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EP-4737457-A1 - POLYSUBSTITUTED MACROCYCLIC COMPOUND, AND PREPARATION METHOD THEREFOR AND USE THEREOF

EP4737457A1EP 4737457 A1EP4737457 A1EP 4737457A1EP-4737457-A1

Abstract

Provided are a compound as represented by general formula (I), or a racemate thereof, or an isomer thereof, or a pharmaceutically acceptable salt thereof, and a method for treating a plurality of specific diseases or conditions using the same.

Inventors

  • WU, JUNJUN
  • LU, Yinsuo
  • XING, WEI
  • XIAO, YING
  • HUANG, YIQIANG
  • WANG, Liulin

Assignees

  • Shenzhen Salubris Pharmaceuticals Co., Ltd.

Dates

Publication Date
20260506
Application Date
20240628

Claims (10)

  1. A compound represented by general formula (I), or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, wherein: X is selected from the group consisting of hydrogen, halogen, and cyano; Y is selected from the group consisting of hydrogen, halogen, and cyano; Z is selected from the group consisting of hydrogen, halogen, and cyano; and at least two of X, Y, and Z are not hydrogen; W is selected from the group consisting of C and N, wherein when W is N, R 1 is absent; T 1 and T 2 are selected from the group consisting of C and N, wherein when T 1 is N, R 2c is absent, when T 2 is N, R 2b is absent, and T 1 and T 2 are not both N; ring A is selected from the group consisting of a substituted or unsubstituted benzene ring and a substituted or unsubstituted pyrazole ring, wherein a substituent is selected from the group consisting of halogen, cyano, alkyl, and haloalkyl; R 1 is selected from the group consisting of halogen, haloalkyl, and cyano; R 2a , R 2b , and R 2c are each independently selected from the group consisting of hydrogen, halogen, and alkoxy; R 3 is selected from the group consisting of alkyl, haloalkyl, alkoxy, -(CH 2 ) n -cycloalkyl, and -(CH 2 ) n -heterocycloalkyl, wherein n is 0 or 1; and R 4 is selected from the group consisting of hydrogen and halogen.
  2. The compound, or the isomer thereof, or the racemate thereof, or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of a compound represented by formula (Ia) or formula (Ib), or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof: X is selected from the group consisting of hydrogen, halogen, and cyano; Y is selected from the group consisting of hydrogen, halogen, and cyano; Z is selected from the group consisting of hydrogen, halogen, and cyano; and at least two of X, Y, and Z are not hydrogen; T 1 and T 2 are selected from the group consisting of C and N, wherein when T 1 is N, R 2c is absent, when T 2 is N, R 2b is absent, and T 1 and T 2 are not both N; R 1 is selected from the group consisting of halogen, haloalkyl, and cyano; R 2a , R 2b , and R 2c are each independently selected from the group consisting of hydrogen, halogen, and alkoxy; R 3 is selected from the group consisting of alkyl, haloalkyl, alkoxy, -(CH 2 ) n -cycloalkyl, and -(CH 2 ) n -heterocycloalkyl, wherein n is 0 or 1; R 4 is selected from the group consisting of hydrogen and halogen; and R 5 is selected from the group consisting of alkyl and haloalkyl.
  3. The compound, or the isomer thereof, or the racemate thereof, or the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the alkyl is C 1-6 alkyl, the C 1-6 alkyl being selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl; and the alkoxy is C 1-6 alkoxy, the C 1-6 alkoxy being selected from the group consisting of methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentoxy, 1,2-dimethylpropoxy, isopentoxy, neopentoxy, n-hexyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy, neohexyloxy, 2-methylpentyloxy, 1,2-dimethylbutoxy, and 1-ethylbutoxy.
  4. The compound, or the isomer thereof, or the racemate thereof, or the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the halogen is selected from the group consisting of fluorine, chlorine, bromine, and iodine.
  5. The compound, or the isomer thereof, or the racemate thereof, or the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the haloalkyl is an alkyl in which one or more hydrogens are replaced by halogen, the halogen being selected from the group consisting of fluorine, chlorine, bromine, and iodine.
  6. The compound, or the isomer thereof, or the racemate thereof, or the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the cycloalkyl is C 3-6 cycloalkyl, the C 3-6 cycloalkyl being selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; and the heterocycloalkyl is a cycloalkyl in which one or more carbon atoms are replaced by a heteroatom, the heteroatom being selected from the group consisting of nitrogen, oxygen, and sulfur, and a number of the heteroatom being one or more.
  7. The compound, or the isomer thereof, or the racemate thereof, or the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: W is selected from the group consisting of C and N, wherein when W is N, R 1 is absent; X is selected from the group consisting of hydrogen and fluorine; Y is selected from the group consisting of hydrogen and fluorine; Z is selected from the group consisting of hydrogen and fluorine; and at least two of X, Y and Z are not hydrogen; T 1 and T 2 are selected from the group consisting of C and N, wherein when T 1 is N, R 2c is absent, when T 2 is N, R 2b is absent, and T 1 and T 2 are not both N; R 1 is selected from the group consisting of chlorine, trifluoromethyl, and difluoromethyl; R 2a , R 2b , and R 2c are each independently selected from the group consisting of hydrogen, methoxy, fluorine, and chlorine; R 3 is methyl; R 4 is selected from the group consisting of hydrogen and fluorine; and R 5 is selected from the group consisting of methyl and difluoromethyl.
  8. The compound, or the isomer thereof, or the racemate thereof, or the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound is selected from the group consisting of: No. Compound Structure No. Compound Structure 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 .
  9. A pharmaceutical composition, comprising a therapeutically effective amount of the compound, or the isomer thereof, or the racemate thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, and a pharmaceutically acceptable carrier.
  10. Use of the compound, or the isomer thereof, or the racemate thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 in the manufacture of a medicament for treating an FXIa-related disease, preferably a thrombus-related disease.

Description

TECHNICAL FIELD The present application belongs to the technical field of chemical pharmaceuticals, and provides a polysubstituted macrocyclic compound and a preparation method therefor and use thereof, as an inhibitor of selective Factor XIa (FXIa). The present application also relates to pharmaceutical compositions comprising these compounds and the use of these compounds in medicaments for treating diseases such as thromboembolism. BACKGROUND Cardiovascular and cerebrovascular diseases such as cerebrovascular diseases, cerebral infarction, myocardial infarction, coronary heart disease, and arteriosclerosis claim nearly 12 million lives worldwide each year, close to one-quarter of the total global death toll, making them the number one enemy of human health. In China, the number of deaths from cardiovascular diseases exceeds 2.6 million annually, with 75% of surviving patients suffering from disability, including over 40% with severe disability. Thrombotic problems caused by cardiovascular and cerebrovascular diseases, diabetes, and their complications have become an urgent issue to be resolved today. The human blood coagulation process consists of the intrinsic pathway, the extrinsic pathway, and the common pathway (Annu. Rev. Med. 2011.62:41-57). It is a cascade reaction where the process is continuously strengthened and amplified through the sequential activation of multiple zymogens. The coagulation cascade is initiated by the intrinsic pathway (also known as the contact activation pathway) and the extrinsic pathway (also known as the tissue factor pathway) to generate FXa, which then proceeds through the common pathway to generate thrombin (FIIa), ultimately forming fibrin. The intrinsic pathway refers to the process where Factor XII is activated to form the XIa-VIIIa-Ca2+-PL complex and activates Factor X, while the extrinsic coagulation pathway is the process where tissue factor (TF) is released to form the TF-FVIIa-Ca2+ complex and activates Factor X. The common pathway refers to the process after Factor Xa is formed, where the two pathways merge, activating prothrombin and ultimately generating fibrin. FXI is essential for maintaining the intrinsic pathway and plays a key role in the amplification process of the coagulation cascade. In the coagulation cascade, thrombin can feedback-activate FXI, and activated FXI (FXIa) in turn promotes the massive production of thrombin, thereby amplifying the coagulation cascade. Therefore, antagonists of FXI are widely developed for the treatment of various thromboses. Traditional anticoagulant drugs, such as warfarin, heparin, low molecular weight heparin (LMWH), and recently marketed new drugs, such as FXa inhibitors (rivaroxaban, apixaban, etc.) and thrombin inhibitors (dabigatran etexilate, hirudin, etc.), have good effects on reducing thrombus formation and occupy a large cardiovascular and cerebrovascular market due to their significant effectiveness. However, their side effects are becoming increasingly significant, among which the "bleeding risk" is one of the most severe and primary concerns (N Engl J Med 1991;325:153-8, Blood.2003;101:4783-4788). Studies have found that in thrombosis models, inhibiting the FXIa factor can effectively inhibit thrombus formation, but in more severe thrombotic conditions, the role of FXIa is minimal (Blood.2010;116(19):3981-3989). Clinical statistics show that increasing the amount of FXIa increases the prevalence of VTE (Blood 2009;114:2878-2883), while those with severe FXIa deficiency have a reduced risk of DVT (Thromb Haemost 2011;105:269-273). FXIa, as an emerging target for inhibiting thrombosis, has been the subject of several patent applications disclosing compounds with FXIa inhibitory activity, including WO9630396, WO9941276, WO2013093484, WO2004002405, WO2013056060, WO2017005725, WO2017/023992, WO2018041122, etc. SUMMARY The present application provides a series of macrocyclic derivatives, a preparation method therefor, and use thereof in medicine. Specifically, in a first aspect, the present application provides a compound represented by general formula (I), or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof: In a second aspect, the present application further provides a pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of the preceding, and a pharmaceutically acceptable carrier. In a third aspect, the present application also provides a medical use of a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, specifically, use in the manufacture of a medicament for treating a condition as an inhibitor of selective Factor XIa (FXIa), and use in the manufacture of a medicament for treating a disease such as thromboembolism. Specifically, the present application is achieved through the following technical solution