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WO2014114186A1 - Inhibiteurs de la jnk - Google Patents

Inhibiteurs de la jnk Download PDF

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Publication number
WO2014114186A1
WO2014114186A1 PCT/CN2014/000089 CN2014000089W WO2014114186A1 WO 2014114186 A1 WO2014114186 A1 WO 2014114186A1 CN 2014000089 W CN2014000089 W CN 2014000089W WO 2014114186 A1 WO2014114186 A1 WO 2014114186A1
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Prior art keywords
group
alkyl
membered
cycloalkyl
alkoxy
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English (en)
Chinese (zh)
Inventor
李丽
张艳
钱林艺
张敏
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KBP Biosciences Co Ltd
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KBP Biosciences Co Ltd
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Priority to CN201480003804.5A priority Critical patent/CN104903331A/zh
Publication of WO2014114186A1 publication Critical patent/WO2014114186A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention belongs to the technical field of medicine, and particularly relates to a JNK inhibitor, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, a preparation method of the compound, a pharmaceutical preparation containing the same, and a preparation and treatment of the compound and/or prevention thereof Use in drugs for ischemia-reperfusion injury, diabetes, neurodegenerative diseases, chronic inflammation, pulmonary fibrosis, liver fibrosis, fatty liver or cirrhosis.
  • JNK also known as stress-activated kinases (SAPK) was a mitogen-activated protein kinase in 1990 and is one of the major members of the MAPK family.
  • the mitogen-activated protein kinase (MAPK) is a serine/threonine protein kinase widely found in the cells of L-like animals.
  • ERK 1/2 Extracellular signal-regu lated kinase 1/2
  • JNK c-Jun N-terminal kinase
  • JNK extracellular signal-regu lated kinase 1/2
  • JNK c-Jun N-terminal kinase
  • the JNK gene has three subtypes, JNK1, JNK2 and JNK3, which are formed by selective shearing.
  • JNK1 and JNK2 are widely expressed in tissues, while JNK3 is expressed only in the brain, heart and testis.
  • Each JNKL can encode a protein product of 46 and 54 kD.
  • the three JNK isoforms activate, bind and phosphorylate different protein substrates in different ways.
  • the JNK signaling pathway can be mediated by cytokines [such as tumor necrosis factor ⁇ (TNFa), interleukin 1, IL-1, epidermal growth factor (EGF)], and some G protein pairs.
  • cytokines such as tumor necrosis factor ⁇ (TNFa), interleukin 1, IL-1, epidermal growth factor (EGF)
  • Recombinant receptors, stress such as ionizing radiation, osmotic pressure, heat shock and oxidative damage
  • stress such as ionizing radiation, osmotic pressure, heat shock and oxidative damage
  • other factors activate, participate in cell proliferation and differentiation, cell morphology maintenance, cytoskeletal construction, apoptosis and cell malignant transformation Learn the reaction.
  • Dysfunction of the JNK signaling pathway can cause ischemia, reperfusion injury, chronic inflammation, neurodegenerative changes, diabetes and tumors.
  • a typical mitogen-activated protein kinase (MAPK) signaling pathway includes three consecutive enzymatic reactions, namely MAPKKKs ⁇ MAPKKs ⁇ MAPKs.
  • JNKs MAPKKs directly upstream kinases MKK4 and currently recognized only MKK7, TXY sequence MKK activation of JNK dual phosphorylation sites, MKK4 and MKK. 7 of threonine residue 183 (Thrl83) by phosphorylation sequence and TXY
  • the 185 tyrosine residue (Tyrl85) activates JNK, causing various biological responses such as cell proliferation and differentiation, apoptosis and malignant transformation.
  • the regulation of the signaling pathway is an extremely complex system. There are two different mechanisms for the regulation of the JN signaling pathway. One is to identify the sequence between MKKK and MKK and between MKK and MAPK. The second is that the scaffold protein assembles the MKKK-MKK-MAPK module into Protein complex. MAPK by conservative order The column is docked with a specific upstream molecule MKK and a substrate such as c-Jun, ATF2, and the like. In all MAPKs (including JK), a group of negatively charged carboxy terminal amino acids are linked to the domain sequence of the kinase, which is called the common docking domain (CD) for ⁇ , ⁇ , specific substrate and docking protein binding.
  • CD common docking domain
  • Another conserved sequence is also used for the docking of MAPK.
  • the docking sites in MKK, substrate, MAPK and scaffold proteins share a common conserved sequence R/K-X4A-0A-X- 0B (0A and 0B are hydrophobic for leucine, isoleucine and valine) Residues).
  • R/K-X4A-0A-X- 0B (0A and 0B are hydrophobic for leucine, isoleucine and valine) Residues.
  • scaffold proteins Another aspect that controls the JK signaling pathway is the combination of signaling pathway complexes via scaffold proteins.
  • the scaffold protein itself has no catalytic function, but can encode docking sites and link MAPK module members MKKK, MKK and MAPK.
  • scaffold proteins interact with other proteins by interacting with SH2, SH3, PTB and other binding domains, which allow the MAPK signaling pathway complex in cells to localize to different sites.
  • Different activators allow scaffold proteins and specific MKKK to selectively activate MAPK with spatiotemporal dynamics.
  • JK-interacting prote ins binds to specific kinesin and MKKK m mixed lineage k inase (MLK); inhibitory protein ⁇ -arrestin is A cofactor for the phosphorylation of the G protein-coupled receptor; the multi-binding domain protein POSH (the majority of SH3s) contains multiple SH3 domains involved in the JNK signaling pathway in mammalian and Drosophila cell apoptosis; the adaptor protein C rk II is passed Adhesion factors bind to the JNK signaling pathway. Furthermore, MEKK1 not only binds to MKK4, but also binds to JNK1/2, indicating that it itself has a scaffold-like effect.
  • JNK inhibitors Knockout of the target homologous recombination gene in the mouse model, resulting in the loss of expression of different JNK or its upstream regulatory molecules, thereby affecting its role in physiology and disease. JNK signaling pathway is further demonstrated by JNK inhibitors in different diseases. The important role. JNK inhibitors inhibit cell death caused by ischemia and other stress-induced apoptosis, which shows great therapeutic potential. JNK inhibitors have been shown to be useful in the treatment or prevention of respiratory diseases (eg pulmonary fibrosis), lipids Fatty liver, liver fibrosis, cirrhosis, ischemia/reperfusion injury, chronic inflammatory diseases, neurodegenerative diseases, diabetes and tumors.
  • respiratory diseases eg pulmonary fibrosis
  • lipids Fatty liver, liver fibrosis, cirrhosis ischemia/reperfusion injury
  • chronic inflammatory diseases eg. pulmonary fibrosis
  • JNK inhibitors are mainly polypeptides and small molecule compounds.
  • WO2005025567 and WO2006076595 have all justified the role of novel JNK small molecule inhibitors in various therapeutic fields.
  • JNK inhibitors listed on the market. Therefore, it is necessary to develop more JNK inhibitor structure types, and select compounds with good efficacy and safety for respiratory diseases, fatty liver, liver fibrosis, and cirrhosis. , the treatment of chronic inflammatory diseases.
  • AS-602801 is a drug developed by Merck for the treatment of fibrosis and is currently in clinical phase II.
  • the structural formula is as follows:
  • X and Y are each independently N or CR 1 , wherein at least one of X and Y is N;
  • Z, W, U, G are independently N or CR 1 , wherein at least one of Z, W, U, G is N;
  • R 1 and R 2 are each independently hydrogen, sulfonyl, halogen, C 1-6 alkyl, halo C alkyl, C 1-6 alkoxy, amino, hydroxy, C 2 - 6 alkenyl, C 2-6 alkynyl, 6-14 membered aryl, 5-14 membered heteroaryl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl;
  • n is selected from 0, 1, 2 or 3;
  • L is a C 1-6 alkyl group, a C 1-6 alkoxy group, -N(R a R b ), a 6-14 membered aryl group which is unsubstituted or substituted with at least one R 3 , and a 5-14 membered heteroaryl group.
  • cycloalkyl group a 3-14 membered cycloalkyl group, a 3-14 membered heterocycloalkyl group, a 7-12 membered spirocyclic group, a 7-12 membered bridged ring group, wherein the cycloalkyl group, heterocycloalkyl group, aryl group or a heteroaryl group can be fused to an additional 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups; O
  • R 3 is / ⁇ ! ⁇ or ⁇ :, r4 , where m is selected from 0, 1, 2 or 3,
  • R 4 is sulfonyl, halogen, C 1-6 alkyl, halo C 1-6 alkyl, -C(0)N(R a R b ), -N(R a R b ), C 1-6 Alkoxy, amino, cyano, hydroxy, C 2-6 alkenyl, C 2 -6 alkynyl, 6-14 membered aryl, 5-14 membered heteroaryl unsubstituted or substituted by at least one R 5 a 3-14 membered cycloalkyl group, a 3-14 membered heterocycloalkyl group, a 7-12 membered spirocyclic group, a 7-12 membered bridged ring group, wherein the cycloalkyl group, heterocycloalkyl group, aryl group or heterocyclic group
  • the aryl group may be fused to another 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups, and any CH 2 of the
  • R 5 is sulfonyl, halogen, C 1-6 alkyl, halo C 6 alkyl, -6 alkoxy, -C(0)-0-Ci -6 alkyl, -C-Cw alkyl, - (CHz C -O-Cw alkyl, -(CH pOC ⁇ alkyl, -(C3 ⁇ 4) p -C(0)N(R a R b ), -(CH 2 ) p -OH, , , hydroxy, C 2 -6 alkenyl, C 2-6 alkynyl, 3-14 membered cycloalkyl, 6-14 membered aryl or 3-14 membered heterocycloalkyl;
  • R a and R b are each independently hydrogen, d. 6 alkyl, -(C 3 ⁇ 4) p -OC 1-6 alkyl or 6-14 member aryl C 6 alkyl.
  • p is selected from 1, 2, 3 or 4.
  • X and Y are each independently N or CR 1 , wherein at least one of X and Y is N;
  • Z, W, U, G are independently N or CR 1 , wherein at least one of Z, W, U, G is N;
  • R 1 and R 2 are each independently hydrogen, sulfonyl, halogen, d- 6 alkyl, C 1-6 alkoxy, cyano, hydroxy, C 2 -6 alkenyl, C 2 -6 alkynyl, 6- 14-membered aryl;
  • n is selected from 0, 1, 2 or 3;
  • L is d. 6 alkyl, d. 6 alkoxy, -N(R a R b ), unsubstituted or substituted by at least one R 3 6-14 membered aryl, 5-14 membered heteroaryl, a 3-14 membered cycloalkyl group, a 3-14 membered heterocycloalkyl group, wherein the cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group may be bonded to another 1-2 cycloalkyl groups, heterocycloalkyl groups , aryl or heteroaryl fused;
  • R 4 is a sulfonyl group, a halogen, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, -C(0)N(R a R b ), -N(R a R b ), d_ 6 alkoxylate a 6-14 membered aryl group, a 5-14 membered heteroaryl group, a 3-14 membered cycloalkyl group, a 3-14 membered heterocycloalkane, which is unsubstituted or substituted with at least one R 5 group, amino group, cyano group, hydroxy group a 7-12 membered spiro group, a 7-12 membered bridged ring group, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl group can be combined with another 1-2 cycloalkyl groups, heterocycloalkanes a aryl, aryl or heteroaryl group can be combined with another
  • R 5 is sulfonyl, halogen, C 1-6 alkyl, halo C 6 alkyl, C 1-6 alkoxy, -C(0)-0-C 1-6 alkyl, -COC alkane , -(CH 2 ) p -C(0)-0-C 1-6 alkyl, -(CH 2 ) p -0-C 1-6 alkyl, -(CH 2 ) p -C(0) N (R a R b), -.
  • R A and R B are each independently hydrogen, C 6 alkyl, -(CH 2 ) P -OC 1-6 alkyl, phenyl C 1-6 alkyl, and p is selected from 1, 2, 3 or 4.
  • X and Y are each independently N or CR 1 , wherein at least one of X and Y is N;
  • Z, W, U, G are independently N or CR 1 , wherein at least one of Z, W, U, G is N;
  • R 1 and R 2 are each independently hydrogen, sulfonyl, halogen, d. 6 alkyl, C 6 alkoxy, amino, cyano, hydroxy;
  • n is selected from 0, 1, 2 or 3;
  • L is d- 6 alkyl, d-6 alkoxy, -N(R a R b ), unsubstituted or at least substituted with one R 3 phenyl, quinolyl, 5-6 membered heteroaryl, 3 -8 membered cycloalkyl or 3-8 membered heterocycloalkyl;
  • R 3 is ⁇ " ⁇ or / R 4 ,
  • n is selected from 0, 1, 2 or 3
  • R 4 is a sulfonyl group, a halogen, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, -C(0)N(R a R b ), -N(R a R b ), an alkoxy group, Amino, cyano, hydroxy, 6-14 membered aryl, 5-14 membered heteroaryl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, unsubstituted or substituted with at least one R 5 , Wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl group may be fused to an additional 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups, 3-14 membered heterocycloalkane Any C3 ⁇ 4 of the base may be replaced by C(O);
  • R 5 is sulfonyl, halogen, -6 alkyl, halogenated d. 6 alkyl, C 1-6 alkoxy, -C(0)-0-Ci -6 Alkyl, -ccc -c ⁇ alkyl, -(CH 2 ) p -C(0)-0-d.
  • R a and R b are each independently hydrogen, ⁇ 6 alkyl, -(CH ⁇ p-OCw alkyl, benzyl or phenylethyl, and p is selected from 1, 2, 3 or 4.
  • X and Y are each independently N or CR 1 , wherein at least one of X and Y is N;
  • Z, W, U, G are independently N or CR 1 , wherein at least one of Z, W, U, G is N;
  • R 1 and R 2 are each independently hydrogen or alkyl
  • n is selected from 0, 1, 2 or 3;
  • L is d- 6 alkyl, C ⁇ 6 alkoxy, -N(R a R b ), unsubstituted or at least substituted with one R 3 phenyl, quinolyl, 5-6 membered heteroaryl, 3 -8 membered cycloalkyl or 3-8 membered heterocycloalkyl;
  • R 3 is / or / C, R4 , wherein m is selected from 0, 1, 2 or 3,
  • R 4 is sulfonyl, halogen, C 1-6 alkyl, -C(0)N(R a R b ), -N(R a R b ), d- 6 alkoxy, amino, cyano, hydroxy, a phenyl group, a 5-6 membered heteroaryl group, a 3-8 membered cycloalkyl group, a 3-8 membered heterocycloalkyl group which is unsubstituted or substituted with at least one R 5 , wherein the cycloalkyl group, heterocycloalkyl group a phenyl or heteroaryl group may be fused to another cycloalkyl, heterocycloalkyl, phenyl or heteroaryl group, and any CH 2 of the 3-8 membered heterocycloalkyl group may be substituted by C(O);
  • R 5 is C 1-6 alkyl, C 1-6 alkoxy, -C(0)-0-C 1-6 alkyl, -C(0)-C 1-6 alkyl, -(CH 2 ) p -C(0)-0-C 1-6 alkyl, -(C3 ⁇ 4) p -0-C 1-6 alkyl, -(CH 2 ) p -C(0)N(R a R b ) -(C3 ⁇ 4) p- OH, amino group, cyano group, hydroxy group, 3-8 membered ring fluorenyl group, phenyl group, 3- 8 membered heterocyclic fluorenyl group;
  • R A and R B are each independently hydrogen, C alkyl, -(C3 ⁇ 4) P -OC 1-6 alkyl, benzyl or phenylethyl; p is selected from 1, 2, 3 or 4.
  • X and Y are each independently N or CR 1 , wherein at least one of X and Y is N;
  • Z, W, U, and G are each independently N or CR 1 , wherein Z, W, U, G have at least 1 N is N;
  • R 1 and R 2 are each independently hydrogen and C 6 alkyl
  • n is selected from 0, 1, 2 or 3;
  • 1 ⁇ is ( ⁇ 6 alkyl, 6 alkoxy, -N(R a R b ), unsubstituted or substituted by at least one R 3 phenyl, quinolyl, 6-membered heteroaryl, 3-8 a cycloalkyl group or a 3-8 membered heterocycloalkyl group;
  • n is selected from 0, 1, 2 or 3
  • R 4 is a sulfonyl group, a halogen, ( ⁇ - 3 alkyl group, -C(0)N(R a R b ), -N(R a R b ), a C 1-6 alkoxy group, an amino group, a cyano group, a hydroxy group, a phenyl group which is unsubstituted or substituted with at least one R 5 , a 5-6 membered heteroaryl group, a 3-8 membered cycloalkyl group, a 3-8 membered heterocycloalkyl group or a 1,2,3,4-tetra Hydrogen isoquinolin-2-yl, wherein any CH 2 of a 3-8 membered heterocycloalkyl group may be substituted by C(O);
  • R 5 is c 1-6 alkyl, c 1-6 alkoxy, -c(o)-oc 1-6 alkyl, -c ⁇ -c ⁇ alkyl, Alkyl, -(CH 2 ) p -0-C 1-6 alkyl, -(CH 2 ) p -C(0)N(R a R b ), -(CH 2 ) p -OH, amino, cyanide Base or hydroxyl group;
  • R A and R B are each independently hydrogen, C alkyl, -(CH 2 ) P -OC 1-3 alkyl or benzyl, and p is selected from 1, 2 or 3.
  • X and Y are each independently N or CR 1 , wherein at least one of X and Y is N;
  • Z, W, U, G are independently N or CR 1 , wherein at least one of Z, W, U, G is N;
  • R 1 , R 2 are independently hydrogen, d. 6 alkyl
  • n is selected from 0, 1, 2 or 3;
  • R 3 is ⁇ R4 or
  • R 4 is a sulfonyl group, a halogen, a C 1-3 alkyl group, -C(0)N(R a R b ), -N(R a R b ), a C 1-6 alkoxy group, an amino group, a cyano group, a 5-6 membered heteroaryl group, a 3-8 membered heterocycloalkyl group or a 1,2,3,4-tetrahydroisoquinolin-2-yl group which is unsubstituted or substituted with at least one R 5 , wherein 3 Any CH 2 of an 8- to 8-membered heterocycloalkyl group may be substituted by C(O);
  • R 5 is Ci -3 alkyl, Ci -6 alkoxy, -C(0)-0-Ci. 6 alkyl, -C(0)-Ci -3 alkyl, -(CH 2 )pC(0 -0-Ci. 3 alkyl, -(CH 2 ) p -0-C 1-3 alkyl, -(CH 2 ) p -C(0)N(R a R b ), -(CH 2 ) p- OH, amino, ⁇ J ⁇ or hydroxy;
  • R a and R b are each independently hydrogen, ( ⁇ 6 alkyl, -(CH 2 ) p -OCw alkyl or benzyl,
  • p is selected from 1, 2 or 3.
  • X and Y are each independently N or CR 1 , wherein at least one of X and Y is N;
  • Z, W, U, G are independently N or CR 1 , wherein at least one of Z, W, U, G is N;
  • R 1 and R 2 are each independently hydrogen, methyl or ethyl
  • n is selected from 0, 1 , 2 or 3 ;
  • L is alkyl, -N(R a R b ), unsubstituted or substituted with at least one R 3 phenyl, quinolyl, pyridyl, pyrimidinyl, cyclohexane, piperidinyl, tetrahydropyridyl Meryl, piperazinyl or morpholinyl;
  • R 3 is ⁇ R 4 or e , R4 ,
  • n is selected from 0 or 1
  • R 4 is a sulfonyl group, a halogen, a C 1-3 alkyl group, -C(0)N(R a R b ), -N(R a R b ), a pyridyl group which is unsubstituted or substituted with at least one R 5 , pyrazolyl, imidazolyl, pyrimidinyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, morpholinyl, piperidinyl, piperazinyl, tetrahydropyrrole 2-keto;
  • R 5 is C 1-3 alkyl, C 1-6 alkoxy, -C(0)-0-C 1-6 alkyl, -C(0)-C 1-3 alkyl, -(CH 2 ) pC(0)-0-C 1 _ 3 alkyl, -(CH 2 ) p -0-C 1-3 alkyl, -(C3 ⁇ 4) p -C(0)N(R a R b ), - (CH 2 ) p -OH;
  • R a and R b are each independently hydrogen, C 1-6 alkyl, -(CH ⁇ -OCw alkyl or benzyl,
  • p is selected from 1, 2 or 3.
  • One of X and Y is N and the other is 0 1 .
  • a pharmaceutical composition comprising the compound according to any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers.
  • ischemia-reperfusion injury diabetes, neurodegenerative diseases, chronic inflammation (such as allergies, asthma, rheumatoid arthritis, osteoarthritis, atherosclerosis, allergic conjunctivitis, a compound according to any one of claims 1 to 12, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or A stereoisomer thereof or a pharmaceutical composition of claim 13.
  • halogen means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C ⁇ 6 alkyl refers to straight or branched chain alkyl group containing 1 to 6 carbon atoms, including, for example “d_ 5 alkyl", “the CM alkyl", “alkoxy Cw of Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 1-mercaptopropyl, 1,1-didecyl Ethyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-mercaptobutyl, 1-ethylpropyl, n-hexyl, 4-decylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 3,3-dimercaptobutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 1,3-dimethylbuty
  • ⁇ 6 6 alkenyl means a straight or branched or cyclic hydrocarbon group having 2 to 6 carbon atoms containing a double bond, and includes, for example, “C 2-5 alkenyl group”, CM alkenyl", “C 2-3 alkenyl", “C 3-6 cycloalkenyl, and the like; examples thereof include, but are not limited to, for example, vinyl, 1-propenyl, 2-propenyl, 1-indole Vinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-decyl-1-propanyl, 2-methylpropenyl,
  • alkynyl means a straight or branched hydrocarbon group having 3 to 3 carbon atoms, and includes, for example, "( 2 _ 5 alkynyl group), "Cw alkynyl group", C 2 _ 3 alkynyl group "and the like; examples thereof include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-propynyl Yue-2-yl, 2- Pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-indolyl-3-butynyl, 2-methyl-3-butynyl, 1 , 1-dimercapto-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1- Methy
  • C1-6 alkoxy means a " C1-6 alkyl-0-" group, wherein "Q- 6 alkyl” is as defined above, including, for example, “Cw alkoxy”","CMalkoxy”,”Cwalkoxy",etc.; examples thereof include, but are not limited to, decyloxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, Tert-butoxy, sec-butoxy, pentyloxy, neopentyloxy, hexyloxy and the like.
  • 3-14 membered cycloalkyl group means a cycloalkyl group having 3 to 14 carbon atoms, and includes, for example, “3-12 membered cycloalkyl group” and "3-10 membered cycloalkane”.
  • the "3-8 membered monocyclic cycloalkyl group” means a monocyclic cycloalkyl group having 3 to 8 carbon atoms, and includes, for example, "3-6 membered monocyclic cycloalkyl group", “5-8 membered single ring” Cycloalkyl", "5-6 membered monocyclic cycloalkyl”, etc.; examples thereof include, but are not limited to: cyclopropyl, cyclobutane, cyclopentanyl, cyclohexane, cycloheptyl, ring Octyl or the like; the "3-8 membered monocyclic cycloalkyl group, which may be further substituted by a C alkyl group, including but not limited to: nonylcyclopropane group, dimethylcyclopropane group, methylcyclobutene Alkyl, dinonylcyclobutane, decylcyclopentyl, dimethylcyclopentanyl, nonylcyclo
  • the "6-14 membered fused ring cycloalkyl group” means a fused ring cycloalkyl group formed by the two or more cyclic structures sharing two adjacent carbon atoms with each other, including, for example, "6-12 yuan fused ring naphthenic ",””8-12 membered fused ring cycloalkyl group", "7-10 membered fused ring cycloalkyl group”, etc.; examples thereof include, but are not limited to: bicyclo[3.1.0]hexane group, bicyclo[4.1 .0]heptyl, bicyclo[2.2.0]hexane, bicyclo[3.2.0]heptyl, bicyclo[4.2.0]octyl, octahydroindenyl, decahydronaphthyl, Tetrahydrophenanthyl and the like.
  • 6-14 membered aryl means an aromatic group having 6 to 14 carbon atoms, including, for example, “6-10 membered aryl group”; also includes “6-8 membered monocyclic aryl group” "And” 8-14 yuan fused ring aryl”.
  • the "6-8 membered monocyclic aryl group” includes, for example, a phenyl group.
  • the "8-14 membered fused ring aryl group” means that 8 to 14 carbon atoms and at least one ring are aromatic by two or more ring structures sharing two adjacent carbon atoms with each other.
  • a fused ring group comprising 10-14 members of a fused ring aryl group in which all rings are aromatic rings, such as naphthalene, phenanthrene, and the like.
  • the term "3-14 membered heterocycloalkyl” means a cyclic group having 3 to 14 ring atoms (having at least one hetero atom), including, for example, “3-10 membered heterocycloalkyl”",”4-12 membered heterocycloalkyl", “3-8 membered heterocycloalkyl", “5-10 membered heterocycloalkyl”, “5-8 membered heterocycloalkyl", "5-6 a heterocycloalkyl group "etc., also includes “3-8 membered monocyclic heterocycloalkyl group” and "6-14 membered fused ring heterocycloalkyl group", and the hetero atom has nitrogen, oxygen, sulfur, etc., ring When the atom is CH 2 , it can be substituted by oxo.
  • the "3-8 membered monocyclic heterocycloalkyl group” means a monocyclic heterocycloalkyl group having 3 to 8 ring atoms (having at least one hetero atom), including, for example, a "5-8 membered monocyclic ring”.
  • a heterocycloalkyl group a "5-6 membered monocyclic heterocycloalkyl group", a "3-6 membered saturated monocyclic heterocycloalkyl group”, etc.; specific examples thereof include, but are not limited to: aziridine group, aza Cyclobutane, thietane, tetrahydrofuranyl, tetrahydropyrrolyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, 1,4-dioxanyl, 1,3-dioxo a heterocyclohexane group, a 1,3-dithiacyclohexane group, a piperidinyl group, a morpholinyl group, a piperazinyl group or the like; further, when the ring atom is CH 2 , it may be substituted with oxo, for example, piperidine-2- Ketones, etc.
  • the "6-14 membered fused ring heterocycloalkyl group” means that 6 to 14 ring atoms (having at least one hetero atom) are bonded to each other by two or more ring structures.
  • a fused ring heterocycloalkyl group formed which includes, for example, "8-12 membered fused ring heterocycloalkyl group", “7-10 membered fused ring heterocycloalkyl group”, “9-10 membered fused ring heterocycloalkane” ",” 9-12 membered fused ring heterocycloalkyl, and the like; specific examples thereof include, but are not limited to, cyclobutanetetrahydropyrrolyl, cyclopentahydrotetrahydropyrrolyl, azetidine Imidazolidinyl and the like.
  • the "5-14 membered heteroaryl group” of the present invention has a ring atom including one or more hetero atoms in addition to a carbon atom, and the "hetero atom” includes but is not limited to an oxygen atom, a nitrogen atom and an ⁇ atom .
  • the heteroaryl group may be bonded through a carbon or a hetero atom. It includes a 5-8 membered monocyclic heteroaryl group and a 8-14 membered fused heterocyclic aryl group.
  • the "5-8 membered monocyclic heteroaryl group” means an aromatic hetero atom-containing cyclic group including, for example, "5-6 membered monocyclic heteroaryl group” and "5-7 membered monocyclic heteroaryl group”.
  • "Equivalent examples include, but are not limited to, furyl, thia- 11 , pyrrolyl, imidazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, oxazolyl, isoxazolyl, isothiazolyl 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadisyl, 1,2,3-triazinyl, 1,2,4- Triazinyl, tetrazolyl, oxatriazole, 2
  • the "8-14 membered fused heterocyclic aryl group” means a fused heterocyclic group in which all of the rings are aromatic rings, and includes, for example, “8-12 membered fused heterocyclic aryl group” and "9-10 member”.
  • a fused heterocyclic aryl group a "10-14 membered fused heterocyclic aryl group", or the like, a fused heterocyclic aryl group formed by a benzo-5-8 membered monocyclic heteroaryl group, a 5-8 membered monocyclic heteroaryl group
  • Chalylene pyridazinyl, quinazolinyl, quinoxalinyl, phenolzinyl, acridinyl, fluorenyl, isoindole, isodecyl, pyridazinyl, benzodiazinyl, benzo Oxazolyl, benzoxazinyl, pyrazolo[3,4-b]pyridyl and the like.
  • the term "7-12 membered bridged ring group” means an aliphatic hydrocarbon group having 7 to 12 ring atoms formed by any two rings sharing two atoms which are not directly connected, and the ring atoms may all be carbon.
  • the "7-12 yuan bridge ring” includes "7-12 yuan saturated bridge ring base" and "7-12 yuan unsaturated bridge ring base”.
  • the "7-12 dollar saturated bridged ring group” refers to a cyclic group in which all rings in the bridge ring are saturated.
  • the "7-12 member unsaturated bridged ring group” means a cyclic group having at least one ring in the bridged ring group which is unsaturated, including, for example, “7-10 member unsaturated bridged ring group”. , "7-8 yuan unsaturated bridge ring base”, etc. Specific examples include, but are not limited to:
  • the term "7-12 membered spirocyclic group” means a type of aliphatic hydrocarbon group having 7 to 12 ring atoms formed by sharing at least two rings with one atom, and the ring atoms may all be carbon atoms or Containing a hetero atom, the hetero atom is selected from the group consisting of nitrogen, oxygen, sulfur, and the like.
  • these include, for example, “7-11 element spiro group”, “8-11 element spiro group”, “9-10 element spiro group”, etc., including "7-12 yuan saturated spiro group” and "7- 12-membered unsaturated spiro ring base.”
  • the "7-12-membered saturated spirocyclic group” means that all of the rings in the spirocyclic group are saturated rings, including, for example, “7-11-membered saturated spiro group", “8-”, “9-” 10 yuan full”
  • the "7-12 member unsaturated spiro group” means that at least one ring of the spiro group is an unsaturated ring, including, for example, "7-11 member unsaturated spiro group”, “8-11” Unsaturated spiro ring base”, "9-10 yuan
  • a hetero atom means 0, N, S, SO and SO:
  • X, Y, G, U, Z, W, L, R 1 , R 2 and n in the upper reaction equation are as defined above, and the compound of formula (I) may be an isomer thereof such as formula (I & Or a compound represented by (I b).
  • the functional group to be protected may be protected by a conventional protective agent, after which the protecting group is removed by a conventional method; if necessary, some compounds may also be prepared, for example, the preparation of the starting material 1.
  • the present invention claims a "stereoisomer" of a compound of formula (I), (la) or (lb) which, when one or more asymmetric carbon atoms are present in the structure of the compound, will give rise to the enantiomer;
  • a compound contains an alkenyl group or a cyclic structure, a cis/trans isomer is produced; when a compound has a ketone or an anthracene, a tautomer or the like is produced. All such isomers and mixtures are within the scope of the invention.
  • the compound of the formula (I), (l a ) or ( l b ), a pharmaceutically acceptable salt thereof or a stereoisomer thereof of the present invention may be formulated into a pharmaceutical preparation together with one or more pharmaceutically acceptable carriers.
  • the pharmaceutical preparation refers to a conventional preparation for clinical use, which can be administered orally or parenterally to a patient in need of such treatment. Such as tablets, granules, capsules, powders, injections, inhalants, sublingual preparations, syrups, gels, ointments, suppositories, lotions, nasal drops, eye drops, sprays, transdermal preparations, etc. .
  • These preparations can be prepared by a conventional method, by adding a pharmaceutically acceptable carrier such as an excipient, a binder, a moisturizer, a disintegrating agent, a thickener or the like.
  • the compound of the formula (I), (la) or (lb) of the present invention, a pharmaceutically acceptable salt thereof or a stereoisomer thereof can be used for the treatment and/or prevention of ischemia-reperfusion injury, diabetes, neurodegenerative Diseases such as pathology, chronic inflammation, pulmonary fibrosis, liver fibrosis, fatty liver or cirrhosis.
  • Chronic inflammation includes allergies, asthma, rheumatoid arthritis, osteoarthritis, atherosclerosis, allergic conjunctivitis, allergic keratitis, dry eye, retinopathy, glaucoma.
  • PE petroleum ether
  • EA ethyl acetate
  • HATU 2-(7-azobenzotriazole) -N,N,N,,N,-tetradecylurea hexafluorophosphate
  • TBS tert-butyl bismuthyl silicon
  • TBSC1 tert-butyldimethylchlorosilane
  • DIPEA N,N-diisopropylethylamine
  • Test sample Part of the compound of the present invention was prepared according to the method of the example; the reference drug AS-602801 was prepared.
  • the test sample was accurately weighed, dissolved in DMSO, and thoroughly mixed to prepare 10 mM. It was diluted to a final concentration of 50 times with DMSO.
  • the ⁇ compound was transferred to a % well plate and serially diluted 3 times for a total of 10 concentrations.
  • the ⁇ compound was transferred to a new 96-well plate, and 90 ul of kinase buffer (50 mM Hepes pH 7.5, 10 mM MgCl 2 , 0.0015% Brij-35, 2 mM DTT) was added to each well of the 96-well plate. The final concentration of the compound is at most 10 ⁇ .
  • Inhibition rate [conversion rate (ZPE) - conversion rate (sample)] ⁇ 100 / [conversion rate (ZPE) - conversion rate (HPE)] Note: ⁇ : blank control without enzyme; ⁇ : blank without compound Control.
  • Test sample A part of the compound of the present invention was prepared according to the method of the example; the reference drug AS-602801 was prepared according to the method of WO2003047570.
  • HTRF JNK2 Assay Standard time-resolved fluorescence technique for the determination of JNK2 enzyme activity: This experiment used the HTRF method (Cisbio) to determine the inhibitory activity of compounds on JNK2. Accurately weigh the test sample, add it to DMSO, mix well, and mix it into 10 mM. It was diluted with DMSO to a final concentration of 50 times. Transfer 30 ⁇ l of the compound to a 96-well plate and perform a 4-fold serial dilution for a total of 7 concentrations. Then transfer 2 ⁇ 1 to 38 ⁇ 1 Kinase buffer to get the maximum concentration.
  • Ratio (665nm fluorescence value / 615nm fluorescence value) ⁇ 4
  • Test sample part of the compound of the invention, prepared according to the method of the example
  • Iv (intravenous bolus) SD rats were administered with blood from the tail vein at 0.083h, 0.25h, 0.5h, lh, 2h, 4h, 6h, 8h, 24h after administration; po (oral) dosed SD Rats were bled from the tail vein at 0.17 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h after administration.
  • the resulting whole blood was placed in a heparinized test tube. Plasma was separated after 8 min of low-speed centrifugation (3500 rpm). C is protected from light. After the experiment was completed, all blood paddle samples were placed at -70. C refrigerator to save.
  • the sample to be tested was taken out from the water tank (-70 ° C), and naturally fused at room temperature and vortexed for 3 min. Precision transfer of 20 ⁇ sample into a 1.5 ml centrifuge tube. After adding 200 ⁇ M of internal standard solution (AS-602801 50 ng/ml sterol solution) for 3 min, centrifuge for 5 min (12,000 rpm). The 50 ⁇ supernatant was accurately transferred to 150 ⁇ l of water, vortexed for 3 min, and then analyzed by LC-MS/MS system. The concentration of the test substance was output using AB's Analyst 1.6.1. Microsoft Excel calculates parameters such as mean, standard deviation, coefficient of variation, etc. (Analyst 1.6.1 direct output is not calculated), and PK parameters are calculated using Pharsight Phoenix 6.2 software non-compartmental model (NCA). 3. Experimental results
  • tl/2 is the half-life
  • AUC is the exposure
  • F% is the bioavailability
  • the half-life of the compound 5 of the present invention is equivalent to that of AS-602801 when administered iv, and the half-life is more than twice that of AS-602801 when po is administered, and the exposure amount and bioavailability of the compound 5 of the present invention are better than those of the compound 5 of the present invention.
  • AS-602801, the half-life, exposure and bioavailability of the compound 29 of the present invention are better than AS-602801, so the compound of the present invention has a strong advantage in PK compared with AS-602801.
  • Test sample part of the compound of the invention, prepared according to the method of the example
  • mice were randomly divided into model group and each drug-administered group according to body weight after 1 week of adaptation in SPF-class animal room. Marks were used to mark the tail of the mouse before the test, and the test number was marked on the cage. Do not compare with the test date; the model group animals were given vehicle for 30 min (10 ml/kg), and the tail vein was given Concanavalin A (ConA, 15 mg/kg); after 30 minutes of administration, the same dose of ConA was given to the tail vein. After 7 days of ConA administration, the mice were anesthetized with sodium pentobarbital (45 mg/kg intraperitoneally), and 30 ( ⁇ 1 (SOP-DS-200024-A) was taken from the iliac sinus of the eye.
  • ConA Concanavalin A
  • the anticoagulant was centrifuged at room temperature for 1 h, and the blood sample was centrifuged using an eppendorf 5424R centrifuge. After centrifugation conditions were 3500 rpm, 4 ° C, lOmin, serum was extracted, and ⁇ serum was measured by automatic biochemical analyzer for ALT and AST content, and the remaining serum was stored in a -80 °C refrigerator.
  • Compound ALT 7h decreased by 0 / 0 AST 7h decreased by 0 / 0
  • the compounds of the present invention can significantly reduce the levels of ALT and AST in acute hepatitis model mice, and the effect is better than AS-602801.
  • Diammonium hydrochloride ( 4.85 g, 59.51 mmol) and triethylamine ( 9.04 g, 89.3 mmol) were dissolved in dichloromethane (100 mL) and added to the above acid chloride in an ice bath. The solution was added dropwise, and the mixture was stirred at room temperature for 2 hr.
  • the preparation method is as described in Reference Example 8. After column chromatography, it is obtained by high pressure liquid phase preparative chromatography.

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Abstract

La présente invention appartient au domaine des techniques pharmaceutiques et concerne en particulier des inhibiteurs de la JNK tels que ceux représentés par les formules générales (I), (1a) ou (1b), leurs sels ou stéréoisomères pharmaceutiquement acceptables, le procédé de préparation de ces composés, des préparations pharmaceutiques contenant ces composés, et l'utilisation de ces composés dans la préparation de médicaments destinés à traiter et/ou à prévenir des lésions de reperfusion d'origine ischémique, le diabète, des troubles neurodégénératifs, une inflammation chronique, une fibrose pulmonaire, une fibrose hépatique, une stéatose hépatique ou une cirrhose hépatique.
PCT/CN2014/000089 2013-01-24 2014-01-24 Inhibiteurs de la jnk Ceased WO2014114186A1 (fr)

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CN104387324A (zh) * 2014-10-31 2015-03-04 上海博康精细化工有限公司 一种4-溴-3-氯甲基-1-甲基-1h-吡唑的制备方法
WO2020116662A1 (fr) 2018-12-06 2020-06-11 第一三共株式会社 Dérivé de cycloalcane-1,3-diamine
EP4134077A1 (fr) * 2021-08-13 2023-02-15 ScandiEdge Therapeutics AB Traitement à petites molécules d'une maladie du foie gras non alcoolique (nafld) ou d'un carcinome hépatocellulaire (hcc)

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WO2001047920A1 (fr) * 1999-12-24 2001-07-05 Applied Research Systems Ars Holding N.V. Derives de benzazole actifs au plan pharmaceutique
WO2003047570A1 (fr) * 2001-12-07 2003-06-12 Applied Research Systems Ars Holding N.V. Derives de benzazole pour le traitement de sclerodermie
WO2005025567A1 (fr) * 2003-09-12 2005-03-24 Applied Research Systems Ars Holding N.V. Derives de benzothiazole pour le traitement du diabete
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104387324A (zh) * 2014-10-31 2015-03-04 上海博康精细化工有限公司 一种4-溴-3-氯甲基-1-甲基-1h-吡唑的制备方法
WO2020116662A1 (fr) 2018-12-06 2020-06-11 第一三共株式会社 Dérivé de cycloalcane-1,3-diamine
US11236106B2 (en) 2018-12-06 2022-02-01 Daiichi Sankyo Company, Limited Cycloalkane-1,3-diamine derivative
US12060365B2 (en) 2018-12-06 2024-08-13 Daiichi Sankyo Company, Limited Cycloalkane-1,3-diamine derivative
US12528822B2 (en) 2018-12-06 2026-01-20 Daiichi Sankyo Company, Limited Cycloalkane-1,3-diamine derivative
EP4134077A1 (fr) * 2021-08-13 2023-02-15 ScandiEdge Therapeutics AB Traitement à petites molécules d'une maladie du foie gras non alcoolique (nafld) ou d'un carcinome hépatocellulaire (hcc)
WO2023016950A1 (fr) * 2021-08-13 2023-02-16 Scandiedge Therapeutics Ab Traitement de petites molécules de la stéatose hépatique et de la chc avec jnk-in-5a

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