WO2022218372A1 - 一种二氢嘧啶并异喹啉酮类衍生物及用途 - Google Patents

一种二氢嘧啶并异喹啉酮类衍生物及用途 Download PDF

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WO2022218372A1
WO2022218372A1 PCT/CN2022/086783 CN2022086783W WO2022218372A1 WO 2022218372 A1 WO2022218372 A1 WO 2022218372A1 CN 2022086783 W CN2022086783 W CN 2022086783W WO 2022218372 A1 WO2022218372 A1 WO 2022218372A1
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formula
compound
dihydropyrimidoisoquinolinone
group
alkyl
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PCT/CN2022/086783
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English (en)
French (fr)
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张学军
臧杨
魏文军
蔡立波
陈浩民
常少华
李莉娥
杨俊�
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武汉人福创新药物研发中心有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicine, and in particular, the invention relates to a dihydropyrimidoisoquinolinone derivative and use 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
  • Embelin an active exogenous agonist
  • 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 dihydropyrimidoisoquinolinone derivative
  • the dihydropyrimidoisoquinolinone derivative includes the dihydropyrimidoisoquinolone represented by the formula I as described in the present invention Linone derivatives, tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, which can be used for the prevention and/or treatment of GPR84-related diseases; or prepared as GPR84 Antagonists, drugs, pharmaceutical compositions or preparations for preventing and/or treating GPR84-related diseases.
  • the first aspect of the present invention provides a dihydropyrimidoisoquinolinone derivative represented by formula I, its tautomer, stereoisomer, hydrate, solvate and pharmaceutically acceptable salt or prodrug:
  • L 1 is -NH-, -N(C 1 -C 5 alkyl)- or -S-;
  • V is absent or -O-;
  • L 2 is absent or L 2 is C 1 -C 5 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 are the same or different substituents;
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are each independently hydrogen, halogen or C 1 -C 5 alkyl; the C 1 -C 5 alkyl is optionally substituted by 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;
  • R 3 , R 4 , R 5 , R 6 are each independently hydrogen, halogen, C 1 -C 5 alkyl or C 1 -C 5 haloalkyl; R 7 , R 8 together with the C atom to which they are commonly attached 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl is formed.
  • L 1 is -N(C 1 -C 5 alkyl)-
  • R 2 is C 1 -C 5 alkyl, C 1 -C substituted by one or more R 21
  • R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently C 1 -C 5 alkyl group, C 1 substituted by R 31
  • the C 1 -C 5 alkyl group is preferably a C 1 -C 3 alkyl group, such as methyl.
  • the C 1 -C 5 alkylene group is preferably a C 1 -C 3 alkylene group, such as -CH 2 - or -CH 2 CH 2 -.
  • L 2 is a C 2 -C 4 alkynylene group having a triple bond, and the C 2 -C 4 alkynylene group is preferably -C ⁇ C-.
  • R 2 is a 3-10-membered cycloalkyl group, a 3-10-membered cycloalkyl group in a 3-10-membered cycloalkyl group substituted by one or more R 21 , the said The 3-10 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group such as cyclopropyl.
  • R 2 is a 4-10-membered heterocycloalkyl, a 4-10-membered heterocycloalkyl in the 4-10-membered heterocycloalkyl substituted by one or more R 21 ,
  • the 4-10-membered heterocycloalkyl is preferably a 4-6-membered heterocycloalkyl, such as piperidinyl, piperazinyl or pyrrolidinyl.
  • R 2 is a 5-10-membered heteroaryl group, a 5-10-membered heteroaryl group in a 5-10-membered heteroaryl group substituted by one or more R 21 , the said The 5-10-membered heteroaryl group is preferably a 5-6-membered heteroaryl group, such as
  • R 21 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 31 are each independently halogen, and the halogen is preferably fluorine, chlorine, or bromine or iodine, such as fluorine.
  • the C 1 -C 6 alkyl group is preferably a C 1 -C 3 alkyl group, such as methyl or ethyl.
  • R 21 is a C 1 -C 6 alkoxy group, and the C 1 -C 6 alkoxy group is preferably a C 1 -C 3 alkoxy group, such as methoxy or ethyl Oxygen.
  • R 21 is a C 3 -C 6 cycloalkyl group
  • the C 3 -C 6 cycloalkyl group is preferably cyclopropyl, cyclobutyl or cyclopentyl.
  • the C 1 -C 6 haloalkyl group is preferably a C 1 -C 3 haloalkyl group, such as trifluoromethyl.
  • R 21 is a C 1 -C 6 haloalkoxy group
  • the C 1 -C 6 haloalkoxy group is preferably a C 1 -C 3 haloalkoxy group, such as -OCF 3 .
  • R 31 is a C 1 -C 3 alkoxy group, and the C 1 -C 3 alkoxy group is preferably a methoxy group or an ethoxy group.
  • the C 1 -C 3 alkylamino group is preferably CH 3 NH- or CH 3 CH 2 NH-.
  • R 3 , R 4 , R 5 , and R 6 are each independently C 1 -C 5 haloalkyl, and the C 1 -C 5 haloalkyl is preferably C 1 -C 3 Haloalkyl such as trifluoromethyl.
  • R 7 and R 8 together with the C atoms to which they are connected together form a 3-6-membered cycloalkyl group in a 3-6-membered cycloalkyl group, the 3-6-membered cycloalkane
  • the radicals are preferably cyclopropyl, cyclobutyl or cyclopentyl.
  • the 4-6 membered heterocycloalkyl is preferably piperidinyl, Piperazinyl or pyrrolidinyl.
  • L 1 is -NH-, -N(CH 3 )- or -S-.
  • L 2 is a C 1 -C 5 alkylene group or a C 2 -C 4 alkynylene group with a triple bond, preferably, L 2 is -CH 2 - or -C ⁇ C-.
  • L 2 when V is absent, L 2 is a C 2 -C 4 alkenylene group with a double bond or a C 2 -C 4 alkynylene group with a triple bond; V is -O -, L 2 is a C 1 -C 5 alkylene group.
  • L 2 when V is absent, L 2 is -C ⁇ C-; when V is -O-, L 2 is -CH 2 -.
  • L 1 is -S-, V is absent, and L 2 is a C 2 -C 4 alkynylene group with a triple bond; preferably, L 2 is -C ⁇ C- .
  • L 1 is -NH- or -N(CH 3 )-, V is absent or -O-, L 2 is C 1 -C 5 alkylene, with one double bond C 2 -C 4 alkenylene group or C 2 -C 4 alkynylene group with one triple bond; preferably, L 2 is -CH 2 -, -CH 2 CH 2 -.
  • L 1 is -NH- or -N(CH 3 )-, V is absent or -O-, L 2 is C 1 -C 5 alkylene or has a triple bond C 2 -C 4 alkynylene; preferably, L 2 is -CH 2 - or -C ⁇ C-.
  • R 2 is C 1 -C 5 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl ; C 5 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl optionally substituted with one or more R 21 ; said R 21 is selected from the following Substituents: hydroxyl, 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 haloalkane Oxy group; when there are multiple substituents, the R 21 is the same or different substituents;
  • the R 21 is a substituent selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy base;
  • the R 21 is a substituent selected from the group consisting of halogen, C 1 -C 6 alkyl; preferably, the halogen is fluorine.
  • R 2 is C 1 -C 5 alkyl, 3-10-membered cycloalkyl, 4-10-membered heterocycloalkyl or 5-10-membered heteroaryl ; C 5 alkyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl or 5-10 membered heteroaryl optionally substituted with one or more R 21 ; said R 21 is selected from the following Substituents: halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy; when there are multiple substituents, the R 21 is the same or different;
  • the R 21 is a substituent selected from the group consisting of halogen, C 1 -C 6 alkyl;
  • the halogen is preferably fluorine.
  • R 2 is C 1 -C 5 alkyl, 3-6 membered cycloalkyl or 5-6 membered heteroaryl; the 5-6 membered heteroaryl contains 1, 2 or 3 heteroatoms selected from N or O; when there are multiple heteroatoms, the heteroatoms are the same or different; the C 1 -C 5 alkyl, 3-6 membered cycloalkyl or 5-6 membered heteroatoms
  • Aryl is optionally substituted with one or more R 21 ; the R 21 is a substituent selected from the group consisting of halogen, C 1 -C 6 alkyl; the halogen is preferably fluorine.
  • R 2 is a C 1 -C 5 alkyl group, a 3-6 membered cycloalkyl group or a 5-6 membered heteroaryl group; wherein, the C 1 -C 5 alkyl group is optionally Substituted with one or more halogens; the 3-6 membered cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, C1 - C5 alkyl, C1 - C5 haloalkyl ;
  • the 5-6-membered heteroaryl group contains 1, 2 or 3 heteroatoms selected from N or O; when there are multiple heteroatoms, the heteroatoms are the same or different;
  • R 2 is cyclopropyl, -CF 3 or In a preferred embodiment of the present invention, the group -VL 2 -R 2 is
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are each independently hydrogen, halogen, C 1 -C 5 alkyl or C 1 -C 5 haloalkyl;
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are hydrogen.
  • the dihydropyrimidoisoquinolinone derivative shown in formula I is a compound shown in formula Ia or a compound shown in formula Ib;
  • L 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , V, L 2 and R 2 are as defined in the present invention.
  • L 1 is -NH-, -N(CH 3 )- or -S-;
  • V is absent or -O-;
  • L 2 is a C 1 -C 5 alkylene group or a C 2 -C 4 alkynylene group with one triple bond;
  • R 2 is a substituent selected from the group consisting of C 1 -C 5 alkyl, 3-10-membered cycloalkyl, or 5-10-membered heteroaryl; the C 1 -C 5 alkyl, 5-10-membered heteroaryl group is optionally substituted by one or more R 21 ; said R 21 is halogen or C 1 -C 5 alkyl;
  • R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently hydrogen.
  • L 1 is -NH-, -N(CH 3 )- or -S-;
  • V is absent or -O-;
  • L 2 is -CH 2 - or -C ⁇ C-;
  • R 2 is cyclopropyl, -CF 3 or
  • R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently hydrogen.
  • the dihydropyrimidoisoquinolinone derivatives include:
  • a pharmaceutical composition comprising: the dihydropyrimidoisoquinolinone derivatives represented by formula I as described in the first aspect of the present invention, their mutual Variants, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs; and pharmaceutically acceptable carriers.
  • a pharmaceutical composition which comprises the dihydropyrimidoisoquinolinone derivatives represented by formula I as described in the first aspect of the present invention, their tautomers, stereoisomers Isomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs; and at least one other antagonist and/or inhibitor of pharmacological activity.
  • a dihydropyrimidoisoquinolinone derivative represented by formula I, its tautomer, stereoisomer and hydrate as described in the first aspect of the present invention the use of solvates, pharmaceutically acceptable salts or prodrugs, or the use of the pharmaceutical composition according to the fourth aspect of the present invention, the uses include:
  • GPR84 antagonists and/or medicines, pharmaceutical compositions or preparations for preventing and/or treating GPR84-related diseases.
  • the GPR84-related diseases include: organ fibrosis diseases, inflammatory diseases, pulmonary diseases, neuroinflammatory diseases, infectious diseases, autoimmune diseases, endocrine, metabolic diseases, or related diseases 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).
  • COPD chronic obstructive pulmonary disease
  • IPF congenital pulmonary fibrosis
  • the inflammatory disease includes vasculitis, inflammatory bowel disease (IBD).
  • IBD inflammatory bowel disease
  • the autoimmune disease includes rheumatoid arthritis.
  • the organ fibrosis diseases include fibrotic diseases of digestive organs, respiratory organs, circulatory organs, urogenital organs, motor organs, cerebral nervous system, endocrine organs, or skin; Fibrosis, renal fibrosis, cardiac fibrosis; preferably, the pulmonary fibrosis includes idiopathic pulmonary fibrosis and congenital pulmonary fibrosis.
  • the GPR84-related diseases are preferably: endotoxemia, diabetes, atherosclerosis, inflammatory bowel disease, non-alcoholic fatty liver, non-alcoholic steatohepatitis, asthma, psoriasis, Pulmonary fibrosis, congenital pulmonary fibrosis, experimental autoimmune encephalomyelitis, multiple sclerosis, Alzheimer's disease.
  • Scheme 1 includes the following steps: in an organic solvent, in the presence of a palladium catalyst, CuI and a base, the compound shown in formula II is subjected to the coupling reaction shown below with cyclopropacetylene to obtain the compound shown in formula I as shown below.
  • Scheme 2 includes the following steps: in an organic solvent, in the presence of a base, the compound shown in formula II and the compound shown in formula IV are subjected to the substitution reaction shown below to obtain the second shown in formula I.
  • Hydropyrimidoisoquinolinone derivatives
  • X is hydroxyl, -OTf, -OTs or -OMs
  • Y is halogen
  • L 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above.
  • the preparation method of the compound represented by the formula II comprises the following steps: in an organic solvent, in the presence of a palladium catalyst and a base, the compound represented by the formula III is prepared. The compound is subjected to the reaction shown below to obtain the compound shown in formula II;
  • L 1 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above.
  • L 1 is -NH-, -N(CH 3 )- or -S-.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are hydrogen.
  • the compound represented by the formula II is the compound represented by the formula IIa or the compound represented by the formula IIb;
  • X is hydroxyl, -OTf, -OTs or -OMs, and the definitions of L 1 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in the present invention.
  • the compound represented by the formula III is the compound represented by the formula IIIa or the compound represented by the formula IIIb;
  • L 1 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in the present invention.
  • the compound represented by the formula II is:
  • the compound represented by the formula III is:
  • the isotopic abundances of all atoms are the same as their natural abundances.
  • the cyclic alkyl group and the heterocycloalkyl group are monocyclic.
  • the 5-10 membered heteroaryl group is monocyclic or bicyclic.
  • 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 refers to -NH2 .
  • nitro means -NO2 .
  • cyano means -CN
  • optionally or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes both instances where the event or circumstance occurs and instances where it does not.
  • optionally substituted aryl means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups.
  • 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 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 - C6 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.
  • 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-).
  • alkylene means a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbon group; that is, one hydrogen in an alkyl group is replaced, as defined above.
  • alkylene groups include methylene ( -CH2- ), ethylene ⁇ including -CH2CH2- or -CH( CH3 )- ⁇ , isopropylidene ⁇ including -CH( CH3 ) )CH 2 -or -C(CH 3 ) 2 - ⁇ and so on.
  • C 1 -C 3 alkylamino alone or as part of other substituents, is understood to mean a straight or branched chain saturated monovalent hydrocarbon radical having 1, 2 or 3 carbon atoms consisting of an amino group. Including but not limited to: CH 3 NH-, CH 3 CH 2 NH-.
  • 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.
  • 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.
  • 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.
  • 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.
  • alkenylene refers to a substituent formed by the elimination of two hydrogens from a straight-chain or branched alkene having a specified number of carbon atoms, containing one or more carbon-carbon double bonds and no carbon-carbon triple bonds.
  • the carbon-carbon double bond can be located at any position in the alkenylene group, and the two eliminated hydrogens can be on the same carbon atom or on different carbon atoms (for example, the two eliminated hydrogens are on the carbon atoms at both ends respectively. ).
  • -C(CH 3 ) CH-
  • alkynylene refers to a straight-chain or branched alkene with a specified number of carbon atoms containing one or more carbon-carbon triple bonds to eliminate two Substituents formed after a hydrogen.
  • the carbon-carbon triple bond can be located at any position in the alkynylene group, and the two eliminated hydrogens can be on the same carbon atom or on different carbon atoms (for example, the two eliminated hydrogens are on the carbon atoms at the two ends respectively. ).
  • C alkynylene ie, ethynylene
  • C alkynylene includes, but is not limited to C 3 alkynylene groups include but are not limited to C alkynylene groups include but are not limited to
  • 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 includes 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 positive progress effect of the present invention is that: the inventors, after extensive and in-depth research, unexpectedly developed a dihydropyrimidoisoquinolinone derivative represented by formula I, its tautomer, stereoisomer body, hydrate, solvate, pharmaceutically acceptable salt or prodrug, which has obvious GPR84 antagonism; the compound of the present invention has high oral exposure in mice, high free fraction in human plasma, and good druggability; The risk of drug interaction is small and the safety is good.
  • the dihydropyrimidoisoquinolinone derivatives represented by formula I of the present invention can be used as GPR84 antagonists to prevent and/or treat GPR84-related diseases; prepare medicines, pharmaceutical compositions or preparations used as GPR84 antagonists , and the preparation of medicines, pharmaceutical compositions or preparations for preventing and/or treating GPR84-related diseases.
  • 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.
  • 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 synthetic route is as follows:
  • the synthesis of compound I-2 refers to the synthesis method of I-1.
  • 9-(allyloxy)-2-chloro-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-4-one (Compound B1-1, 1.7 g, 5.89 mmol ) was placed in a 100mL single-necked flask, anhydrous DCM (50mL) was added, and 1-(1,4-dioxan-2-yl)-N-methylmethanamine hydrochloride (compound B2-2, 1.08 g, 6.48 mmol) and DIEA (3.13 mL, 17.7 mmol), stirred at room temperature overnight.
  • the synthetic route is as follows:
  • the synthesis of compound I-3 refers to the synthesis method of I-1.
  • 9-(allyloxy)-2-chloro-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-4-one (Compound B1-1, 1.7 g, 5.89 mmol ) was placed in a 100mL single-necked flask, anhydrous DCM (50mL) was added, (S)-(1,4-dioxan-2-yl)methanamine hydrochloride (compound B3-2, 0.96g, 6.48 mmol) and DIEA (3.13 mL, 17.7 mmol), stirred at room temperature overnight.
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthesis of compound I-7 refers to the synthesis method of I-1.
  • 9-(allyloxy)-2-chloro-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-4-one (Compound B1-1, 1.7 g, 5.89 mmol ) was placed in a 100mL single-necked flask, anhydrous DCM (50mL) was added, and (S)-(1,4-dioxan-2-yl)methanethiol (Compound B7-2, 0.96g, 6.48mmol) was added at room temperature ) and DIEA (3.13 mL, 17.7 mmol) and stirred at room temperature overnight.
  • the preparation of reference compound refers to the preparation method of compound 122 in patent WO 2013/092791Al, and its structure is as follows:
  • the GPR84 antagonistic effect of compound I-1 was tested, 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 trypsinization, and after counting, 2000 cells per well were seeded into 384-well plates.
  • Use 1 ⁇ Stimulation Buffer to prepare 10 ⁇ compound working solution add 1 ⁇ L of 10 ⁇ compound to the corresponding experimental well, centrifuge and incubate at 37°C for 20 min; then add 4 ⁇ L of 2.5 ⁇ M Forskolin&200nM 6-OAU solution, centrifuge and place in 37 Incubate at °C for 30 min. After the reaction was completed, 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, and blood was collected before administration and at 15, 30 minutes and 1, 2, 4, 8, and 24 hours after administration.
  • the blood sample was 6800g, centrifuged at 2-8°C for 6 minutes, and the plasma was collected and stored at -80°C. Take the plasma at each time point, add 3-5 times the volume of acetonitrile solution containing the internal standard to mix, vortex for 1 minute, centrifuge at 13,000 rpm for 10 minutes at 4°C, take the supernatant and add 3 times the volume of water to mix, take an appropriate amount of the mixture LC-MS/MS analysis was performed.
  • the main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software.

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Abstract

提供了一种式I所示二氢嘧啶并异喹啉酮类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药；其具有明显的GPR84拮抗作用，成药性好，安全性高；其中，L 1为-NH-、-N(C 1-C 5烷基)-或-S-；V不存在或为-O-；L 2不存在或L 2为C 1-C 5亚烷基、具有一个双键的C 2-C 4亚烯基或具有一个三键的C 2-C 4亚炔基；R 2、R 3、R 4、R 5、R 6、R 7、R 8的定义如说明书中所述。

Description

一种二氢嘧啶并异喹啉酮类衍生物及用途
本申请要求申请日为2021/4/14的中国专利申请CN202110401213.5的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于医药领域，具体地，本发明涉及到一种二氢嘧啶并异喹啉酮类衍生物及用途。
背景技术
G蛋白偶联受体84(GPR84)是一种G蛋白偶联受体，与百日咳毒素敏感的Gi/o通路偶联，当其与配体结合被激活后，可以通过Gi蛋白抑制腺苷酸环化酶活性，从而降低细胞内cAMP的水平。GPR84属于脂肪酸受体，主要在骨髓中表达，其次是在外周白细胞和肺中，能够被中链饱和脂肪酸激活，其中癸酸(C10)、十一酸(C11)、月桂酸(C12)激动活性最好。除内源性配体中链脂肪酸外，研宄人员还发现了一些活性更好的外源性激动剂如二吲哚甲烷(DIM)、6-正辛基氨基尿嘧啶(6-OAU)、恩贝酸(embelin)等。
正常生理状态下，免疫细胞中GPR84表达量较低，在LPS存在的条件下，中链脂肪酸及二吲哚甲烷可以通过激活GPR84上调IL-12P40亚基的分泌，促进炎症的发生。研究表明外源性激动剂6-OAU通过激活GPR84导致趋化反应，上调AKT、ERK和核因子κB(NFκB)信号通路，引起炎性介质TNFα、IL-6、IL-12B、CCL2、CCL5和CXCL1的表达水平升高，增强细胞因子(IL-8、IL-12)和肿瘤坏死因子α(TNF-α)的释放，从而放大炎症部位的巨噬细胞炎症反应，加剧炎症发生，引发多种炎症性疾病(Carlota Recio et al，2018)。
有研究表明，在纤维化条件下，成纤维细胞、足细胞、近端小管上皮细胞和巨噬细胞中观察到更高水平的GPR84mRNA表达(Gagnon et al，2018；Grouix et al，2018；Li et al，2018)。在特发性肺纤维化模型中，GPR84拮抗剂(口服，30mg/kg，每天两次)连续2周，从7天开始极大地降低了Ashcroft评分(Edward Jenner，2020)。在内毒素血症的小鼠模型中，急性炎症期间观察到GPR84mRNA的表达上调。此外，在糖尿病和动脉粥样硬化等慢性炎症模型中也观察到GPR84表达上调(Recio et al，2018)。有报道称GPR84在炎症性肠病(IBD)患者的结肠组织和血液样本中表达增加(Arijs et al，2011；Planell et al，2017)。非酒精性脂肪性肝病(NAFLD)患者的肝活检组织中GPR84mRNA转录也有增加(Puengel et al，2020)。此外，GPR84上调的观察结果不仅限于外周疾病，而且在神经炎性环境中也得到了证实。早期研究报道GPR84在健康成年小鼠的大脑中低水平表达(Bouchard et al，2007)，但炎症刺激诱导中枢神经系统(CNS)小胶质细胞显著上调，例如在内毒素休克模型中(Audoy-Remus et al，2015)。肿瘤坏死因子α和白细胞介素-1被认为在GPR84上调中起关键作用，因为缺乏这些分子的小鼠大脑皮层中GPR84的表达降低。据报道，在其他影响中枢神经系统的动物疾病模型中也有较高水平的GPR84 mRNA表达，这些疾病包括实验性自身免疫性脑脊髓炎，一种多发性硬化症模型(Bouchard et al，2007)，Cuprizone诱导的脱髓鞘和轴突切断(Bedard et al，2007)以及阿尔茨海默病的小鼠模型(APP-PS1) (Audoy-Remus et al，2015)。
特发性肺纤维化(IPF)是一种原因不明的慢性，进行性纤维化间质性肺疾病，其特征是局限于肺部间质空间的进行性瘢痕形成或纤维化，导致肺功能丧失并最终死亡。IPF具有快速发展和死亡的高风险，通常被认为是一种罕见病。IPF患者的临床预后较差，诊断时的中位生存期约为3年。监管机构已批准吡非尼酮和Inetedanib用于治疗IPF。吡非尼酮和Inttedanib可以减缓IPF患者肺功能下降的速度，然而，两种药物都没有改善肺功能，尽管接受了治疗，但大多数患者的病情仍在继续发展。此外，这些疗法的不良反应包括腹泻、服用Inetedanib后肝功能检查异常、吡非尼酮引起的恶心和皮疹。因此，仍有大量未得到满足的医疗需求，IPF仍然是发病率和死亡率的主要原因，非常需要有效的治疗方法。
发明内容
本发明的目的是提供一种二氢嘧啶并异喹啉酮类衍生物，所述二氢嘧啶并异喹啉酮类衍生物包括如本发明所述的式I所示二氢嘧啶并异喹啉酮类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，可用于预防和/或治疗GPR84相关的疾病；或者制备作为GPR84拮抗剂、预防和/或治疗GPR84相关的疾病的药物、药物组合物或制剂。
本发明第一方面，提供了一种式I所示二氢嘧啶并异喹啉酮类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：
Figure PCTCN2022086783-appb-000001
其中，L 1为-NH-、-N(C 1-C 5烷基)-或-S-；
V为不存在或为-O-；
L 2不存在或L 2为C 1-C 5亚烷基、具有一个双键的C 2-C 4亚烯基或具有一个三键的C 2-C 4亚炔基；
R 2为选自下列的取代基：C 1-C 5烷基、3-10元环烷基、4-10元杂环烷基或5-10元杂芳基；
所述C 1-C 5烷基、3-10元环烷基、4-10元杂环烷基或5-10元杂芳基任选地被一个或多个R 21取代；所述R 21为选自下列的取代基：羟基、氰基、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；当取代基为多个时，所述R 21为相同或不同的取代基；
R 3、R 4、R 5、R 6、R 7、R 8分别独立地为氢、卤素或C 1-C 5烷基；所述C 1-C 5烷基任选地被R 31取代；所述R 31为选自下列的取代基：卤素、羟基、氨基、C 1-C 3烷氧基、C 1-C 3烷基氨基；
或者，R 3、R 4、R 5、R 6分别独立地为氢、卤素、C 1-C 5烷基或C 1-C 5卤代烷基；R 7、R 8与它们共 同连接的C原子一起形成3-6元环烷基或4-6元杂环烷基。
在本发明一优选实施方式中，L 1为-N(C 1-C 5烷基)-中，R 2为C 1-C 5烷基、被一个或多个R 21取代的C 1-C 5烷基里的C 1-C 5烷基中，R 3、R 4、R 5、R 6、R 7、R 8分别独立地为C 1-C 5烷基、被R 31取代的C 1-C 5烷基里的C 1-C 5烷基中，所述的C 1-C 5烷基优选为C 1-C 3烷基，例如甲基。
在本发明一优选实施方式中，L 2为C 1-C 5亚烷基中，所述的C 1-C 5亚烷基优选为C 1-C 3亚烷基，例如-CH 2-或-CH 2CH 2-。
在本发明一优选实施方式中，L 2为具有一个双键的C 2-C 4亚烯基中，所述的C 2-C 4亚烯基优选为-CH＝CH-。
在本发明一优选实施方式中，L 2为具有一个三键的C 2-C 4亚炔基中，所述的C 2-C 4亚炔基优选为-C≡C-。
在本发明一优选实施方式中，R 2为3-10元环烷基、被一个或多个R 21取代的3-10元环烷基里的3-10元环烷基中，所述的3-10元环烷基优选为3-6元环烷基，例如环丙基。
在本发明一优选实施方式中，R 2为4-10元杂环烷基、被一个或多个R 21取代的4-10元杂环烷基里的4-10元杂环烷基中，所述的4-10元杂环烷基优选为4-6元杂环烷基，例如哌啶基、哌嗪基或吡咯烷基。
在本发明一优选实施方式中，R 2为5-10元杂芳基、被一个或多个R 21取代的5-10元杂芳基里的5-10元杂芳基中，所述的5-10元杂芳基优选为5-6元杂芳基，例如
Figure PCTCN2022086783-appb-000002
在本发明一优选实施方式中，R 21、R 3、R 4、R 5、R 6、R 7、R 8、R 31分别独立地为卤素中，所述的卤素优选为氟、氯、溴或碘，例如氟。
在本发明一优选实施方式中，R 21为C 1-C 6烷基中，所述的C 1-C 6烷基优选为C 1-C 3烷基，例如甲基或乙基。
在本发明一优选实施方式中，R 21为C 1-C 6烷氧基中，所述的C 1-C 6烷氧基优选为C 1-C 3烷氧基，例如甲氧基或乙氧基。
在本发明一优选实施方式中，R 21为C 3-C 6环烷基中，所述的C 3-C 6环烷基优选为环丙基、环丁基或环戊基。
在本发明一优选实施方式中，R 21为C 1-C 6卤代烷基中，所述的C 1-C 6卤代烷基优选为C 1-C 3卤代烷基，例如三氟甲基。
在本发明一优选实施方式中，R 21为C 1-C 6卤代烷氧基中，所述的C 1-C 6卤代烷氧基优选为C 1-C 3卤代烷氧基，例如-OCF 3。
在本发明一优选实施方式中，R 31为C 1-C 3烷氧基中，所述的C 1-C 3烷氧基优选为甲氧基或乙氧基。
在本发明一优选实施方式中，R 31为C 1-C 3烷基氨基中，所述的C 1-C 3烷基氨基优选为CH 3NH-或CH 3CH 2NH-。
在本发明一优选实施方式中，R 3、R 4、R 5、R 6分别独立地为C 1-C 5卤代烷基中，所述的C 1-C 5卤代烷基优选为C 1-C 3卤代烷基，例如三氟甲基。
在本发明一优选实施方式中，R 7、R 8与它们共同连接的C原子一起形成3-6元环烷基里的3-6元环烷基中，所述的3-6元环烷基优选为环丙基、环丁基或环戊基。
在本发明一优选实施方式中，R 7、R 8与它们共同连接的C原子一起形成4-6元杂环烷基中，所述的4-6元杂环烷基优选为哌啶基、哌嗪基或吡咯烷基。
在本发明一优选实施方式中，L 1为-NH-、-N(CH 3)-或-S-。
在本发明一优选实施方式中，L 2为C 1-C 5亚烷基或具有一个三键的C 2-C 4亚炔基，较佳地，L 2为-CH 2-或-C≡C-。
在本发明一优选实施方式中，V为不存在时，L 2为具有一个双键的C 2-C 4亚烯基或具有一个三键的C 2-C 4亚炔基；V为-O-时，L 2为C 1-C 5亚烷基。
在本发明一优选实施方式中，V为不存在时，L 2为-CH＝CH-或-C≡C-；V为-O-时，L 2为-CH 2-或-CH 2CH 2-。
在本发明一优选实施方式中，V为不存在时，L 2为-CH＝CH-；V为-O-时，L 2为-CH 2-。
在本发明一优选实施方式中，V为不存在时，L 2为-C≡C-；V为-O-时，L 2为-CH 2-。
在本发明一优选实施方式中，L 1为-S-，V为不存在，L 2为具有一个双键的C 2-C 4亚烯基；较佳地，L 2为-CH＝CH-。
在本发明一优选实施方式中，L 1为-S-，V为不存在，L 2为具有一个三键的C 2-C 4亚炔基；较佳地，L 2为-C≡C-。
在本发明一优选实施方式中，L 1为-NH-或-N(CH 3)-，V为不存在或为-O-，L 2为C 1-C 5亚烷基、具有一个双键的C 2-C 4亚烯基或具有一个三键的C 2-C 4亚炔基；较佳地，L 2为-CH 2-、-CH 2CH 2-。
在本发明一优选实施方式中，L 1为-NH-或-N(CH 3)-，V为不存在或为-O-，L 2为C 1-C 5亚烷基或具有一个三键的C 2-C 4亚炔基；较佳地，L 2为-CH 2-或-C≡C-。
在本发明一优选实施方式中，R 2为C 1-C 5烷基、3-6元环烷基、4-6元杂环烷基或5-6元杂芳基；所述C 1-C 5烷基、3-6元环烷基、4-6元杂环烷基或5-6元杂芳基任选地被一个或多个R 21取代；所述R 21为选自下列的取代基：羟基、氰基、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；当取代基为多个时，所述R 21为相同或不同的取代基；
较佳地，所述R 21为选自下列的取代基：卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
更佳地，所述R 21为选自下列的取代基：卤素、C 1-C 6烷基；较佳地，所述卤素为氟。
在本发明一优选实施方式中，R 2为C 1-C 5烷基、3-10元环烷基、4-10元杂环烷基或5-10元杂芳基；所述C 1-C 5烷基、3-10元环烷基、4-10元杂环烷基或5-10元杂芳基任选地被一个或多个R 21取代；所述R 21为选自下列的取代基：卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；当取代基为多个时，所述R 21为相同或不同；
较佳地，所述R 21为选自下列的取代基：卤素、C 1-C 6烷基；
所述卤素较佳地为氟。
在本发明一优选实施方式中，R 2为C 1-C 5烷基、3-6元环烷基或5-6元杂芳基；所述5-6元杂芳基含有1、2或3个选自N或O的杂原子；当杂原子为多个时，所述杂原子相同或不同；所述C 1-C 5烷基、3-6元环烷基或5-6元杂芳基任选地被一个或多个R 21取代；所述R 21为选自下列的取代基：卤素、C 1-C 6烷基；所述卤素较佳地为氟。
在本发明一优选实施方式中，R 2为C 1-C 5烷基、3-6元环烷基或5-6元杂芳基；其中，所述C 1-C 5烷基任选地被一个或多个卤素取代；所述3-6元环烷基任选地被一个或多个选自下列的取代基取代：卤素、C 1-C 5烷基、C 1-C 5卤代烷基；所述5-6元杂芳基含有1、2或3个选自N或O的杂原子；当杂原子为多个时，所述杂原子相同或不同；
较佳地，R 2为环丙基、-CF 3或
Figure PCTCN2022086783-appb-000003
在本发明一优选实施方式中，基团-V-L 2-R 2为
Figure PCTCN2022086783-appb-000004
在本发明一优选实施方式中，R 3、R 4、R 5、R 6、R 7、R 8分别独立地为氢、卤素、C 1-C 5烷基或C 1-C 5卤代烷基；较佳地，R 3、R 4、R 5、R 6、R 7、R 8为氢。
在本发明一优选实施方式中，所述的如式I所示二氢嘧啶并异喹啉酮类衍生物为如式Ia所示的化合物或如式Ib所示的化合物；
Figure PCTCN2022086783-appb-000005
其中，L 1、R 3、R 4、R 5、R 6、R 7、R 8、V、L 2和R 2的定义如本发明所定义。
在本发明一优选实施方式中，L 1为-NH-、-N(CH 3)-或-S-；
V为不存在或为-O-；
L 2为C 1-C 5亚烷基或具有一个三键的C 2-C 4亚炔基；
R 2为选自下列的取代基：C 1-C 5烷基、3-10元环烷基或5-10元杂芳基；所述C 1-C 5烷基、5-10元杂芳基任选地被一个或多个R 21取代；所述R 21为卤素或C 1-C 5烷基；
R 3、R 4、R 5、R 6、R 7、R 8分别独立地为氢。
在本发明一优选实施方式中，L 1为-NH-、-N(CH 3)-或-S-；
V为不存在或为-O-；
L 2为-CH 2-或-C≡C-；
R 2为环丙基、-CF 3或
Figure PCTCN2022086783-appb-000006
R 3、R 4、R 5、R 6、R 7、R 8分别独立地为氢。
在本发明一优选实施方式中，所述二氢嘧啶并异喹啉酮类衍生物包括：
Figure PCTCN2022086783-appb-000007
在本发明第二方面，提供了一种药物组合物，所述药物组合物包括：如本发明第一方面中所述的式I所示二氢嘧啶并异喹啉酮类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药；和药学上可接受的载体。
另外还提供了一种药物组合物，所述药物组合物包括如本发明第一方面中所述的式I所示二氢嘧啶并异喹啉酮类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药；和至少一种其他药理学活性拮抗剂和/或抑制剂。
在本发明第三方面，提供了一种如本发明第一方面所述的式I所示二氢嘧啶并异喹啉酮类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药的用途，或本发明第四方面所述的药物组合物的用途，所述用途包括：
作为GPR84拮抗剂；
和/或，预防和/或治疗GPR84相关的疾病；
和/或，制备GPR84拮抗剂，和/或预防和/或治疗GPR84相关的疾病的药物、药物组合物或制剂。
在本发明一优选实施方式中，所述GPR84相关的疾病包括：器官纤维化疾病、炎性疾病、肺病、神经炎性疾病、感染性疾病、自身免疫性疾病、内分泌、代谢性疾病、或与免疫功能受损相关的疾病。
较佳地，所述肺病包括慢性阻塞性肺病(COPD)和肺间质疾病；所述肺间质疾病包括先天性肺纤维 化(IPF)。
较佳地，所述炎性疾病包括血管炎、炎症性肠病(IBD)。
较佳地，所述自身免疫性疾病包括类风湿性关节炎。
较佳地，所述器官纤维化疾病包括消化器官、呼吸器官、循环器官、泌尿生殖器官、运动器官、脑神经系统、内分泌器官、或皮肤的纤维化疾病；较佳地包括肝纤维化、肺纤维化、肾纤维化、心纤维化；较佳地，所述肺纤维化包括特发性肺纤维化、先天性肺纤维化。
更具体地，所述GPR84相关的疾病优选为：内毒素血症、糖尿病、动脉粥样硬化、炎症性肠病、非酒精性脂肪肝、非酒精性脂肪性肝炎、哮喘、银屑病、特发性肺纤维化、先天性肺纤维化、实验性自身免疫性脑脊髓炎、多发性硬化症、阿尔茨海默症。
在本发明的第四方面，提供了一种如上所述的式I所示的二氢嘧啶并异喹啉酮类衍生物的制备方法，所述制备方法为如下方案一或方案二：
方案一包括下述步骤：在有机溶剂中，在钯催化剂、CuI和碱的存在下，将式II所示的化合物与环丙乙炔进行如下所示的偶联反应，得到所述的式I所示的二氢嘧啶并异喹啉酮类衍生物；
Figure PCTCN2022086783-appb-000008
方案二包括下述步骤：在有机溶剂中，在碱存在下，将式II所示的化合物与式IV所示的化合物进行如下所示的取代反应，得到所述的如式式I所示二氢嘧啶并异喹啉酮类衍生物；
Figure PCTCN2022086783-appb-000009
其中，X为羟基、-OTf、-OTs或-OMs，Y为卤素，L 1、R 2、R 3、R 4、R 5、R 6、R 7和R 8的定义如前所述。
在本发明一优选实施方式中，当X为羟基时，所述的式II所示的化合物的制备方法包括如下步骤：在有机溶剂中，在钯催化剂和碱存在下，将式III所示的化合物进行如下所示的反应，得到所述的如式II所示的化合物即可；
Figure PCTCN2022086783-appb-000010
其中，L 1、R 3、R 4、R 5、R 6、R 7和R 8的定义如前所述。
在本发明的第五方面，提供了一种所述的式II所示的化合物或所述的式III所示的化合物，
Figure PCTCN2022086783-appb-000011
其中，X为羟基、-OTf、-OTs或-OMs，L 1、R 3、R 4、R 5、R 6、R 7和R 8的定义如前所述。较佳地，L 1为-NH-、-N(CH 3)-或-S-。较佳地，R 3、R 4、R 5、R 6、R 7、R 8为氢。
在本发明一优选实施方式中，所述式II所示的化合物为式IIa所示的化合物或式IIb所示的化合物；
Figure PCTCN2022086783-appb-000012
其中，X为羟基、-OTf、-OTs或-OMs，L 1、R 3、R 4、R 5、R 6、R 7和R 8的定义如本发明所定义。
在本发明一优选实施方式中，所述式III所示的化合物为式IIIa所示的化合物或式IIIb所示的化合物；
Figure PCTCN2022086783-appb-000013
其中，L 1、R 3、R 4、R 5、R 6、R 7和R 8的定义如本发明所定义。
在本发明一优选实施方式中，所述式II所示的化合物为：
Figure PCTCN2022086783-appb-000014
Figure PCTCN2022086783-appb-000015
在本发明一优选实施方式中，所述式III所示的化合物为：
Figure PCTCN2022086783-appb-000016
Figure PCTCN2022086783-appb-000017
在本发明一优选实施方式中，所述的化合物中，所有原子的同位素丰度与其自然丰度相同。
在本发明一优选实施方式中，环状烷基、杂环烷基为单环。
在本发明一优选实施方式中，5-10元杂芳基为单环或双环。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
术语和定义
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义，以本章的定义为准。
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4THED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，CH 2O等同于OCH 2。如本文所用，
Figure PCTCN2022086783-appb-000018
表示基 团的连接位点。如本文所用，“R 1”、“R1”和“R 1”的含义相同，可相互替换。对于R 2等其它其他符号，类似定义的含义相同。
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。
本申请说明书和权利要求书记载的数值范围，当该数值范围被理解为“整数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如，“0～5的整数”应当理解为记载了0、1、2、3、4和5的每一个整数。
在本申请中，在单独或作为其他取代基一部分时，术语“卤素”是指氟、氯、溴、碘。
如本文所用，在单独或作为其他取代基一部分时，术语"氨基"表示-NH 2。
如本文所用，在单独或作为其他取代基一部分时，术语"硝基"表示-NO 2。
如本文所用，在单独或作为其他取代基一部分时，术语"氰基"表示-CN。
如本文所用，“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。
如本文所用，在单独或作为其他取代基一部分时，术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至6个碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基，叔丁基，戊基，异戊基，新戊基和己基。烷基也可以是富含碳和/或氢的同位素(即氘或氚)的天然丰度烷基的同位素异构体。如本文所用，术语“烯基”表示无支链或支链的单价烃链，其含有一个或多个碳-碳双键。如本文所用，术语“炔基”是指无支链或支链的一价烃链，其含有一个或多个碳-碳三键。
在单独或作为其他取代基一部分时，术语“C 1-C 6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。术语“C 1-C 5烷基”应理解为表示具有1、2、3或5个碳原子的直链或支链饱和一价烃基。特别地，所述基团具有1、2或3个碳原子(“C 1-C 3烷基”)，例如甲基、乙基、正丙基或异丙基。
在单独或作为其他取代基一部分时，术语“C 1-C 6烷氧基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基和氧原子组成，或者表示为C 1-C 6烷基-O-C 1-C 6烷基的定义如本说明书中所述，氧原子可以连接在C 1-C 6烷基的直链或直链的任何一个碳原子上。包括但不限于：甲氧 基(CH 3-O-)、乙氧基(C 2H 5-O-)、丙氧基(C 3H 7-O-)、丁氧基(C 4H 9-O-)。
术语“亚烷基”表示从饱和的直链或支链烃基中去掉两个氢原子所得到的饱和的二价烃基基团；即烷基中的一个氢被取代，烷基的定义如上所述。亚烷基基团的实例包括亚甲基(-CH 2-)，亚乙基{包括-CH 2CH 2-或-CH(CH 3)-}，亚异丙基{包括-CH(CH 3)CH 2-或-C(CH 3) 2-}等等。
在单独或作为其他取代基一部分时，术语“C 1-C 3烷基氨基”应理解为表示具有1、2或3个碳原子的直链或支链饱和一价烃基和氨基组成。包括但不限于：CH 3NH-、CH 3CH 2NH-。
在单独或作为其他取代基一部分时，术语“环烷基”或“碳环基”是指一种环状烷基。术语“m-n元环烷基”或者“C m-C n环烷基”应理解为表示具有m至n个原子的饱和、不饱和或部分饱和的碳环。例如，“3-10元环烷基”或者“C 3-C 10环烷基”是指含有3至10个碳原子的环状烷基，它可能包含1至3个环。所述环状烷基包括单环、二环、三环、螺环或桥环。未取代的环烷基的实例包括但不限于环丙基，环丁基，环戊基，环己基和金刚烷基，或者是双环烃基如十氢化萘环。
在单独或作为其他取代基一部分时，术语“杂环烷基”或“杂环基”是指其中一个或多个(在一些实施方案中为1至3个)碳原子被杂原子取代的环烷基，所述杂原子例如但不限于N、O、S和P。术语“m-n元杂环烷基”或者“C m-C n杂环烷基”应理解为表示具有m至n个原子的饱和、不饱和或部分饱和的环。例如，术语“4-10元杂环烷基”应理解为表示具有4至10个原子的饱和、不饱和或部分饱和的环。在一些实施方案中，杂环烷基可以是与芳基或杂芳基稠合的杂环烷基。当诸如3-8元的前缀用于表示杂环烷基时，碳的数目也意味着包括杂原子。包括单环、二环、三环、螺环或桥环。
在单独或作为其他取代基一部分时，术语“杂芳基”可与术语“杂芳环”或“杂芳族基”互换使用，是指单环或多环芳环系统，在某些实施方案中，环系统中1至3个原子是杂原子，即除碳以外的元素，包括但不限于N，O、S或P。例如呋喃基，咪唑基，二氢吲哚基，吡咯烷基，嘧啶基，四唑基，噻吩基，吡啶基，吡咯基，N-甲基吡咯基，喹啉基和异喹啉基。
在单独或作为其他取代基一部分时，术语“5-10元杂芳基”应理解为具有5-10个环原子且包含选自N、O和S的杂原子的一价单环、双环或三环芳族环基团，应理解为具有5、6、7、8、9或10个环原子——特别是5或6或9或10个碳原子——且其包含1-5个，优选1-3个——独立选自N、O和S的杂原子的一价单环、双环或三环芳族环基团，并且，另外在每一种情况下可为苯并稠合的。“5-8元杂芳基”则应理解为具有5-8个环原子——特别是5或6个碳原子——且包含1-5个独立选自N、O和S的杂原子的一价单环、双环或三环芳族环基团。优选1-3个——独立选自N、O和S的杂原子的一价单环、双环或三环芳族环基团，并且，另外在每一种情况下可为苯并稠合的。杂芳基的实例包括但不限于：噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。
在单独或作为其他取代基一部分时，术语“卤代”可与术语“卤素取代”互换使用。“卤代烷基”或“卤素取代的烷基”指包括具有特定数目的碳原子、被一或多个卤素取代的支链和直链的饱和脂族烃基(如-CvFw，其中v＝1至3，w＝1至(2v+1))。卤代烷基的实例包括，但不限于三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。
在单独或作为其他取代基一部分时，术语“螺环”指单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2022086783-appb-000019
也包含单螺环烷基与杂环烷基共用螺原子的螺环烷基，非限制性实例包括：
Figure PCTCN2022086783-appb-000020
术语“桥环”是指化合物中的任意两个环共用两不直接相连的碳原子的环烃,根据组成环的数目分为二环烃、三环烃、四环烃等。非限制性实例包括：
Figure PCTCN2022086783-appb-000021
在单独或作为其他取代基一部分时，术语“C 2-C 4烯基”应理解为表示直连或支链的一价烃基，其包含一个或多个双键并且具有例如2、3或4个碳原子，或具有2或3个碳原子。应理解，在所述烯基包含多于一个双键的情况下，所述双键可相互分离或者共轭。所述烯基是例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基。
在单独或作为其他取代基一部分时，术语“C 2-C 4炔基”应理解为表示直连或支链的一价烃基，其包含一个或多个三键并且具有例如2、3或4个碳原子，或具有2或3个碳原子。所述炔基是例如乙炔基、甲基取代的乙炔基、乙基取代的乙炔基。
术语“亚烯基”是指具有特定碳原子数的、含有一个或多个碳碳双键并且没有碳碳三键的直链或支链的烯烃消除两个氢后形成的取代基。其中碳碳双键可以位于亚烯基内的任何位置，消除的两个氢可以在同一个碳原子上，也可以在不同的碳原子上(例如消除的两个氢分别在两端的碳原子上)。由此，
C 2亚烯基(即亚乙烯基)包括但不限于-CH＝CH-，C 3亚烯基包括但不限于-CH 2-CH＝CH-、
Figure PCTCN2022086783-appb-000022
和-C(CH 3)＝CH-，C 4亚烯基包括但不限于-CH 2-CH＝CH-CH 2-、
Figure PCTCN2022086783-appb-000023
-CH 2＝CH-CH 2-CH 2-和-CH 2-CH-CH 2＝CH 2-。
在本申请中，作为基团或是其它基团的一部分，术语“亚炔基”是指具有特定碳原子数的、含有一个或多个碳碳三键的直链或支链的烯烃消除两个氢后形成的取代基。其中碳碳三键可以位于亚炔基内的任何位置，消除的两个氢可以在同一个碳原子上，也可以在不同的碳原子上(例如消除的两个氢分别在两端的碳原子上)。由此，C 2亚炔基(即亚乙炔基)包括但不限于
Figure PCTCN2022086783-appb-000024
C 3亚炔基包括但不限于
Figure PCTCN2022086783-appb-000025
C 4亚炔基包括但不限于
Figure PCTCN2022086783-appb-000026
本文提供的化合物，包括可用于制备本文提供的化合物的中间体，其含有反应性官能团(例如但不限于羧基，羟基和氨基部分)，还包括其保护的衍生物。“受保护的衍生物”是其中一个或多个反应性位点被一个或多个保护基团(也称为保护基团)封闭的那些化合物。合适的羧基部分保护基包括苄基，叔丁基等，以及同位素等。合适的氨基和酰氨基保护基包括乙酰基，三氟乙酰基，叔丁氧基羰基，苄氧基羰基等。合适的羟基保护基包括苄基等。其他合适的保护基团是本领域普通技术人员所熟知的。
在本申请中，术语“盐”或“药学上可接受的盐”，包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。除了药学可接受的盐外，本发明还考虑其他盐。它们可以在化合物纯化中或在制备其它药学上课接受的盐中充当中间体或可用于本发明化合物的鉴别、表征或纯化。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对应异构体和构象异构体。
依据原料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物的形式存在，例如作为纯旋光异构体，或作为异构体混合物，如作为外消旋和非对映异构体混合物，这取决于不对称碳原子的数量。当描述具有光学活性的化合物时，使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀D和L或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号，其中(–)或L表示化合物是左旋的。前缀为(+)或D的化合物是右旋的。
当将本发明式中与手性碳的键描写直成线时，应当理解为，手性碳的(R)和(S)两种构型和由此产生的其对映体纯的化合物和混合物两者包括在该通式范围内。用楔形键和虚线键表示一个立体中心的绝对构型。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发 明包含化合物的所有互变异构形式。
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。
在本申请中，“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
在本申请中，术语“溶剂化物”指本发明化合物或其盐包括以分子间非共价力结合的化学计量或非化学计量的溶剂，当溶剂为水时，则为水合物。
在本申请中，术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备，该修饰可以按常规的操作或者在体内被除去，而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物，当本发明化合物的前药被施予哺乳动物个体时，前药被割裂而分别形成游离的羟基、游离的氨基。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氘( 2H)、氚( 3H)、碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
在本申请中，术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。
本文所用的术语“治疗”和其它类似的同义词包括以下含义：
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；
(iv)减轻该疾病或病症所造成的症状。
本发明的积极进步效果在于：本发明人经过广泛而深入地研究，意外地开发了一种式I所示二氢嘧啶并异喹啉酮类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其具有明显的GPR84拮抗作用；本发明化合物在小鼠口服暴露量高，在人血浆中的游离分数高，成药性好；药物相互作用风险小，安全性好。
本发明所述式I所示二氢嘧啶并异喹啉酮类衍生物可以作为GPR84拮抗剂，预防和/或治疗GPR84相关的疾病；制备用于作为GPR84拮抗剂的药物、药物组合物或制剂，以及制备用于预防和/或治疗GPR84相关的疾病的药物、药物组合物或制剂。所述GPR84相关的疾病实例包括但不限于：内毒素血症、糖尿病、动脉粥样硬化、炎症性肠病、非酒精性脂肪肝、特发性肺纤维化、实验性自身免疫性 脑脊髓炎、多发性硬化症、阿尔茨海默症。
具体实施方式
以下结合具体实施例，进一步说明本发明。需理解，以下的描述仅为本发明的最优选实施方式，而不应当被认为是对于本发明保护范围的限制。在充分理解本发明的基础上，下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件，本领域技术人员可以对本发明的技术方案作出非本质的改动，这样的改动应当被视为包括于本发明的保护范围之中的。
本申请具有如下定义：
符号或单位：
IC 50：半数抑制浓度，指达到最大抑制效果一半时的浓度
M：mol/L，例如正丁基锂(14.56mL，29.1mmol，2.5M的正己烷溶液)表示摩尔浓度为2.5mol/L的正丁基锂的正己烷溶液
N：当量浓度，例如2N盐酸表示2mol/L盐酸溶液
试剂：
DCM：二氯甲烷
DIPEA：也可写为DIEA，二异丙基乙胺，亦即N,N-二异丙基乙胺
DMF：N,N-二甲基甲酰胺
DMSO：二甲基亚砜
EA：乙酸乙酯
Et 3N：三乙胺
MeOH：甲醇
PE：石油醚
THF：四氢呋喃
实施例1：化合物I-1的制备
化合物I-1的合成路线如下所示：
Figure PCTCN2022086783-appb-000027
第一步：(R)-2-(((1,4-二氧六环-2-基)甲基)氨基)-9-(烯丙氧基)-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-4-酮(化合物B1-3)的合成
Figure PCTCN2022086783-appb-000028
将9-(烯丙氧基)-2-氯-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-4-酮(化合物B1-1,1.7g，5.89mmol)置于100mL单口瓶中加入无水DCM(50mL)，室温下加入(R)-(1,4-二氧六环-2-基)甲胺盐酸盐(化合物B1-2,0.995g,6.48mmol)和DIEA(3.13mL,17.7mmol)，室温过夜搅拌。点板检测，待反应结束后，浓缩干溶剂，得到粗品用硅胶柱分离纯化(DCM:MeOH(V/V)＝50:1-20:1)得(R)-2-(((1,4-二氧六环-2-基)甲基)氨基)-9-(烯丙氧基)-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-4-酮(化合物B1-3)(黄色固体，1.3g,产率59.8％)。
LC-MS,M/Z(ESI):370.2[M+H] +。
第二步：(R)-2-(((1,4-二氧六环-2-基)甲基)氨基)-9-羟基-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-4-酮(化合物B1-4)的合成
Figure PCTCN2022086783-appb-000029
将(R)-2-(((1,4-二氧六环-2-基)甲基)氨基)-9-(烯丙氧基)-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-4-酮(化合物B1-3)(1.3g,3.52mmol)置于100mL单口瓶中加入DCM/MeOH(20mL/20mL)，室温下加入K 2CO 3(0.973g,7.04mmol)和Pd(PPh 3) 4(0.203g,7.04mmol)，室温过夜搅拌。点板检测，待反应结束后，浓缩干溶剂，得到粗品用EA(20mL)稀释，有机相用水萃取三次(20mL),合并水相，然后调节pH＝4，水相再用DCM萃取三次(20mL),合并有机相，有机相用饱和食盐水洗涤一次(20mL)，然后干燥过滤浓缩得粗品(R)-2-(((1,4-二氧六环-2-基)甲基)氨基)-9-羟基-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-4-酮(化合物B1-4，黄色固体，0.6g,产率51.8％)。
LC-MS,M/Z(ESI):330.0[M+H] +。
第三步：(R)-2-(((1,4-二氧六环-2-基)甲基)氨基)-4-氧代-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-9-基三氟甲磺酸酯(化合物B1-5)的合成
Figure PCTCN2022086783-appb-000030
将粗品(R)-2-(((1,4-二氧六环-2-基)甲基)氨基)-9-羟基-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-4-酮(化合 物B1-4)(0.6g,1.82mmol)溶于DCM(10mL)中，加入1,1,1-三氟-N-苯基-N-((三氟甲基)磺酰基)甲磺酰胺(0.716g,2.01mmol)和三乙胺(0.46mL,3.3mmol),然后室温下搅拌5小时,浓缩干溶剂，得到粗品用硅胶柱分离纯化(DCM:MeOH(V/V)＝50:1-20:1)得(R)-2-(((1,4-二氧六环-2-基)甲基)氨基)-4-氧代-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-9-基三氟甲磺酸酯(化合物B1-5)(黄色固体，0.55g，产率65.4％)。
LC-MS,M/Z(ESI):461.9[M+H] +。
第四步：(R)-2-(((1,4-二氧六环-2-基)甲基)氨基)-9-(环丙基乙炔基)-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-4-酮(化合物I-1)的合成
Figure PCTCN2022086783-appb-000031
将Pd(PPh 3) 2Cl 2(0.042g,0.06mmol),CuI(0.045g,0.238mmol)和(R)-2-(((1,4-二氧六环-2-基)甲基)氨基)-4-氧代-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-9-基三氟甲磺酸酯(化合物B1-5,0.55g,1.19mmol)置于封管中，氮气保护。将环丙乙炔(0.394g,5.96mmol)和三乙胺(0.63g,5.96mmol)溶于无水DMF(10mL)中，加入到封管中50℃过夜搅拌。点板检测，待原料完全反应后。除去DMF浓缩得到粗品，用硅胶柱分离纯化(DCM:MeOH(V/V)＝50:1-10:1)得(R)-2-(((1,4-二氧六环-2-基)甲基)氨基)-9-(环丙基乙炔基)-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-4-酮(化合物I-1)(淡黄色固体，269mg，产率59.8％)。
LC-MS,M/Z(ESI):378.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.63–7.47(m,1H),7.32(d,J＝8.0Hz,1H),7.27(s,1H),6.00(s,1H),5.35(s,1H),4.15(dd,J＝13.4,7.1Hz,2H),3.91–3.68(m,6H),3.65–3.56(m,1H),3.36(dd,J＝14.0,7.5Hz,2H),2.92(t,J＝6.3Hz,2H),1.47(tt,J＝8.2,5.1Hz,1H),0.95–0.88(m,2H),0.86–0.80(m,2H)。
实施例2：化合物I-2的制备
合成路线如下所示：
Figure PCTCN2022086783-appb-000032
化合物I-2的合成参考I-1合成方法。将9-(烯丙氧基)-2-氯-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-4-酮(化合物B1-1,1.7g，5.89mmol)置于100mL单口瓶中加入无水DCM(50mL)，室温下加入1-(1,4-二氧六环-2-基)-N-甲基甲胺盐酸盐(化合物B2-2,1.08g,6.48mmol)和DIEA(3.13mL,17.7mmol)，室温过夜搅拌。点板检测，待反应结束后，浓缩干溶剂，得到粗品用硅胶柱分离纯化(DCM:MeOH(V/V)＝50:1-20:1)得2-(((1,4-二氧六环-2-基)甲基)(甲基)氨基)-9-(烯丙氧基)-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-4-酮(化合物B2-3)(黄色固体，1.2g,产率58.1％)。
LC-MS,M/Z(ESI):384.2[M+H] +。
参考I-1合成方法，经过三步反应得到2-(((1,4-二氧六环-2-基)甲基)(甲基)氨基)-9-(环丙基乙炔基)-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-4-酮(化合物I-2)(淡黄色固体，12.1mg，产率29.1％)。
LC-MS,M/Z(ESI):392.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.62(d,J＝7.6Hz,1H),7.33-7.31(m,1H),7.28(s,1H),6.19(s,1H),4.15(t,J＝6.3Hz,2H),3.89(s,2H),3.77–3.51(m,5H),3.33(s,1H),3.21(s,3H),2.96-2.85(m,2H),1.52-1.43(m,2H),0.95–0.87(m,2H),0.87–0.80(m,2H)。
实施例3：化合物I-3的制备
合成路线如下所示：
Figure PCTCN2022086783-appb-000033
化合物I-3的合成参考I-1合成方法。将9-(烯丙氧基)-2-氯-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-4-酮(化合物B1-1,1.7g，5.89mmol)置于100mL单口瓶中加入无水DCM(50mL)，室温下加入(S)-(1,4-二氧六环-2-基)甲胺盐酸盐(化合物B3-2,0.96g,6.48mmol)和DIEA(3.13mL,17.7mmol)，室温过夜搅拌。点板检测，待反应结束后，浓缩干溶剂，得到粗品用硅胶柱分离纯化(DCM:MeOH(V/V)＝50:1-20:1)得(S)-2-(((1,4-二氧六环-2-基)甲基)氨基)-9-(烯丙氧基)-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-4-酮(化合物B3-3)(黄色固体，1.25g,产率58.8％)。
LC-MS,M/Z(ESI):370.2[M+H] +。
参考I-1合成方法，经过三步反应得到(S)-2-(((1,4-二氧六环-2-基)甲基)氨基)-9-(环丙基乙炔基)-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-4-酮(化合物I-3)(淡黄色固体，26.7mg，产率16.3％)。
LC-MS,M/Z(ESI):378.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.63–7.47(m,1H),7.37(s,1H),7.27(d,J＝7.3Hz,1H),6.37(s,1H),4.13(s,2H),3.91–3.68(m,6H),3.65–3.56(m,1H),3.42(s,2Hz,2H),2.95(d,J＝7.0Hz,2H),1.48(dd,J＝8.4,5.1Hz,1H),0.95–0.88(m,2H),0.86–0.80(m,2H)。
实施例4：化合物I-4的制备
合成路线如下所示：
Figure PCTCN2022086783-appb-000034
将(R)-2-(((1,4-二氧六环-2-基)甲基)氨基)-9-羟基-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-4-酮(化合物B1-4,0.1g，0.31mmol)置于100mL单口瓶中加入无水DMF(2mL)，室温下加入一溴三氟乙烷(0.1g,0.61mmol)和碳酸钾(85mg,0.61mmol)，室温过夜搅拌。点板检测，待反应结束后，浓缩干溶剂，得到粗品分离纯化(DCM:MeOH(V/V)＝50:1-20:1)得(R)-2-(((1,4-二氧六环-2-基)甲基)氨基)-9-(2,2,2-三氟乙氧基)-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-4-酮(化合物I-4)(黄色固体，39mg,产率30.6％)。
LC-MS,M/Z(ESI):412.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.64(s,1H),6.96(d,J＝23.9Hz,1H),6.84(s,1H),5.98(s,1H),4.41(q,J＝7.8Hz,2H),4.15(t,J＝6.4Hz,2H),3.93–3.67(m,6H),3.61(dd,J＝15.3,7.1Hz,1H),3.35(dd,J＝13.5,7.4Hz,2H),2.96(s,2H)。
实施例5：化合物I-5的制备
合成路线如下所示：
Figure PCTCN2022086783-appb-000035
将(R)-2-(((1,4-二氧六环-2-基)甲基)氨基)-9-羟基-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-4-酮(化合物B1-4,0.1g，0.31mmol)置于100mL单口瓶中加入无水DMF(2mL)，室温下加入3-甲基-5-(氯甲基)-1,2,4-噁二唑(0.081g,0.61mmol)和碳酸钾(85mg,0.61mmol)，室温过夜搅拌。点板检测，待反应结束后，浓缩干溶剂，得到粗品，经过纯化反应得到(R)-2-(((1,4-二氧六环-2-基)甲基)氨基)-9-((3-甲基-1,2,4-噁二唑-5-基)甲氧基)-6,7-二氢-4H-嘧啶[6,1-a]异喹啉-4-酮(化合物I-5)(淡黄色固体，48.6mg，产率37.6％)。
LC-MS,M/Z(ESI):426.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.62(d,J＝8.2Hz,1H),6.96(d,J＝8.3Hz,1H),6.87(s,1H),5.94(s,1H),5.32(s,2H),4.15(t,J＝6.4Hz,2H),3.90–3.68(m,6H),3.60(td,J＝11.4,3.2Hz,1H),3.35(dd,J＝13.5,7.2Hz,2H),2.95(t,J＝6.3Hz,2H),2.44(s,3H)。
实施例6：化合物I-6的制备
合成路线如下所示：
Figure PCTCN2022086783-appb-000036
将(R)-2-(((1,4-二氧六环-2-基)甲基)氨基)-9-羟基-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-4-酮(化合物B1-4,0.2g，0.61mmol)置于100mL单口瓶中加入无水DMF(2mL)，室温下加入(溴甲基)环丙烷(0.1g,0.73mmol)和碳酸钾(130mg,0.91mmol)，室温过夜搅拌。点板检测，待反应结束后，浓缩干溶剂，得到粗品，经过纯化反应得到(R)-2-(((1,4-二氧六环-2-基)甲基)氨基)-9-(环丙基甲氧基)-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-4-酮(化合物I-6)(淡黄色固体，48.6mg，产率20.1％)。
LC-MS,M/Z(ESI):384.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.58(d,J＝8.9Hz,1H),6.86(dd,J＝8.7,2.5Hz,1H),6.76(d,J＝2.4Hz,1H),5.91(s,1H),5.22(s,1H),4.19–4.11(m,2H),3.94–3.66(m,8H),3.64–3.54(m,1H),3.41–3.31(m,2H),2.92(t,J＝6.4Hz,2H),1.32–1.24(m,1H),0.71–0.64(m,2H),0.37(q,J＝4.9Hz,2H)。
实施例7：化合物I-7的制备
化合物I-7的合成路线如下所示：
Figure PCTCN2022086783-appb-000037
化合物I-7的合成参考I-1合成方法。将9-(烯丙氧基)-2-氯-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-4-酮(化合物B1-1,1.7g，5.89mmol)置于100mL单口瓶中加入无水DCM(50mL)，室温下加入(S)-(1,4-二氧六环-2-基)甲硫醇(化合物B7-2,0.96g,6.48mmol)和DIEA(3.13mL,17.7mmol)，室温过夜搅拌。点板检测，待反应结束后，浓缩干溶剂，得到粗品用硅胶柱分离纯化 (DCM:MeOH(V/V)＝50:1-20:1)得(S)-2-(((1,4-二氧六环-2-基)甲基)硫代)-9-(烯丙氧基)-6,7-二氢-4H-
嘧啶并[6,1-a]异喹啉-4-酮(化合物B7-3)(黄色固体，1.3g,产率59.6％)。
LC-MS,M/Z(ESI):387.1M+H] +。
参考I-1合成方法，经过三步反应得到(S)-2-(((1,4-二氧六环-2-基)甲基)硫基)-9-(环丙基乙炔基)-6,7-二氢-4H-嘧啶并[6,1-a]异喹啉-4-酮(化合物I-7)。
LC-MS,M/Z(ESI):395.2[M+H] +。
在本发明的测试例中，对照化合物的制备参考专利WO 2013/092791Al中化合物122的制备方法，其结构如下：
Figure PCTCN2022086783-appb-000038
测试例1：GPR84拮抗作用测定实验
测试化合物I-1对GPR84拮抗作用，测定在高表达人源GPR84受体的CHO稳转细胞株中进行。稳转细胞培养至80％融合度；胰酶消化处理收集细胞，经计数后按2000个细胞每孔接种于384孔板中。用1×Stimulation Buffer制备10×化合物工作液，取1μL 10×的化合物加入至相应实验孔中,离心后放置于37℃孵育20min；然后加入4μL 2.5μM Forskolin&200nM 6-OAU溶液，离心后放置于37℃孵育30min。反应完成后，根据cAMP测试试剂盒(Perkin Elmer,Cat#TRF0263)说明书中的方法对细胞中的cAMP的含量进行定量。计算测试化合物的拮抗作用(IC 50值)。
表1 测试化合物对GPR84的拮抗作用
测试化合物 IC 50(nM)
对照化合物 76.46
I-1 28.39
I-3 4959
I-4 189.2
I-6 299.3
结果表明：本发明化合物具有较强的GPR84拮抗作用。
测试例2：药代动力学实验
在本实验中，分别在小鼠和大鼠个体上测试化合物I-1的药代动力学参数。
小鼠药代动力学实验，使用雄性ICR小鼠，20-25g，禁食过夜。取3只小鼠，口服灌胃给药3mg/kg，在给药前和在给药后15、30分钟以及1、2、4、8、24小时采血。血液样品6800g，2-8℃离 心6分钟，收集血浆，于-80℃保存。取各时间点血浆，加入3-5倍量含内标的乙腈溶液混合，涡旋混合1分钟，13000转/分钟4℃离心10分钟，取上清液加入3倍量水混合，取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。
大鼠药代动力学实验，使用雄性SD大鼠，180-240g，禁食过夜。取3只SD大鼠，口服灌胃给药2.5mg/kg，其余操作同小鼠药代动力学试验。
表2 小鼠药代动力学试验结果
Figure PCTCN2022086783-appb-000039
表3 大鼠药代动力学试验结果
Figure PCTCN2022086783-appb-000040
结果表明：本发明化合物在小鼠和大鼠上口服暴露量更高，成药性好。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (14)

  1. 式I所示二氢嘧啶并异喹啉酮类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：
    Figure PCTCN2022086783-appb-100001
    其中，L 1为-NH-、-N(C 1-C 5烷基)-或-S-；
    V为不存在或为-O-；
    L 2不存在或L 2为C 1-C 5亚烷基、具有一个双键的C 2-C 4亚烯基或具有一个三键的C 2-C 4亚炔基；
    R 2为选自下列的取代基：C 1-C 5烷基、3-10元环烷基、4-10元杂环烷基或5-10元杂芳基；
    所述C 1-C 5烷基、3-10元环烷基、4-10元杂环烷基或5-10元杂芳基任选地被一个或多个R 21取代；所述R 21为选自下列的取代基：羟基、氰基、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；当取代基为多个时，所述R 21为相同或不同的取代基；
    R 3、R 4、R 5、R 6、R 7、R 8分别独立地为氢、卤素或C 1-C 5烷基；所述C 1-C 5烷基任选地被R 31取代；所述R 31为选自下列的取代基：卤素、羟基、氨基、C 1-C 3烷氧基、C 1-C 3烷基氨基；
    或者，R 3、R 4、R 5、R 6分别独立地为氢、卤素、C 1-C 5烷基或C 1-C 5卤代烷基；R 7、R 8与它们共同连接的C原子一起形成3-6元环烷基或4-6元杂环烷基。
  2. 如权利要求1所述的式I所示二氢嘧啶并异喹啉酮类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，L 1为-NH-或-N(CH 3)-，
    V为不存在，
    L 2为C 1-C 5亚烷基、具有一个双键的C 2-C 4亚烯基或具有一个三键的C 2-C 4亚炔基；
    较佳地，L 1为-NH-；
    较佳地，L 2为-CH 2-、-CH 2CH 2-或-C≡C-，更佳地，L 2为-C≡C-。
  3. 如权利要求1所述的式I所示二氢嘧啶并异喹啉酮类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，R 2为C 1-C 5烷基、3-6元环烷基或5-6元杂芳基；
    其中，所述C 1-C 5烷基任选地被一个或多个卤素取代；所述3-6元环烷基任选地被一个或多个选自下列的取代基取代：卤素、C 1-C 5烷基、C 1-C 5卤代烷基；所述5-6元杂芳基含有1、2或3个选自N 或O的杂原子；当杂原子为多个时，所述杂原子相同或不同；
    较佳地，R 2为环丙基、-CF 3或
    Figure PCTCN2022086783-appb-100002
    较佳地，所述的式I所示的化合物中，所有原子的同位素丰度与其自然丰度相同。
  4. 如权利要求1所述的式I所示二氢嘧啶并异喹啉酮类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，V为不存在，-V-L 2-R 2为
    Figure PCTCN2022086783-appb-100003
  5. 如权利要求1所述的式I所示二氢嘧啶并异喹啉酮类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，R 3、R 4、R 5、R 6、R 7、R 8分别独立地为氢、卤素、C 1-C 5烷基或C 1-C 5卤代烷基；
    较佳地，R 3、R 4、R 5、R 6、R 7、R 8为氢。
  6. 如权利要求1所述的式I所示二氢嘧啶并异喹啉酮类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述的如式I所示二氢嘧啶并异喹啉酮类衍生物为如式Ia所示的化合物或如式Ib所示的化合物；
    Figure PCTCN2022086783-appb-100004
  7. 如权利要求1所述的式I所示二氢嘧啶并异喹啉酮类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述二氢嘧啶并异喹啉酮类衍生物包括：
    Figure PCTCN2022086783-appb-100005
    Figure PCTCN2022086783-appb-100006
  8. 一种药物组合物，其特征在于，所述药物组合物包括：如权利要求1-7中任一所述的式I所示二氢嘧啶并异喹啉酮类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药；和药学上可接受的载体。
  9. 一种药物组合物，其特征在于，所述药物组合物包括：如权利要求1-7中任一所述的式I所示二氢嘧啶并异喹啉酮类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药；和至少一种其他药理学活性拮抗剂和/或抑制剂。
  10. 一种如权利要求1-7中任一所述的式I所示二氢嘧啶并异喹啉酮类衍生物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药的用途，或如权利要求8或9所述的药物组合物的用途，所述用途包括：
    作为GPR84拮抗剂；
    和/或，预防和/或治疗GPR84相关的疾病；
    和/或，制备作为GPR84拮抗剂，和/或预防和/或治疗GPR84相关的疾病的药物、药物组合物或制剂。
  11. 如权利要求10所述的用途，其特征在于，所述GPR84相关的疾病包括：器官纤维化疾病、炎性疾病、肺病、神经炎性疾病、感染性疾病、自身免疫性疾病、内分泌、代谢性疾病、或与免疫功能受损相关的疾病；
    较佳地，所述肺病包括慢性阻塞性肺病和肺间质疾病；
    较佳地，所述肺间质疾病包括先天性肺纤维化；
    较佳地，所述炎性疾病包括血管炎、炎症性肠病；
    较佳地，所述自身免疫性疾病包括类风湿性关节炎；
    较佳地，所述器官纤维化疾病包括消化器官、呼吸器官、循环器官、泌尿生殖器官、运动器官、脑神经系统、内分泌器官、或皮肤的纤维化疾病；较佳地包括肝纤维化、肺纤维化、肾纤维化、心纤维化；
    较佳地，所述肺纤维化包括特发性肺纤维化、先天性肺纤维化。
  12. 一种如权利要求1-7中任一项所述的式I所示二氢嘧啶并异喹啉酮类衍生物的制备方法，所述制备方法为如下方案一或方案二：
    方案一包括下述步骤：在有机溶剂中，在钯催化剂、CuI和碱的存在下，将式II所示的化合物与 环丙乙炔进行如下所示的偶联反应，得到所述的式I所示的二氢嘧啶并异喹啉酮类衍生物；
    Figure PCTCN2022086783-appb-100007
    方案二包括下述步骤：在有机溶剂中，在碱存在下，将式II所示的化合物与式IV所示的化合物进行如下所示的取代反应，得到所述的如式式I所示二氢嘧啶并异喹啉酮类衍生物；
    Figure PCTCN2022086783-appb-100008
    其中，X为羟基、-OTf、-OTs或-OMs，Y为卤素；
    例如，当X为羟基时，所述的式II所示的化合物的制备方法包括如下步骤：在有机溶剂中，在钯催化剂和碱存在下，将式III所示的化合物进行如下所示的反应，得到所述的式II所示的化合物即可；
    Figure PCTCN2022086783-appb-100009
  13. 一种式II所示的化合物或式III所示的化合物，
    Figure PCTCN2022086783-appb-100010
    其中，X为羟基、-OTf、-OTs或-OMs，L 1、R 3、R 4、R 5、R 6、R 7和R 8的定义如权利要求1所述；
    例如，所述式II所示的化合物为式IIa所示的化合物或式IIb所示的化合物；
    Figure PCTCN2022086783-appb-100011
    又例如，所述式III所示的化合物为式IIIa所示的化合物或式IIIb所示的化合物；
    Figure PCTCN2022086783-appb-100012
  14. 如权利要求13所述的化合物，其特征在于，所述式II所示的化合物为：
    Figure PCTCN2022086783-appb-100013
    Figure PCTCN2022086783-appb-100014
    所述式III所示的化合物为：
    Figure PCTCN2022086783-appb-100015
    Figure PCTCN2022086783-appb-100016
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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 (en) * 2014-06-25 2015-12-30 Galapagos Nv Novel dihydropyridoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
CN107531703A (zh) * 2015-04-23 2018-01-02 加拉帕戈斯股份有限公司 用于治疗炎症性疾病的新二氢吡啶并异喹啉酮类及其药物组合物
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

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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)
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