WO2022117090A1 - Composé polycyclique, son procédé de préparation et son utilisation - Google Patents

Composé polycyclique, son procédé de préparation et son utilisation Download PDF

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WO2022117090A1
WO2022117090A1 PCT/CN2021/135493 CN2021135493W WO2022117090A1 WO 2022117090 A1 WO2022117090 A1 WO 2022117090A1 CN 2021135493 W CN2021135493 W CN 2021135493W WO 2022117090 A1 WO2022117090 A1 WO 2022117090A1
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alkyl
cycloalkyl
heterocycloalkyl
alkenyl
aryl
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Chinese (zh)
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黄金昆
谢德建
王寿平
冯超阳
刘俊强
张伟
鲁岳
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成都科岭源医药技术有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • the invention relates to the field of medicinal chemistry, in particular to a polycyclic compound and a preparation method and application thereof.
  • Cytokines play an important role in the regulation of immunity and inflammation.
  • Janus kinase is an intracellular non-receptor tyrosine kinase that mediates the process of signal transmission from extracellular to nucleus of various cytokines.
  • the JAK kinase family is divided into four subtypes, JAK1, JAK2, JAK3 and TYK2, and each subtype mediates different types of cytokine signaling pathways.
  • JAK1, JAK2 and TYK2 are expressed in various human tissue cells, and JAK3 is mainly expressed in various hematopoietic tissue cells.
  • JAK family members are composed of four JAK homology regions (JAK homology regions, JH), including a catalytically activated kinase domain (JH1), a catalytically inactive kinase-like domain (JH2), and a SH2-like domain. (JH3) and four FERM domains (JH4-7).
  • JH2 domain is the most special structure. It has a high degree of similarity with the amino acid sequence of the JH1 domain. However, due to the lack of several key amino acids, it does not have phosphatase activity, so it cannot exert catalytic activity. Therefore, Known as the kinase-like domain, and play a role in regulating catalytic activity.
  • the JAK protein coupled to the intracellular receptor is phosphorylated, and the activated JAK further phosphorylates the receptor.
  • the phosphorylated tyrosine site can be used as a structure containing SH2.
  • the binding site of the protein with the SH2 domain so the signal transducer and activator of transcription (STAT) with the SH2 domain can be recruited to the receptor and phosphorylated by JAKs, and the phosphorylated STAT is formed by dimerization After the dimer is transferred to the nucleus, it combines with the target gene and promotes its transcription, thereby regulating the growth, activation, differentiation and other functions of various cells.
  • STAT signal transducer and activator of transcription
  • TYK2 is the first subtype discovered in the JAK family, and a number of cytokine signaling pathways that require TYK2 to participate in the transduction have been found, including interleukin (IL) and interferon (IFN) with different subtypes. In these signaling pathways, TYK2 is coupled to transmembrane cytokine receptor proteins including IFNAR1, IL-12R ⁇ 1, IL-10R2 and IL-13R ⁇ 1, and to another receptor chain coupled to JAK1 or JAK2 via heterologous Dimerization forms distinct cytokine receptor complexes that provide the binding sites required for STAT binding.
  • IL interleukin
  • IFN interferon
  • TYK2 is coupled to transmembrane cytokine receptor proteins including IFNAR1, IL-12R ⁇ 1, IL-10R2 and IL-13R ⁇ 1, and to another receptor chain coupled to JAK1 or JAK2 via heterologous Dimerization forms distinct cytokine receptor complexes that provide the binding sites required for STAT binding
  • cytokines including IFN- ⁇ , IL-6, IL-12, and IL-23, activate downstream specific STAT proteins by utilizing different cytokine receptor complexes.
  • Some cytokines make helper T cells Th17, Th1, B cells or myeloid cells through TYK2-mediated signaling pathways, including systemic lupus erythematosus, psoriasis, lupus nephritis, Sjogren's disease, Crohn's disease, systemic sclerosis, etc. Function in autoimmune and chronic inflammatory diseases.
  • TYK2 deletion mutations can effectively inhibit the occurrence of immune diseases such as allergy, autoimmunity and inflammation.
  • IL-23 plays a crucial role in the occurrence and development of psoriasis.
  • the latest research shows that the pathogenesis of psoriasis is that endogenous unknown antigens activate antigen-presenting cells (APCs) to secrete IL-23.
  • APCs antigen-presenting cells
  • IL-23 activates Th17 cells to secrete IL-17 and other cytokines, and induces keratinocytes to differentiate and secrete IL-23. , which further stimulates validation and keratinocyte proliferation to produce psoriasis.
  • TYK2 and JAK2 jointly mediate the downstream signaling pathway of IL-23, and inhibition of JAK2 can lead to anemia and other blood-related side effects, so targeting TYK2 is a good strategy for the treatment of psoriasis by inhibiting the IL-23 signaling pathway.
  • the ATP-binding sites of members of the whole kinome tend to have a high degree of homology, among which TYK2 has a higher similarity to the ATP-binding sites of other members of the JAK family.
  • FDA-approved all JAK family kinase inhibitors including Tofacitinib, can act on the ATP-binding pocket of TYK2, and can also bind well to JAK1, 2, and 3 isoforms.
  • JAK1, JAK2 and JAK3 can act on the ATP-binding pocket of TYK2, and can also bind well to JAK1, 2, and 3 isoforms.
  • JAK2 activity is related to erythrocyte differentiation and lipid metabolism
  • the above-mentioned adverse reactions such as anemia are thought to be related to the insufficient selectivity of tofacitinib for JAK2, which is caused by the non-selective inhibition of the drug. Therefore, ATP-competitive TYK2 inhibitors have severely limited their clinical use due to their severe side effects. Finding a small molecule inhibitor with a new binding mode and highly selective specificity of TYK2 can effectively improve the therapeutic window of the drug, thereby improving its clinical use.
  • the purpose of the present invention is to provide a polycyclic compound which can be used as a TYK2 inhibitor and its preparation method and use.
  • the present invention provides the compound represented by formula I, or its stereoisomer, or its solvate, or its salt, or its ester, or its prodrug, or its hydrate:
  • Z 1 and Z 2 are independently selected from -O-, -S- or -NR Z -;
  • R Z is selected from hydrogen or alkyl
  • L 1 and L 2 are independently selected from alkyl or alkyl substituted by one or more RL ;
  • R 1 is selected from hydrogen, alkyl or haloalkyl
  • Ring A is selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
  • n is an integer of 0, 1, 2, 3 or 4;
  • Z 1 and Z 2 are independently selected from -O-, -S- or -NR Z -;
  • R Z is selected from hydrogen or C 1 -C 6 alkyl
  • L 1 and L 2 are independently selected from C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by one or more RL ;
  • R 1 is selected from hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl
  • Ring A is selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
  • n is an integer of 0, 1, 2, 3 or 4;
  • R b is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C2 - C6alkynyl , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl
  • R c and R d are independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 Alkenyl, C2 - C6alkynyl , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl
  • Z 1 and Z 2 are independently selected from -O-, -S- or -NR Z -;
  • R Z is selected from hydrogen or C 1 -C 6 alkyl
  • L 1 and L 2 are independently selected from C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by one or more RL ;
  • R 1 is selected from hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl
  • Ring A is selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
  • n is an integer of 0, 1, 2, 3 or 4;
  • R b is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C2 - C6alkynyl , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl
  • R c and R d are independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 Alkenyl, C2 - C6alkynyl , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl
  • Z 1 and Z 2 are independently selected from -O-, -S- or -NR Z -;
  • R Z is selected from hydrogen or C 1 -C 6 alkyl
  • L 1 and L 2 are independently selected from C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by one or more RL ;
  • Z 1 and Z 2 are independently selected from -O- or -NR Z -;
  • R Z is selected from hydrogen or C 1 -C 6 alkyl;
  • L 1 and L 2 are independently selected from C 1 -C 6 alkane base;
  • Z 1 and Z 2 are independently selected from -O- or -NR Z -;
  • R Z is selected from hydrogen;
  • L 1 and L 2 are independently selected from C 1 -C 6 alkyl groups;
  • L is selected from
  • Ring A is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridin-2(1H)-one, thienyl, pyrazolyl, pyrrolyl, imidazolyl, indolyl, indazole base, azaindolyl, benzimidazolyl, benzotriazaazolyl, benzofuranyl, benzothiazolebenzoxazolyl, benzisoxazolyl, benzothienyl, naphthyl.
  • the 3-6 membered epoxy group is selected from
  • R 1 , R 2 , R 3 , A ring, n and RA are as described above;
  • the compound is shown in formula III:
  • n and RA are as previously described;
  • X, Y are independently selected from N or CR B ; and X and Y are not N at the same time;
  • R B is selected from hydrogen or C 1 -C 6 alkyl
  • n and RA are as previously described;
  • n and RA are as previously described;
  • n and RA are as previously described;
  • the compound is one of the following compounds:
  • the present invention also provides a method for preparing the aforementioned compound, or its stereoisomer, or its solvate, or its salt, or its ester, or its prodrug, or its hydrate, which comprises the following steps:
  • the present invention also provides the use of the aforementioned compound, or its stereoisomer, or its solvate, or its salt, or its ester, or its prodrug, or its hydrate, in the preparation of a TYK2 inhibitor drug; and /or, use in the preparation of a medicament for a disease related to TYK2 kinase dysfunction;
  • the disease is inflammatory disease, autoimmune disease, hyperproliferative disease in mammals, cancer, bone disease, neurological disease, metabolic disease, respiratory disease and/or heart disease;
  • the inflammatory and autoimmune diseases are rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease;
  • the inflammatory bowel disease is ulcerative colitis and Crohn's disease.
  • the present invention also provides a pharmaceutical composition, which is based on the aforementioned compound, or its stereoisomer, or its solvate, or its salt, or its ester, or its prodrug, or its hydrate. ingredients, and preparations prepared with pharmaceutically acceptable excipients or auxiliary ingredients;
  • the pharmaceutically acceptable adjuvant or auxiliary component is one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
  • substitution means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
  • the hydrogen atoms in the compounds of the present invention can be various isotopes of hydrogen, such as: protium ( 1 H), deuterium ( 2 H) or tritium ( 3 H).
  • the structures of the compounds described in the present invention all refer to structures that can exist stably.
  • the minimum and maximum carbon content of the hydrocarbon groups in the present invention are indicated by prefixes, eg, the prefix ( Ca - Cb )alkyl denotes any alkyl group containing "a" to "b" carbon atoms.
  • the prefix ( Ca - Cb )alkyl denotes any alkyl group containing "a" to "b” carbon atoms.
  • C1 - C6 alkyl refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms
  • C2 - C6 alkynyl refers to an alkynyl group containing 1 to 6 carbon atoms.
  • halogen is fluorine, chlorine, bromine or iodine.
  • haloalkyl, hydroxyalkyl, and aminoalkyl are halogen, hydroxy, and amino substituted alkyl groups, respectively.
  • cycloalkyl refers to a monocyclic or polycyclic carbocyclic ring without double bonds
  • heterocycloalkyl refers to a monocyclic or polycyclic carbocyclic ring containing at least one heteroatom without double bonds.
  • O, S or N Aryl refers to a monocyclic or polycyclic carbocycle containing at least one double bond
  • Heteroaryl refers to a monocyclic or polycyclic carbocycle containing at least one double bond and at least 1 heteroatom , the heteroatom is O, S or N
  • the structural formula of the epoxy group is that one carbon atom on the cycloalkyl group is replaced by an O atom.
  • Methods of treatment include administering to a subject a therapeutically effective amount of a compound.
  • the present invention provides methods of treating inflammatory diseases, including autoimmune diseases, in mammals.
  • the method comprises administering to the mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
  • the compound of the present invention has a good inhibitory effect on TYK2, and can be used to treat diseases related to TYK2 kinase dysfunction, such as cancer, bone disease, inflammatory disease, immune disease, nervous system disease, metabolic disease, respiratory disease and heart disease and other diseases.
  • diseases related to TYK2 kinase dysfunction such as cancer, bone disease, inflammatory disease, immune disease, nervous system disease, metabolic disease, respiratory disease and heart disease and other diseases.
  • the compound of the present invention has high selectivity for the TYK2 JH2 binding domain, is safe when used, and has few toxic and side effects.
  • the compounds of the invention can be used for preparing TYK2 inhibitors and medicines for treating diseases related to TYK2 kinase dysfunction, and have good application prospects.
  • the raw materials and equipment used in the specific embodiments of the present invention are all known products, which are obtained by purchasing commercially available products, or can be synthesized by adopting or following methods known in the art.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was four Methylsilane (TMS).
  • DMSO-d 6 dimethyl sulfoxide
  • CD 3 OD deuterated methanol
  • CDCl 3 deuterated chloroform
  • TMS Methylsilane
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of TLC is 0.15mm ⁇ 0.20mm, and the size of TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • Thin-layer chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the first step the preparation of 4-bromomethyl-1-methoxy-2-nitrobenzene
  • the third step preparation of 2-aminopropyl-(4-methoxy-3-nitrobenzyl) ether
  • the fourth step the preparation of 2-(2-(N-Boc-amino) ethyl) dimethyl malonate
  • the fifth step preparation of 6-(2-(N-Boc-aminoethyl))-5,7-dihydroxypyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester
  • Step 6 Preparation of ethyl 5-chloro-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxylate
  • Step 7 Preparation of 5-chloro-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxylic acid
  • Step 8 5-Chloro-N-(1-(((4-methoxy-3-nitrobenzyl)oxy)prop-2-yl)-7,8-dihydro-6H-pyrazole Preparation of [1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide
  • Step 9 5-Chloro-N-(1-(((4-methoxy-3-nitrobenzyl)oxy)prop-2-yl)-N-Boc-7,8-dihydro- Preparation of 6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide
  • Step 10 5-Chloro-N-(1-(((4-methoxy-3-aminobenzyl)oxy)propan-2-yl)-N-Boc-7,8-dihydro-6H -
  • the first step preparation of (S)-2-(N-Boc-amino)propyl-(4-methoxy-3-nitrobenzyl) ether
  • the second step the preparation of (S)-2-aminopropyl-(4-methoxy-3-nitrobenzyl) ether
  • the first step preparation of (R)-2-(N-tert-butoxycarbonyl-amino)propyl-(4-methoxy-3-nitrobenzyl) ether
  • the third step preparation of (R)-(1-((3-fluoro-5-nitrobenzyl)oxy)propan-2-yl)amine
  • the fifth step tert-butyl (R)-5-chloro-3-((1-((3-fluoro-5-nitrobenzyl)oxy)propan-2-yl)carbamoyl)-6, Preparation of 7-dihydro-8H-pyrazolo[1,5-a]pyrro[3,2-e]pyrimidine-8-carboxylate
  • the sixth step (tert-butyl(R)-3-((1-((3-amino-5-fluorobenzyl)oxy)propan-2-yl)carbamoyl)-5-chloro-6, Preparation of 7-dihydro-8H-pyrazolo[1,5-a]pyrro[3,2-e]pyrimidine-8-carboxylate
  • the seventh step tert-butyl (R)-(1 3 E, 1 4 E)-3 5 -fluoro-7-methyl-9-oxo-1 7 ,1 8 -dihydro-1 6 H-5 -Oxo-2,8-diazo-1(5,3)-pyrazo[1,5-a]pyrro[3,2-e]pyrimidine-3(1,3)-phenylcyclononane-1
  • the first step the preparation of 5-methyl-2-methoxy-3-nitropyridine
  • the second step the preparation of 5-bromomethyl-2-methoxy-3-nitropyridine
  • the third step preparation of (R)-5-(2-(N-Boc-amino)propoxymethyl)-2-methoxy-3-nitropyridine
  • the fourth step the preparation of (R)-5-((2-aminopropoxy) methyl)-2-methoxy-3-nitropyridine
  • the seventh step (R)-5-chloro-N-(2-((2-methoxy-3-aminopyridin-5-yl)methoxy)propyl)-N-Boc-7,8- Preparation of Dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide
  • the first step the preparation of 5-bromomethyl-3-methoxybromobenzene
  • the third step preparation of (R)-2-(N-Boc-amino)propyl-(3-(N-Boc-amino)-5-methoxybenzyl)ether
  • the fourth step the preparation of (R)-2-aminopropyl-(3-amino-5-methoxybenzyl) ether
  • N-Boc-5-chloro-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxylic acid (300.0 mg, 1.3 mmol), ( R)-2-aminopropyl-(3-amino-5-methoxybenzyl) ether (230.0 mg, 0.9 mmol), 2-(7-azabenzotriazole)-N,N,N ',N'-Tetramethylurea hexafluorophosphate (0.1 g, 0.3 mmol), triethylamine (57.0 mg, 0.6 mmol) were mixed in dichloromethane (14.0 mL), and the reaction was stirred at 25 °C for 16 h under reduced pressure.
  • the first step the preparation of 2-fluoro-4-methoxy-5-nitrobenzaldehyde
  • 2-Fluoro-4-methoxybenzaldehyde (2.0g, 13.0mmol) was dissolved in concentrated sulfuric acid (1.6mL), the ice brine was cooled to -12°C, and concentrated sulfuric acid (1.6mL) was added dropwise to concentrated nitric acid ( 1.6mL), then add the mixed acid dropwise to the reaction system, control the temperature not to exceed 0 ° C, react for 2h, pour the reaction solution into ice water, stir for 15 minutes, filter, filter cake column chromatography to obtain a pale yellow solid compound 2-Fluoro-4-methoxy-5-nitrobenzaldehyde (1.6 g, 61.8%).
  • the second step preparation of 2-fluoro-4-methoxy-5-nitrobenzyl alcohol
  • 2-Fluoro-4-methoxy-5-nitrobenzaldehyde (0.5g, 2.5mmol) was dissolved in methanol (7.0mL), the ice water was cooled to 0°C, and sodium borohydride (0.2g, 2.5 mmol) was added in batches. 5mmol), react at 0°C for 1 h, pour the reaction solution into water, extract twice with dichloromethane, combine the dichloromethane, wash with saturated brine, separate the layers, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain 2-Fluoro-4-methoxy-5-nitrobenzyl alcohol (0.5 g, 98.0%).
  • the third step preparation of 2-fluoro-4-methoxy-5-nitrobenzyl bromide
  • the fifth step preparation of (R)-(1-((5-amino-2-fluoro-4-methoxybenzyl)oxy)prop-2-yl)carbamic acid tert-butyl ester
  • the sixth step the preparation of (R)-5-((2-aminopropoxy) methyl)-4-fluoro-2-methoxyaniline hydrochloride
  • the seventh step (R)-N-(1-((5-amino-2-fluoro-4-methoxybenzyl)oxy)propan-2-yl)-5-chloro-8-((2 -(Trimethylsilyl)ethoxy)methyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrro[3,2-e]pyrimidine-3-carboxamide preparation
  • the ninth step ( R ,13E,14E)-34 - fluoro-36-methoxy- 7 -methyl- 17,18 -dihydro - 16H- 5 -oxa -2,8-Diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-phenylcyclocyclononyl- Preparation of 9-keto (Ia-2)
  • the first step the synthesis of 2-chloro-6-(2-oxypyrrolidin-1-yl) isonicotinic acid methyl ester
  • Methyl 2,6-dichloroisonicotinate (5.0 g, 24.5 mmol), 2-pyrrolidone (0.4 g, 24.5 mmol), tris(dibenzylidene-BASE acetone)dipalladium (2.3 g, 2.5 mmol), 2 -(Dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (2.0 g, 3.7 mmol), mixed in 1, 4-dioxane (100.0 mL) was reacted in an oil bath at 90°C for 20.0 h, the reaction solution was cooled, concentrated, and directly passed through the column to obtain 2-chloro-6-(2-oxopyrrolidin-1-yl) Methyl isonicotinate (3.3 g, 53% yield).
  • Methyl 2-chloro-6-(2-oxopyrrolidin-1-yl)isonicotinate (3.3 g, 13.0 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL), and anhydrous lithium chloride (818.0 mg, 19.5mmol), in an ice-water bath at 0°C, sodium borohydride (593.0mg, 15.6mmol) was added in batches, after the addition was completed, the ice-water bath was removed, the temperature was naturally raised, and the reaction was performed at room temperature for 12.0h.
  • the third step synthesis of 1-(4-(bromomethyl)-6-chloropyridin-2-yl)pyrrolidin-2-one
  • the seventh step tert-butyl (R)-N-(1-((2-amino-6-(2-oxypyrrolidin-1-yl)pyridin-4-yl)methoxy)propan-2-yl )-5-chloro-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3-carboxamide
  • the eighth step tert-butyl (R, 1 3 E, 1 4 E)-7-methyl-9-oxo-3 6 -(2-oxopyrrolidin-1-yl)-1 7 ,1 8 - Dihydro-1 6 H-5-oxo-2,8-diazo-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(2 Synthesis of ,4)-pyridinecyclononane-1 8 -carboxylic acid amine
  • the ninth step (R, 1 3 E, 1 4 E)-7-methyl-3 6 -(2-oxopyrrolidin-1-yl)-1 7 ,1 8 -dihydro-1 6 H-5 -oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(2,4)-pyridinecyclononane Synthesis of Alk-9-one (Ia-4)
  • the first step (R, 1 3 E, 1 4 E)-7-methyl-3 6 -(2-oxopyrrolidin-1-yl)-1 7 ,1 8 -dihydro-1 6 H-5 -oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(2,4)-pyridinecyclononane
  • Alkan-9-one (10 mg, 0.02 mmol) was added with dichloromethane (4 mL) and 2 drops of dimethyl sulfoxide. After the solution was clarified, manganese dioxide (2.0 mg, 4.0 mmol) was added and reacted at room temperature for 2 h.
  • the first step the synthesis of 5-bromomethyl-3-bromo-benzonitrile
  • the third step Synthesis of 2-(N-Boc-amino)propyl-(5-N-Boc-amino-3-cyanobenzyl)ether
  • the fourth step the synthesis of (R)-2-aminopropyl-(5-amino-3-cyanobenzyl) ether
  • the seventh step ( R ,13E,14E)-35 - cyano- 7 -methyl- 9 -oxo- 17,18 -dihydro-16H- 5 -oxo- 2,8-diazo-1(5,3)-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine-3(1,3)-benzocyclononane-1 8 -Synthesis of Carboxylic Acid Amines (Ia-3)
  • Test Example 1 Study on the binding ability of the compounds of the present invention to the TYK2 JH2 domain
  • the binding ability of the compounds to the JH2 domain of TYK2 kinase was evaluated by in vitro biochemical experiments.
  • the specific experimental steps are as follows.
  • the expression of the human TYK2-like kinase domain (575-869 amino acids) used was obtained by the insect cell-baculovirus expression system (Bac-to-Bac Expression System), and the specific experimental steps were carried out according to the operation manual of Invitrogen Company.
  • Virus-infected Sf-9 insect cells for 66 hours were centrifuged using a 2.5:1 mass ratio of Buffer A solution (50 mM Hepes, pH 7.7, 500 mM NaCl, 25 mM imidazole, 5% (v/v) glycerol) with protease inhibitors added.
  • Buffer A solution 50 mM Hepes, pH 7.7, 500 mM NaCl, 25 mM imidazole, 5% (v/v) glycerol
  • HTRF homogeneous time-resolved fluorescence
  • the test results show that: the compound of the present invention has good binding ability to the TYK2 JH2 domain, the compound of the present invention can exert an allosteric regulation effect by binding to the TYK2 JH2 domain, inhibit the activity of TYK2 kinase, and be useful for preventing and/or treating related to TYK2 potential for autoimmune diseases such as psoriasis, systemic lupus erythematosus, inflammatory bowel disease, etc.
  • Test Example 2 The ability of the compounds of the present invention to inhibit pSTAT5 in human peripheral blood mononuclear cells (PBMC) induced by IFNa
  • Human PBMC cells were plated in a 96-well plate, and compound diluted in DMSO was added, and incubated at 37°C for 60 minutes. Add 20ng/mL of IFN-a to stimulate cells and incubate at 37°C for 15 minutes. Add 1 ⁇ L of anti-human CD3 antibody to each well and incubate at 4 degrees Celsius for 30 minutes. Transfer the cells to a 96-well deep-well plate, add 1 mL of fixative to each well, shake to mix, and incubate in a 37-degree water bath for 10 minutes. Centrifuge at 600g for 5 minutes, rinse with PBS, add 1000 ⁇ L of Perm III to each well, incubate at 4 degrees Celsius for 30 minutes, and centrifuge.
  • FACS buffer PBS+0.2%BSA+1mM EDTA
  • FACS buffer PBS+0.2%BSA+1mM EDTA
  • Table 2 shows the inhibitory activity of the compounds of the present invention on pSTAT5 in PBMC cells.
  • autoimmune diseases including psoriasis, IBD, and systemic lupus erythematosus
  • cytokines play an important role through the JAK/STAT signaling pathway.
  • Type I interferons IFN ⁇ , IFN ⁇ , etc.
  • IL-12, IL-23, etc. activate downstream STATs (STAT1, STAT2, STAT3, STAT5) through TYK2 to complete signal transduction.
  • results of this test show that the compound of the present invention has a good inhibitory effect on pSTAT5 in IFN ⁇ -induced PBMC cells, further indicating that the compound of the present invention can volatilize the inhibitory effect on TYK2, and be used for the prevention and/or treatment of TYK2-related diseases.
  • Test Example 3 The ability of the compounds of the present invention to inhibit IFNa-induced pSTAT5 in human whole blood
  • Human whole blood cells were plated in a 96-well plate, and compounds serially diluted in DMSO were added, and incubated at 37°C for 60 minutes. Add 20ng/mL of IFN-a to stimulate cells and incubate at 37°C for 15 minutes. Add 1 ⁇ L of anti-human CD3 antibody to each well and incubate at 4 degrees Celsius for 30 minutes. Transfer the cells to a 96-well deep-well plate, add 1 mL of fixative to each well, shake to mix, and incubate in a 37-degree water bath for 10 minutes. Centrifuge at 600g for 5 minutes, rinse with PBS, add 1000 ⁇ L of Perm III to each well, incubate at 4 degrees Celsius for 30 minutes, and centrifuge.
  • FACS buffer PBS+0.2%BSA+1mM EDTA
  • FACS buffer PBS+0.2%BSA+1mM EDTA
  • Table 3 shows the inhibitory activity of the compounds of the present invention on pSTAT5 in human whole blood cells.
  • Test Example 2 The same as Test Example 2, the test results show that the compounds of the present invention have a good inhibitory effect on pSTAT5 in human whole blood cells induced by IFN ⁇ , and further illustrate that the compounds of the present invention can volatilize the inhibitory effect on TYK2, and be used for the prevention and/or treatment of TYK2. related diseases.
  • Test Example 4 The compounds of the present invention inhibit the activity of JAK1, JAK2, JAK3, TYK2 and JH1
  • the inhibitory effect of the compounds and purified kinases JAK1, JAK2, JAK3, TYK2 kinases on the kinase activity of the JH1 domain of the kinases was detected by homogeneous time-resolved fluorescence (HTRF).
  • HTRF homogeneous time-resolved fluorescence
  • JAK1 JH1, JAK2 JH1, JAK3 JH1 and TYK2 JH1 Dilute JAK1 JH1, JAK2 JH1, JAK3 JH1 and TYK2 JH1 with 1 ⁇ assay buffer, add 5 ⁇ L per well to a 384-well plate, centrifuge at 1000 rpm for 30 seconds, and incubate at room temperature for 15 minutes.
  • Use 1 ⁇ assay buffer to prepare the substrate solution add 5 ⁇ L per well to a 384-well plate, and centrifuge at 1000 rpm for 30 seconds.
  • the 384-well plates of JAK1 JH1 and JAK2 JH1 were incubated at room temperature for 45 minutes, respectively, and the 384-well plates of JAK3 JH1 and TYK2 JH1 were incubated at room temperature for 60 minutes, respectively.
  • JAK inhibitors targeting the JH1-binding domain of JAK tend to have high side effects.
  • the compound of the present invention has no binding activity to JAK family kinases including the JH1 domain of TYK2, has high selectivity, and can effectively avoid off-target effects.
  • HTRF homogeneous time-resolved fluorescence
  • the current JAK inhibitors all have the disadvantage of low selectivity.
  • the compounds of the present invention can effectively inhibit TYK2 kinase activity through allosteric effect, have high selectivity, and can effectively avoid off-target effects.
  • the compounds of the present invention have a good inhibitory effect on TYK2, and can be used to treat diseases related to TYK2 kinase dysfunction, such as cancer, bone diseases, inflammatory diseases, immune diseases, nervous system diseases, metabolic diseases, and respiratory diseases. and heart disease.
  • diseases related to TYK2 kinase dysfunction such as cancer, bone diseases, inflammatory diseases, immune diseases, nervous system diseases, metabolic diseases, and respiratory diseases. and heart disease.
  • the compound of the present invention has high selectivity for the TYK2 JH2 binding domain, is safe when used, and has little toxic and side effects.
  • the compounds of the present invention can be used for preparing TYK2 inhibitors and medicines for treating diseases related to TYK2 kinase dysfunction, and have good application prospects.

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Abstract

L'invention concerne un composé polycyclique représenté par la formule I ou un stéréoisomère, un solvate, un sel, un ester, un promédicament ou un hydrate de celui-ci, son procédé de préparation et son utilisation. Le composé a un bon effet inhibiteur sur TYK2, et peut être utilisé pour traiter des maladies liées à un dysfonctionnement de la kinase TYK2, tels que le cancer, les maladies osseuses, les maladies inflammatoires, les maladies immunitaires, les maladies du système nerveux, les maladies métaboliques, les maladies respiratoires et les maladies cardiaques. Le composé a une sélectivité élevée pour un domaine de liaison TYK2 JH2 et est sûr à utiliser avec peu d'effets secondaires toxiques. Le composé peut être utilisé dans la préparation d'un inhibiteur de TYK2 et d'un médicament pour le traitement de maladies liées à un dysfonctionnement de la kinase TYK2, et possède ainsi de bonnes perspectives d'application.
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Publication number Priority date Publication date Assignee Title
WO2023076161A1 (fr) 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Agents de dégradation de tyk2 et leurs utilisations

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CN103547580A (zh) * 2011-03-22 2014-01-29 阿迪维纳斯疗法有限公司 取代的稠合三环化合物、其组合物及医药用途
CN103732597A (zh) * 2011-08-12 2014-04-16 日产化学工业株式会社 三环杂环化合物和jak抑制剂
CN107735399A (zh) * 2015-07-02 2018-02-23 Tp生物医药公司 作为蛋白质激酶的调节剂的手性二芳基大环
WO2019126122A1 (fr) * 2017-12-19 2019-06-27 Tp Therapeutics, Inc. Inhibiteurs macrocycliques de kinase et leur utilisation
WO2020185755A1 (fr) * 2019-03-11 2020-09-17 Fronthera U.S. Pharmaceuticals Llc Inhibiteurs de tyk2 et leurs utilisations
WO2020198379A1 (fr) * 2019-03-26 2020-10-01 Ventyx Biosciences, Inc. Ligands de pseudokinase tyk2

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103547580A (zh) * 2011-03-22 2014-01-29 阿迪维纳斯疗法有限公司 取代的稠合三环化合物、其组合物及医药用途
CN103732597A (zh) * 2011-08-12 2014-04-16 日产化学工业株式会社 三环杂环化合物和jak抑制剂
CN107735399A (zh) * 2015-07-02 2018-02-23 Tp生物医药公司 作为蛋白质激酶的调节剂的手性二芳基大环
WO2019126122A1 (fr) * 2017-12-19 2019-06-27 Tp Therapeutics, Inc. Inhibiteurs macrocycliques de kinase et leur utilisation
WO2020185755A1 (fr) * 2019-03-11 2020-09-17 Fronthera U.S. Pharmaceuticals Llc Inhibiteurs de tyk2 et leurs utilisations
WO2020198379A1 (fr) * 2019-03-26 2020-10-01 Ventyx Biosciences, Inc. Ligands de pseudokinase tyk2

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023076161A1 (fr) 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Agents de dégradation de tyk2 et leurs utilisations

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