WO2022194267A1 - Gpr84 antagonist, and preparation method therefor and use thereof - Google Patents

Abstract

A GPR84 antagonist, and a preparation method therefor and a use thereof, specifically a compound represented by formula (I), and a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof. The compound represented by formula (I) has obvious GPR84 antagonism function, good druggability, and high safety, wherein R1 is a ring Cy optionally substituted by one or more R11, R2 is a substituent selected from C1-C5 alkyl, 3-10-membered cycloalkyl, 4-10-membered heterocycloalkyl, or 5-10-membered heteroaryl, and the definitions of R3, R4, R5, R6, L1, L2, L3 are as described in the description.

Description

A kind of GPR84 antagonist and preparation method and use thereof

This application claims the priority of Chinese patent application 2021102926974 with the filing date of 2021/3/18. This application cites the full text of the above Chinese patent application.

technical field

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.

Background technique

G protein-coupled receptor 84 (GPR84) 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. In addition to the endogenous ligand medium-chain fatty acids, researchers also found some more active exogenous agonists such as diindolylmethane (DIM), 6-n-octylaminouracil (6-OAU), Beric acid (embelin) and so on.

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. Studies have shown that the exogenous agonist 6-OAU leads to chemotactic responses by activating GPR84, upregulating AKT, ERK and nuclear factor kappa B (NFκB) signaling pathways, causing inflammatory mediators TNFα, IL-6, IL-12B, CCL2, CCL5 and The increased expression level of CXCL1 enhances the release of cytokines (IL-8, IL-12) and tumor necrosis factor alpha (TNF-α), thereby amplifying the inflammatory response of macrophages at the site of inflammation, aggravating the occurrence of inflammation, and triggering a variety of Inflammatory diseases (Carlota Recio et al, 2018).

Studies have shown that under fibrotic conditions, higher levels of GPR84 mRNA expression are observed in fibroblasts, podocytes, proximal tubule epithelial cells, and macrophages (Gagnon et al, 2018; Grouix et al, 2018; Li et al. al, 2018). In an idiopathic pulmonary fibrosis model, GPR84 antagonists (oral, 30 mg/kg twice daily) for 2 consecutive weeks greatly reduced Ashcroft scores from day 7 (Edward Jenner, 2020). In a mouse model of endotoxemia, upregulation of GPR84 mRNA expression was observed during acute inflammation. In addition, upregulation of GPR84 expression 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. Earlier studies reported that 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). 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. Higher levels of GPR84 mRNA expression have 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 (IPF) 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. In addition, adverse effects of these therapies included diarrhea, abnormal liver function tests after taking Inetedanib, nausea and rash due to pirfenidone. Therefore, there is still a large unmet medical need, IPF remains a major cause of morbidity and mortality, and effective treatments are greatly needed.

SUMMARY OF THE INVENTION

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.

In the first aspect of the present invention, there is provided a compound shown in formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:

in,

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;

Alternatively, 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;

Alternatively 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.

In a preferred embodiment of the present invention, 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.

In a preferred embodiment of the present invention, 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.

In a preferred embodiment of the present invention, 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;

Preferably, L ₁ is -O-.

In a preferred embodiment of the present invention, 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 ;

Alternatively, 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.

In a preferred embodiment of the present invention, 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.

In a preferred embodiment of the present invention, R ₁ is a ring Cy optionally substituted with 1 or 2 R ₁₁ ;

较佳地，所述环Cy为

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)

Heteroaryl; preferably, 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.

所述R ₁₁为羟基、卤素、C ₁-C ₄烷基、C ₁-C ₄卤代烷基、C ₁-C ₄烷氧基；较佳地，R ₁₁为卤素、C ₁-C ₄烷基；更佳地，R ₁₁为氟、氯、甲基、乙基或丙基；当取代基为多个时，R ₁₁相同或不同。 In a preferred embodiment of the present invention, 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.

其中，R ₁₁为氟、氯、甲基、乙基或丙基；较佳地，R ₁₁为甲基。 In a preferred embodiment of the present invention, R ₁ is a substituent selected from the following:

Wherein, R ₁₁ is fluorine, chlorine, methyl, ethyl or propyl; preferably, R ₁₁ is methyl.

In a preferred embodiment of the present invention, L ₃ does not exist or L ₃ is -CH ₂ -, -CH=CH- or -C≡C-; preferably, L ₃ does not exist or L ₃ is -C≡C -.

In a preferred embodiment of the present invention, 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.

In a preferred embodiment of the present invention, 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;

Preferably, R ₂ is a substituent selected from the group consisting of methyl,

In a preferred embodiment of the present invention, -L ₃ -R ₂ is a substituent selected from the following:

In a preferred embodiment of the present invention, 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.

In a preferred embodiment of the present invention, 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;

Preferably, R ₄ and R ₅ together with the C atom to which they are connected together form a 4-6 membered cycloalkyl;

Preferably, 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.

In a preferred embodiment of the present invention, R ₃ and R ₆ are hydrogen.

In a preferred embodiment of the present invention, the compound shown in the formula I includes:

In a second aspect of the present invention, there is provided an intermediate B having the structure

Wherein, the definitions of 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.

In a preferred embodiment of the present invention, in the intermediate B, 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;

Alternatively, 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;

Alternatively 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.

In a preferred embodiment of the present invention, 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.

In a preferred embodiment of the present invention, 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-.

In a preferred embodiment of the present invention, 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 ;

Alternatively, 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.

In a preferred embodiment of the present invention, 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;

Preferably, 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.

In a preferred embodiment of the present invention, 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 ;

更佳地，所述环Cy为

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)

Heteroaryl; preferably, 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 ₁₁为羟基、卤素、C ₁-C ₄烷基、C ₁-C ₄卤代烷基、C ₁-C ₄烷氧基；较佳地，R ₁₁为卤素、C ₁-C ₄烷基；更佳地，R ₁₁为氟、氯、甲基、乙基或丙基；当取代基为多个时，R ₁₁相同或不同。 In a preferred embodiment of the present invention, R ₁ is a group optionally substituted with 1, 2 or 3 R ₁₁

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.

其中，R ₁₁为氟、氯、甲基、乙基或丙基；较佳地，R ₁₁为甲基。 In a preferred embodiment of the present invention, R ₁ is a substituent selected from the following:

Wherein, R ₁₁ is fluorine, chlorine, methyl, ethyl or propyl; preferably, R ₁₁ is methyl.

In a preferred embodiment of the present invention, 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.

In a preferred embodiment of the present invention, the intermediate B comprises:

In the third aspect of the present invention, there is provided 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.

In a preferred embodiment of the present invention, the method further includes:

2) the intermediate B is reacted with the compound HL ₃ -R ₂ in the presence of a catalyst; and/or

3) The intermediate B reacts with the compound HL ₃ -R ₂ under the protection of an inert gas; and/or

4) The intermediate B is reacted with compound HL ₃ -R ₂ under basic conditions;

Preferably, the catalyst is a palladium catalyst and/or a copper catalyst;

Preferably, 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 ;

Preferably, the copper catalyst is a monovalent copper catalyst; more preferably, the copper catalyst is CuI;

Preferably, the inert gas is nitrogen, helium, neon or argon.

In a preferred embodiment of the present invention, in the compound HL ₃ -R ₂ , 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. C ₂ -C ₄ alkynylene with 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.

In a preferred embodiment of the present invention, 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.

In a preferred embodiment of the present invention, in compound HL ₃ -R ₂ , L ₃ does not exist or L ₃ is -CH ₂ -, -CH=CH- or -C≡C-; preferably, L ₃ does not exist Or L ₃ is -C≡C-.

In a preferred embodiment of the present invention, in compound HL ₃ -R ₂ , 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.

In a preferred embodiment of the present invention, in compound HL ₃ -R ₂ , 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;

Preferably, R ₂ is a substituent selected from the group consisting of methyl,

In a preferred embodiment of the present invention, in the compound HL ₃ -R ₂ , -L ₃ -R ₂ is a substituent selected from the following:

In a preferred embodiment of the present invention, in the above preparation method, according to the difference of each group in the compound, different reaction conditions and intermediates can be selected according to the embodiment of the present invention, when there is an active group in the substituent (eg carboxyl group, amino group, hydroxyl group, etc.), the active group can be protected by a protective group as required before participating in the reaction, and after the reaction is completed, the protective group can be deprotected. Those compounds in which one or more reactive sites are blocked by one or more protecting groups (also referred to as protecting groups) are "protected derivatives" of compounds of formula I described herein. For example, suitable protecting groups for the carboxy moiety include benzyl, t-butyl, 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.

In a preferred embodiment of the present invention, in the above preparation method, 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.

In the fourth aspect of the present invention, a pharmaceutical composition is provided, the pharmaceutical composition comprises: 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.

In addition, a pharmaceutical composition is provided, 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;

Preferably, the other pharmacologically active antagonists are GPR84 antagonists;

Preferably, the other pharmacologically active inhibitor is a GPR84 inhibitor.

In the fifth aspect of the present invention, there is provided 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:

as a GPR84 antagonist;

and/or, prevention and/or treatment of GPR84-related diseases;

And/or, preparing medicines, pharmaceutical compositions or preparations as GPR84 antagonists, and/or preventing and/or treating GPR84-related diseases.

In a preferred embodiment of the present invention, 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.

In a preferred embodiment of the present invention, 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.

Further, 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).

More specifically, 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.

Additional aspects and advantages of the present invention will be set forth, in part, from the following description, and in part will be apparent from the following description, or may be learned by practice of the invention.

Terms and Definitions

Unless otherwise stated, definitions of groups and terms set forth in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions set forth in tables, and definitions of specific compounds in the examples etc., can be arbitrarily combined and combined with each other. Such combinations, group definitions and compound structures after the combination should fall within the scope described in the specification of the present application.

Unless otherwise defined, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, publications cited throughout this document are incorporated by reference in their entirety unless otherwise indicated. If there are multiple definitions of terms in this document, the definitions in this chapter shall prevail.

It is to be understood that both the foregoing brief description and the following detailed description are exemplary and explanatory only and do not limit the subject matter of the invention in any way. In this application, the use of the singular also includes the plural unless specifically stated otherwise. It must be noted that the singular forms used in this specification and the claims include the plural forms of referents unless the context clearly dictates otherwise. It should also be noted that the use of "or" and "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "including" and other forms such as "comprising", "including" and "comprising" is not intended to be limiting.

Definitions of standard chemical terms can be found in references including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4THED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise stated, conventional methods within the skill in the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy and pharmacological methods are employed. Unless specific definitions are presented, the terms employed herein in the related descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and treatment of patients. For example, the 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. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds.

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。 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 . As used herein,

Indicates the attachment site of the group. As used herein, " _R1 ", "R1" and " ^R1 " have the same meaning and are interchangeable. For other symbols such as R ₂ , similar definitions have the same meaning.

Section headings used herein are for the purpose of organizing the article only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are hereby incorporated by reference in their entirety.

In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings shown below unless specifically indicated otherwise.

The numerical range described in the specification and claims of the present application, when the numerical range is understood as an "integer", should be understood as describing the two endpoints of the range and each integer in the range. For example, "an integer of 0 to 5" should be understood as reciting each integer of 0, 1, 2, 3, 4, and 5.

In this application, the term "halogen", alone or as part of other substituents, refers to fluorine, chlorine, bromine, iodine.

As used herein, alone or as part of other substituents, the term "amino" means -NH2.

As used herein, alone or as part of other substituents, the term "nitro" means -NO2.

As used herein, alone or as part of other substituents, the term "cyano" means -CN.

As used herein, the term "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. Examples of 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). As used herein, the term "alkenyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds. As used herein, the term "alkynyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.

The term " _C1 - _C5 alkyl", alone or as part of other substituents, 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, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers. The term "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. In particular, the groups have 1, 2 or ₃ carbon atoms (" _C1 -C3 alkyl"), such as methyl, ethyl, n-propyl or isopropyl.

As used herein, alone or as part of other substituents, the term "alkylene" refers to a saturated divalent hydrocarbyl group obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbyl group. Examples of 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.

The term " _{C1 -} C6alkoxy", alone or as part of other substituents, 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-).

The term "cycloalkyl" or "carbocyclyl", alone or as part of other substituents, refers to a cyclic alkyl group. The term "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. For example, "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. Examples of 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. In some embodiments, a cycloalkyl group can be a cycloalkyl group fused to an aryl or heteroaryl group.

The term "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. The term "mn-membered heterocycloalkyl" or " _Cm - _{Cnheterocycloalkyl} " is understood to mean a saturated, unsaturated or partially saturated ring having m to n atoms. For example, the term "4-10 membered heterocycloalkyl" is understood to mean a saturated, unsaturated or partially saturated ring having 4 to 10 atoms. In some embodiments, a heterocycloalkyl group can be a heterocycloalkyl group fused to an aryl or heteroaryl group. When a prefix such as 3-8 membered is used to denote a heterocycloalkyl, the number of carbons is also meant to include the heteroatom. Includes monocyclic, bicyclic, tricyclic, spirocyclic or bridged rings.

The term "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 In the scheme, 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.

The term "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 . Examples of heteroaryl groups include, but are not limited to: thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl , thiadiazolyl, etc. and their benzo derivatives, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indium oxazolyl, indolyl, isoindolyl, etc; , isoquinolinyl, etc.; or azine, indolizinyl, purinyl, etc. and their benzo derivatives; , pteridyl, carbazolyl, acridine, phenazinyl, phenothiazinyl, phenoxazinyl, etc.

The term "halo" is used interchangeably with the term "halo-substituted" alone or as part of other substituents. "Haloalkyl" or "halogen-substituted alkyl" is meant to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens (eg -CvFw, where v = 1 to 3 , w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

The term "spirocycle", alone or as part of other substituents, 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. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups. Non-limiting examples of spirocycloalkyl include:

Also included are spirocycloalkyl groups in which a monospirocycloalkyl group shares a spiro atom with a heterocycloalkyl group, non-limiting examples include:

The term "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:

The term "C2 _{- C4alkenyl} ", alone or as part of other substituents, 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.

The term "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. The alkenylene group is for example -CH=CH-, _-CH2 -CH=CH-, -CH2- _CH2 -CH=CH-, _-CH2 - _CH = _CH -CH2- or -CH=CH -CH=CH2- and so _on .

The term "C2 _{- C4alkynyl} ", alone or as part of other substituents, 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.

The term "C2 _{- C4alkynylene} ", alone or as part of other substituents, 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.

The term "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.

Compounds provided herein, including intermediates useful in the preparation of compounds provided herein, which contain reactive functional groups (such as, but not limited to, carboxyl, hydroxyl, and amino moieties), also include protected derivatives 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.

In this application, "optional" 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. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups.

In this application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "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. In addition to the pharmaceutically acceptable salts, 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.

The term "stereoisomer" refers to isomers resulting from different arrangements of atoms in a molecule in space, and includes cis-trans isomers, enantiomers, diastereomers and conformers.

Depending on the choice of starting materials and methods, 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. A mixture of enantiomers, depending on the number of asymmetric carbon atoms. When describing an optically active compound, 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.

When the bond to the chiral carbon in the formula of the present invention is depicted in line, it should be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and Mixtures of both are included within the scope of this formula. A schematic representation of racemate or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. The absolute configuration of a stereocenter is represented by wedge and dashed bonds.

The term "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. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form predominates; in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

As used herein, 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.

In this application, "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.

In this application, the term "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.

In this application, the term "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. For example, 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.

In this application, the term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of 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.

As used herein, the term "treatment" and other similar synonyms include the following meanings:

(i) preventing the emergence of a disease or disorder in mammals, particularly when such mammals are susceptible to, but have not been diagnosed with, the disease or disorder;

(ii) inhibiting the disease or disorder, i.e. arresting its development;

(iii) alleviating the disease or disorder, i.e. causing the state of the disease or disorder to resolve; or

(iv) alleviating symptoms caused by the disease or disorder.

In the reaction of each step, the reaction temperature can be appropriately selected according to the solvent, starting materials, reagents, etc., and the reaction time can also be appropriately selected according to the reaction temperature, solvent, starting materials, reagents, and the like. After the reaction of each step, 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.

beneficial effect

After extensive and in-depth research, 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. Examples of such 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.

On the other hand, 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.

Detailed ways

The present invention will be further described below in conjunction with specific embodiments. It should be understood that the following descriptions are only the most preferred embodiments of the present invention, and should not be considered as limiting the protection scope of the present invention. On the basis of fully understanding the present invention, in the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions suggested by the manufacturer, those skilled in the art can make non-essential technical solutions of the present invention. Modifications, such modifications should be deemed to be included in the protection scope of the present invention.

This application has the following definitions:

Symbol or unit:

IC ₅₀ : half inhibitory concentration, refers to the concentration at which half of the maximum inhibitory effect is achieved

M: mol/L, for example n-butyllithium (14.56mL, 29.1mmol, 2.5M n-hexane solution) represents a n-butyl lithium solution with a molar concentration of 2.5mol/L in n-hexane

N: equivalent concentration, for example, 2N hydrochloric acid means 2mol/L hydrochloric acid solution

Reagents:

DCM: dichloromethane

DIPEA: can also be written as DIEA, diisopropylethylamine, that is, N,N-diisopropylethylamine

DMF: N,N-Dimethylformamide

DMSO: Dimethyl Sulfoxide

EA: Ethyl acetate

Et ₃ N: triethylamine

MeOH: methanol

PE: petroleum ether

THF: Tetrahydrofuran

Example 1: Preparation of Compound I-1

(S)-9-(((1,4-dioxan-2-yl)methoxy)-2-(cyclopropylethynyl)-4,5-dihydro-7H-thieno[2 ',3':3,4]pyrido[1,2-c]pyrimidin-7-one

The synthetic route of compound I-1 is as follows:

The first step: Synthesis of 2-(5-bromothiophen-3-yl)acetonitrile (B1-2)

In a 500 mL three-necked flask, p-methylbenzenesulfonylmethylisonitrile (TosMIC, 20.4 g, 105 mmol) and tetrahydrofuran (50 mL) were added under nitrogen protection. The temperature was lowered to -20°C, a solution of potassium tert-butoxide in tetrahydrofuran (209 mmol, 1 M) was added dropwise, and the mixture was stirred for 1 hour. 5-Bromothiophene-3-carbaldehyde (B1-1) (10.0 g, 52.3 mmol) was slowly added dropwise, and the mixture was stirred for two hours after the dropwise addition. Spot plate detection, after the raw materials completely disappeared, methanol (50 mL) was added dropwise, and the mixture was refluxed at 80° C. for two hours. The reaction mixture was concentrated to dryness, acetic acid (2 mL) was added dropwise, then extracted with ethyl acetate (100 mL×2), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product . Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=50:1-10:1) gave 2-(5-bromothiophen-3-yl)acetonitrile (B1-2) (yellow oil, 4.5 g, 42.5% yield).

The second step: Synthesis of 2-(5-bromothiophen-3-yl)ethan-1-amine (B1-3)

2-(5-Bromothiophen-3-yl)acetonitrile (B1-2) (4.5g, 22.3mmol) was placed in a 500mL single-necked flask, anhydrous tetrahydrofuran (50mL) was added, and borane tetrahydrofuran was added dropwise under ice bath conditions Compound (66.8 mmol, 1 M) was added dropwise and stirred at room temperature overnight. Spot plate detection, after the reaction was completed, methanol (50 mL) was slowly added dropwise to quench the reaction. The dry solvent was concentrated to obtain crude 2-(5-bromothiophen-3-yl)ethan-1-amine (B1-3) (4.3 g), which was directly used in the next reaction.

The third step: synthesis of 1-(2-(5-bromothiophen-3-yl)ethyl)urea (B1-4)

Add 2-(5-bromothiophen-3-yl)ethan-1-amine (B1-3) (4.3g) and urea (1a) into a 100mL single-neck flask, add acetic acid (2mL), hydrochloric acid (1mL), 120 Reflux for 48 hours. Dot plate detection, after the raw materials were fully reacted, the reaction was cooled to room temperature, extracted with dichloromethane (100 mL×2), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain Crude 1-(2-(5-bromothiophen-3-yl)ethyl)urea (B1-4) (4.5 g). The crude product was directly put into the next reaction.

The fourth step: Synthesis of 1-(2-(5-bromothiophen-3-yl)ethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (B1-5)

Ethanol (50 mL) was placed in a reaction flask and sodium (1.19 g, 51.8 mmol) was added portionwise. After stirring at room temperature for half an hour, diethyl malonate (1b) (5.53 g, 34.5 mmol) was added, and the mixture was refluxed at 75°C for 1 hour. 1-(2-(5-Bromothiophen-3-yl)ethyl)urea (B1-4) (4.3 g) was slowly added and refluxed overnight. Dot plate detection, after the raw materials are completely reacted, add 1M dilute hydrochloric acid to quench the reaction, remove excess ethanol, extract with dichloromethane (100mL×2), combine the organic layers, wash the organic phase with saturated brine (50mL), anhydrous sulfuric acid Dry over sodium and concentrate to give crude 1-(2-(5-bromothiophen-3-yl)ethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (B1-5) (4.0 g) . The crude product was directly put into the next reaction.

Step 5: (2-Bromo-9-chloro-4,5-dihydro-7H-thieno[2',3':3,4]pyrido[1,2-c]pyrimidin-7-one ( Synthesis of B1-6)

1-(2-(5-Bromothiophen-3-yl)ethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (B1-5) (4g) and phosphorus oxychloride ( 10 mL) was placed in a single-necked bottle and refluxed at 50°C for 72 hours. Dot plate detection, after the raw materials are completely reacted, phosphorus oxychloride is removed. Water (100 mL) was added to dilute the reaction solution, and saturated sodium bicarbonate (5 mL) was added to adjust pH to 3. 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 (B1-6) (4.8g). The crude product was directly put into the next reaction.

The sixth step: (S)-9-((1,4-dioxan-2-yl)methoxy)-2-bromo-4,5-dihydro-7H-thieno[2',3 Synthesis of ':3,4]pyrido[1,2-c]pyrimidin-7-one (B1-7)

Sodium hydride (0.435 g, 10.9 mmol, 60% content) was suspended in anhydrous dichloromethane (10 mL) under nitrogen protection, and (R)-(1,4-dioxan-2-yl) was added dropwise Methanol (1c) (1.28 g, 10.9 mmol) was added dropwise and stirred at 0 °C for 30 minutes, then (2-bromo-9-chloro-4,5-dihydro-7H-thieno[2', 3':3,4]pyrido[1,2-c]pyrimidin-7-one (B1-6) (4.8g) was added to the reaction solution, and 10 minutes later, it was moved to room temperature for overnight reaction. Spot plate detection, When the raw materials were completely consumed, the reaction mixture was quenched with saturated ammonium chloride (20 mL), then extracted with dichloromethane (20 mL×2), the organic layers were combined, and the organic phase was washed with saturated brine (50 mL). Dry with sodium sulfate and concentrate to obtain crude product. Separation and purification with silica gel column (dichloromethane:methanol (V/V)=50:1-10:1) to obtain (S)-9-((1,4-dioxane) Cyclo-2-yl)methoxy)-2-bromo-4,5-dihydro-7H-thieno[2',3':3,4]pyrido[1,2-c]pyrimidine-7- Ketone (B1-7) (yellow oil, 400 mg).

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)

Pd(PPh ₃ ) ₂ Cl ₂ (10.55 mg, 0.015 mmol), CuI (11.45 mg, 0.06 mmol) were placed in a aliquot tube under nitrogen. (S)-9-((1,4-dioxan-2-yl)methoxy)-2-bromo-4,5-dihydro-7H-thieno[2',3':3 ,4]pyrido[1,2-c]pyrimidin-7-one (B1-7) (120 mg, 0.3 mmol), cyclopropethyne (99 mg, 1.5 mmol) and triethylamine (76 mg, 0.75 mmol) were dissolved in Anhydrous DMF was added to a sealed tube at 50°C and stirred overnight. Spot plate detection, after the raw materials are completely reacted. Remove DMF and concentrate to obtain crude product, which is separated and purified by silica gel column (dichloromethane:methanol (V/V)=50:1-10:1) to obtain compound (S)-9-((1,4-dioxane) -2-yl)methoxy)-2-(cyclopropynyl)-4,5-dihydro-7H-thieno[2',3':3,4]pyrido[1,2-c] Pyrimidine-7-one (Compound I-1) (pale yellow solid, 22 mg, 19% yield).

¹ H NMR (400MHz, DMSO-d6)δ7.14(s,1H), 6.06(s,1H), 4.22-4.12(m,2H), 4.02-3.95(m,2H), 3.81-3.74(m, 1H), 3.73–3.66 (m, 2H), 3.63–3.49 (m, 2H), 3.47–3.38 (m, 1H), 2.89 (t, J=6.9Hz, 2H), 1.97–1.85 (m, 1H) , 1.59 (ddd, J=13.3, 8.3, 5.0 Hz, 1H), 0.94–0.85 (m, 2H), 0.78–0.71 (m, 2H).

LC-MS, M/Z (ESI): 385.1 [M+H] ⁺ .

Example 2: Preparation of target compound I-2

Pd(PPh ₃ ) ₂ Cl ₂ (10.55 mg, 0.015 mmol), CuI (11.45 mg, 0.06 mmol) were placed in a aliquot tube under nitrogen. (S)-9-((1,4-dioxan-2-yl)methoxy)-2-bromo-4,5-dihydro-7H-thieno[2',3':3 ,4]pyrido[1,2-c]pyrimidin-7-one (B1-7) (120 mg, 0.3 mmol), 1-ethynyl-1-methylcyclopropane (120 mg, 1.5 mmol) and triethylamine (76 mg, 0.75 mmol) was dissolved in dry DMF, added to a sealed tube and stirred at 50°C overnight. Spot plate detection, after the raw materials are completely reacted, remove DMF, concentrate to obtain crude product, and use silica gel column separation and purification (dichloromethane: methanol (V/V) = 50: 1-10: 1) to obtain compound (S)-9- ((1,4-Dioxan-2-yl)methoxy)-2-((1-methylcyclopropyl)ethynyl)-4,5-dihydro-7H-thieno[2',3':3,4]pyrido[1,2-c]pyrimidin-7-one (Compound 1-2) (pale yellow solid, 22 mg, 18% yield).

¹ H NMR (400MHz, DMSO-d6)δ7.17(s,1H), 6.10(s,1H), 4.25–4.15(m,2H), 4.10–4.00(m,2H), 3.85–3.78(m, 1H), 3.77–3.69 (m, 2H), 3.67–3.59 (m, 2H), 3.57–3.53 (m, 1H), 3.50–3.45 (m, 1H), 2.92 (t, J=6.9Hz, 2H) ,1.30(s,3H),0.88–0.73(m,4H).

LC-MS, M/Z (ESI): 399.2 [M+H] ⁺ .

Example 3: Preparation of Compound 1-3

Pd(PPh ₃ ) ₂ Cl ₂ (10.55 mg, 0.015 mmol), CuI (11.45 mg, 0.06 mmol) were placed in a aliquot tube under nitrogen. (S)-9-((1,4-dioxan-2-yl)methoxy)-2-bromo-4,5-dihydro-7H-thieno[2',3':3 ,4]pyrido[1,2-c]pyrimidin-7-one (B1-7) (120 mg, 0.3 mmol), 3-ethynyl-3-methyloxetane (144.1 mg, 1.5 mmol) and triethylamine (76 mg, 0.75 mmol) were dissolved in anhydrous DMF, added to a sealed tube and stirred at 50°C overnight. Spot plate detection, after the raw materials are completely reacted, remove DMF, concentrate to obtain crude product, and use silica gel column separation and purification (dichloromethane: methanol (V/V) = 50: 1-10: 1) to obtain compound (S)-9- ((1,4-Dioxan-2-yl)methoxy)-2-((3-methyloxetan-3-yl)ethynyl)-4,5-dihydro-7H - Thieno[2',3':3,4]pyrido[1,2-c]pyrimidin-7-one (Compound 1-3) (white solid, 22 mg, 17% yield).

¹ H NMR(400MHz,DMSO-d6)δ7.26(s,1H),6.13(s,1H),4.70(d,J=5.6Hz,2H),4.41(d,J=5.6Hz,2H), 4.26–4.14 (m, 2H), 4.04 (t, J=6.9Hz, 2H), 3.83–3.67 (m, 3H), 3.60–3.51 (m, 2H), 3.48–3.40 (m, 1H), 2.93 ( t, J=6.9Hz, 2H), 2.00–1.91(m, 1H), 1.60(s, 3H).

LC-MS, M/Z (ESI): 415.1 [M+H] ⁺ .

Example 4: Preparation of Compound 1-4

Pd(PPh ₃ ) ₂ Cl ₂ (10.55 mg, 0.015 mmol), CuI (11.45 mg, 0.06 mmol) were placed in a aliquot tube under nitrogen. (S)-9-((1,4-dioxan-2-yl)methoxy)-2-bromo-4,5-dihydro-7H-thieno[2',3':3 ,4]pyrido[1,2-c]pyrimidin-7-one (B1-7) (120 mg, 0.3 mmol), propyne (6.0 mg, 1.5 mmol) and triethylamine (76 mg, 0.75 mmol) were dissolved in Anhydrous DMF was added to a sealed tube at 50°C and stirred overnight. Spot plate detection, after the raw materials are completely reacted. Remove DMF and concentrate to obtain crude product, which is separated and purified by silica gel column (dichloromethane:methanol (V/V)=50:1-10:1) to obtain compound (S)-9-((1,4-dioxane) -2-yl)methoxy)-2-(prop-1-yn-1-yl)-4,5-dihydro-7H-thieno[2',3':3,4]pyrido[1 ,2-c]pyrimidin-7-one (Compound 1-4) (white solid, 30 mg, 28% yield).

¹ H NMR (400MHz, DMSO-d6)δ7.20(s,1H),6.11(s,1H),4.24-4.16(m,2H),4.05(t,J=6.9Hz,2H),3.84-3.77 (m, 1H), 3.77–3.70 (m, 2H), 3.66–3.59 (m, 1H), 3.58–3.53 (m, 1H), 3.43–3.30 (m, 1H), 2.94 (t, J=6.9Hz) , 2H), 2.11(s, 3H), 2.01–1.92(m, 1H).

LC-MS, M/Z (ESI): 359.1 [M+H] ⁺ .

Example 5: Preparation of Compound 1-5

Pd(PPh ₃ ) ₂ Cl ₂ (10.55 mg, 0.015 mmol), CuI (11.45 mg, 0.06 mmol) were placed in a aliquot tube under nitrogen. (S)-9-((1,4-dioxan-2-yl)methoxy)-2-bromo-4,5-dihydro-7H-thieno[2',3':3 ,4]pyrido[1,2-c]pyrimidin-7-one (B1-7) (120 mg, 0.3 mmol), 2-methyl-3-butyn-2-ol (126 mg, 1.5 mmol) and tris Ethylamine (76 mg, 0.75 mmol) was dissolved in dry DMF, added to a sealed tube and stirred at 50°C overnight. Spot plate detection, after the raw materials are completely reacted, remove DMF, concentrate to obtain crude product, and use silica gel column separation and purification (dichloromethane: methanol (V/V) = 50: 1-10: 1) to obtain compound (S)-9- ((1,4-Dioxan-2-yl)methoxy)-2-(3-hydroxy-3-methylbut-1-yn-1-yl)-4,5-dihydro-7H - Thieno[2',3':3,4]pyrido[1,2-c]pyrimidin-7-one (Compound 1-5) (white solid, 35 mg, 29% yield).

¹ H NMR(400MHz,DMSO-d6)δ7.24(s,1H),6.15(s,1H),5.65(s,1H),4.23-4.16(m,1H),4.05(t,J=6.9Hz ,2H),3.85–3.78(m,1H),3.77–3.68(m,2H),3.66–3.52(m,3H),3.51–3.42(m,1H),2.94(t,J=6.9Hz,2H ), 2.01–1.93 (m, 1H), 1.44 (s, 6H).

LC-MS, M/Z (ESI): 403.1 [M+H] ⁺ .

Example 6: Preparation of Compound 1-6

Pd(OAc) ₂ (10.68 mg, 0.048 mmol), n-butylbis(1-adamantyl)phosphine (cataCXiumA, 34.1 mg, 0.95 mmol) was placed in a septum under nitrogen. (S)-9-((1,4-dioxan-2-yl)methoxy)-2-bromo-4,5-dihydro-7H-thieno[2',3':3 ,4]pyrido[1,2-c]pyrimidin-7-one (B1-7) (190 mg, 0.47 mmol), cyclopropylboronic acid (205 mg, 2.4 mmol) and cesium carbonate (465 mg, 1.43 mmol) were dissolved in Anhydrous toluene was added to a sealed tube and stirred at 110°C overnight. Spot plate detection, after the raw materials are completely reacted, remove toluene, concentrate to obtain crude product, and use silica gel column separation and purification (dichloromethane: methanol (V/V) = 50: 1-10: 1) to obtain compound (S)-9- ((1,4-Dioxan-2-yl)methoxy)-2-cyclopropyl-4,5-dihydro-7H-thieno[2',3':3,4]pyrido [1,2-c]pyrimidin-7-one (Compound 1-6) (white solid, 40 mg, 23% yield).

¹ H NMR (400MHz, DMSO-d6)δ6.78(s,1H), 5.88(s,1H), 4.23–4.07(m,2H), 4.02–3.93(m,2H), 3.80–3.66(m, 3H), 3.64–3.47 (m, 2H), 3.46–3.38 (m, 1H), 2.84 (t, J=6.9Hz, 2H), 2.15 (ddd, J=13.2, 8.4, 5.0Hz, 1H), 2.00 –1.82(m,1H),1.10–0.95(m,2H),0.76–0.61(m,2H).

LC-MS, M/Z (ESI): 361.1 [M+H] ⁺ .

Example 7: Preparation of Compound 1-7

Pd(PPh ₃ ) ₂ Cl ₂ (10.55 mg, 0.015 mmol), CuI (11.45 mg, 0.06 mmol) were placed in a aliquot tube under nitrogen. (S)-9-((1,4-dioxan-2-yl)methoxy)-2-bromo-4,5-dihydro-7H-thieno[2',3':3 ,4]pyrido[1,2-c]pyrimidin-7-one (B1-7) (120 mg, 0.3 mmol), cyclobutylacetylene (120 mg, 1.5 mmol) and triethylamine (76 mg, 0.75 mmol) were dissolved in In anhydrous DMF, it was added to a sealed tube at 50°C and stirred overnight. Spot plate detection, after the raw materials are completely reacted. Remove DMF and concentrate to obtain crude product, which is separated and purified by silica gel column (dichloromethane:methanol (V/V)=50:1-10:1) to obtain compound (S)-9-((1,4-dioxane) -2-yl)methoxy)-2-(cyclobutylethynyl)-4,5-dihydro-7H-thieno[2',3':3,4]pyrido[1,2-c ]pyrimidin-7-one (Compound 1-7) (white solid, 5 mg, 4.2% yield).

¹ H NMR (400MHz, DMSO-d6)δ7.20(s,1H),6.11(s,1H),4.30-4.16(m,2H),4.05(t,J=6.9Hz,2H),3.85-3.69 (m, 3H), 3.66–3.54 (m, 2H), 3.50–3.40 (m, 1H), 3.40–3.38 (m, 1H), 2.93 (t, J=6.9Hz, 2H), 2.37–2.23 (m ,2H),2.21–2.06(m,2H),2.04–1.76(m,3H).

LC-MS, M/Z (ESI): 399.1 [M+H] ⁺ .

Example 8: Preparation of Compound 1-8

Pd(PPh ₃ ) ₂ Cl ₂ (10.55 mg, 0.015 mmol), CuI (11.45 mg, 0.06 mmol) were placed in a aliquot tube under nitrogen. (S)-9-((1,4-dioxan-2-yl)methoxy)-2-bromo-4,5-dihydro-7H-thieno[2',3':3 ,4]pyrido[1,2-c]pyrimidin-7-one (B1-7) (120 mg, 0.3 mmol), N-methyl-4-ynylpyrazole (159 mg, 1.5 mmol) and triethylamine (76 mg, 0.75 mmol) was dissolved in dry DMF, added to a sealed tube and stirred at 50°C overnight. Spot plate detection, after the raw materials are completely reacted, remove DMF, concentrate to obtain crude product, and use silica gel column separation and purification (dichloromethane: methanol (V/V) = 50: 1-10: 1) to obtain compound (S)-9- ((1,4-Dioxan-2-yl)methoxy)-2-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4,5-dihydro-7H - Thieno[2',3':3,4]pyrido[1,2-c]pyrimidin-7-one (Compound 1-8) (yellow solid, 15 mg, 11.8% yield).

¹ H NMR (400MHz, DMSO-d6) δ8.15(s,1H), 7.74(s,1H), 7.30(s,1H), 6.15(s,1H), 4.25–4.15(m,2H), 4.12 –4.04(m,2H), 3.84(s,3H), 3.83–3.69(m,3H), 3.67–3.53(m,2H), 3.50–3.42(m,1H), 3.38–3.33(m,1H) ,2.96(t,J=6.9Hz,2H).

LC-MS, M/Z (ESI): 425.1 [M+H] ⁺ .

Example 9: Preparation of Compound 1-9

For the synthesis of compound I-9, refer to the synthesis method of I-1, and replace (R)-(1,4-dioxan-2-yl)methanol in the sixth step with (2-oxabicyclo[2.1.1]hexane) -1-yl)methanol to give 9-((2-oxabicyclo[2.1.1]hex-1-yl)methoxy)-2-(cyclopropylethynyl)-4,5-dihydro- 7H-thieno[2',3':3,4]pyrido[1,2-c]pyrimidin-7-one (Compound 1-9).

LC-MS, M/Z (ESI): 381.1 [M+H] ⁺ .

In the test example of the present invention, 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:

Test Example 1: GPR84 Antagonism Assay Experiment

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 μL of 10× compound to the corresponding experimental well, centrifuge and incubate at 37°C for 20 min; then add 4 μL 2.5 μM 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.

Table 1 Antagonism of test compounds to GPR84

test compound _IC50 (nM) control compound 76.46 I-1 72.76 I-6 117

The results show that the thieno ring structure-containing compounds of the present invention have strong GPR84 antagonism, especially compound I-1.

Test Example 2: Pharmacokinetic Experiment

In this experiment, pharmacokinetic parameters were tested on individual 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. 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.

Table 2 Results of oral gavage administration in mice pharmacokinetic test

Table 3 Pharmacokinetic test results of intravenous injection in mice

The results show that the compounds containing the thieno ring structure of the present invention have higher oral exposure in mice and have good druggability.

Test Example 3: Liver Microsome Stability Test

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. Use PBS to dilute the corresponding species of liver microsomes (Corning) into a microsome/buffer solution, and use this solution to dilute 0.5 mM of the compound to become a working solution. The concentration of the compound in the working solution is 1.5 μM, and the concentration of each liver microsome is 0.75mg/mL. Take a deep-well plate, add 30 μL of working solution to each well, and then add 15 μL of pre-warmed 6mM NADPH solution to start the reaction, and incubate at 37°C. Reactions were terminated by adding 135 μL of acetonitrile to the corresponding wells at 0, 5, 15, 30, and 45 minutes of incubation. After quenching the reaction with acetonitrile at the final 45 minute time point, the deep well plate was vortexed for 10 minutes (600 rpm/min) and then centrifuged for 15 minutes. After centrifugation, the supernatant was taken, and purified water was added at 1:1 for LC-MS/MS detection to obtain the ratio of the peak area of the compound to the peak area of the internal standard at each time point. The ratios were compared to the peak area ratios at 0 minutes, the percentage of compound remaining at each time point was calculated, and T _1/2 was calculated using Graphpad 5 software.

Table 4 Results of liver microsome stability test

The experimental results show that the compounds containing the thieno ring structure of the present invention have slow metabolism, long half-life and good druggability.

Although the embodiments of the present invention have been shown and described above, it should be understood that the above-mentioned embodiments are exemplary and should not be construed as limiting the present invention. Embodiments are subject to variations, modifications, substitutions and variations.

Claims (22)

The compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:

in, 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; Alternatively, the C ₁ -C ₅ alkylene 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 heterocycle alkyl; 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; Alternatively 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 compound of formula I as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein 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; Preferably, L ₁ is -O-. The compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of claim ₁ , wherein L 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 - is optionally substituted by 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 the substituents are multiple , the _Ra is the same or different Alternatively, 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. The compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof as claimed in claim 1, wherein R ₁ is any Ring Cy optionally substituted with one or more R ₁₁ ; 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 -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. The compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof as claimed in claim 1, wherein R ₁ is any Ring Cy optionally substituted with ₁ or 2 R11; The ring Cy is

More preferably, the ring Cy is

Ring A is phenyl or a 5-6 membered heteroaryl group containing 1 or 2 atoms selected from O or N; preferably, 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. The compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof as claimed in claim 1, wherein R ₁ is any Groups 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 plural substituents, R ₁₁ is the same or different. The compound shown in the formula I according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein R ₁ is selected from the following substituents:

Wherein, R ₁₁ is fluorine, chlorine, methyl, ethyl or propyl; preferably, R ₁₁ is methyl. The compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of claim 1, wherein _L does not exist Or L ₃ is -CH ₂ -, -CH=CH- or -C≡C-; Preferably, L ₃ is absent or L ₃ is -C≡C-. The compound of formula I as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein R ₂ is selected from Substituents 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 or 5-6-membered heteroaryl optionally contains 1, 2 or 3 heteroatoms selected from N, O and S; when the number of heteroatoms is 2 or 3, the said 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. The compound of formula I as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein R ₂ is selected from Substituents 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 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, 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 following: hydroxyl, C ₁ -C ₆ alkyl; when there are multiple substituents, the R ₂₁ is a different or different substituent; Preferably, R ₂ is a substituent selected from the group consisting of methyl,

The compound represented by formula I as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein -L ₃ - R ₂ is a substituent selected from the group consisting of:

The compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein R ₃ , R ₄ , R ₅ , R ₆ are independently hydrogen, methyl, ethyl, propyl, fluorine or chlorine; Preferably, R ₃ , R ₄ , R ₅ , R ₆ are each independently hydrogen or a substituent selected from the following: methyl, ethyl, propyl, fluorine or chlorine; more preferably, R ₃ , R ₄ , R ₅ and R ₆ are hydrogen. The compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein R ₄ , R ₅ together with the C atoms to which they are commonly attached form a 4-7 membered cycloalkyl or 4-7 membered heterocycloalkyl; Preferably, R ₄ and R ₅ together with the C atom to which they are connected together form a 4-6 membered cycloalkyl; Preferably, 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. The compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of claim 1, wherein the compound comprises :

A kind of intermediate B, it is characterized in that, has structure

Wherein, the definitions of R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , L ₁ and L ₂ are as described in claim 1; X is selected from: -OTf, -OTs, -OMs, fluorine, chlorine, bromine or iodine; Preferably, X is bromine or iodine; Preferably, the structure of the intermediate B is

The preparation method of the compound shown in formula I as described in any one of claim 1-14, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, It is characterized in that, described method comprises step: 1) intermediate B as claimed in claim 15 reacts with compound HL ₃ -R ₂ , obtains the compound shown in formula I; In the compound HL ₃ -R ₂ , L ₃ is absent 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 with a triple bond ₄ alkynylene; 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 method of claim 16, wherein the method further comprises: 2) the intermediate B is reacted with the compound HL ₃ -R ₂ in the presence of a catalyst; and/or 3) The intermediate B reacts with the compound HL ₃ -R ₂ under the protection of an inert gas; and/or 4) The intermediate B is reacted with compound HL ₃ -R ₂ under basic conditions; Preferably, the catalyst is a palladium catalyst and/or a copper catalyst; Preferably, 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 ; Preferably, the copper catalyst is a monovalent copper catalyst; more preferably, the copper catalyst is CuI; Preferably, the inert gas is nitrogen, helium, neon or argon. A pharmaceutical composition, characterized in that the pharmaceutical composition comprises: the compound shown in formula I as described in any one of claims 1-14, its tautomer, stereoisomer, hydrate, A solvate, a pharmaceutically acceptable salt or prodrug; and a pharmaceutically acceptable carrier. A pharmaceutical composition, characterized in that, the pharmaceutical composition comprises the compound shown in formula I as described in any one of claims 1-14, its tautomer, stereoisomer, hydrate, solvent compound, pharmaceutically acceptable salt or prodrug; and at least one other antagonist and/or inhibitor of pharmacological activity; Preferably, the other pharmacologically active antagonists are GPR84 antagonists; Preferably, the other pharmacologically active inhibitor is a GPR84 inhibitor. A compound shown in the formula I as described in any one of claims 1-14, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or the purposes of prodrug, or the use of the pharmaceutical composition of claim 18 or 19, comprising: as a GPR84 antagonist; and/or, prevention and/or treatment of GPR84-related diseases; And/or, preparing medicines, pharmaceutical compositions or preparations as GPR84 antagonists, and/or preventing and/or treating GPR84-related diseases. The use according to claim 20, wherein 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 use according to claim 21, wherein the lung disease is chronic obstructive pulmonary disease and/or interstitial lung disease; the inflammatory disease is inflammatory bowel disease; the interstitial lung disease is preferably congenital Pulmonary Fibrosis.