WO2021078227A1

WO2021078227A1 - Fused heteroaryl derivative, preparation method therefor, and application thereof in medicine

Info

Publication number: WO2021078227A1
Application number: PCT/CN2020/123072
Authority: WO
Inventors: 张晓敏; 胡伟民; 贺峰; 白昌; 陶维康
Original assignee: 江苏恒瑞医药股份有限公司; 上海恒瑞医药有限公司
Priority date: 2019-10-25
Filing date: 2020-10-23
Publication date: 2021-04-29
Also published as: TW202128686A; CN114423759B; CN114423759A

Abstract

The present disclosure relates to a fused heteroaryl derivative, a preparation method therefor, and an application thereof in medicine. In particular, the present disclosure relates to a fused heteroaryl derivative represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing same, use thereof as an ATX inhibitor, and use thereof in the preparation of a drug for treating cancers or fibrotic diseases or disorders. The substituents in general formula (I) have the same definition as those in the description.

Description

Condensed heteroaryl derivatives, preparation method thereof and application in medicine

Technical field

The present disclosure belongs to the field of medicine, and relates to a fused heteroaryl derivative, a preparation method thereof, and application in medicine. In particular, the present disclosure relates to a fused heteroaryl derivative represented by the general formula (I), its preparation method and pharmaceutical composition containing the derivative, and its use as an ATX inhibitor to treat cancer or fibrotic diseases or disorders the use of.

Background technique

Autotaxin (ATX), also known as ENPP2, is a secreted enzyme, which is mainly expressed in cancer cells, bronchial epithelial cells of the lung, and alveolar macrophages. ATX was first isolated from melanoma cells in 1992 (Stracke, ML et al. J. Biol. Chem. 1992, 267, 2524-2529), and belongs to one of the seven members of the ENPP family, of which ENPP1 and ENPP3 are closest to ATX ( Albers, HMHG et al. Chem. Rev. 2012, 112, 2593-2603). ATX is the only ENPP enzyme with lysophospholipase D (lysoPLD) activity, and mainly converts LPC into lipid lysophosphatidic acid (LPA) with biological activity. LPA is a kind of lipid, mainly LPA 16:0, LPA 18:1, LPA 18:2, LPA 20:4 in plasma (Bandoh, K. et al. FEBS Lett. 2000, 478, 159-165). LPA works through six receptor proteins (LPA1-6) on the cell surface, that is, protein-coupled receptors (GPCRs) (Lin, M.E. et al. Prostaglandins Other Lipid Mediators 2010, 91, 130-138). The LPA receptor family can be further divided into two categories: (1) EDG receptor family, including LPA1-3; (2) non-EDG receptor family LPA4-6. The similarity between the two is less than 40% (Zhao, Y. et al. Cell Signalling 2009, 21, 367-377). Each LPA receptor mediates a series of cell signaling cascades through a specific G body protein. The main signaling pathways include protein kinase (MAPK) activation, inhibition of adenylate cyclase pathway, arachidonic acid release, activation of PI3K-AKT pathway, regulation of cell apoptosis and survival, activation of Rho, Rock, Rac and Ras signaling pathways (Mills, GB et al. Nat. Rev. Cancer 2003, 3, 582-591). The ATX-LPA signaling pathway involves many physiological and pathological processes, leading to important connections with many serious diseases, including cancer, fibrotic diseases, pain, immune diseases, inflammatory nervous system, and cardiovascular diseases (Nicolas, D., etc.) US8993590B2). Experiments have shown that ATX is related to the invasion and metastasis of tumor cells, such as in ovarian cancer (Vidot, S., et al. Cell Signal, 2010, 22,926-935), breast cancer (Panupinthu, N. et al., British Journal of Cancer 2010, 102, 941-946), prostate cancer (Nouh, MA et al. Cancer Sci. 2009, 100, 1631-1638), hepatocellular carcinoma (Wu, J. et al. Mol Cancer, 2010, 9, 71) and lung cancer (Xu, X . Et al. Cancer, 2010, 116, 1739-1750) overexpression of ATX can be observed in tumor tissues. The LPA produced by it promotes tumor formation by increasing cell motility and aggressiveness. Therefore, ATX inhibitors can prevent the production of LPA and have the potential to treat a variety of diseases.

IPF (Idiopathic Pulmonary Fibrosis) is a very important research field in the ATX-LPA signaling pathway, which is a progressive, chronic, and fibrotic disease of the lung. The pathogenesis of IPF is generally believed to be through repeated stimulation of alveolar cells, resulting in the activation of alveolar epithelial cells, thereby secreting some pro-fibrotic growth factors (TGFβ, PDGF, FGF, etc.) and pro-fibrotic cytokines, these factors will fibrosis Cells are recruited to the alveolar surface to deposit and activate, which further leads to the deposition of collagen and the precipitation of extracellular matrix. Collagen production and matrix changes will in turn promote the production of these factors, and these factors will in turn further promote the alveolar epithelial cells The activation of pulmonary fibrosis leads to a vicious circle and ultimately leads to pulmonary fibrosis. Studies related to IPF have shown that the levels of ATX and LPA in patients' bronchoalveolar lavage (BAL) fluid are significantly increased (Tager, A.M. et al. Nat. Med. 2008, 14, 45-54). Through the study of LPA1 knockout and inhibitors, it has proved the important role of LPA in the process of lung fibrosis. Further studies on mice with bronchial epithelial cells and macrophages knocked out ATX have shown that these mice are less sensitive to lung fibrosis models (Oikonomo, N. et al. Am.J.Repir.Cell Mol.Biol.2012, 47,566-574). The role of LPA in lung remodeling is related to the effects of LPA on both lung fibroblasts (through LPA1) and epithelial cells (through LPA2), showing that the activation of TGFβ on epithelial cells by LPA2 is directly related to fibrotic disorders (Xu , M. et al. Am. J. pathol. 2009, 174, 1264-1279). The role of LPA in remodeling and fibrosis is related to COPD, IPF and asthma.

The main symptoms of IPF are dyspnea, dry cough, and fever and flu-like symptoms in the acute phase. The disease is very poor after recovery. The median survival period is 2-4 years, and the 5-year survival rate is 20-30%, which is lower than many malignant tumors. There is currently no good treatment for this disease, mainly by controlling symptoms Stabilize the condition.

Currently in the market for IPF, only Pirfenidone and Nintedanib have been approved for marketing. The mechanism of action of pirfenidone is still unclear, while nintedanib is tyramine. Acid kinase inhibitors, mainly targeting PDGFR, FGFR, and VEGFR receptors. Neither of these two drugs can improve lung function, but can only delay the progression of the disease, and have certain side effects. Therefore, people have been working hard to find effective drugs for IPF treatment. At present, the most advanced ATX inhibitor drug development is GLGP-1690 (Clinical Phase III), which is used for the treatment of idiopathic pulmonary fibrosis, and its Phase II clinical trial has shown good efficacy.

Compared with traditional kinase inhibitors, ATX inhibitors regulate the signal pathways related to cell proliferation, survival, apoptosis and migration by inhibiting the formation of LPA, and can potentially be used in the treatment of a variety of cancers, and due to the signal of LPA The pathway is closely related to the fibrosis of multiple organs and is an important target for the study of new types of fibrotic diseases.

Currently, patents related to ATX inhibitors are WO2018212534, WO2012024620, WO2014018891, WO2014110000, WO2015008229, WO2016031987 and WO2017050732.

Summary of the invention

The purpose of the present disclosure is to provide a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof,

among them:

Ring A is selected from cycloalkyl or heterocyclyl;

Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, Substituted by one or more substituents among haloalkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Ring C is selected from heteroaryl or heterocyclyl;

Ring D is selected from heteroaryl or heterocyclic group;

G ¹ and G ^{2 are the} same or different, and each independently is a CR ⁶ or N atom;

G ^{3 is} selected from CR ⁶ , N atom, O atom or S atom;

L ¹ does not exist, or is selected from -C(O)-(CH ₂ ) _r -, O atom and S atom;

R ¹ are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a carboxyl group, an aldehyde group, and a cycloalkyl group. , Heterocyclyl, aryl and heteroaryl;

R ^{2 is} selected from a hydrogen atom, an alkyl group and a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy , Hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;

R ^{3 is} selected from a hydrogen atom, an alkyl group and a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy , Hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;

R ⁴ are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxy, aldehyde, hydroxyl, hydroxyalkyl, cycloalkyl , Heterocyclyl, aryl and heteroaryl;

R ⁵ are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a carboxyl group, an aldehyde group, a hydroxyl group, a hydroxyalkyl group, and an oxo group. , Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen , Alkyl, alkoxy, cyano, amino, nitro, carboxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl substituted by one or more substituents;

R ^{6 is} selected from hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group and cycloalkyl group;

n is 0, 1, 2, 3, 4, 5 or 6;

s is 0, 1, 2 or 3;

t is 0, 1, 2, 3 or 4; and

r is 0, 1, 2 or 3.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer In the form of a mixture, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is a cycloalkyl group or a heterocyclic group.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring B is selected from a phenyl group, a 3-membered to 12-membered cycloalkyl group, or a 3-membered to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 ~3 heteroatoms selected from N atom, O atom or S atom; preferably ring B is a 3- to 8-membered cycloalkyl group.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is a 3-membered to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 atoms selected from N atoms, O atoms or S atoms Of heteroatoms.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is a 5-membered or 6-membered heterocyclic group, wherein the heterocyclic group contains 1 to 5 selected from N atoms, O atoms or S atoms Of heteroatoms.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Body, or its mixture form, or its pharmaceutically acceptable salt,

among them

Selected from

R ^c are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxy, cycloalkyl, heterocycle Group, aryl and heteroaryl;

g is 0, 1, 2 or 3;

h is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

q is 0, 1, 2 or 3;

y is 0, 1, 2, 3 or 4;

G ¹ , G ² and R ³ are as defined in the general formula (I).

among them

Selected from

g is 0, 1, 2 or 3;

h is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

q is 0, 1, 2 or 3;

y is 0, 1, 2, 3 or 4;

R ^{3 is} as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer In the form of a compound, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^c is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G ³ is a N atom.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II) or a tautomer, meso, racemate, enantiomer, Diastereoisomers or their mixture forms, or their pharmaceutically acceptable salts:

among them:

p is 0, 1, 2 or 3;

q is 0, 1, 2 or 3;

Ring A, ring C, ring D, G ¹ , G ² , L ¹ , R ¹ to R ⁵ , n, s, and t are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G ¹ and G ² are N atoms.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IIIG) or a tautomer, meso, racemate, enantiomer, Diastereoisomers or their mixture forms, or their pharmaceutically acceptable salts:

among them:

g is 0, 1, 2 or 3;

h is 0, 1, 2 or 3;

Ring A, ring C, ring D, L ¹ , R ¹ to R ⁵ , n, s, and t are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer R is selected from 1, 2 or 3, preferably 1 ^{, wherein L 1} is -C(O)-(CH ₂ ) _r -; r is selected from 1, 2 or 3, or a pharmaceutically acceptable salt thereof.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring D is a 7 to 11-membered bicyclic fused heterocyclic group, wherein the bicyclic fused heterocyclic group contains 1 to 5 atoms selected from the group consisting of N and O Or S atom heteroatom, more preferably 6-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group, most preferably 6-membered/5-membered bicyclic fused heterocyclic group, more preferably 5-membered heterocyclic group Aryl/6-membered heterocyclic bicyclic fused heterocyclic group.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer In the form of a compound, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is indanyl; preferably the following structure:

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer In the form of a compound, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring D is triazolopyridyl or triazolopiperidinyl; preferably the following structure:

More preferably, it has the following structure:

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer In the form of a mixture, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring D is triazolopyridyl; preferably the following structure:

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein s is zero. In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring C is a 5-membered heteroaryl group, which contains 1 to 3 heteroatoms selected from N atoms, O atoms or S atoms, preferably oxadiazolyl ; More preferably the following structure:

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer In the form of a compound, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Forms or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by the general formula (IIIM) or tautomers, mesoisomers, racemates, enantiomers, non- Enantiomers or their mixture forms, or their pharmaceutically acceptable salts:

among them:

R ^1a and R ^1b are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a carboxyl group, an aldehyde group, Cycloalkyl, heterocyclic, aryl and heteroaryl; preferably a hydrogen atom;

e is 0, 1, 2, 3 or 4;

f is 0, 1 or 2;

Ring B, R ³ , R ⁵ , and t are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Form or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (III), (IIIa) or (IIIb) or a tautomer, a mesoform, or a racemate , Enantiomers, diastereomers or mixtures thereof, or their pharmaceutically acceptable salts:

among them:

g is 0, 1, 2 or 3;

h is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

q is 0, 1, 2 or 3;

e is 0, 1, 2, 3 or 4;

f is 0, 1 or 2;

R ⁵ and t are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein p is 1; q is 1 or 2.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Form or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IIIb-1) or (IIIb-2) or a tautomer, a mesoform, or a racemate , Enantiomers, diastereomers or mixtures thereof, or their pharmaceutically acceptable salts:

Wherein, R ^1a , R ^1b , R ⁵ , t, e, f, g, and h are as defined in the general formula (IIIb).

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein g is 0, 1, 2 or 3, and h is 0, 1, 2 or 3; provided that when g is 0, h is 2 or 3; When g is 1, h is 1 or 2; when g is 2, h is 1 or 0; when g is 3, h is 0.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^1a and R ^1b are hydrogen atoms.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom.

Typical compounds of the present disclosure include but are not limited to:

Or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

The present disclosure additionally provides a compound represented by general formula (IIIMA) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or a mixture thereof Or its pharmaceutically acceptable salt:

among them:

R ^d is a hydrogen atom or an alkyl group; preferably a hydrogen atom;

e is 0, 1, 2, 3 or 4; and

f is 0, 1, or 2.

The present disclosure additionally provides a compound represented by the general formula (IIIA), (IIIaA) or (IIIbA) or its tautomer, meso, racemate, enantiomer, diastereomer Isomer, or its mixture form or its pharmaceutically acceptable salt:

among them:

g is 0, 1, 2 or 3;

h is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

q is 0, 1, 2 or 3;

e is 0, 1, 2, 3 or 4; and

f is 0, 1, or 2.

Typical intermediate compounds of the present disclosure include but are not limited to:

The present disclosure additionally provides a method for preparing a compound represented by the general formula (IIIM) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or a mixture thereof , Or a pharmaceutically acceptable salt thereof, the method includes:

A compound of general formula (IIIMA) and a compound of general formula (IIIB) or a pharmaceutically acceptable salt thereof (preferably hydrochloride) react under basic conditions to obtain a compound of general formula (IIIM);

Among them, R ^d is a hydrogen atom or an alkyl group; preferably a hydrogen atom;

Ring B, R ^1a , R ^1b , R ³ , R ⁵ , t, e, and f are as defined in the general formula (IIIM).

The present disclosure additionally provides a method for preparing a compound represented by general formula (III) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or a mixture thereof , Or a pharmaceutically acceptable salt thereof, the method includes:

A compound of general formula (IIIA) and a compound of general formula (IIIB) or a pharmaceutically acceptable salt thereof (preferably hydrochloride) react under basic conditions to obtain a compound of general formula (III);

Wherein, R ^1a , R ^1b , R ⁵ , t, p, q, e, and f are as defined in the general formula (III).

The present disclosure additionally provides a method for preparing a compound represented by general formula (IIIa) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or a mixture thereof , Or a pharmaceutically acceptable salt thereof, the method includes:

The compound of general formula (IIIaA) and the compound of general formula (IIIB) or a pharmaceutically acceptable salt thereof (preferably hydrochloride) react under basic conditions to obtain a compound of general formula (IIIa);

Wherein, R ^1a , R ^1b , R ⁵ , t, e, and f are as defined in the general formula (IIIa).

The present disclosure additionally provides a method for preparing a compound represented by the general formula (IIIb) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or a mixture thereof , Or a pharmaceutically acceptable salt thereof, the method includes:

A compound of general formula (IIIbA) and a compound of general formula (IIIB) or a pharmaceutically acceptable salt thereof (preferably hydrochloride) react under basic conditions to obtain a compound of general formula (IIIb);

The present disclosure additionally provides a method for preparing compounds represented by general formula (IIIb-1) or (IIIb-2) or tautomers, mesosomes, racemates, enantiomers, and diastereomers thereof The method of isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, the method includes:

The compounds of general formula (IIIb) are prepared by chiral preparation to obtain compounds of general formula (IIIb-1) and general formula (IIIb-2);

Another aspect of the present disclosure relates to a pharmaceutical composition, which contains a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, or non-pair Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. The present disclosure also relates to a method for preparing the above-mentioned pharmaceutical composition, which comprises combining the compounds represented by the general formulas or their tautomers, mesosomes, racemates, enantiomers, and non-pairs The enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof are mixed with pharmaceutically acceptable carriers, diluents or excipients.

Another aspect of the present disclosure relates to a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, and mixture thereof Use of the form, or pharmaceutically acceptable salt thereof, or pharmaceutical composition protecting the same in the preparation of ATX inhibitors.

Another aspect of the present disclosure relates to a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, and mixture thereof Forms, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them are used in the preparation of prevention and/or treatment of fibrotic diseases, cancer, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, Use in drugs for neurodegenerative diseases, dermatological diseases, metabolic diseases, myelodysplastic syndromes, abnormal angiogenesis-related diseases and pain; preferably, use in the preparation of drugs for the prevention and/or treatment of fibrotic diseases and cancer; More preferably, it is the use in preparing a medicine for preventing and/or treating pulmonary fibrosis, idiopathic pulmonary fibrosis, liver fibrosis and scleroderma.

Another aspect of the present disclosure relates to a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, and mixture thereof Form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same in the preparation of a medicament for preventing and/or treating diseases with the pathological characteristics of increased ATX expression; wherein said having the pathological characteristics of increased ATX expression The disease is selected from: fibrotic diseases, cancer, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological diseases, metabolic diseases, myelodysplastic syndromes, abnormalities Angiogenesis-related diseases and pain; preferably fibrotic diseases and cancer; more preferably pulmonary fibrosis, idiopathic pulmonary fibrosis, liver fibrosis and scleroderma, and the cancer is selected from kidney cancer and pancreatic cancer.

Another aspect of the present disclosure relates to a method for inhibiting ATX, which comprises administering an effective amount of the compound represented by the general formula (I) of the present disclosure or its tautomer, meso, Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.

Another aspect of the present disclosure relates to a prevention and/or treatment of fibrotic diseases, cancer, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological diseases, metabolic diseases , Myelodysplastic syndrome, abnormal angiogenesis-related diseases and pain methods, the method comprising administering to a patient in need thereof a preventive or therapeutically effective amount of a compound represented by the general formula (I) of the present disclosure or its tautomers Isomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.

Another aspect of the present disclosure relates to a method for preventing and/or treating a disease with the pathological characteristics of increased expression of ATX, the method comprising administering to a patient in need thereof a preventive and/or therapeutically effective dose of the general formula (I ) Shown in the compound or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or containing Its pharmaceutical composition. Diseases with pathological characteristics of increased ATX expression can be fibrotic diseases, cancer, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological diseases, metabolic diseases, Myelodysplastic syndrome, abnormal angiogenesis-related diseases or pain; preferably fibrotic diseases and cancer; more preferably pulmonary fibrosis, idiopathic pulmonary fibrosis, liver fibrosis and scleroderma, the cancer is selected from Kidney cancer and pancreatic cancer.

Another aspect of the present disclosure relates to a compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a medicine.

Another aspect of the present disclosure relates to a compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, it is used as an ATX inhibitor.

Another aspect of the present disclosure relates to a compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as the prevention and/or treatment of fibrotic diseases, cancer, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, Drugs for cardiovascular diseases, neurodegenerative diseases, dermatological diseases, metabolic diseases, myelodysplastic syndromes, abnormal angiogenesis-related diseases and pain; preferably drugs for the prevention and/or treatment of fibrotic diseases and cancer; more preferably drugs for prevention And/or drugs for the treatment of pulmonary fibrosis, idiopathic pulmonary fibrosis, liver fibrosis and scleroderma.

Another aspect of the present disclosure relates to a compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a medicine for preventing and/or treating diseases with the pathological characteristics of increased ATX expression, wherein the diseases with increased ATX expression The diseases with physical characteristics are selected from: fibrotic diseases, cancer, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological diseases, metabolic diseases, myelodysplastic syndromes , Abnormal angiogenesis-related diseases and pain; preferably fibrotic diseases and cancer; more preferably pulmonary fibrosis, idiopathic pulmonary fibrosis, liver fibrosis and scleroderma, the cancer is selected from kidney cancer and pancreatic cancer .

The active compound can be formulated into a form suitable for administration by any appropriate route, and the active compound is preferably in a unit dose form, or in a form in which the patient can self-administer in a single dose. The unit dose of the compound or composition of the present disclosure can be expressed in the form of a tablet, capsule, cachet, bottled syrup, powder, granule, lozenge, suppository, rejuvenated powder or liquid preparation.

The dosage of the compound or composition used in the treatment methods of the present disclosure will generally vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compound. However, as a general guide, a suitable unit dose may be 0.1-1000 mg.

In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions. Such compositions can contain one or more ingredients selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives, To provide pleasing and delicious medicinal preparations. The tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing. These excipients can be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

Oral preparations can also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or the active ingredient is mixed with a water-soluble carrier or oil vehicle.

Aqueous suspensions contain the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending agents, dispersing agents or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

Oil suspensions can be formulated by suspending the active ingredients in vegetable oil or mineral oil. The oil suspension may contain thickeners. The above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

By adding water, dispersible powders and granules suitable for preparing water suspensions can be provided with active ingredients and dispersing or wetting agents for mixing, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can illustrate the above examples. Other excipients such as sweeteners, flavoring agents and coloring agents may also be added. These compositions are preserved by adding antioxidants such as ascorbic acid.

The pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase can be vegetable oil, or mineral oil or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids, and the emulsions can also contain sweeteners, flavoring agents, preservatives and antioxidants. Such preparations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.

The pharmaceutical composition of the present disclosure may be in the form of a sterile injectable aqueous solution. Acceptable solvents or solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injection preparation may be a sterile injection oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injection or microemulsion can be injected into the patient's bloodstream by local large-volume injection. Alternatively, it is best to administer the solution and microemulsion in a manner that can maintain a constant circulating concentration of the compound of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.

The pharmaceutical composition of the present disclosure may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injection preparation may also be a sterile injection solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, sterile fixed oil can be conveniently used as a solvent or suspending medium. For this purpose, any blended fixed oil can be used. In addition, fatty acids can also be used to prepare injections.

The compounds of the present disclosure can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thus will melt in the rectum to release the drug.

As is well known to those skilled in the art, the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, and the behavior of the patient. , The patient’s diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the best mode of treatment such as the mode of treatment, the daily dosage of the compound (I) or the amount of pharmaceutically acceptable salt The type can be verified according to the traditional treatment plan.

The ATX inhibitor provided by the present disclosure has high activity, low cardiotoxicity, and good properties such as high solubility.

Detailed description of the invention

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-Dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl 2-methylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Hexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers. More preferred are lower alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl. Group, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted. When substituted, substituents may be substituted at any available attachment point. The substituents are preferably one or more of the following groups, which are independently selected from alkanes Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane One or more substituents among oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo groups are substituted.

The term "alkylene" refers to a saturated linear or branched aliphatic hydrocarbon group, which has two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is A straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbons Atom, more preferably an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH ₂ -), 1,1-ethylene (-CH(CH ₃ )-), 1,2-ethylene (-CH _{2 -)} CH ₂ -), 1,1-propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylene (-CH ₂ CH(CH ₃ )-), 1,3-propylene (-CH ₂ CH ₂ CH ₂ -), 1,4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), etc. The alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably independently optionally selected from alkyl, alkenyl, alkynyl , Alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy Substituted by one or more substituents among the group, cycloalkylthio group, heterocycloalkylthio group and oxo group.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms (which may be specific points, It can also be a range composed of two optional points, such as 3, 4, 5, 6 ring atoms, 4 to 11 ring atoms, 6 to 12 ring atoms, etc.), more preferably 3 to 8 carbon atoms, most It preferably contains 3 to 6 (e.g. 3, 4, 5 or 6) carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.

The term "spirocycloalkyl" refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings, which may contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiro atoms between the ring and the ring, the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan /5-membered and 6-membered/6-membered, most preferably 6-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring includes the above-mentioned cycloalkyl (for example, monocyclic, fused ring, spiro ring and bridged cycloalkyl) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring is connected to the parent structure The ring together is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.; preferably indanyl, tetrahydronaphthyl.

Cycloalkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio and oxo groups are substituted by one or more substituents.

The term "alkoxy" refers to -O-(alkyl) and -O-(cycloalkyl), where alkyl and cycloalkyl are as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, and a halogenated alkyl group , Hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl substituted by one or more substituents.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) _m (wherein m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms (it can be a specific point or a range composed of two optional points, such as 3, 4, 5, 6 ring atoms, 4 to 11 ring atoms, 6 to 12 ring atoms) Atoms, etc.), of which 1 to 5 (for example, 1, 2, 3, 4, and 5) are heteroatoms; preferably 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; more preferably 3 to 6 Ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydrofuranyl Hydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, and pyrrolidinyl. Polycyclic heterocyclic groups include spirocyclic, condensed, and bridged heterocyclic groups.

The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5- to 20-membered monocyclic rings, in which one or more ring atoms are selected from nitrogen, oxygen or S(O ) _m (where m is an integer of 0 to 2) heteroatoms, and the remaining ring atoms are carbon, which may contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 11 yuan. According to the number of spiro atoms shared between the ring and the ring, the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group. Non-limiting examples of spiroheterocyclic groups include:

The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more Double bonds, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 11 yuan. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/ 6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan , 6-membered/5-membered and 6-membered/6-membered, most preferably 6-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, one or more of the ring atoms Is a heteroatom selected from nitrogen, oxygen or S(O) _m (wherein m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 11 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

The heterocyclic ring includes the above heterocyclic groups (such as monocyclic, fused ring, spiro ring and bridged heterocyclic group) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the parent structure is connected to The ring together is a heterocyclic group, non-limiting examples of which include:

Wait.

The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio and oxo groups are substituted by one or more substituents.

The term "aryl" refers to a 6 to 20-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group with a conjugated π-electron system, preferably 6 to 10-membered, more preferably 6 members, such as phenyl and naphthyl. The aryl ring includes the above-mentioned aryl group fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:

The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocycle One or more substituents in the alkylthio group are substituted.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 20 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 5- to 10-membered, containing 1 to 3 heteroatoms; more preferably 5-membered or 6-membered, containing 1 to 3 heteroatoms; non-limiting examples are pyrazolyl, imidazolyl, furanyl, Thienyl, thiazolyl, oxazolyl, oxadiazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc. The heteroaryl ring includes the aforementioned heteroaryl group fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:

Heteroaryl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio And one or more substituents in the heterocycloalkylthio group.

The above-mentioned cycloalkyl, heterocyclic, aryl and heteroaryl groups have one residue derived from the removal of one hydrogen atom from the parent carbon atom, or two residues derived from the same carbon atom or two different carbon atoms of the parent Excluding the residues derived from two hydrogen atoms, the two residues are "divalent cycloalkyl", "divalent heterocyclic group", "arylene", and "heteroarylene".

The term "alkylthio" refers to -S- (alkyl) and -S- (unsubstituted cycloalkyl), where the definition of alkyl is as described above. Non-limiting examples of alkylthio include methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio. The alkylthio group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio And one or more substituents in the heterocycloalkylthio group.

The term "amino protecting group" is to keep the amino group unchanged when other parts of the molecule react, and to protect the amino group with a group that is easy to remove. Non-limiting examples include tert-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro. The amino protecting group is preferably tert-butoxycarbonyl.

The term "cycloalkyloxy" refers to -O-cycloalkyl, where cycloalkyl is as defined above.

The term "haloalkyl" refers to an alkyl substituted by halogen, where alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy substituted by halogen, wherein alkoxy is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.

The term "hydroxy" refers to the -OH group.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "amino" refers to -NH ₂ .

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

The term "aldehyde group" refers to -C(O)H.

The term "carboxy" refers to -C(O)OH.

The term "carboxylate group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

The term "tautomer" refers to isomers of compounds that differ from each other in proton position and/or electron distribution. Examples of tautomers include, but are not limited to, enol-keto tautomers, imine-enamine tautomers, amide-imine tautomers, amine-imine tautomers Conformers and tautomeric forms of heteroaryls, the heteroaryls containing ring atoms connected to the -NH- part of the ring and the =N- part of the ring, such as pyrazole, imidazole, benzimidazole, triazole , Pyridotriazole, piperidinotriazole and tetrazole. In the general formula (I) of the present disclosure, when ring D is

When, ring D can exist in tautomeric form:

For example, the compound represented by the general formula (IIIM) of the present disclosure may exist in at least the following tautomeric forms:

Among them, ring B, R ^1a , R ^1b , R ³ , R ⁵ , t, e, and f are as defined in the general formula (IIIM). Unless clearly defined otherwise, the present disclosure includes all tautomers of the compounds described in detail herein, even if only one tautomer is explicitly shown (e.g., both tautomeric forms are desired And described by presenting a tautomeric form, in which there may be a pair of two tautomers). When there are more than two tautomers, even if only a single tautomeric form is described by the chemical name and/or structure, the present disclosure includes all such tautomers.

The term "fibrotic disease" refers to a disease characterized by excessive seizures caused by excessive production, deposition and contraction of extracellular matrix, and it is associated with abnormal accumulation of cells and/or fibronectin and/or collagen and/ Or increased fibroblast recruitment is related, and includes, but is not limited to, fibrosis of individual organs or tissues (such as heart, kidney, liver joint, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, muscle bone marrow, and digestive tract) . Preferably selected from the group consisting of idiopathic pulmonary fibrosis (IPF, idiopathic pulmonary fibrosis), cystic fibrosis, scleroderma, radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), bleomycin-induced lung Fibrosis (bleomycin-induced pulmonary fibrosis), chronic asthma, sand lung, asbestos-induced pulmonary fibrosis, acute respiratory distress syndrome (ARDS) and other diffuse parenchymal lung diseases of different etiology (including iatrogenic drug-induced Fibrosis, occupational and/or environmentally induced fibrosis), granulomatous diseases (sarcoidosis, allergic pneumonia), collagen angiopathy, alveolar protein deposition, Langerhans cell granulomatosis, lymphatic vessels Leiomyosarcosis, genetic diseases (Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromas, metabolic accumulation disorders, familial interstitial lung disease); renal fibrosis, Liver fibrosis, liver cirrhosis, intestinal fibrosis, skin fibrosis, skin scleroderma, bone marrow fibrosis, systemic sclerosis, vascular restenosis and atherosclerosis; more preferably selected from idiopathic pulmonary fibrosis (IPF ).

"Optional" or "optionally" means that the event or environment described later can but does not have to occur, and the description includes occasions where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms independently of each other by a corresponding number of substituents, wherein each substituent has an independent (I.e. the substituents can be the same or different). It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers And excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and thus the biological activity.

"Pharmaceutically acceptable salt" refers to the salt of the compound of the present disclosure. Such salt is safe and effective when used in mammals, and has due biological activity.

The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms. For example, with the structure of the present disclosure, except for replacing hydrogen with "deuterium" or "tritium", or replacing ^{fluorine with 18} F-fluorine label ( ¹⁸ F isotope), or enriching ^{with 11} C-, ¹³ C- or ^{14 C-} Compounds in which carbon atoms ( ¹¹ C-, ¹³ C-, or ¹⁴ C-carbon labels; ¹¹ C-, ¹³ C- or ¹⁴ C- isotope) replace carbon atoms are within the scope of the present disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies. Deuterated compounds can generally retain the same activity as non-deuterated compounds, and when deuterated at certain specific sites, they can achieve better metabolic stability, thereby obtaining certain therapeutic advantages (such as increased in vivo half-life or reduced dosage requirements) ).

For drugs or pharmacologically active agents, the term "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.

Synthesis method of the compound of the present disclosure

In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical solutions:

Option One

The compound represented by the general formula (IIIM) of the present disclosure or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or The preparation method of medicinal salt includes the following steps:

The compound of general formula (IIIMA) and the compound of general formula (IIIB) or a pharmaceutically acceptable salt thereof (preferably hydrochloride) undergo condensation reaction under alkaline conditions in the presence of a condensing agent to obtain a compound of general formula (IIIM);

Option II

The compound represented by the general formula (III) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or The preparation method of medicinal salt includes the following steps:

The compound of general formula (IIIA) and the compound of general formula (IIIB) or a pharmaceutically acceptable salt thereof (preferably hydrochloride) undergo a condensation reaction in the presence of a condensing agent under alkaline conditions to obtain a compound of general formula (III);

third solution

The compound represented by the general formula (IIIa) of the present disclosure or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof The preparation method of medicinal salt includes the following steps:

The compound of general formula (IIIaA) and the compound of general formula (IIIB) or a pharmaceutically acceptable salt thereof (preferably hydrochloride) undergo a condensation reaction under alkaline conditions in the presence of a condensing agent to obtain a compound of general formula (IIIa);

Option Four

The compound represented by the general formula (IIIb) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture form thereof, or The preparation method of medicinal salt includes the following steps:

The compound of general formula (IIIbA) and the compound of general formula (IIIB) or a pharmaceutically acceptable salt thereof (preferably hydrochloride) undergo a condensation reaction under alkaline conditions in the presence of a condensing agent to obtain a compound of general formula (IIIb);

Option Five

The compound represented by the general formula (IIIb-1) or (IIIb-2) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, Or its mixture form, or its pharmaceutically acceptable salt preparation method, including the following steps:

The reagents that provide basic conditions in Scheme 1 to Scheme 4 include organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and two Lithium isopropylamide, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate or cesium carbonate, Sodium hydroxide, lithium hydroxide and potassium hydroxide; preferably N,N-diisopropylethylamine.

The above-mentioned Scheme 1 to Scheme 4 reactions are preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, and dichloromethane. Methyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof, preferably N,N-dimethylformamide.

The condensing agent used in the reaction of Scheme 1 to Scheme 4 includes but not limited to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide , N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole Azole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-azobenzene Triazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyl Urea hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate Phosphorus is preferably benzotriazol-1-yl-oxytripyrrolidinyl phosphorus hexafluorophosphate.

Detailed ways

The present disclosure is further described below in conjunction with embodiments, but these embodiments do not limit the scope of the present disclosure.

Example

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is given in units of ^{10 -6 (ppm).} The NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four Methylsilane (TMS).

For MS measurement, Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid-mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

High performance liquid chromatography (HPLC) analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.

Chiral HPLC analysis and determination use Agilent 1260 DAD high performance liquid chromatograph.

The HPLC preparation uses Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson-281 preparative chromatographs.

For chiral preparation, Shimadzu LC-20AP preparative chromatograph was used.

CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm～0.2mm, and the size of the thin layer chromatography separation and purification product is 0.4mm. ~0.5mm.

The silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

The average value of ₅₀ measured kinase inhibition rate and IC NovoStar using a microplate reader (BMG, Germany).

The known starting materials of the present disclosure can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Companies such as Darui Chemicals.

There is no special description in the examples, and the reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.

The argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.

The hydrogen atmosphere refers to the reaction flask connected to a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.

The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

The microwave reaction uses CEM Discover-S 908860 microwave reactor.

There is no special description in the examples, and the solution refers to an aqueous solution.

There are no special instructions in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.

The monitoring of the reaction progress in the examples adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used in the purification of the compound, and the developing reagent system of thin layer chromatography include: A: N-hexane/ethyl acetate system, B: dichloromethane/methanol system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

Example 1

2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)- Yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c ]Pyridin-5-yl)ethan-1-one 1

first step

N-(2,3-Dihydro-1H-inden-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine trifluoroacetate 1b

2-((2,3-Dihydro-1H-inden-2-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylic acid tert-butyl ester 1a (5.5g, 15.0mmol, prepared by the patent application "WO 2014168824, page 10 Intermediate 2 published method") was dissolved in dichloromethane (50mL), trifluoroacetic acid (10.0mL, adamas) was added, and the reaction was stirred. 1 hour. Concentrate under reduced pressure to obtain the title product crude product 1b (5.7 g, yield: 99.8%).

MS m/z(ESI): 267.2[M+1].

Second step

2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) ethyl acetate 1e

Ethyl 3-oxo-3-hydrazinopropionate 1c (2.0g, 13.7mmol, adamas) and triethylamine (1.5g, 14.9mmol, Sinopharm) were dissolved in tetrahydrofuran (50mL), and N,N'- Carbonyl diimidazole 1d (2.4 g, 4.8 mmol, adamas) was stirred and reacted for 16 hours. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 1e (1.6 g, yield: 67.9%).

MS m/z(ESI): 173.2[M+1].

third step

2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)- Yl)-1,3,4-oxadiazol-2-yl)ethyl acetate 1f

Compound 1b (1.0g, 2.6mmol) and compound 1e (500mg, 2.9mmol) were dissolved in N,N-dimethylformamide (10mL), and N,N'-diisopropylethylamine (2.0g, 15.5mmol, adamas) and Carter condensing agent (3.5g, 7.9mmol, complete), stirred and reacted for 16 hours. Water (100 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×2), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 1f (600 mg, yield: 54.3%).

MS m/z(ESI): 421.2[M+1].

the fourth step

2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)- Yl)-1,3,4-oxadiazol-2-yl)acetic acid 1g

Compound 1f (600 mg, 1.43 mmol) was dissolved in THF (10 mL) and water (5.0 mL), at 0° C., lithium hydroxide monohydrate (300 mg, 7.14 mmol, Sinopharm) was added, and the reaction was stirred for 1 hour. The organic solvent was removed by concentration under reduced pressure, and the pH was adjusted to 3-4 with 1N dilute hydrochloric acid. The solid precipitated out and was filtered and dried to obtain 1 g (280 mg, yield: 50.0%) of the title product.

MS m/z(ESI): 393.2[M+1].

the fifth step

Compound 1g (160mg, 0.41mmol) and 4,5,6,7-tetrahydro-3H-[1,2,3]triazolo[4,5-c]pyridine hydrochloride 1h (90mg, 0.56mmol) , Prepared by the patent application "WO 2018212534A1, p.53 intermediate im-7 published method") was dissolved in N,N-dimethylformamide (2.0mL), and N,N'-diisopropyl ethyl was added Amine (150 mg, 1.16 mmol, adamas) and benzotriazol-1-yl-oxytripyrrolidinyl phosphorus hexafluorophosphate (600 mg, 1.15 mmol, adamas) were stirred and reacted for 1 hour. Water (10mL) was added to the reaction solution, extracted with ethyl acetate (10mL), concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Sharpsil-T C18 Column 21.2*150mm 5um, elution system: water (10mmoL/ L ammonium acetate), acetonitrile) to obtain the title product 1 (70 mg, yield: 34.4%).

MS m/z(ESI): 499.2[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.20 (s, 1H), 7.38 (d, 1H), 7.21-7.19 (m, 2H), 7.14-7.12 (m, 2H), 4.77-4.67 (m ,2H),4.60-4.57(m,1H),4.44-4.40(m,2H),4.20-4.15(m,2H),3.81(s,2H),3.74-3.67(m,2H),3.33-3.31 (m, 1H), 3.25-3.19 (m, 2H), 2.88-2.83 (m, 4H), 2.27-2.23 (m, 2H).

Example 2

2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6- Yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c ]Pyridin-5-yl)ethan-1-one 2

first step

2-((2,3-Dihydro-1H-inden-2-yl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester 2c

Combine 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester 2a (900mg, 3.52mmol, medicine stone) and N,N'-diisopropyl Ethylamine (1.4g, 10.8mmol, adamas) was dissolved in ethanol (10mL), and 2,3-dihydro-1H-indene-2-amine hydrochloride 2b (1.2g, 7.07mmol, Shaoyuan), 80 Stir at °C for 24 hours. After concentration under reduced pressure, the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 2c (1.1 g, yield: 88.7%).

MS m/z(ESI): 353.2[M+1].

Second step

N-(2,3-dihydro-1H-inden-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine trifluoroacetate 2d

Compound 2c (1.1 g, 3.12 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3.0 mL, adamas) was added, and the reaction was stirred for 1 hour. Concentrate under reduced pressure to obtain the title product crude product 2d (1.2 g, yield: 104.9%).

MS m/z(ESI): 253.2[M+1].

third step

2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6- (Base)-1,3,4-oxadiazol-2-yl)ethyl acetate 2e

Compound 2d (500mg, 1.36mmol) and compound 1e (240mg, 1.39mmol) were dissolved in N,N-dimethylformamide (10mL), and N,N'-diisopropylethylamine (1.1g, 10.1 mmol, adamas) and Carter condensing agent (1.82 g, 4.11 mmol, complete), and the reaction was stirred for 16 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL×2), the organic phases were combined, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 2e (500mg, yield: 90.1%).

MS m/z(ESI): 407.2[M+1].

the fourth step

2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6- Yl)-1,3,4-oxadiazol-2-yl)acetic acid 2f

Compound 2e (500mg, 1.23mmol) was dissolved in THF (10mL) and water (5.0mL), at 0°C, lithium hydroxide monohydrate (250mg, 5.95mmol, Sinopharm) was added, and the reaction was stirred for 1 hour. The organic solvent was removed by concentration under reduced pressure, and the pH was adjusted to 3-4 with 1N dilute hydrochloric acid. The solid precipitated out and was filtered and dried to obtain the title product 2f (400 mg, yield: 85.9%).

MS m/z(ESI): 379.1 [M+1].

the fifth step

Compound 2f (150mg, 0.40mmol) and compound 1h (90mg, 0.56mmol) were dissolved in N,N-dimethylformamide (2.0mL), and N,N'-diisopropylethylamine (160mg, 1.24 mmol, adamas) and benzotriazol-1-yl-oxytripyrrolidinyl phosphorus hexafluorophosphate (600 mg, 1.15 mmol, adamas), and the reaction was stirred for 1 hour. Water (10mL) was added to the reaction solution, extracted with ethyl acetate (10mL), concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Sharpsil-T C18Column 21.2×150mm 5um, elution system: water (10mmoL/L) Ammonium acetate), acetonitrile) to obtain the title product 2 (60 mg, yield: 31.2%).

MS m/z(ESI): 485.2[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.35 (s, 1H), 7.64 (d, 1H), 7.23-7.20 (m, 2H), 7.15-7.13 (m, 2H), 4.78 (s, 1H) )4.68-4.62(m,4H),4.55-4.51(m,2H),4.22-4.18(m,2H),3.82(s,2H),3.27-3.23(m,4H),2.92-2.88(m, 3H).

Example 3

2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)quinazolin-6-yl)-1,3,4-oxadiazol-2-yl) -1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one 3

first step

6-Bromo-N-(2,3-dihydro-1H-inden-2-yl)quinazolin-2-amine 3b

6-Bromo-2-chloroquinazoline 3a (1.0g, 4.1mmol, Shaoyuan) and potassium carbonate (1.7g, 12.3mmol) were dissolved in acetonitrile (50mL), and compound 2b (1.0g, 5.9mmol, adamas) was added The reaction was stirred at 60°C for 16 hours. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 3b (1.2 g, yield: 85.9%).

MS m/z(ESI): 339.9[M+1].

Second step

2-((2,3-Dihydro-1H-inden-2-yl)amino)quinazolin-6-carboxylic acid ethyl ester 3c

Compound 3b (1.0g, 2.9mmol) was dissolved in 50mL of a mixed solvent of N,N-dimethylformamide and ethanol (V/V=4/1), and N,N'-diisopropylethylamine (900mg , 8.9mmol, adamas), palladium acetate (130mg, 0.58mmol, Shaoyuan) and 1,1'-bis(diphenylphosphine) ferrocene (550mg, 0.94mmol, adamas), under carbon monoxide atmosphere, at 80 The reaction was stirred at °C for 16 hours. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 3c (510 mg, yield: 52.0%).

MS m/z(ESI): 334.1[M+1].

third step

2-((2,3-Dihydro-1H-inden-2-yl)amino)quinazolin-6-carboxylic acid 3d

Compound 3c (500 mg, 1.5 mmol) was dissolved in tetrahydrofuran (10 mL), water (10 mL) and lithium hydroxide monohydrate (300 mg, 7.1 mmol) were added, and the reaction was stirred for 16 hours. The organic solvent was removed by concentration under reduced pressure, 1M dilute hydrochloric acid was slowly added dropwise to adjust the pH to 3-4, and the solid precipitated out, filtered and dried to obtain the title product 3d (410 mg, yield: 89.5%).

MS m/z(ESI): 306.2[M+1].

the fourth step

3-(2-(2-((2,3-dihydro-1H-inden-2-yl)amino)quinazolin-6-carbonyl)hydrazino)-3-oxopropionate 3e

Compound 3d (400mg, 1.3mmol) and compound 1c (290mg, 2.0mmol) were dissolved in N,N-dimethylformamide (20mL), and N,N'-diisopropylethylamine (550mg, 4.3mmol) was added ) And benzotriazol-1-yl-oxytripyrrolidinyl phosphorous hexafluorophosphate (820 mg, 1.6 mmol, Shaoyuan), and the reaction was stirred for 1 hour. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 3e (140 mg, yield: 24.7%) .

MS m/z(ESI): 434.2[M+1].

the fifth step

2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)quinazolin-6-yl)-1,3,4-oxadiazol-2-yl) Ethyl acetate 3f

Compound 3e (100mg, 0.23mmol) was dissolved in anhydrous tetrahydrofuran (10mL), N,N'-diisopropylethylamine (35mg, 0.35mmo) and 4-toluenesulfonyl chloride (53mg, 0.28mmol) were added and stirred React for 4 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 3f (85 mg, yield: 88.7%) .

MS m/z(ESI): 416.2[M+1].

Sixth step

2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)quinazolin-6-yl)-1,3,4-oxadiazol-2-yl) Acetic acid 3g

Compound 3f (85 mg, 0.2 mmol) was dissolved in tetrahydrofuran (5 mL), water (5 mL) and lithium hydroxide monohydrate (50 mg, 1.2 mmol) were added, and the reaction was stirred for 2 hours. The organic solvent was removed by concentration under reduced pressure, 1M dilute hydrochloric acid was slowly added dropwise to adjust the pH to 3-4, and the solid precipitated, filtered and dried to obtain the title product 3g (65mg, yield: 82.0%).

MS m/z(ESI): 387.9[M+1].

Seventh step

Compound 3g (65mg, 0.17mmol) and compound 1h (40mg, 0.25mmol) were dissolved in N,N-dimethylformamide (5.0mL), and N,N'-diisopropylethylamine (65mg, 0.5 mmol) and benzotriazol-1-yl-oxytripyrrolidinyl phosphorus hexafluorophosphate (131 mg, 0.25 mmol, Shaoyuan), and the reaction was stirred for 1 hour. Water (10mL) was added to the reaction solution, extracted with ethyl acetate (10mL), concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Sharpsil-T C18 Column 21.2×150mm 5um, elution system: water (10mmoL/ L ammonium acetate), acetonitrile) to obtain the title product 3 (17 mg, yield: 20.5%).

MS m/z(ESI): 494.1[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.30 (brs, 1H), 8.44-8.40 (m, 1H), 8.22-8.19 (m, 2H), 7.64-7.62 (m, 1H), 7.23-7.14 (m, 4H), 4.84-4.70 (m, 3H), 4.50-4.46 (m, 2H), 3.87-3.83 (m, 2H), 3.75-3.50 (m, 2H), 3.00-2.92 (m, 4H) ,2.77-2.74(m,1H).

Example 4

2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5-yl)- 1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine- 5-yl)ethan-1-one 4

first step

2-((2,3-Dihydro-1H-inden-2-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylic acid 4b

The 2-((dimethylamino)methylene)-3-oxocyclopentane-1-carboxylic acid methyl ester 4a (2.2g, 11.2mmol, using Intermediate 63 on page 96 of the specification in the patent application "WO 2013028474Al) "Prepared by the disclosed method) and 1-(2,3-dihydro-1H-inden-2-yl)guanidine hydrochloride (2.35g, 13.4mmol, using the middle of page 6 of the specification in the patent application "US20140200231A1 Body 1" prepared by the disclosed method) was dissolved in anhydrous methanol (50 mL), sodium methoxide (1.0 g, 40.7 mmol, adamas) was added, and the mixture was stirred at 80°C for 16 hours. Add water (10mL) to quench, then adjust the pH to 3-4 with 1N dilute hydrochloric acid, then extract with n-butanol, dry, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography with eluent system B to obtain the title Product 4b (2.0 g, yield: 60.7%).

MS m/z(ESI): 296.0[M+1].

Second step

3-(2-(2-((2,3-dihydro-1H-inden-2-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carbonyl)hydrazine Yl)-3-oxopropionate 4c

Compound 4b (500mg, 1.69mmol) and compound ethyl 3-hydrazino-3-oxopropionate (371mg, 2.53) were dissolved in N,N-dimethylformamide (10mL), and then 1H-benzo Triazol-1-yloxytripyrrolidinyl hexafluorophosphate (1.06g, 2.04mmol, Shaoyuan) and N,N-diisopropylethylamine (657mg, 5.08mmol, adamas), stirred at room temperature 3 hour. It was quenched by adding water, then extracted with ethyl acetate, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 4c (365 mg, yield: 50.9%).

MS m/z(ESI): 424.0[M+1].

third step

2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5-yl)- 1,3,4-oxadiazol-2-yl) ethyl acetate 4d

Compound 4c (360 mg, 0.85 mmol) was dissolved in tetrahydrofuran (10 mL), Burgess reagent (608 mg, 2.55 mmol, adamas) was added, and the tube was sealed and stirred at 80°C for 4 hours. The organic solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 4d (167 mg, yield: 48.5%).

MS m/z(ESI): 406.0[M+1].

the fourth step

2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5-yl)- 1,3,4-oxadiazol-2-yl)acetic acid 4e

Using the synthetic route of compound 1g in Example 1, the starting compound 1f was replaced with the starting compound 4d to obtain the title compound 4e (151 mg, yield: 97.0%).

MS m/z(ESI): 378.0[M+1].

the fifth step

Using the synthetic route of compound 1 in Example 1, the starting compound 1g was replaced with the starting compound 4e to obtain the title compound 4 (88 mg, yield: 45.0%).

MS m/z(ESI): 484.0[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 14.70 (brs, 1H), 8.17 (s, 1H), 7.54-7.52 (m, 1H), 7.21-7.12 (m, 4H), 4.76-4.60 (m , 4H), 4.37-4.33 (m, 2H), 3.81-3.79 (m, 2H), 3.26-3.20 (m, 2H), 2.89-2.84 (m, 4H), 2.73-2.67 (m, 3H), 2.28 -2.21(m,1H).

Example 4-1 and Example 4-2

(S)-2-(5-(2-((2,3-Dihydro-1H-inden-2-yl)amino)-6,7-dihydro-5H-cyclopenta(d)pyrimidine-5 -Yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5- c)Pyridin-5-yl)ethan-1-one 4-1

(R)-2-(5-(2-((2,3-Dihydro-1H-inden-2-yl)amino)-6,7-dihydro-5H-cyclopenta(d)pyrimidine-5 -Yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5- c)pyridin-5-yl)ethan-1-one 4-2

Compound 4 (88mg, 0.16mmol) was chirally prepared (separation conditions: chiral preparation column CHIRALPAK AS, 5.0cm ID×25cm, 10μm; mobile phase: methanol (100%), flow rate: 60mL/min), and collected The corresponding fractions were concentrated under reduced pressure to obtain the title compound (26 mg, 24 mg).

Single configuration compound (shorter retention time):

MS m/z(ESI): 484.0[M+1].

Chiral HPLC analysis: retention time 5.84 minutes, chiral purity: 100% (column: CHIRALPAKAS-H, 0.46cm I.D.×15cm; mobile phase: methanol (100%)).

Single configuration compound (longer retention time):

MS m/z(ESI): 484.0[M+1].

Chiral HPLC analysis: retention time 11.83 minutes, chiral purity: 99.7% (column: CHIRALPAKAS-H, 0.46 cm I.D.×15 cm; mobile phase: methanol (100%)).

Example 5

2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-6-yl)- 1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine- 5-yl)ethan-1-one 5

Using the synthetic route of Example 4, the starting compound 4a was replaced with the starting compound 5a to obtain the title compound 5 (54 mg, yield: 13.4%).

MS m/z(ESI): 484.0[M+1].

¹ H NMR (400MHz, CD ₃ OD) δ 8.15 (s, 1H), 7.23-7.13 (m, 4H), 4.85-4.69 (m, 3H), 4.05-3.92 (m, 3H), 3.39-3.36 ( m, 4H), 3.33-3.14 (m, 4H), 2.98-2.85 (m, 4H).

Example 5-1 and Example 5-2

(S)-2-(5-(2-((2,3-Dihydro-1H-inden-2-yl)amino)-6,7-dihydro-5H-cyclopenta(d)pyrimidine-6 -Yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5- c)pyridin-5-yl)ethan-1-one 5-1

(R)-2-(5-(2-((2,3-Dihydro-1H-inden-2-yl)amino)-6,7-dihydro-5H-cyclopenta(d)pyrimidine-6 -Yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5- c)pyridin-5-yl)ethan-1-one 5-2

Compound 5 (54mg, 0.11mmol) was chirally prepared (separation conditions: chiral preparation column CHIRALPAK OJ, 5.0cm ID×25cm, 10μm; mobile phase: methanol (100%), flow rate: 50mL/min), and collected The corresponding fractions were concentrated under reduced pressure to obtain the title compound (12mg, 13mg).

Single configuration compound (shorter retention time):

MS m/z(ESI): 484.0[M+1].

Chiral HPLC analysis: retention time 7.04 minutes, chiral purity: 100% (chromatographic column: CHIRALPAKOJ-H, 0.46cm I.D.×15cm; mobile phase: methanol (100%)).

Single configuration compound (longer retention time):

MS m/z(ESI): 484.0[M+1].

Chiral HPLC analysis: retention time 9.84 minutes, chiral purity: 99.4% (chromatographic column: CHIRALPAKOJ-H, 0.46cm I.D.×15cm; mobile phase: methanol (100%)).

Example 6

2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl)- 1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine- 5-yl)ethan-1-one 6

Using the synthetic route of Example 5, the compound 5a was replaced with 3-((dimethylamino)methylene)-2-oxocyclopentane-1-carboxylic acid methyl ester to obtain the title compound 6.

Example 6-1 and Example 6-2

(S)-2-(5-(2-((2,3-Dihydro-1H-inden-2-yl)amino)-6,7-dihydro-5H-cyclopenta(d)pyrimidine-7 -Yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5- c)pyridin-5-yl)ethan-1-one 6-1

(R)-2-(5-(2-((2,3-Dihydro-1H-inden-2-yl)amino)-6,7-dihydro-5H-cyclopenta(d)pyrimidine-7 -Yl)-1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5- c)Pyridin-5-yl)ethan-1-one 6-2

The compound 6 is prepared by chiral preparation, and the target compounds 6-1 and 6-2 can be obtained.

Example 7

2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-5,6,7,8-tetrahydroquinazolin-8-yl)-1,3 ,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl )Ethan-1-one 7

Using the synthetic route of Example 5, the compound 5a was replaced with 3-((dimethylamino)methylene)-2-oxocyclohexane-1-carboxylic acid methyl ester to obtain the title compound 7.

Example 7-1 and Example 7-2

(S)-2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-5,6,7,8-tetrahydroquinazolin-8-yl) -1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine -5-yl)ethan-1-one 7-1

(R)-2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-5,6,7,8-tetrahydroquinazolin-8-yl) -1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine -5-yl)ethan-1-one 7-2

The compound 7 can be prepared by chiral preparation to obtain the target compounds 7-1 and 7-2.

Example 8

2-(5-(2-((2,3-Dihydro-1H-inden-2-yl)amino)-5,6,7,8-tetrahydroquinazolin-7-yl)-1,3 ,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl )Ethan-1-one 8

Using the synthetic route of Example 5, the compound 5a was replaced with methyl 4-((dimethylamino)methylene)-3-oxocyclohexane-1-carboxylate to obtain the title compound 8.

Example 8-1 and Example 8-2

(S)-2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-5,6,7,8-tetrahydroquinazolin-7-yl) -1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine -5-yl) ethyl-1-one 8-1

(R)-2-(5-(2-((2,3-Dihydro-1H-inden-2-yl)amino)-5,6,7,8-tetrahydroquinazolin-7-yl) -1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine -5-yl) ethyl-1-one 8-2

The compound 8 is prepared by chiral preparation, and the target compounds 8-1 and 8-2 can be obtained.

Example 9

2-(5-(2-((2,3-Dihydro-1H-inden-2-yl)amino)-5,6,7,8-tetrahydroquinazolin-6-yl)-1,3 ,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl )Ethan-1-one 9

Using the synthetic route of Example 5, the compound 5a was replaced with 3-((dimethylamino)methylene)-4-oxocyclohexane-1-carboxylic acid methyl ester to obtain the title compound 9.

Example 9-1 and Example 9-2

(R)-2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-5,6,7,8-tetrahydroquinazolin-6-yl) -1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine -5-yl) ethyl-1-one 9-1

(S)-2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-5,6,7,8-tetrahydroquinazolin-6-yl) -1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine -5-yl)ethan-1-one 9-2

Chiral preparation of compound 9 can obtain target compounds 9-1 and 9-2.

Example 10

2-(5-(2-((2,3-Dihydro-1H-inden-2-yl)amino)-5,6,7,8-tetrahydroquinazolin-5-yl)-1,3 ,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl ) Ethan-1-one 10

Using the synthetic route of Example 5, the compound 5a was replaced with methyl 2-((dimethylamino)methylene)-3-oxocyclohexane-1-carboxylate to obtain the title compound 10.

Example 10-1 and Example 10-2

(R)-2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-5,6,7,8-tetrahydroquinazolin-5-yl) -1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine -5-yl) ethyl-1-one 10-1

(S)-2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-5,6,7,8-tetrahydroquinazolin-5-yl) -1,3,4-oxadiazol-2-yl)-1-(3,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine -5-yl) ethyl-1-one 10-2

The compound 10 is chirally prepared to obtain the target compounds 10-1 and 10-2.

Biological evaluation

The following further describes and explains the present disclosure in conjunction with test examples, but these examples are not meant to limit the scope of the present disclosure.

Test Example 1 Enzymology experiment of the compound of the present disclosure

ATX (autocrine motility factor) catalyzes the substrate lysophosphatidylcholine (LPC) to produce choline. Choline is oxidized by choline oxidase to generate betaine and hydrogen peroxide. Peroxidase is in the presence of hydrogen peroxide. Next, the catalytic substrate 2-hydroxy-3-m-toluidine propanesulfonate sodium (TOOS) reacts with 4-aminoantipyrine to develop color, with absorption at 555nm. The measured absorbance is positively correlated with the amount of choline released by the enzyme-catalyzed reaction in the first step, thereby reflecting the inhibitory effect of the compound on the ATX enzyme activity.

1) Experimental purpose

Using the characteristics of the compounds of the present disclosure that can inhibit ATX enzyme activity, the compounds are screened in vitro.

2) Experimental method

Buffer A: 50mM Tris-Hydrochloric Acid pH8.5 (Beijing Tianenze Biology, #101207-250), 500mM Sodium Chloride (Sinopharm Group, #10019318), 5mM Potassium Chloride (Sinopharm Group, #10016318 ), 10mM calcium chloride (China National Pharmaceutical Group, #10005861) and 0.1% bovine serum albumin (Sigma, #B2064).

Buffer B: 50mM tris-hydrochloric acid pH8.5, 500mM sodium chloride, 5mM potassium chloride, 10mM calcium chloride, 0.1% bovine serum albumin and 20mM EGTA (ethylene glycol bis(2-amino) Ethyl ether) tetraacetic acid, Sigma, #E3889).

The compound was formulated with dimethyl sulfoxide (Sigma, #D2650), with an initial concentration of 500 μM, 7-fold dilution, and a total of 8 doses. With buffer A, ATX (R&D, #5255-EN) was formulated to a final concentration of 0.5 ng/μl, and LPC 16:0 (Sigma, #855675P) was formulated to a final concentration of 150 uM. Add 20 μl ATX, 1 μl compound and 30 μl LPC to each well in a 96-well plate (Corning, #3799), and incubate at 37°C for 3 hours.

Prepare buffer B containing 0.6U/ml choline oxidase (Sigma, #C5896), 0.6U/ml peroxidase (Sigma, #P8375), 1.8mM TOOS (Sigma, #04340) and 1.2mM 4- Aminoantipyrine (Sigma, #A4382) detection solution. Add 50μl/well of the detection solution to the 96-well plate after 3 hours of incubation. After shaking at room temperature for 15 minutes, read the OD value of 555nm with a microplate reader (Molecular Devices, Flexstation 3).

3) Test results

_{Table 1. The IC 50} value of the inhibitory effect of the compounds in the present disclosure on ATX enzyme activity

Conclusion: The compound of the present disclosure has a significant inhibitory effect on ATX enzyme activity.

Test Example 2 The effect of the compound of the present disclosure on the secretion of IL-6 induced by TGF-β (transforming growth factor β)

1) Experimental purpose

The compound of the present disclosure was tested for its inhibitory effect on TGF-β (transforming growth factor β)-induced human skin fibroblasts to secrete IL-6 (interleukin 6).

2) Experimental method

The primary human skin fibroblasts (NHDF, PromoCell, #C-12303) were resuspended in FGM medium (Fibroblast Growth Medium2, PromoCell, #C-23020) to 8000 cells/well and plated on a 96-well plate (Corning, #C-23020) 3799) in 37°C, 5% CO ₂ incubator (thermo scientific, #STERI-CYCLEi160) for 48 hours. Recombinant human TGF-β (Cell Signaling Technology, #8915LC) was configured to 10ng/ml with FGM medium (Fibroblast Growth Medium2, PromoCell, #C-23020). The compound to be tested was prepared with FGM medium to an initial concentration of 100 μM, diluted 10 times, and a total of 8 doses. The medium in the cell plate was removed, and 80 μl of fresh FGM medium and 10 μl of test compound solutions of different concentrations were added respectively, and incubated in a 37° C., 5% CO ₂ incubator for 1.5 hours. Then add 10ul TGF-β solution and place it in a 37°C, 5% CO ₂ incubator to continue incubating. After 24 hours, the cell supernatant was collected, and the IL-6 content in the supernatant was detected by ELISA (Xinbosheng Biotechnology, #EHC007.96) and its IC ₅₀ value was calculated.

3) Data analysis

_{Table 2. IC 50} values of the compounds of the present disclosure on TGF-β-induced IL-6 secretion by human skin fibroblasts

Conclusion: The compound of the present disclosure has a significant inhibitory effect on the production of IL-6 induced by TGF-β.

Test Example 3 In vitro human plasma LPA inhibitory effect of the compound of the present disclosure

1) Experimental purpose

The compound of the present disclosure was tested for its inhibitory effect on the 18:2 level of LPA in the plasma of healthy people by inhibiting the activity of ATX enzyme.

2) Experimental method

The blood of healthy volunteers was collected into heparin blood collection tube (BD, #367886), centrifuged at 3000 rpm at 4°C for 15 minutes, and the supernatant was taken. The plasma was dispensed into 96-well plates (Corning, #3788) at 99 μl/well. The compound was formulated with dimethyl sulfoxide (Sigma, #D2650) to an initial concentration of 100 μM, diluted 10 times, and a total of 7 doses. Add 1 μl to the plasma plate and incubate at 37°C for 2 hours. Xevo TQ-S triple quadrupole tandem mass spectrometer and ACQUITY UPLC ultra-high performance liquid chromatography system (Waters) were used to detect the content of LPA 18:2 in plasma. Using LPA 17:0 (Sigma, #857127P) as the internal standard, the relative amount is evaluated based on the peak area of LPA 18:2.

3) Test results

_{Table 3. The IC 50} value of the inhibitory effect of the compounds of the present disclosure on the level of LPA 18:2 in the plasma of healthy people

实施例编号Example number	IC ₅₀(nM) IC ₅₀ (nM)	最大抑制率(％)Maximum inhibition rate (%)
11	2.42.4	9595
22	2.22.2	9494
33	4.54.5	9191
44	2.12.1	9292
4-1和4-2中较短保留时间Shorter retention time in 4-1 and 4-2	2.02.0	9191
4-1和4-2中较长保留时间Longer retention time in 4-1 and 4-2	11	9292
55	2.92.9	9696
5-1和5-2中较短保留时间Shorter retention time in 5-1 and 5-2	8.78.7	8989
5-1和5-2中较长保留时间Longer retention time in 5-1 and 5-2	1.41.4	9292

Conclusion: The compound of the present disclosure has a significant inhibitory effect on the level of LPA 18:2 in the plasma of healthy people.

Test Example 4 The blocking effect of the compound of the present disclosure on hERG potassium current

1) Experimental purpose

Fully automatic patch clamp was used to test the blocking effect of the compounds of the present disclosure on hERG potassium current on stable cell lines transfected with hERG potassium channels.

2) Experimental method

2.1) Experimental materials and instruments

Experimental Materials:

laboratory apparatus:

2.2) Fully automatic patch clamp experiment procedure

The HEK293-hERG stable cell line (built in-house according to known techniques) was subcultured in DMEM/HIGH glucose medium (10% FBS, 1.5μg/ml puromycin dihydrochloride) at a density of 1:4, and cultured 48 -Perform fully automatic patch clamp experiments within 72 hours. After the cells were digested with 0.25% trypsin on the day of the experiment, the cells were collected by centrifugation, and the cells were resuspended in extracellular fluid to make a cell suspension. The cell suspension is placed on the cell bank of the Patchliner instrument. The Patchliner instrument uses a negative pressure controller to add cells to the chip (NPC-16), and the negative pressure attracts single cells to the small holes of the chip. When the whole cell mode is formed, the instrument will obtain the hERG current according to the set hERG current and voltage program, and then the instrument will automatically change from low concentration to high concentration for compound perfusion. The data analysis software provided by HEAK Patchmaster, HEAK EPC10 Patch Clamp Amplifier (Nanion) and Pathlinersoftware and Pathcontrol HT software are used to analyze the currents at each concentration of the compound and the blank control current.

2.3) Test results

The blocking effect of the compounds of the present disclosure on hERG potassium current was determined by the above test, and the measured IC ₅₀ values are shown in Table 3 below.

_{Table 4. IC 50} of the blocking effect of the compounds of the present disclosure on hERG potassium current

实施例编号Example number	IC ₅₀(μM) IC ₅₀ (μM)
11	24twenty four
5-1和5-2中较长保留时间Longer retention time in 5-1 and 5-2	>30>30

Conclusion: The compound of the present disclosure has a weak inhibitory effect on hERG and can reduce the side effects caused by the hERG pathway.

Test Example 5 The solubility of the compound of the present disclosure

1) Experimental materials

Reagents: dimethyl sulfoxide (analytical grade), ethanol (analytical grade), acetonitrile (chromatographic grade), NaH ₂ PO ₄ ·2H ₂ O (analytical grade), ammonium acetate (analytical grade), sodium taurosulfonate, egg Phospholipids, sodium hydroxide, sodium chloride (analytical grade)

Instrument: Liquid Chromatograph (Agilent 1200, Agilent Company, USA))

2) Experimental steps

2.1) Dissolution test in FassIF solution and FesSIF solution

a. Weigh an appropriate amount of the compound to be tested and use DMSO as a solvent to prepare a 10 mM stock solution. Precisely measure 10μL of stock solution (concentration 10mM, dissolved in DMSO) and 990μL of organic mixed solvent (usually DMSO: acetonitrile: ethanol = 1:1:1) in a 2mL sample bottle, mix well to obtain a clear 100μM sample solution , As a reference solution.

The preparation method of FassIF solution is as follows: Add 4.441g NaH ₂ PO ₄ ·2H ₂ O, 0.348g NaOH particles and 6.186g NaCl to 900mL ultrapure water, mix well, and add 1M NaOH to adjust the pH of the solution to 6.5±0.05, set with water Volume up to 1000mL, as the solution (A). Take 20 mL of solution (A), dissolve 0.161 g sodium taurosulfonate (NaTC) and 59 mg lecithin, stir vigorously overnight to form a clear micellar solution, add solution (A) to a volume of 100 mL, and refrigerate at 4°C for later use.

The preparation method of FesSIF solution is as follows: 20.2g NaOH particles, 43.25g glacial acetic acid and 59.37g sodium chloride are dissolved in an appropriate amount of ultrapure water and the volume is adjusted to 5L, and the pH is adjusted to 5.0 with 1M NaOH or 1M HCl as solution (A). Take 25mL of solution (A) to dissolve 0.80652g sodium taurosulfonate (NaTC) and 295.5mg lecithin, stir vigorously overnight to form a clear micellar solution, add solution (A) to a volume of 100mL, and refrigerate at 4°C for later use.

b. Dissolve 1 mg of the sample to be tested to 900 μL FassIF solution (or FesSIF solution), mix vigorously, and prepare two solutions in parallel; shake in a 37°C water bath for 24 hours, centrifuge at 4000 rpm for 30 minutes, and transfer the supernatant as the sample solution. To liquid chromatography analysis.

2.2) Dissolution test in pH 7.4 PBS buffer solution

a. Preparation of pH 7.4 PBS solution: Weigh 0.57g NaH ₂ PO ₄ ·2H ₂ O, 5.55g Na ₂ HPO ₄ ·12H ₂ O and 6.48g NaCl, add ultrapure water, adjust the pH with 1M NaOH or 1M HCl To 7.4±0.05, add water and make the volume to 1L. Store in a refrigerator at 4°C.

b. Preparation of compound PBS 7.4 solution: Weigh an appropriate amount of the test compound and dissolve it with DMSO or DMSO: acetonitrile: ethanol = 1:1:1 to prepare a 10 mM test compound stock solution. Precisely measure 10 μL of the test compound stock solution and 990 μL pH 7.4 PBS solution in a 2 mL sample bottle and mix them. The final solution DMSO concentration is 1% (v/v). Two copies of the solution were prepared in parallel, shaken on a flat bed at room temperature for 24 hours, centrifuged at 5000 rpm for 20 minutes, and the supernatant was transferred to a liquid chromatograph for analysis.

c. Preparation of reference solution: accurately measure 10μL of the sample stock solution to be tested (concentration 10mM, dissolved in DMSO) and 990μL of organic mixed solvent (usually DMSO: acetonitrile: ethanol = 1:1:1) in a 2mL sample bottle Mix well to obtain a clear 100μM sample solution. Filter with a 0.45μm organic phase microporous filter membrane (Zhejiang Oersaisi Technology Co., Ltd.), and then enter the filtrate into the liquid chromatograph for analysis.

3) Experimental results

Solubility (μM)=peak area of the sample/peak area of the reference×concentration of the reference solution (μM)×the dilution factor of the sample solution.

Take the average of the two measurements as the final solubility in FassIF solution, PBS solution 7.4, and FesSIF solution.

Table 5. Solubility of the compounds of the present disclosure.

Conclusion: The compound of the present disclosure has good solubility in FassIF, pH 7.4 PBS and FesSIF solutions.

Pharmacokinetic evaluation

Test Example 6. Pharmacokinetic test of the compound of the present disclosure

1. Summary

Using rats as the test animals, the LC/MS/MS method was used to determine the drug concentration in plasma at different times after the rats were given the compound of Example 3 by intragastric administration. To study the pharmacokinetic behavior of the compound of the present disclosure in rats and evaluate its pharmacokinetic characteristics.

2. Test plan

2.1 Experimental drugs

Example 3 compound.

2.2 Experimental animals

4 healthy adult SD rats, half male and half male, were purchased from Weitong Lihua Experimental Animal Co., Ltd.

2.3 Drug preparation

Weigh a certain amount of the compound of Example 3, add 5% DMSO, 5% Tween 80 and 90% normal saline to prepare a colorless and clear solution.

2.4 Administration

SD rats were fasted overnight and then administered by gavage. The dosage was 2 mg/kg and the dosage was 10.0 mL/kg.

3. Operation

Rats were intragastrically administered the compound of Example 3, and 0.2 mL of blood was collected from the orbit at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours before and after the administration, and placed in EDTA-K2kk for anticoagulation In the test tube, centrifuge at 4°C and 10,000 rpm for 1 minute, separate plasma within 1 hour, store at -20°C, and eat 2 hours after administration.

To determine the content of the test compound in rat plasma after gavage of different concentrations of drugs: Take 25μL of rat plasma at each time after administration, add 50μL of internal standard solution camptothecin, 200μL of acetonitrile, vortex and mix for 5 minutes, Centrifuge for 15 minutes (3600 rpm), and take 3.0 μL of the supernatant from the plasma sample for LC/MS/MS analysis.

4. Results of pharmacokinetic parameters

Table 6. Pharmacokinetic parameters of the compounds of the present disclosure

Conclusion: The compound of the present disclosure has good pharmacokinetic absorption and has obvious pharmacokinetic advantages.

Claims

A compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its Medicinal salt,

among them:

Ring A is selected from cycloalkyl or heterocyclyl;

Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, Substituted by one or more substituents among haloalkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Ring C is selected from heteroaryl or heterocyclyl;

Ring D is selected from heteroaryl or heterocyclic group;

G 1 and G 2 are the same or different, and each independently is a CR 6 or N atom;

G 3 is selected from CR 6 , N atom, O atom or S atom;

L 1 does not exist, or is selected from -C(O)-(CH 2 ) r -, O atom and S atom;

R 1 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a carboxyl group, an aldehyde group, and a cycloalkyl group. , Heterocyclyl, aryl and heteroaryl;

R 2 is selected from a hydrogen atom, an alkyl group and a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy , Hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;

R 3 is selected from a hydrogen atom, an alkyl group and a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy , Hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;

R 4 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxy, aldehyde, hydroxyl, hydroxyalkyl, cycloalkyl , Heterocyclyl, aryl and heteroaryl;

R 5 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a carboxyl group, an aldehyde group, a hydroxyl group, a hydroxyalkyl group, and an oxo group. , Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen , Alkyl, alkoxy, cyano, amino, nitro, carboxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl substituted by one or more substituents;

R 6 is selected from hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group and cycloalkyl group;

n is 0, 1, 2, 3, 4, 5 or 6;

s is 0, 1, 2 or 3;

t is 0, 1, 2, 3 or 4; and

r is 0, 1, 2 or 3.
The compound represented by the general formula (I) according to claim 1 or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from phenyl, 3- to 12-membered cycloalkyl, or 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 selected from Heteroatoms of N atom, O atom or S atom.
The compound represented by the general formula (I) according to claim 1 or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or its pharmaceutically acceptable salt,

among them
Selected from

R c are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxy, cycloalkyl, heterocycle Group, aryl and heteroaryl;

g is 0, 1, 2 or 3;

h is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

q is 0, 1, 2 or 3; y is 0, 1, 2, 3 or 4;

G 1 , G 2 and R 3 are as defined in claim 1.
The compound represented by the general formula (I) according to claim 1 or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, or diastereomer Body or its mixture form, or its pharmaceutically acceptable salt:

among them:

p is 0, 1, 2 or 3;

q is 0, 1, 2 or 3;

Ring A, ring C, ring D, G 1 , G 2 , L 1 , R 1 to R 5 , n, s, and t are as defined in claim 1.
The compound represented by the general formula (I) according to any one of claims 1 to 4 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G 1 and G 2 are N atoms.
The compound represented by the general formula (I) according to any one of claims 1 to 3 and 5 or its tautomer, meso, racemate, enantiomer, or non-pair Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by the general formula (IIIG) or tautomers, mesoisomers, racemates, enantiomers Conformer, diastereoisomer or its mixture form, or its pharmaceutically acceptable salt:

among them:

g is 0, 1, 2 or 3;

h is 0, 1, 2 or 3;

Ring A, ring C, ring D, L 1 , R 1 to R 5 , n, s, and t are as defined in claim 1.
The compound represented by the general formula (I) according to any one of claims 1 to 6 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 is -C(O)-(CH 2 ) r -; r is selected from 1, 2 or 3, preferably 1.
The compound represented by the general formula (I) according to any one of claims 1 to 7 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring D is a 7 to 11-membered bicyclic fused heterocyclic group, wherein the bicyclic fused heterocyclic group contains 1 to 5 selected from N atoms, O A hetero atom or S atom, more preferably a 6-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group, most preferably a 6-membered/5-membered bicyclic fused heterocyclic group, more preferably a 5-membered Heteroaryl/6-membered heterocyclic bicyclic fused heterocyclic group.
The compound represented by the general formula (I) according to any one of claims 1 to 8 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is indanyl.
The compound represented by the general formula (I) according to any one of claims 1 to 9 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring D is triazolopyridyl or triazolopiperidinyl, preferably the following structure:
The compound represented by the general formula (I) according to any one of claims 1 to 10 or its tautomer, meso, racemate, enantiomer, diastereomer A structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring C is a 5-membered heteroaryl group, which contains 1 to 3 heteroatoms selected from N atoms, O atoms or S atoms, preferably oxadiazole base.
The compound represented by the general formula (I) according to any one of claims 1 to 11 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is a hydrogen atom.
The compound represented by the general formula (I) according to any one of claims 1 to 12 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is a hydrogen atom.
The compound represented by the general formula (I) according to any one of claims 1 to 13 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is a hydrogen atom.
The compound represented by the general formula (I) according to any one of claims 1 to 14 or its tautomer, meso, racemate, enantiomer, diastereomer Conformer, or its mixture form, or its pharmaceutically acceptable salt, which is a compound represented by the general formula (IIIM) or its tautomer, meso, racemate, enantiomer , Diastereoisomers or their mixtures, or their pharmaceutically acceptable salts:

among them:

R 1a and R 1b are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a carboxyl group, an aldehyde group, Cycloalkyl, heterocyclyl, aryl and heteroaryl;

e is 0, 1, 2, 3 or 4;

f is 0, 1 or 2;

Ring B, R 3 , R 5 , and t are as defined in claim 1.
The compound represented by the general formula (I) according to any one of claims 1 to 15 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom.
The compound represented by the general formula (I) according to any one of claims 1 to 16 or its tautomer, meso, racemate, enantiomer, diastereomer Conformer or its mixture form, or its pharmaceutically acceptable salt, which is a compound represented by the general formula (III), (IIIa) or (IIIb) or its tautomer, meso, racemic Forms, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them:

g is 0, 1, 2 or 3;

h is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

q is 0, 1, 2 or 3;

R 1a and R 1b are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a carboxyl group, an aldehyde group, Cycloalkyl, heterocyclic, aryl and heteroaryl; preferably a hydrogen atom;

e is 0, 1, 2, 3 or 4;

f is 0, 1 or 2;

R 5 and t are as defined in claim 1.
The compound represented by the general formula (I) according to claim 17, or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, wherein p is 1; q is 1 or 2.
The compound represented by the general formula (I) according to claim 17, or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, wherein g is 0, 1, 2 or 3 and h is 0, 1, 2 or 3; provided that when g is 0, h is 2 or 3; when g is 1, h is 1 or 2; when g is 2, h is 1 or 0; when g is 3, h is 0.
The compound represented by the general formula (I) according to any one of claims 15 to 19 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b are hydrogen atoms.
The compound represented by the general formula (I) according to any one of claims 1 to 20 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 5 is a hydrogen atom.
The compound represented by the general formula (I) according to any one of claims 1 to 21 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is selected from any of the following compounds:
A compound represented by the general formula (IIIMA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of its form or its pharmacologically Salt used:

among them:

Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, Substituted by one or more substituents among haloalkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R 3 is selected from a hydrogen atom, an alkyl group and a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy , Hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;

R 1a and R 1b are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a carboxyl group, an aldehyde group, Cycloalkyl, heterocyclyl, aryl and heteroaryl;

R d is a hydrogen atom or an alkyl group; preferably a hydrogen atom;

e is 0, 1, 2, 3 or 4; and

f is 0, 1, or 2.
A compound represented by general formula (IIIA), (IIIaA) or (IIIbA) or its tautomer, meso, racemate, enantiomer, diastereomer, Or its mixture form or its pharmaceutically acceptable salt:

among them:

g is 0, 1, 2 or 3;

h is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

q is 0, 1, 2 or 3;

R 1a and R 1b are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a carboxyl group, an aldehyde group, Cycloalkyl, heterocyclic, aryl and heteroaryl; preferably a hydrogen atom;

e is 0, 1, 2, 3, or 4; and f is 0, 1, or 2.
A compound represented by the general formula (IIIMA) according to claim 23 or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, it is selected from any of the following compounds:
A method for preparing a compound represented by general formula (IIIM) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its The method of medicinal salt, the method includes:

Compounds of general formula (IIIMA) and compounds of general formula (IIIB) or their pharmaceutically acceptable salts react under basic conditions to obtain compounds of general formula (IIIM) or their tautomers, mesosomes, and exogenous Rotates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

Among them, R d is a hydrogen atom or an alkyl group; preferably a hydrogen atom;

Ring B, R 1a , R 1b , R 3 , R 5 , t, e, and f are as defined in claim 15.
A method for preparing a compound represented by the general formula (III) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its The method of medicinal salt, the method includes:

The compound of the general formula (IIIA) and the compound of the general formula (IIIB) or their pharmaceutically acceptable salts react under basic conditions to obtain the compound of the general formula (III) or its tautomers, mesosomes, and exogenous compounds. Rotates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

Wherein, R 1a , R 1b , R 5 , t, p, q, e, and f are as defined in claim 17.
A pharmaceutical composition comprising the compound represented by the general formula (I) according to any one of claims 1 to 22 or its tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
The compound represented by the general formula (I) according to any one of claims 1 to 22 or its tautomer, meso, racemate, enantiomer, diastereomer Use of the construct, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 28 in the preparation of an ATX inhibitor.
The compound represented by the general formula (I) according to any one of claims 1 to 22 or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 28 is used in the preparation of the prevention and/or treatment of fibrotic diseases, cancer, proliferative diseases, inflammatory diseases, autoimmune diseases Use in medicines for diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological diseases, metabolic diseases, myelodysplastic syndromes, abnormal angiogenesis-related diseases, and pain.
The compound represented by the general formula (I) according to any one of claims 1 to 22 or its tautomer, meso, racemate, enantiomer, diastereomer Use of the construct, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 28 in the preparation of a medicament for preventing and/or treating diseases with pathological characteristics of increased ATX expression.
The use according to claim 31, wherein the disease with the pathological characteristics of increased ATX expression is selected from: fibrotic diseases, cancer, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases Diseases, neurodegenerative diseases, dermatological diseases, metabolic diseases, myelodysplastic syndromes, abnormal angiogenesis-related diseases and pain; preferably fibrotic diseases and cancer.
The use according to claim 30 or 32, wherein the fibrotic disease is selected from pulmonary fibrosis, idiopathic pulmonary fibrosis, liver fibrosis and scleroderma, and the cancer is selected from kidney cancer and pancreatic cancer .