease comprises: renal fibrosis, liver fibrosis, pulmonary fibrosis, chronic kidney disease, diabetic nephropathy, pulmonary hypertension, tumor.
  • the invention also provides a pharmaceutical composition for the prevention and treatment of a disease mediated by ASK1.
  • the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof can be prepared with a pharmaceutically acceptable adjuvant or carrier to obtain a pharmaceutical composition for preventing and treating ASK1-mediated diseases.
  • the pharmaceutically acceptable excipient or carrier may be an excipient or a sustained release agent or the like.
  • 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.
  • the present invention demonstrates by experiments that a series of novel fused ring compounds provided by the present invention can effectively bind to ASK1 and act as ASK1 inhibitors, thereby blocking the downstream pathway of ASK1 control, and alleviating or curing ASK1-mediated related diseases.
  • the compounds of the invention have important scientific research significance and good clinical application prospects.
  • alkyl or "alkyl group” as used herein, denotes a saturated straight or branched monovalent hydrocarbon group containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally selected The ground is replaced by one or more substituents described herein. Unless otherwise specified, an alkyl group contains from 1 to 20 carbon atoms. In one embodiment, the alkyl group contains from 1 to 12 carbon atoms; in another embodiment, the alkyl group contains from 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 - 4 carbon atoms; also in one embodiment, the alkyl group contains 1-3 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH) (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C(CHCH
  • alkenyl denotes a straight or branched chain monovalent hydrocarbon radical containing from 2 to 12 carbon atoms, wherein at least one site of unsaturation, i.e., has a carbon-carbon sp 2 double bond, wherein the alkenyl group
  • the group may be optionally substituted with one or more substituents described herein, including the positioning of "cis” and “tans", or the 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 at least one site of unsaturation, i.e., has a carbon-carbon sp triple bond, wherein the alkynyl group It may be optionally substituted with one or more of the substituents described herein.
  • 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. .
  • alkoxy denotes an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains from 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains from 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains from 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy group can be optionally substituted with one or more substituents described herein.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propyloxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butyl Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH
  • haloalkyl denotes an alkyl, alkenyl or alkoxy group substituted by one or more halogen atoms, examples of which include, but are not limited to, Trifluoromethyl, trifluoromethoxy, and the like.
  • cycloalkyl denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic system containing from 3 to 12 carbon atoms. In one embodiment, the cycloalkyl group contains 3 to 12 carbon atoms; in another embodiment, the cycloalkyl group contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atom.
  • the cycloalkyl group can be independently unsubstituted or substituted with one or more substituents described herein. Suitable cycloalkyl groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl.
  • Examples of the cycloalkyl group further include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a 1-cyclopentyl-1-alkenyl group, a 1-cyclopentyl-2-alkenyl group, a 1-cyclopentyl group- 3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl Base, cyclodecyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic, bicyclic ring containing 3-12 or 3-7 ring atoms. Or a tricyclic ring wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms.
  • the sulfur atom of the ring can be optionally oxidized to an S-oxide.
  • heterocyclic or heterocycloalkyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, 2-pyrroline, 3-pyrroline, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentane , dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholine Base, piperazinyl, oxiranyl, azetidinyl, oxetanyl
  • Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, a sulfolane group and a 1,1-dioxothiomorpholinyl group.
  • the heterocyclyl group can be optionally substituted with one or more substituents described herein.
  • halogen means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • aryl denotes a monocyclic, bicyclic and tricyclic carbocyclic ring system containing from 6 to 14 ring atoms, or from 6 to 12 ring atoms, or from 6 to 10 ring atoms, wherein at least one ring system is aromatic Of the family, wherein each ring system comprises a ring of 3-7 atoms and one or more attachment points are attached to the remainder of the molecule.
  • aryl can be used interchangeably with the term "aromatic ring”. Examples of the aryl group may include a phenyl group, a naphthyl group, and an anthracene. The aryl group may be independently and optionally substituted with one or more substituents described herein.
  • heteroaryl denotes a monocyclic, bicyclic and tricyclic ring system containing from 5 to 12 ring atoms, or from 5 to 10 ring atoms, or from 5 to 6 ring atoms, wherein at least one ring system is aromatic, And at least one ring system comprises one or more heteroatoms, wherein each ring system comprises a ring of 5-7 atoms and one or more attachment points are attached to the remainder of the molecule.
  • heteroaryl can be used interchangeably with the terms “heteroaryl ring” or “heteroaromatic compound”.
  • the heteroaryl group is optionally substituted with one or more substituents described herein.
  • a heteroaryl group of 5-10 atoms comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (eg 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-thi
  • fused aryl refers to a monovalent aromatic ring group formed by the two aromatic rings sharing two carbon atoms, such as a naphthyl group.
  • Condensed aryl means a monovalent aromatic ring group in which at least one carbon atom of the ring is replaced by a hetero atom selected from nitrogen, oxygen or sulfur to share two carbon atoms.
  • spirocycloalkyl refers to a cyclic group formed by the two rings sharing one carbon atom
  • spiroheterocyclyl means a ring shared by at least one hetero atom selected from nitrogen, oxygen or sulfur. a cyclic group formed by one carbon atom. Examples of spiroheterocyclyl groups include, but are not limited to: Wait.
  • fused cycloalkyl refers to a cyclic group formed by the two rings sharing two carbon atoms
  • fused heterocyclic group means two having at least one hetero atom selected from nitrogen, oxygen or sulfur.
  • bridged cycloalkyl refers to a cyclic group formed by two rings sharing three or more carbon atoms
  • bridge heterocyclic group means a hetero atom containing at least one selected from nitrogen, oxygen or sulfur.
  • the two rings share a cyclic group formed by three or more carbon atoms. Examples include but are not limited to: Wait.
  • 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.
  • substituents include, but are not limited to, H, D, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 - C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, halogen, thiol, hydroxy, nitro, cyano, C 3 -C 8 cycloalkyl, 3-8 Heterocyclic alkyl group consisting of a hetero atom, a C 6 -C 14 aryl group, a heteroaryl group of 5-14 atoms, a C 3 -C 8 cycloalkoxy group, a heterocycloalkoxy group of 3-8 atoms a cycloalkylthio group of 3-8 atoms, a heterocycloalkyl
  • 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 Formulas I-VI, 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.
  • the salt of the basic compound is prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric or excess amount of the desired salt or mixture of the inorganic or organic acid in a suitable solvent or combination of solvents.
  • 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
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluron hexafluorophosphate
  • NBS N-bromosuccinimide
  • AIBN azobisisobutyronitrile
  • PE petroleum ether
  • EA ethyl acetate
  • 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.
  • Methyl 6-aminopyridine-2-carboxylate (5.0 g, 32.7 mmol) was dissolved in methanol (60 mL), and EtOAc (EtOAc, EtOAc (EtOAc) It was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate. The filter cake was dried to give 4.25 g of white solid.
  • the intermediate 1-3 (6.0 g, 25.3 mmol) was dissolved in acetonitrile (28 mL) and acetic acid (7 mL), and then isopropylamine (11 mL, 126.6 mmol) was added, and the mixture was refluxed at 80 ° C for 3 hours. Cool to room temperature, spin dry, add water (30 mL) to dissolve, adjust the pH to about 8 with 2M NaOH solution, precipitate a white solid, filter, wash the filter cake with water, and the filter cake is dried to give a white solid 2.35 g. Yield: 46%.
  • the intermediate 1-11 (1.2 g, 2.82 mmol) was dissolved in tetrahydrofuran (20 mL), and borane tetrahydrofuran (11.2 mL, 11.2 mmol) was added dropwise.
  • the reaction solution was cooled to room temperature, and the reaction was quenched by dropwise addition of methanol. After the reaction was stopped, then 1N HCl (10 mL) was added and stirred at room temperature overnight.
  • 6-Amino-1,2,3,4-tetrahydro-1-naphthalenone (9.8 g, 60.87 mmol) was dissolved in a mixed solvent of 40 mL of DMF and 80 mL of o-dichlorobenzene, cooled to 0 ° C, and added dropwise.
  • Boron fluoride-diethyl ether (12.96 g, 91.3 mmol) was added and stirring was continued for 30 min.
  • Tert-butyl nitrite (7.5 g, 72.81 mmol) was added dropwise, and after completion of the dropwise addition, stirring was continued for 1 hour.
  • the reaction was heated to 130-135 ° C, and a condenser was connected during the temperature rise to recover the DME solvent.
  • the intermediate 14-4 (2.3g, 9.47mmol) was dissolved in chloroform (20mL), was added NaN 3 (1.8g, 28.3mmol) at, 20-30 °C, 9mL of concentrated sulfuric acid was added dropwise over 30 minutes. After the completion of the dropwise addition, the reaction was carried out for 30 minutes, and the mixture was adjusted to pH 10 with a saturated solution of K 2 CO 3 , extracted with ethyl acetate (100 mL ⁇ 3), washed with saturated brine, dried over anhydrous sodium sulfate and dried . The yield is 100%.
  • the intermediate 18-7 (30 mg, 0.063 mmol) was dissolved in acetonitrile, 4-trifluoromethylbenzyl chloride (19 ⁇ L, 0.13 mmol) and triethylamine (26 ⁇ L, 0.19 mmol) were added, and the reaction was stopped at room temperature for 3 hours, then the reaction was stopped. , spin dry, purified by thick preparation of a white solid 25 mg, yield: 63%.
  • Example 27 the compound 30 was obtained by substituting 1-chloro-4-bromo-2-(trifluoromethyl)benzene for 1-bromo-4-(trifluoromethyl)benzene.
  • Methyl 2,4-difluoro-4-nitrobenzoate (5.0 g, 23 mmol) was dissolved in tetrahydrofuran (50 mL).
  • Methyl 3-aminopropanoate hydrochloride (4.8 g, 34.5 mmol) Under the protection, it was cooled to 0 ° C, and triethylamine (5.8 g, 57.5 mmol) was added dropwise. After the dropwise addition was completed, stirring was continued at 0 ° C for 5 hours. Water (100 mL) and ethyl acetate (50 mL) were evaporated andEtOAc evaporated. The organic phase was combined, dried over anhydrous sodium sulfate and evaporated to dryness
  • Methyl 2-fluoro-4-hydroxybenzoate (10g, 64.2mmol) was dissolved in methanol (80mL), concentrated sulfuric acid (2mL) was added, and the reaction was heated to reflux for 4 hours, cooled to room temperature, and the pH was adjusted by adding NaHCO 3 solution. The mixture was extracted with ethyl acetate (100 mL ⁇ 3), and the organic phase was combined, dried over anhydrous sodium sulfate and dried to give 11 g of product.
  • the intermediate 40-6 (4.0 g, 11.2 mmol) was dissolved in dioxane (20 mL), and then 5N HCl / dioxane solution (8 mL). The residue was added to EtOAc (EtOAc) (EtOAc) The reaction was carried out for 2 days at room temperature. Water (50 mL) was added, and the organic layer was evaporated. EtOAcjjjjjjjj 1) Yielded 700 mg of pale yellow solid, yield: 26%.
  • Example 31 the compound 41 was obtained by substituting the intermediate 41-1 for the intermediate 31-4.
  • Example 23 the compound 47 was obtained by substituting 2,4-difluorobenzoic acid for 2-methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid.
  • Example 23 the compound 71 was obtained by substituting 3-fluoro-4-bromobenzoic acid for 2-methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid.
  • Triphosgene (18.7 mg, 0.063 mmol) was dissolved in dichloromethane (1 mL) and cooled to 0 °C.
  • the intermediate 18-7 (30 mg, 0.063 mmol) was dissolved in dichloromethane (1 mL), triethylamine (53 ⁇ L, 0.38 mmol) was added, and the obtained mixture was added dropwise to the above-mentioned reaction mixture at 0 ° C. After stirring at 0 ° C for 1 hour, 3,3-difluoroazetidine hydrochloride (41 mg, 0.32 mmol) and triethylamine (53 ⁇ L, 0.38 mmol) were added, and the mixture was slowly warmed to room temperature and stirred overnight.
  • Example 78 compound 80 was obtained by substituting 1-cyanocyclopropylamine hydrochloride for 3,3-difluoroazetidine hydrochloride.
  • Example 73 the compound 82 was obtained by substituting 1,1,1-trifluoro-2-methylpropan-2-amine hydrochloride for 3,3-difluoropyrrolidine hydrochloride.
  • the intermediate 18-7 was dissolved in tetrahydrofuran (3 mL), triethylamine (31 ⁇ L, 0.22 mmol) and trifluoroethyl trifluoromethanesulfonate (16 ⁇ L, 0.11 mmol).
  • Example 78 compound 105 was obtained by substituting 3-hydroxy-3-trifluoromethylazetidine hydrochloride for 3,3-difluoroazetidine hydrochloride. Ms (m/z): 640.2 [M + 1].
  • Methyl 2,4-dichlorochloride (5 g, 24.3 mmol) was dissolved in ethanol (100 mL) and lithium bromide (3.17 g, 36.5 mmol) was added, and sodium borohydride (2.75 g, 72.8 mmol) was added portionwise. After the reaction was carried out for 2 hours at room temperature, the ethanol was evaporated, EtOAc (EtOAc)EtOAc. g, yield: 97%. Ms (m/z): 206.0 [M + 1].
  • the enzymatic activity of an inhibitor of apoptosis signal-regulating kinase was determined using HTRF (Homogeneous Time-Resolved Fluorescence) technology. Fluorescence resonance energy transfer between a donor and a receptor (second fluorescent label) based on Eu cryptate is utilized as a donor using chelating and labeling elements of Eu elements having a cryptate structure. When two fluorophores are brought close due to biomolecular interaction, part of the energy captured by the cryptate at the time of excitation is released, and the emission wavelength is 620 nm; the other part of the energy is transferred to the receptor at an emission wavelength of 665 nm.
  • HTRF Homogeneous Time-Resolved Fluorescence
  • the emission light of 665 nm is only produced by the FRET caused by the donor. Therefore, when the biomolecules interact, there are two excitation lights of 620 nm and 665 nm; when there is no interaction, only one excitation light of 620 nm, and finally by a fluorometer Detection.
  • HTRF kinEASE-STK kit (Cisbio, 62ST3PEC), MAP3K5 (ASK1) (Invitrogen, PV3809), DMSO (Sigma, D8418-1L), ATP (Sigma, A7699), DTT (Sigma, D0632), MgCl2 ( Sigma, M1028).
  • Plate shaker Thermo, 4625-1CECN/THZ Q
  • Centrifuge Eppendorf, 5810R
  • Envision 2014 multilabel Reader PerkinElmer, 2104-0010
  • Echo (Labcyte, 550).
  • test compound was formulated into a 10 mM stock solution in DMSO, and the test compound was diluted 3 times from 10 mM for a total of 10 gradients.
  • 1X Kinase Reaction Buffer (5 mM MgCl 2 , 1 mM DTT) was prepared by adding 4 volumes of water to 1 volume of 5X kinase reaction solution. 10 nL of the diluted compound was added to the corresponding well of the reaction plate, and the reaction plate was sealed with a sealing plate, centrifuged at 1000 g for 1 minute, and 5X ASK1 (15 nM) was prepared by using 1X enzyme reaction buffer, and the reaction plate of the compound was added per well.
  • 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.
  • Compound number Activity level Compound number Activity level Compound number Activity level Compound number Activity level Compound number Activity level 1 B 2 C 3 A 4 A 5 A 6 C 7 C 8 A 9 A 10 A 11 A 12 B 13 B 14 C 15 A 17 A 18 A 19 A 20 A twenty one A twenty two A twenty three A twenty four A 25 A 26 A 27 A 28 A 29 A 30 A 31 B 32 C 33 A 34 A 35 A 36 A 37 A 38 A 39 A 40 A 41 A 42 C 43 A 44 A 45 A 46 A 47 A 48 A 49 A 50 A 51 A 52 A 53 A 54 A 55 A 56 A 57 A 58 A 59 A 60 A 61 A 62 A 63 A 64 A 65 A 66 A 67 A 68 A 69 A 70 A

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Abstract

La présente invention concerne un composé cyclique fusionné ayant la structure représentée par la formule I, un sel pharmaceutiquement acceptable, un stéréoisomère, un solvate, ou une molécule de promédicament de celui-ci. Le nouveau composé cyclique fusionné selon la présente invention peut se lier de manière efficace à la kinase 1 de régulation du signal apoptotique (ASK1) et agit en tant qu'inhibiteur de ASK1, ce qui permet de bloquer une voie aval contrôlée par ASK1 et de soulager ou de guérir des maladies associées à médiation par ASK1.
PCT/CN2019/070465 2018-01-05 2019-01-04 Inhibiteur de kinase-1 régulateur du signal apoptotique et utilisation associée Ceased WO2019134680A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110526878A (zh) * 2019-09-16 2019-12-03 成都睿智化学研究有限公司 一种2-(噁唑基)乙胺的制备方法
WO2020063727A1 (fr) * 2018-09-30 2020-04-02 山东轩竹医药科技有限公司 Inhibiteurs de l'ask1 à noyau tricyclique et leur utilisation
WO2021031071A1 (fr) * 2019-08-19 2021-02-25 广东东阳光药业有限公司 Dérivé d'amide et son utilisation dans la médecine
US11564930B2 (en) 2019-09-06 2023-01-31 Rigel Pharmaceuticals, Inc. RIP1 inhibitory compounds and methods for making and using the same
US11667643B2 (en) 2020-07-01 2023-06-06 Rigel Pharmaceuticals, Inc. RIP1K inhibitors
WO2024226685A1 (fr) * 2023-04-25 2024-10-31 Aeovian Pharmaceuticals, Inc. Composés imidazole fusionnés tricycliques en tant que modulateurs de cd38 et leurs utilisations

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111423422A (zh) * 2019-01-09 2020-07-17 苏州泽璟生物制药股份有限公司 芳基酰胺类抑制剂及其制备方法和应用
CN113233957B (zh) * 2021-06-03 2023-05-02 成都工业学院 一种2-溴-5-碘-苄醇的制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102482257A (zh) * 2009-07-13 2012-05-30 吉利德科学股份有限公司 凋亡信号调节激酶抑制剂
CN102985418A (zh) * 2010-07-02 2013-03-20 吉利德科学股份有限公司 凋亡信号调节激酶抑制剂
CN104693199A (zh) * 2015-03-09 2015-06-10 中国科学院化学研究所 2,9-双苯乙烯取代的邻菲罗啉类化合物及其制备方法与应用
WO2015147247A1 (fr) * 2014-03-28 2015-10-01 塩野義製薬株式会社 Dérivé tricyclique présentant une activité inhibitrice de la réplication du vih
CN105209448A (zh) * 2013-02-28 2015-12-30 Sk化学公司 三环化合物及其用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102482257A (zh) * 2009-07-13 2012-05-30 吉利德科学股份有限公司 凋亡信号调节激酶抑制剂
CN102985418A (zh) * 2010-07-02 2013-03-20 吉利德科学股份有限公司 凋亡信号调节激酶抑制剂
CN105209448A (zh) * 2013-02-28 2015-12-30 Sk化学公司 三环化合物及其用途
WO2015147247A1 (fr) * 2014-03-28 2015-10-01 塩野義製薬株式会社 Dérivé tricyclique présentant une activité inhibitrice de la réplication du vih
CN104693199A (zh) * 2015-03-09 2015-06-10 中国科学院化学研究所 2,9-双苯乙烯取代的邻菲罗啉类化合物及其制备方法与应用

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020063727A1 (fr) * 2018-09-30 2020-04-02 山东轩竹医药科技有限公司 Inhibiteurs de l'ask1 à noyau tricyclique et leur utilisation
CN112384508A (zh) * 2018-09-30 2021-02-19 山东轩竹医药科技有限公司 三并环类ask1抑制剂及其应用
WO2021031071A1 (fr) * 2019-08-19 2021-02-25 广东东阳光药业有限公司 Dérivé d'amide et son utilisation dans la médecine
CN114585616A (zh) * 2019-08-19 2022-06-03 广东东阳光药业有限公司 酰胺衍生物及其在药物中的应用
CN114585616B (zh) * 2019-08-19 2024-01-16 广东东阳光药业股份有限公司 酰胺衍生物及其在药物中的应用
US11564930B2 (en) 2019-09-06 2023-01-31 Rigel Pharmaceuticals, Inc. RIP1 inhibitory compounds and methods for making and using the same
CN110526878A (zh) * 2019-09-16 2019-12-03 成都睿智化学研究有限公司 一种2-(噁唑基)乙胺的制备方法
US11667643B2 (en) 2020-07-01 2023-06-06 Rigel Pharmaceuticals, Inc. RIP1K inhibitors
WO2024226685A1 (fr) * 2023-04-25 2024-10-31 Aeovian Pharmaceuticals, Inc. Composés imidazole fusionnés tricycliques en tant que modulateurs de cd38 et leurs utilisations

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