[go: up one dir, main page]

WO2022194267A1 - Antagoniste gpr84, son procédé de préparation et son utilisation - Google Patents

Antagoniste gpr84, son procédé de préparation et son utilisation Download PDF

Info

Publication number
WO2022194267A1
WO2022194267A1 PCT/CN2022/081614 CN2022081614W WO2022194267A1 WO 2022194267 A1 WO2022194267 A1 WO 2022194267A1 CN 2022081614 W CN2022081614 W CN 2022081614W WO 2022194267 A1 WO2022194267 A1 WO 2022194267A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compound
membered
group
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2022/081614
Other languages
English (en)
Chinese (zh)
Inventor
张学军
臧杨
蔡立波
魏文军
陈浩民
刘礼飞
王俊南
张辛
李莉娥
杨俊�
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
Original Assignee
Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co filed Critical Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
Publication of WO2022194267A1 publication Critical patent/WO2022194267A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial 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
    • 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
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention belongs to the field of medicine, and in particular, the invention relates to a GPR84 antagonist and a preparation method and application thereof.
  • G protein-coupled receptor 84 is a G protein-coupled receptor that is coupled to the pertussis toxin-sensitive Gi/o pathway, and when activated by ligand binding, inhibits adenylate through Gi protein Cyclase activity, thereby reducing intracellular cAMP levels.
  • GPR84 is a fatty acid receptor and is mainly expressed in bone marrow, followed by peripheral leukocytes and lung, and can be activated by medium-chain saturated fatty acids, among which capric acid (C10), undecanoic acid (C11), and lauric acid (C12) have agonistic activity most.
  • DIM diindolylmethane
  • 6-OAU 6-n-octylaminouracil
  • Beric acid embelin
  • GPR84 Under normal physiological conditions, the expression of GPR84 in immune cells is low. In the presence of LPS, medium-chain fatty acids and diindolylmethane can up-regulate the secretion of IL-12P40 subunit by activating GPR84 and promote the occurrence of inflammation.
  • GPR84 mRNA expression was observed during acute inflammation.
  • GPR84 upregulation has also been observed in chronic inflammatory models such as diabetes and atherosclerosis (Recio et al, 2018). Increased expression of GPR84 has been reported in colon tissue and blood samples from patients with inflammatory bowel disease (IBD) (Arijs et al, 2011; Planell et al, 2017). GPR84 mRNA transcription is also increased in liver biopsies from patients with nonalcoholic fatty liver disease (NAFLD) (Puengel et al, 2020). Furthermore, the observation of GPR84 upregulation was not limited to peripheral disease but was also confirmed in neuroinflammatory settings.
  • IBD inflammatory bowel disease
  • NAFLD nonalcoholic fatty liver disease
  • GPR84 is expressed at low levels in the brains of healthy adult mice (Bouchard et al, 2007), but inflammatory stimuli induced marked upregulation of central nervous system (CNS) microglia, such as in models of endotoxic shock (Audoy- Remus et al, 2015).
  • CNS central nervous system
  • Tumor necrosis factor alpha and interleukin-1 are thought to play key roles in GPR84 upregulation, as GPR84 expression is reduced in the cerebral cortex of mice lacking these molecules.
  • GPR84 mRNA expression has also been reported in other animal models of diseases affecting the central nervous system, including experimental autoimmune encephalomyelitis, a model of multiple sclerosis (Bouchard et al, 2007), Cuprizone Induced demyelination and axotomy (Bedard et al, 2007) and a mouse model of Alzheimer's disease (APP-PS1) (Audoy-Remus et al, 2015).
  • Idiopathic pulmonary fibrosis is a chronic, progressive fibrotic interstitial lung disease of unknown cause characterized by progressive scarring or fibrosis confined to the interstitial spaces of the lungs, resulting in loss of lung function and eventually die. With a high risk of rapid progression and death, IPF is generally considered a rare disease. Patients with IPF have a poor clinical prognosis, with a median survival of approximately 3 years at diagnosis. Regulators have approved pirfenidone and Inetedanib for the treatment of IPF. Pirfenidone and inttedanib slowed the rate of decline in lung function in IPF patients, however, neither drug improved lung function, and the disease continued to progress in most patients despite treatment.
  • the object of the present invention is to provide a GPR84 antagonist
  • the GPR84 antagonist includes the compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound according to the present invention. Accepted salt or prodrug. It can be used for preventing and/or treating GPR84-related diseases; or preparing medicines, pharmaceutical compositions or preparations as GPR84 antagonists, preventing and/or treating GPR84-related diseases.
  • L 1 is -NR d -, -O- or -S-;
  • R d is hydrogen or is unsubstituted or halogen-substituted C 1 -C 5 alkyl
  • L 2 does not exist or is C 1 -C 5 alkylene
  • the C 1 -C 5 alkylene is optionally substituted with one or more R a ;
  • the R a is a substituent selected from the group consisting of halogen, hydroxyl, amino, 3-6 membered cycloalkyl, 4- 6-membered heterocycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino; when there are multiple substituents, the said Ra is the same or different;
  • the C 1 -C 5 alkyl group is substituted with R b , R c which together with the C atom to which they are commonly attached form a 3-6 membered cycloalkyl or 4-6 membered heterocycloalkane base;
  • R1 is ring Cy optionally substituted with one or more R11;
  • the R 11 is hydroxyl, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy; when there are multiple substituents, the R 11 is the same or different;
  • the ring Cy is
  • Z 1 does not exist or is -O-;
  • Z 2 does not exist or is C 1 -C 3 alkylene
  • Z 3 does not exist or is -O-, C 1 -C 2 alkylene
  • Ring A is phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl;
  • L 3 is absent or L 3 is C 1 -C 4 alkylene, C 2 -C 4 alkenylene with one double bond or C 2 -C 4 alkynylene with one triple bond;
  • R 2 is a substituent selected from the group consisting of C 1 -C 5 alkyl, 3-10-membered cycloalkyl, 4-10-membered heterocycloalkyl, or 5-10-membered heteroaryl;
  • the C 1 -C 5 alkyl, 3-10-membered cycloalkyl, 4-10-membered heterocycloalkyl, or 5-10-membered heteroaryl is optionally substituted with one or more R 21 ;
  • the R 21 is a substituent selected from the group consisting of hydroxy, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy; when there are multiple substituents, the R 21 is different or different substituents;
  • R 3 , R 4 , R 5 , R 6 are each independently hydrogen, halogen or C 1 -C 4 alkyl; the C 1 -C 4 alkyl is optionally substituted by one or more R 31 ; the R 31 is a substituent selected from the group consisting of halogen, hydroxyl, amino, C 1 -C 3 alkoxy, C 1 -C 3 alkylamino; when there are multiple substituents, the R 31 are the same or different;
  • R 4 , R 5 together with the C atom to which they are commonly attached form a 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl.
  • the 5-6 membered heteroaryl or 4-6 membered heterocycloalkyl optionally contains 1, 2 or 3 heteroatoms selected from N, O and S; When there are 2 or 3 atoms, the heteroatoms are the same or different.
  • the 4-10-membered heterocycloalkyl or 5-10-membered heteroaryl optionally contains 1, 2 or 3 heteroatoms selected from N, O and S; When there are 2 or 3 atoms, the heteroatoms are the same or different.
  • L 1 is -NR d -, -O-;
  • R d is hydrogen or an unsubstituted or halogen-substituted C 1 -C 5 alkyl; preferably, R d is hydrogen or an unsubstituted or halogen-substituted C 1 -C 3 alkyl; preferably, the halogen is fluorine or chlorine;
  • L 1 is -O-.
  • L 2 does not exist or L 2 is -CH 2 - or -CH 2 CH 2 -; preferably, L 2 is -CH 2 -; the -CH 2 - or -CH 2 CH 2 - optionally substituted with one or more R a ; said R a is a substituent selected from halogen, hydroxy, amino, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino; when there are multiple substituents, the R a is the same or different ;
  • the -CH2- or -CH2CH2- is substituted with Rb , Rc , which together with the C atom to which they are commonly attached, form a 3-6 membered cycloalkyl group.
  • R 1 is a ring Cy optionally substituted by one or more R 11 ; the R 11 is hydroxy, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkane group, C 1 -C 4 alkoxy; when there are multiple substituents, the R 11 are the same or different;
  • the ring Cy is
  • Z 1 does not exist or is -O-;
  • Z 2 does not exist or is -CH 2 -;
  • Z 3 does not exist or is -O-, -CH 2 -;
  • Ring A is phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl;
  • the 5-6 membered heteroaryl or 4-6 membered heterocycloalkyl optionally contains 1, 2 or 3 heteroatoms selected from N, O and S; when the number of heteroatoms is 2 or 3, the The heteroatoms are the same or different.
  • R 1 is a ring Cy optionally substituted with 1 or 2 R 11 ;
  • the ring Cy is Preferably, the ring Cy is
  • Ring A is phenyl or 5-6 membered containing 1 or 2 atoms selected from O or N (preferably O)
  • Ring A is phenyl
  • R said R 11 is hydroxyl, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy; preferably, R 11 is halogen, C 1 -C 4 alkane more preferably, R 11 is fluorine, chlorine, methyl, ethyl or propyl; when there are multiple substituents, R 11 is the same or different.
  • R 1 is a group optionally substituted with 1, 2 or 3 R 11
  • the R 11 is hydroxyl, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy; preferably, R 11 is halogen, C 1 -C 4 alkyl ; more preferably, R 11 is fluorine, chlorine, methyl, ethyl or propyl; when there are multiple substituents, R 11 is the same or different.
  • R 1 is a substituent selected from the following: Wherein, R 11 is fluorine, chlorine, methyl, ethyl or propyl; preferably, R 11 is methyl.
  • R 2 is a substituent selected from the group consisting of C 1 -C 5 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl base; the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl optionally contains 1, 2 or 3 heteroatoms selected from N, O and S; when the heteroatoms are 2 or 3 , the heteroatoms are the same or different;
  • the C 1 -C 5 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl is optionally substituted with one or more R 21 ;
  • the R 21 is a substituent selected from the group consisting of hydroxyl, halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy; when there are multiple substituents, the R 21 is a different or different substituent.
  • R 2 is a substituent selected from the group consisting of C 1 -C 5 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl the 4-6 membered heterocycloalkyl group has 1 or 2 O heteroatoms; the 5-6 membered heteroaryl group has 1, 2 or 3 N heteroatoms; the C 1 -C 5 alkyl group , 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl optionally substituted by one or more R 21 ; said R 21 is a substituent selected from the group consisting of: hydroxy , C 1 -C 6 alkyl; when there are multiple substituents, the R 21 is different or different substituents;
  • R 2 is a substituent selected from the group consisting of methyl,
  • -L 3 -R 2 is a substituent selected from the following:
  • R 3 , R 4 , R 5 , and R 6 are each independently hydrogen, methyl, ethyl, propyl, fluorine or chlorine; preferably, R 3 , R 4 , and R 5 and R 6 are each independently hydrogen or a substituent selected from the group consisting of methyl, ethyl, propyl, fluorine or chlorine; more preferably, R 3 , R 4 , R 5 and R 6 are hydrogen.
  • R 4 and R 5 together with the C atom to which they are connected together form a 4-7 membered cycloalkyl or a 4-7 membered heterocycloalkyl;
  • R 4 and R 5 together with the C atom to which they are connected together form a 4-6 membered cycloalkyl
  • the 4-6 membered heterocycloalkyl optionally contains 1 or 2 heteroatoms selected from N, O and S; when there are 2 heteroatoms, the heteroatoms are the same or different.
  • R 3 and R 6 are hydrogen.
  • the compound shown in the formula I includes:
  • R 1 , R 3 , R 4 , R 5 , R 6 , L 1 and L 2 are as described in the first aspect of the present invention
  • X is selected from: -OTf, -OTs, -OMs, fluorine, chlorine, bromine or iodine; preferably, X is bromine or iodine.
  • L 1 is -NR d -, -O- or -S-;
  • R d is hydrogen or is unsubstituted or halogen-substituted C 1 -C 5 alkyl
  • L 2 does not exist or is C 1 -C 5 alkylene
  • the C 1 -C 5 alkylene is optionally substituted with one or more R a ;
  • the R a is a substituent selected from the group consisting of halogen, hydroxyl, amino, 3-6 membered cycloalkyl, 4- 6-membered heterocycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino; when there are multiple substituents, the said Ra is the same or different;
  • the C 1 -C 5 alkyl group is substituted with R b , R c which together with the C atom to which they are commonly attached form a 3-6 membered cycloalkyl or 4-6 membered heterocycloalkane base;
  • R1 is ring Cy optionally substituted with one or more R11;
  • the R 11 is hydroxyl, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy; when there are multiple substituents, the R 11 is the same or different;
  • the ring Cy is
  • Z 1 does not exist or is -O-;
  • Z 2 does not exist or is C 1 -C 3 alkylene
  • Z 3 does not exist or is -O-, C 1 -C 2 alkylene
  • Ring A is phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl;
  • R 3 , R 4 , R 5 , R 6 are each independently hydrogen, halogen or C 1 -C 4 alkyl; the C 1 -C 4 alkyl is optionally substituted by one or more R 31 ; the R 31 is a substituent selected from the group consisting of halogen, hydroxyl, amino, C 1 -C 3 alkoxy, C 1 -C 3 alkylamino; when there are multiple substituents, the R 31 are the same or different;
  • R 4 , R 5 together with the C atom to which they are commonly attached form a 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl.
  • the 5-6 membered heteroaryl or 4-6 membered heterocycloalkyl optionally contains 1, 2 or 3 heteroatoms selected from N, O and S; When there are 2 or 3 atoms, the heteroatoms are the same or different.
  • L 1 is -NR d -, -O-;
  • R d is hydrogen or unsubstituted or halogen-substituted C 1 -C 5 alkyl; preferably, R d is hydrogen or unsubstituted or halogen-substituted C 1 -C 3 alkyl; preferably, the halogen is fluorine or chlorine; preferably, L 1 is -O-.
  • L 2 does not exist or L 2 is -CH 2 - or -CH 2 CH 2 -; preferably, L 2 is -CH 2 -; the -CH 2 - or -CH 2 CH 2 - optionally substituted with one or more R a ; said R a is a substituent selected from halogen, hydroxy, amino, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino; when there are multiple substituents, the R a is the same or different ;
  • the -CH2- or -CH2CH2- is substituted with Rb , Rc , which together with the C atom to which they are commonly attached, form a 3-6 membered cycloalkyl group.
  • R 1 is a ring Cy optionally substituted by one or more R 11 ; the R 11 is hydroxy, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkane group, C 1 -C 4 alkoxy; when there are multiple substituents, the R 11 are the same or different;
  • the ring Cy is
  • Z 1 does not exist or is -O-;
  • Z 2 does not exist or is -CH 2 -;
  • Z 3 does not exist or is -O-, -CH 2 -;
  • Ring A is phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl;
  • the 5-6 membered heteroaryl or 4-6 membered heterocycloalkyl optionally contains 1, 2 or 3 heteroatoms selected from N, O and S; when the heteroatom is 2 or 3 In each case, the heteroatoms are the same or different.
  • R 1 is a ring Cy optionally substituted with 1, 2 or 3 R 11 ; preferably, R 1 is a ring Cy optionally substituted with 1 or 2 R 11 ;
  • the ring Cy is More preferably, the ring Cy is
  • Ring A is phenyl or 5-6 membered containing 1 or 2 atoms selected from O or N (preferably O)
  • Ring A is phenyl
  • the R 11 is hydroxyl, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy; preferably, R 11 is halogen, C 1 -C 4 alkyl ; more preferably, R 11 is fluorine, chlorine, methyl, ethyl or propyl; when there are multiple substituents, R 11 is the same or different.
  • R 1 is a group optionally substituted with 1, 2 or 3
  • R 11 is hydroxyl, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy; preferably, R 11 is halogen, C 1 -C 4 alkyl; more Preferably, R 11 is fluorine, chlorine, methyl, ethyl or propyl; when there are multiple substituents, R 11 is the same or different.
  • R 1 is a substituent selected from the following: Wherein, R 11 is fluorine, chlorine, methyl, ethyl or propyl; preferably, R 11 is methyl.
  • R 3 , R 4 , R 5 , and R 6 are each independently hydrogen, methyl, ethyl, propyl, fluorine or chlorine; preferably, R 3 , R 4 , and R 5 and R 6 are each independently hydrogen or a substituent selected from the group consisting of methyl, ethyl, propyl, fluorine or chlorine; more preferably, R 3 , R 4 , R 5 and R 6 are hydrogen.
  • the intermediate B comprises:
  • a compound represented by formula I as described in the first aspect of the present invention its tautomer, stereoisomer, hydrate, solvate and pharmaceutically acceptable salt Or the preparation method of the prodrug, the method comprises the steps: 1) The intermediate B according to the second aspect of the present invention reacts with the compound HL 3 -R 2 to obtain the compound represented by the formula I.
  • the method further includes:
  • the catalyst is a palladium catalyst and/or a copper catalyst;
  • the palladium catalyst includes: Pd(PPh 3 ) 2 Cl 2 , Pd(OAc) 2 , Pd(TFA) 2 , PdCl 2 , Pd(PPh 3 ) 4 , Pd(dba) 3 ; more preferably , the palladium catalyst is Pd(PPh 3 ) 2 Cl 2 , Pd(OAc) 2 ;
  • the copper catalyst is a monovalent copper catalyst; more preferably, the copper catalyst is CuI;
  • the inert gas is nitrogen, helium, neon or argon.
  • L 3 does not exist or L 3 is a C 1 -C 4 alkylene group, a C 2 -C 4 alkenylene group with a double bond or a C 2 -C 4 alkenylene group with a double bond.
  • R 2 is a substituent selected from the group consisting of C 1 -C 5 alkyl, 3-10-membered cycloalkyl, 4-10-membered heterocycloalkyl, or 5-10-membered heteroaryl;
  • the C 1 -C 5 alkyl, 3-10-membered cycloalkyl, 4-10-membered heterocycloalkyl, or 5-10-membered heteroaryl is optionally substituted with one or more R 21 ;
  • the R 21 is a substituent selected from the group consisting of hydroxy, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy; when there are multiple substituents, the R 21 is different or different substituents.
  • the 4-10-membered heterocycloalkyl or 5-10-membered heteroaryl optionally contains 1, 2 or 3 heteroatoms selected from N, O and S; When there are 2 or 3 atoms, the heteroatoms are the same or different.
  • R 2 is a substituent selected from the following: C 1 -C 5 alkyl, 3-6-membered cycloalkyl, 4-6-membered heterocycloalkane or 5-6 membered heteroaryl; preferably, the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl optionally contains 1, 2 or 3 selected from N, O and S Heteroatom; when there are 2 or 3 heteroatoms, the heteroatoms are the same or different;
  • the C 1 -C 5 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl is optionally substituted with one or more R 21 ;
  • the R 21 is a substituent selected from the group consisting of hydroxyl, halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy; when there are multiple substituents, the R 21 is a different or different substituent.
  • R 2 is a substituent selected from the following: C 1 -C 5 alkyl, 3-6-membered cycloalkyl, 4-6-membered heterocycloalkane the 4-6 membered heterocycloalkyl group has 1 or 2 O heteroatoms; the 5-6 membered heteroaryl group has 1, 2 or 3 N heteroatoms; the The C 1 -C 5 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl is optionally substituted by one or more R 21 ; the R 21 is Substituents selected from the following: hydroxyl, C 1 -C 6 alkyl; when there are multiple substituents, the R 21 is different or different substituents;
  • R 2 is a substituent selected from the group consisting of methyl,
  • -L 3 -R 2 is a substituent selected from the following:
  • Suitable amino and amido protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl, benzyloxycarbonyl, and the like.
  • Suitable hydroxy protecting groups include benzyl and the like.
  • Other suitable protecting groups are well known to those of ordinary skill in the art.
  • each step of the reaction is preferably carried out in an inert solvent, and an appropriate inert solvent can be selected according to specific conditions, and the inert solvent includes but is not limited to: toluene, benzene, water , methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dichloromethane Methylformamide, N,N-dimethylacetamide, dioxane, or a combination thereof.
  • an appropriate inert solvent can be selected according to specific conditions, and the inert solvent includes but is not limited to: toluene, benzene, water , methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydr
  • a pharmaceutical composition comprising: the compound represented by the formula I as described in the first aspect of the present invention, its tautomer, stereoisomer, A hydrate, solvate, pharmaceutically acceptable salt or prodrug; and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition which comprises the compound represented by formula I according to any one of the first aspect of the present invention, its tautomer, stereoisomer, hydrate, solvent compound, pharmaceutically acceptable salt or prodrug; and at least one other antagonist and/or inhibitor of pharmacological activity;
  • the other pharmacologically active antagonists are GPR84 antagonists
  • the other pharmacologically active inhibitor is a GPR84 inhibitor.
  • a compound represented by formula I as described in the first aspect of the present invention its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts Or the use of the prodrug, or the use of the pharmaceutical composition described in the fourth aspect of the present invention, the use includes:
  • the dosage of the compound represented by the formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is an effective treatment quantity.
  • the GPR84-related diseases include: inflammatory diseases, rheumatoid arthritis, vasculitis, lung diseases, neuroinflammatory diseases, infectious diseases, autoimmune diseases, endocrine and/or Metabolic diseases and/or diseases associated with impaired immune function.
  • the lung diseases include chronic obstructive pulmonary disease (COPD) and interstitial lung diseases; the interstitial lung diseases include congenital pulmonary fibrosis (IPF); and the inflammatory diseases include inflammatory bowel disease (IBD).
  • COPD chronic obstructive pulmonary disease
  • interstitial lung diseases include congenital pulmonary fibrosis (IPF); and the inflammatory diseases include inflammatory bowel disease (IBD).
  • IBD inflammatory bowel disease
  • the GPR84-related diseases are preferably: endotoxemia, diabetes, atherosclerosis, inflammatory bowel disease, non-alcoholic fatty liver disease, asthma, psoriasis, idiopathic pulmonary fibrosis, experimental Autoimmune encephalomyelitis, multiple sclerosis, Alzheimer's disease.
  • reaction and purification can be carried out using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in the present invention.
  • the techniques and methods described above can generally be carried out according to conventional methods well known in the art from the descriptions in the various general and more specific documents cited and discussed in this specification.
  • groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds.
  • substituents When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2 .
  • halogen alone or as part of other substituents, refers to fluorine, chlorine, bromine, iodine.
  • amino means -NH2.
  • nitro means -NO2.
  • cyano means -CN
  • alkyl alone or as part of other substituents, means consisting only of carbon and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms, and is bonded to the molecule by a single bond A straight or branched hydrocarbon chain group to which the remainder is attached.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl.
  • Alkyl groups can be unsubstituted or substituted with one or more suitable substituents.
  • Alkyl groups can also be isotopic isomers of naturally-abundant alkyl groups that are enriched in carbon and/or hydrogen isotopes (ie, deuterium or tritium).
  • alkenyl refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds.
  • alkynyl refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.
  • C1 - C5 alkyl is understood to mean a straight or branched chain saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl,
  • C 1 -C 5 alkyl is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3 or 5 carbon atoms.
  • the groups have 1, 2 or 3 carbon atoms (“ C1 -C3 alkyl”), such as methyl, ethyl, n-propyl or isopropyl.
  • alkylene refers to a saturated divalent hydrocarbyl group obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbyl group.
  • alkylene groups include methylene ( -CH2- ), ethylene (including -CH2CH2- or -CH( CH3 )-), isopropylidene (including -CH( CH3 ) - ) )CH 2 - or -C(CH 3 ) 2 -) and the like.
  • C1 - C6alkoxy is understood to mean a straight or branched chain saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms and oxygen atom, or expressed as C 1 -C 6 alkyl-OC 1 -C 6 alkyl as defined in this specification, the oxygen atom can be attached to the straight or straight chain of C 1 -C 6 alkyl on any carbon atom. Including but not limited to: methoxy (CH 3 -O-), ethoxy (C 2 H 5 -O-), propoxy (C 3 H 7 -O-), butoxy (C 4 H 9 -O-).
  • cycloalkyl or “carbocyclyl”, alone or as part of other substituents, refers to a cyclic alkyl group.
  • mn-membered cycloalkyl or “ Cm - Cncycloalkyl” is to be understood to mean a saturated, unsaturated or partially saturated carbocyclic ring having m to n atoms.
  • 3-10 membered cycloalkyl or “C3 - C10 cycloalkyl” refers to a cyclic alkyl group containing 3 to 10 carbon atoms, which may contain 1 to 3 rings.
  • the cyclic alkyl group includes monocyclic, bicyclic, tricyclic, spirocyclic or bridged rings.
  • unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl, or bicyclic hydrocarbon groups such as decalin rings.
  • Cycloalkyl groups may be substituted with one or more substituents.
  • a cycloalkyl group can be a cycloalkyl group fused to an aryl or heteroaryl group.
  • heterocycloalkyl or “heterocyclyl”, alone or as part of other substituents, refers to a ring in which one or more (in some embodiments 1 to 3) carbon atoms are replaced by heteroatoms Alkyl, the heteroatoms such as but not limited to N, O, S and P.
  • mn-membered heterocycloalkyl or " Cm - Cnheterocycloalkyl” is understood to mean a saturated, unsaturated or partially saturated ring having m to n atoms.
  • the term “4-10 membered heterocycloalkyl” is understood to mean a saturated, unsaturated or partially saturated ring having 4 to 10 atoms.
  • a heterocycloalkyl group can be a heterocycloalkyl group fused to an aryl or heteroaryl group.
  • a prefix such as 3-8 membered is used to denote a heterocycloalkyl, the number of carbons is also meant to include the heteroatom.
  • heteroaryl alone or as part of other substituents, is used interchangeably with the term “heteroaromatic ring” or “heteroaromatic” and refers to a monocyclic or polycyclic aromatic ring system, in certain implementations
  • 1 to 3 atoms in the ring system are heteroatoms, ie, elements other than carbon, including, but not limited to, N, O, S, or P. Examples are furyl, imidazolyl, indoline, pyrrolidinyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, N-methylpyrrolyl, quinolinyl and isoquinolinyl.
  • Heteroaryl groups can be optionally fused to a benzene ring, and can also include monocyclic, bicyclic, tricyclic, spirocyclic or bridged rings.
  • 5-10 membered heteroaryl alone or as part of other substituents, is to be understood as a monovalent monocyclic, bicyclic or A tricyclic aromatic ring group is understood to have 5, 6, 7, 8, 9 or 10 ring atoms - in particular 5 or 6 or 9 or 10 carbon atoms - and which comprises 1 to 5, 1-3 monovalent monovalent monocyclic, bicyclic or tricyclic aromatic ring groups of heteroatoms independently selected from N, O and S, and, in addition, in each case may be benzo-fused .
  • 5-8 membered heteroaryl is then to be understood as having 5-8 ring atoms - in particular 5 or 6 carbon atoms - and containing 1-5 heteroatoms independently selected from N, O and S
  • a monovalent monocyclic, bicyclic or tricyclic aromatic ring group 1-3 monovalent monovalent monocyclic, bicyclic or tricyclic aromatic ring groups of heteroatoms independently selected from N, O and S, and, in addition, in each case may be benzo-fused .
  • heteroaryl groups include, but are not limited to: thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl , thiadiazolyl, etc.
  • Halo is used interchangeably with the term “halo-substituted” alone or as part of other substituents.
  • haloalkyl examples include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
  • spirocycle refers to a polycyclic group in which a single carbon atom (called a spiro atom) is shared between the single rings, which may contain one or more double bonds, but none of the rings have Fully conjugated pi electron system.
  • spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups.
  • spirocycloalkyl include:
  • spirocycloalkyl groups in which a monospirocycloalkyl group shares a spiro atom with a heterocycloalkyl group, non-limiting examples include:
  • bridged ring refers to a cyclic hydrocarbon in which any two rings in a compound share two non-directly connected carbon atoms, and can be divided into bicyclic hydrocarbons, tricyclic hydrocarbons, tetracyclic hydrocarbons, etc. according to the number of formed rings.
  • Non-limiting examples include:
  • C2 - C4alkenyl is understood to mean a straight or branched monovalent hydrocarbon group containing one or more double bonds and having, for example, 2, 3 or 4 carbon atoms, or has 2 or 3 carbon atoms. It is understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated.
  • the alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl.
  • C 2 -C 4 alkenylene alone or as part of other substituents refers to a divalent hydrocarbyl group obtained by removing multiple hydrogen atoms from a straight or branched chain hydrocarbyl group, containing one or more Double bonds and have, for example, 2, 3 or 4 carbon atoms, or 2 or 3 carbon atoms.
  • C2 - C4alkynyl is understood to mean a straight or branched monovalent hydrocarbon group containing one or more triple bonds and having, for example, 2, 3 or 4 carbon atoms, or has 2 or 3 carbon atoms.
  • the alkynyl group is, for example, ethynyl, methyl-substituted ethynyl, ethyl-substituted ethynyl.
  • C2 - C4alkynylene refers to a divalent hydrocarbyl group obtained by removing a plurality of hydrogen atoms from a straight or branched chain hydrocarbyl group, comprising one or more Triple bonds and have, for example, 2, 3 or 4 carbon atoms, or have 2 or 3 carbon atoms.
  • the alkynylene group is for example -C ⁇ C-, -CH2 -C ⁇ C-, -CH2 - CH2 -C ⁇ C-, -CH2 - C ⁇ C-CH2- or -C ⁇ CC ⁇ C - and so on.
  • inert solvent includes, but is not limited to: toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran dichloromethane, chloroform, 1 , 2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a combination thereof.
  • Protected derivatives are those compounds in which one or more reactive sites are blocked by one or more protecting groups (also referred to as protecting groups).
  • Suitable protecting groups for the carboxy moiety include benzyl, t-butyl, and the like, as well as isotopes and the like.
  • Suitable amino and amido protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable hydroxy protecting groups include benzyl and the like. Other suitable protecting groups are well known to those of ordinary skill in the art.
  • salt or “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without more toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable acid addition salts” refers to salts with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects.
  • “Pharmaceutically acceptable base addition salts” refers to salts with inorganic or organic bases that retain the biological availability of the free acid without other adverse effects.
  • other salts are also contemplated by the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be used in the identification, characterization or purification of the compounds of the present invention.
  • stereoisomer refers to isomers resulting from different arrangements of atoms in a molecule in space, and includes cis-trans isomers, enantiomers, diastereomers and conformers.
  • the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, for example, as pure optical isomers, or as mixtures of isomers, such as racemic and non-isomeric isomers.
  • the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule.
  • the prefixes D and L or (+) and (–) are symbols used to designate the rotation of plane polarized light by the compound, where (–) or L indicates that the compound is levorotatory.
  • Compounds prefixed with (+) or D are dextrorotatory.
  • tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist as two or more interconvertible species.
  • Proton tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms.
  • Tautomers generally exist in equilibrium, and attempts to separate individual tautomers usually result in a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the ketone form predominates; in phenols, the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • a "pharmaceutical composition” refers to a formulation of a compound of the present invention with a medium generally accepted in the art for delivering a biologically active compound to a mammal (eg, a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government regulatory authority as acceptable for human or livestock use , diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • solvate refers to a compound of the present invention or a salt thereof including a stoichiometric or non-stoichiometric amount of solvent bound by intermolecular non-covalent force, and when the solvent is water, it is a hydrate.
  • prodrug refers to a compound of the invention that can be converted under physiological conditions or by solvolysis to a biologically active compound.
  • the prodrugs of the present invention are prepared by modifying functional groups in the compounds, which modifications can be removed by conventional procedures or in vivo to yield the parent compounds.
  • Prodrugs include compounds formed by connecting a hydroxyl or amino group in the compounds of the present invention to any group. When the prodrugs of the compounds of the present invention are administered to mammalian individuals, the prodrugs are cleaved to form free hydroxyl, free the amino group.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • classes of the term “excipient” include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flowability and/or stickiness.
  • treatment and other similar synonyms include the following meanings:
  • the reaction temperature can be appropriately selected according to the solvent, starting materials, reagents, etc.
  • the reaction time can also be appropriately selected according to the reaction temperature, solvent, starting materials, reagents, and the like.
  • the target compound can be separated and purified from the reaction system according to common methods, such as filtration, extraction, recrystallization, washing, silica gel column chromatography and other methods. Under the condition of not affecting the next reaction, the target compound can also directly enter the next reaction without separation and purification.
  • Each step of the reaction of the present invention is preferably carried out in an inert solvent, including but not limited to: toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethylmethylene Sulfone, tetrahydrofuran dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a combination thereof thing.
  • an inert solvent including but not limited to: toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethylmethylene Sulfone, tetrahydrofuran dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide,
  • the present inventor unexpectedly developed a compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug,
  • the compound of formula I contains a thieno ring core structure and has obvious GPR84 antagonistic effect; the compound of the present invention has high oral exposure in mice, high free fraction in human plasma, slow metabolism, long half-life, and good druggability ; The risk of drug interaction is small and the safety is good.
  • the compounds of the present invention can be used as GPR84 antagonists to prevent and/or treat GPR84-related diseases; to prepare medicines, pharmaceutical compositions or preparations for GPR84 antagonists, and to prevent and/or treat GPR84-related diseases medicaments, pharmaceutical compositions or preparations.
  • GPR84-related diseases include, but are not limited to: endotoxemia, diabetes, atherosclerosis, inflammatory bowel disease, nonalcoholic fatty liver disease, idiopathic pulmonary fibrosis, experimental autoimmune encephalomyelitis , multiple sclerosis, Alzheimer's disease.
  • the present invention provides a kind of intermediate B, and the preparation method of compound shown in formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug
  • the method has the advantages of simple operation, high yield and high purity of the obtained product.
  • IC 50 half inhibitory concentration, refers to the concentration at which half of the maximum inhibitory effect is achieved
  • n-butyllithium 14.56mL, 29.1mmol, 2.5M n-hexane solution
  • M mol/L
  • N equivalent concentration, for example, 2N hydrochloric acid means 2mol/L hydrochloric acid solution
  • DIPEA can also be written as DIEA, diisopropylethylamine, that is, N,N-diisopropylethylamine
  • PE petroleum ether
  • the fourth step Synthesis of 1-(2-(5-bromothiophen-3-yl)ethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (B1-5)
  • Extract with dichloromethane 100 mL ⁇ 2), combine the organic layers, wash the organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, and concentrate to obtain the crude product (2-bromo-9-chloro-4,5-dihydrogen).
  • -7H-thieno[2',3':3,4]pyrido[1,2-c]pyrimidin-7-one (4.8g). The crude product was directly put into the next reaction.
  • Step 7 (S)-9-((1,4-dioxan-2-yl)methoxy)-2-(cyclopropynyl)-4,5-dihydro-7H-thieno Synthesis of [2',3':3,4]pyrido[1,2-c]pyrimidin-7-one (I-1)
  • the preparation of the reference compound refers to the preparation method of compound 122 in patent WO 2013/092791 Al, and its structure is as follows:
  • the GPR84 antagonism effect of the control compound and the compound of the present invention was tested respectively, and the assay was carried out in a CHO cell line stably transfected with high expression of human GPR84 receptor.
  • the stably transfected cells were cultured to 80% confluence; cells were collected by trypsin digestion, and after counting, 2000 cells per well were seeded into 384-well plates.
  • Prepare 10 ⁇ compound working solution with 1 ⁇ Stimulation Buffer add 1 ⁇ L of 10 ⁇ compound to the corresponding experimental well, centrifuge and incubate at 37°C for 20 min; then add 4 ⁇ L 2.5 ⁇ M Forskolin&200nM 6-OAU solution, centrifuge and place in 37 Incubate at °C for 30 min.
  • the content of cAMP in the cells was quantified according to the method in the instructions of the cAMP test kit (Perkin Elmer, Cat#TRF0263).
  • Antagonism ( IC50 values) of the test compounds was calculated.
  • mice Pharmacokinetic experiments in mice, using male ICR mice, 20-25g, fasted overnight. Three mice were taken and administered orally orally at 3 mg/kg. Blood was collected before administration and at 15, 30 minutes and 1, 2, 4, 8, and 24 hours after administration; another 3 mice were taken and administered 3 mg/kg intravenously, before administration and after administration Blood was collected at 15, 30 minutes and 1, 2, 4, 8, and 24 hours. Blood samples were centrifuged at 6800g at 2-8°C for 6 minutes, and plasma was collected and stored at -80°C.
  • Liver microsome stability assays (human and mouse) were performed using in vitro co-incubation of control compounds and compounds of the invention with liver microsomes of the corresponding species.
  • the compounds to be tested were first formulated as 10 mM stock solutions in DMSO solvent, and then the compounds were diluted to 0.5 mM using acetonitrile.
  • the concentration of the compound in the working solution is 1.5 ⁇ M, and the concentration of each liver microsome is 0.75mg/mL.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Oncology (AREA)
  • Endocrinology (AREA)
  • Communicable Diseases (AREA)
  • Obesity (AREA)
  • Rheumatology (AREA)
  • Hematology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Transplantation (AREA)
  • Dermatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Psychiatry (AREA)
  • Emergency Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)

Abstract

L'invention concerne un antagoniste de GPR84, son procédé de préparation et son utilisation, en particulier un composé représenté par la formule (I), et un tautomère, un stéréoisomère, un hydrate, un solvate, un sel pharmaceutiquement acceptable, ou un promédicament de celui-ci. Le composé représenté par la formule (I) a une fonction d'antagonisme du GPR84 évidente, une bonne pharmacopotentialité, et une sécurité élevée, R1 étant un cycle Cy éventuellement substitué par un ou plusieurs R11, R2 étant un substituant choisi parmi alkyle en C1-C5, cycloalkyle de 3 à 10 chaînons, hétérocycloalkyle de 4 à 10 chaînons, ou hétéroaryle de 5 à 10 chaînons, et les définitions de R3, R4, R5, R6, L1, L2, L3 étant tels que décrits dans la description.
PCT/CN2022/081614 2021-03-18 2022-03-18 Antagoniste gpr84, son procédé de préparation et son utilisation Ceased WO2022194267A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110292697.4 2021-03-18
CN202110292697 2021-03-18

Publications (1)

Publication Number Publication Date
WO2022194267A1 true WO2022194267A1 (fr) 2022-09-22

Family

ID=83322059

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/081614 Ceased WO2022194267A1 (fr) 2021-03-18 2022-03-18 Antagoniste gpr84, son procédé de préparation et son utilisation

Country Status (2)

Country Link
CN (1) CN115109072A (fr)
WO (1) WO2022194267A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2024523460A (ja) * 2021-06-21 2024-06-28 武漢人福創新薬物研発中心有限公司 Ｇｐｒ８４アンタゴニストとしての三環式化合物

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024140969A1 (fr) * 2022-12-30 2024-07-04 广州市联瑞制药有限公司 Composé tricyclique, son procédé de préparation et son utilisation

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103998448A (zh) * 2011-12-22 2014-08-20 加拉帕戈斯股份有限公司 用于治疗炎性疾病的新的二氢嘧啶并异喹啉酮化合物及其药用组合物
CN104870445A (zh) * 2012-12-20 2015-08-26 加拉帕戈斯股份有限公司 用于治疗炎性疾病的新二氢嘧啶并异喹啉酮类及其药物组合物(gpr84拮抗剂)
WO2015197550A1 (fr) * 2014-06-25 2015-12-30 Galapagos Nv Nouvelles dihydropyridoisoquinolinones et leurs compositions pharmaceutiques pour le traitement de troubles inflammatoires
CN111343986A (zh) * 2017-11-15 2020-06-26 加拉帕戈斯股份有限公司 用于治疗纤维化疾病的化合物及其药物组合物
WO2021122415A1 (fr) * 2019-12-19 2021-06-24 Bayer Aktiengesellschaft Dérivés furoindazole

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103998448A (zh) * 2011-12-22 2014-08-20 加拉帕戈斯股份有限公司 用于治疗炎性疾病的新的二氢嘧啶并异喹啉酮化合物及其药用组合物
CN104870445A (zh) * 2012-12-20 2015-08-26 加拉帕戈斯股份有限公司 用于治疗炎性疾病的新二氢嘧啶并异喹啉酮类及其药物组合物(gpr84拮抗剂)
WO2015197550A1 (fr) * 2014-06-25 2015-12-30 Galapagos Nv Nouvelles dihydropyridoisoquinolinones et leurs compositions pharmaceutiques pour le traitement de troubles inflammatoires
CN111343986A (zh) * 2017-11-15 2020-06-26 加拉帕戈斯股份有限公司 用于治疗纤维化疾病的化合物及其药物组合物
WO2021122415A1 (fr) * 2019-12-19 2021-06-24 Bayer Aktiengesellschaft Dérivés furoindazole

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DINESS FREDERIK, JÜRGEN BEYER, MORTEN MELDAL: "Solid-Phase Synthesis of Tetrahydro-β-carbolines and Tetrahydroisoquinolines by Stereoselective Intramolecular N-Carbamyliminium Pictet-Spengler Reactions", CHEMISTRY-A EUROPEAN JOURNAL, vol. 12, no. 31, 25 October 2006 (2006-10-25), pages 8056 - 8066, XP055968158, DOI: 10.1002/chem.200600138 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2024523460A (ja) * 2021-06-21 2024-06-28 武漢人福創新薬物研発中心有限公司 Ｇｐｒ８４アンタゴニストとしての三環式化合物
JP7705966B2 (ja) 2021-06-21 2025-07-10 武漢人福創新薬物研発中心有限公司 Ｇｐｒ８４アンタゴニストとしての三環式化合物

Also Published As

Publication number Publication date
CN115109072A (zh) 2022-09-27

Similar Documents

Publication Publication Date Title
WO2021032074A1 (fr) Dérivé cyclicque aromatique condensé de benzamide, son procédé de préparation et son utilisation en médecine
WO2018210298A1 (fr) Dérivés d'hétéroaryle pyrazole, leur procédé de préparation et leur application médicale
US20230227445A1 (en) Benzamide compound and use thereof
CN114149423B (zh) 四氢吡啶并嘧啶二酮类衍生物、其制备方法及其在医药上的应用
CN107849049A (zh) 脲衍生物或其药用盐
WO2018041248A1 (fr) Inhibiteur sélectif de bcl -2, sa préparation et son utilisation
CN116354926A (zh) 作为Polθ抑制剂的杂环化合物及其制备方法和用途
WO2022194267A1 (fr) Antagoniste gpr84, son procédé de préparation et son utilisation
US10131642B1 (en) Aldosterone synthase inhibitors
US11261170B2 (en) Aromatic compound, pharmaceutical composition and use thereof
JP2010043004A (ja) 新規２環性複素環化合物
CN111825667B (zh) Fxr小分子激动剂及其制备方法和用途
WO2020156505A1 (fr) Dérivé de 2-amionpyrimidine, son procédé de préparation et son utilisation en médecine
US20050059673A1 (en) Benzofuranyl-and benzothienyl-piperazinyl quinolines and methods of their use
CN118724883A (zh) 作为at2r拮抗剂的杂环化合物
JP7705966B2 (ja) Ｇｐｒ８４アンタゴニストとしての三環式化合物
CN115197216A (zh) 一种二氢嘧啶并异喹啉酮类衍生物及用途
WO2022218372A1 (fr) Dérivé de dihydropyrimidoisoquinoléinone et son utilisation
JPWO2011136192A1 (ja) イミダゾ［１，２−ａ］ピリジン誘導体
CN114591317A (zh) P2x3抑制剂及其用途
CN119080754A (zh) 作为α5-GABAA受体调节剂的杂环化合物及其用途
WO2019057158A1 (fr) Dérivés hétéroaryles condensés, procédé de préparation de ceux-ci et leur application en médecine
CN101759665A (zh) 取代苯基哌嗪芳烷醇衍生物及其在制备镇痛药物中的应用
TW201827442A (zh) 雜芳基並噻二嗪－２，２－二氧化物類衍生物、其製備方法及其在醫藥上的應用
WO2022156788A1 (fr) Composé de benzimidazole et son utilisation

Legal Events

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

Ref document number: 22770619

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22770619

Country of ref document: EP

Kind code of ref document: A1