Spirocyclic derivatives, pharmaceutical compositions thereof, processes for their preparation and uses thereof

Abstract

This disclosure relates to a spirocyclic derivative and its uses, specifically providing a class of spirocyclic compounds of formula (I) or pharmaceutically acceptable salts thereof, which can be used in the preparation of medicaments, particularly medicaments for the prevention and / or treatment of FXIa-mediated diseases or conditions. The groups in formula (I) are as defined in the specification.

Description

[0001] This disclosure claims priority to an earlier application filed on May 16, 2022, with China National Intellectual Property Administration, patent application number 202210533778.3, entitled "Spirocyclic Derivatives and Pharmaceutical Compositions Thereof, Preparation Methods and Uses thereof"; the entire contents of the aforementioned earlier application are incorporated herein by reference. Technical Field

[0002] This disclosure pertains to the pharmaceutical field, specifically relating to a spirocyclic derivative as an FXIa inhibitor, its pharmaceutical composition, preparation method, and uses. Background Technology

[0003] Blood coagulation is the result of the coordinated activation of various plasma proteins, cofactors, and platelets. This cascade reaction is divided into the intrinsic (contact activation) pathway, the extrinsic (tissue factor activation) pathway, and the common (prothrombin and thrombin production) pathway. The most important physiological process in blood coagulation is the activation of tissue factor. Tissue factor forms a complex with factor VIIa, catalyzing the activation of factor X (FX). Activated FXa then cleaves prothrombin to produce activated thrombin (FIIa). Activated thrombin (FIIa), as the central catalytic enzyme in the coagulation process, catalyzes the cleavage of fibrinogen into fibrin, thus playing a role in coagulation. This extrinsic pathway involves fewer enzymes and has a rapid effect. The intrinsic pathway is the body's inherent coagulation pathway, which activates factor 12 (FXIIa), factor XIa (FXIa), factor IXa (FIXa), and factor VIIIa (FVIIIa) through a cascade reaction, thereby activating factor Xa (FXa) and the downstream central thrombin (FIIa). Thrombin, in turn, activates factor XIa (FXIa), producing an amplification effect and accelerating coagulation. The intrinsic pathway involves more enzymes in coagulation, all of which originate from the blood, and generally takes longer to show results.

[0004] FXa plays a crucial role in the entire coagulation process. As a downstream co-regulator of both extrinsic and intrinsic coagulation pathways, its antagonists are widely used for the prevention and treatment of various types of thrombosis. Several FXa antagonists are currently on the market, dominating the cardiovascular drug market due to their significant efficacy. However, they also have a relatively high probability of side effects, the most prominent being the risk of bleeding. To address the bleeding problem, FXa from the intrinsic pathway has become a research hotspot for major companies and institutions.

[0005] The potential of FXIa as a safer anticoagulant target was demonstrated in hemophilia C patients. FXIa-deficient hemophilia C patients did not experience active bleeding, a stark contrast to the bleeding prevalence in hemophilia A (factor VIIIa deficiency) and hemophilia B (factor IXa deficiency). Although a limited sample size (115 patients) showed that FXIa deficiency did not protect patients from acute myocardial ischemia, it did reveal a lower incidence of ischemic stroke and deep vein thrombosis.

[0006] Gene knockout mouse experiments revealed that selective knockout of common pathway factors (FX, FV, and FIX) and exogenous factors (tissue factor and FVII) in mice leads to prenatal or perinatal lethality. While FVIII and FIX knockout mice can survive, they frequently experience severe bleeding, similar to hemophilia A and B in humans where the absence of FVIII and FIX causes a severe bleeding risk. Mice with selective FXI knockout, however, can reproduce normally. Furthermore, FXI deficiency protects mice from ferric chloride-induced arterial thrombosis. Simultaneously, FXI deficiency does not affect bleeding or hemostasis in mice. Therefore, this experiment demonstrates that inhibiting FXI not only prevents thrombosis but is also safe and well-tolerated.

[0007] Numerous antibodies, small molecules, and antisense nucleotides targeting FXIa have demonstrated in animals and clinical settings that inhibiting FXIa can effectively prevent thrombosis. Compared to existing antithrombotic drugs (such as enoxaparin), the risk of bleeding is significantly reduced. This indicates that FXIa is closely linked to thrombotic diseases in humans; inhibiting FXIa has a significant anticoagulant effect without a marked bleeding tendency, thus greatly reducing the bleeding risk during clinical anticoagulation. Therefore, developing drugs with good anticoagulant effects and few side effects is of significant research importance.

[0008] Currently, publicly disclosed patents for FXIa inhibitors include WO2013093484, WO2015120777, and WO2016093285. Summary of the Invention

[0009] This disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0010]

[0011] in:

[0012] R 1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, cyano, -C(O)C 1-6 Alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic and 5- to 6-membered heteroaryl, wherein the C1-6 Alkyl, C 1-6 Alkoxy, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic and 5- to 6-membered heteroaryl groups are optionally surrounded by one or more R 1A Replaced;

[0013] R 1A Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyl, cyano, and carboxyl groups;

[0014] R 2 It is H or halogen;

[0015] X is N or CR 6 ;

[0016] R 6 Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyl alkyl, cyano, and 3- to 8-membered cycloalkyl;

[0017] Ring A is a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocyclic group;

[0018] Each R 3 They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyl and cyano groups;

[0019] Ring B is a 5- to 6-membered heteroaryl group;

[0020] Each R 4 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyl and cyano groups;

[0021] The ring C is selected from 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclic, 6- to 14-membered aryl, and 5- to 14-membered heteroaryl;

[0022] Each R 5 They may be the same or different, and each is independently selected from halogens, C 1-6Alkyl, oxo, C 1-6 Alkoxy, cyano, hydroxy, -NR 7 R 8 -C(O)NR 7 R 8 -C(S)NR 7 R 8 -C(O)OR 9 -NHC(O)R 10 -NHC(O)OR 9 -NHC(O)R 10 -S(O)R 11 -S(O)2R 11 , 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic groups, wherein the C 1-6 Alkyl or C 1-6 Alkoxy groups are optionally surrounded by one or more R groups. 5A Replaced;

[0023] R 5A Selected from halogens, hydroxyl groups, and -NR 7 R 8 -C(O)NR 7 R 8 -C(S)NR 7 R 8 -C(O)OR 9 -NHC(O)R 10 -NHC(O)OR 9 -NHC(O)R 10 -S(O)R 11 -S(O)2R 11 3 to 8-membered cycloalkyl groups and 3 to 8-membered heterocyclic groups;

[0024] R 7 and R 8 They are the same or different, and each is independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 8-membered cycloalkyl groups;

[0025] R 9 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 8-membered cycloalkyl groups;

[0026] R 10 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 8-membered cycloalkyl groups;

[0027] R 11 Selected from C 1-6 Alkyl, C 1-6Halogenated alkyl groups and 3- to 8-membered cycloalkyl groups;

[0028] n is selected from 0, 1, 2, 3, 4, 5, and 6;

[0029] m is selected from 0, 1, and 2; and

[0030] p is selected from 0, 1, 2, 3, 4, and 5.

[0031] In some embodiments, this disclosure provides compounds of formula (I-1) or formula (I-2) or pharmaceutically acceptable salts thereof.

[0032]

[0033] in:

[0034] Ring A, Ring B, Ring C, R 1 R 2 R 3 R 4 R 5 X, n, m and p are as defined in equation (I).

[0035] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1) or formula (I-2) or pharmaceutically acceptable salts thereof, wherein ring B is a 5-membered heteroaryl group.

[0036] In some embodiments, this disclosure provides compounds of formula (IM) or pharmaceutically acceptable salts thereof.

[0037]

[0038] in:

[0039] Z 1 For N or CR 4a Z 2 For N or CR 4b ;R 4a and R 4b They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0040] n is selected from 0, 1, 2, 3, and 4;

[0041] Ring A, Ring C, R 1 R 2 R 3 R 5 X and p are as defined by equation (I).

[0042] In some embodiments, this disclosure provides compounds of formula (I), formula (IM), formula (I-1) or formula (I-2) or pharmaceutically acceptable salts thereof, wherein ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, tetrahydrofuranyl, aziridine, and tetrahydropyrroleyl.

[0043] In some embodiments, this disclosure provides compounds of formula (I), formula (IM), formula (I-1) or formula (I-2) or pharmaceutically acceptable salts thereof, wherein ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl and oxacyclobutyl.

[0044] In some embodiments, this disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0045]

[0046] in:

[0047] Z 1 For N or CR 4a Z 2 For N or CR 4b ;R 4a and R 4b They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0048] n is selected from 0, 1, 2, 3, and 4;

[0049] Ring C, R 1 R 2 R 3 R 5 X and p are as defined by equation (I).

[0050] In some embodiments, this disclosure provides compounds of formula (II-1) or formula (II-2) or pharmaceutically acceptable salts thereof.

[0051]

[0052] in:

[0053] Ring C, R 1 R 2 R 3 R 5 Z 1 Z 2 X and p are as defined in equation (II).

[0054] In some embodiments, this disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0055]

[0056] in:

[0057] Y is selected from O, NH and CR. 3e R 3f ;

[0058] R 3a R 3b R 3c R 3d R 3e and R 3f They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0059] Z 1 For N or CR 4a Z 2 For N or CR 4b ;R 4a and R 4b They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0060] Ring C, R 1 R 2 R 5 X and p are as defined by equation (I).

[0061] In some embodiments, this disclosure provides compounds of formula (III-1) or formula (III-2) or pharmaceutically acceptable salts thereof.

[0062]

[0063] in:

[0064] Ring C, R 1 R 2 R 3a R 3b R 3c R 3d R 5 Z 1 Z 2 X, Y and p are as defined in equation (III).

[0065] In some embodiments, this disclosure provides a compound of formula (IV) or a pharmaceutically acceptable salt thereof.

[0066]

[0067] in:

[0068] Z 1 For N or CR 4a Z 2 For N or CR 4b ;R 4a and R 4b They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0069] Ring C, R 1 R 2 R 3 R 5 X, n, and p are as defined in equation (I).

[0070] In some embodiments, this disclosure provides compounds of formula (IV-1) or formula (IV-2) or pharmaceutically acceptable salts thereof.

[0071]

[0072] in:

[0073] Ring C, R 1 R 2 R 3 R 5 Z 1 Z 2 X and p are as defined by equation (IV).

[0074] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein for R 4a and R 4b They may be the same or different, and each is independently H or halogen; the a end is connected to the spiro ring portion.

[0075] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein for R 4a and R 4bThey may be the same or different, and each is independently selected from H, F and Cl; the a end is connected to the helical part.

[0076] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2) or pharmaceutically acceptable salts thereof, wherein the ring C is selected from phenyl, 5- to 6-membered heteroaryl, benzo5- to 10-membered cycloalkyl, benzo5- to 10-membered heterocyclic, benzo5- to 10-membered heteroaryl, pyrido5- to 10-membered cycloalkyl, pyrido5- to 10-membered heterocyclic, and pyrido5- to 10-membered heteroaryl.

[0077] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2) or pharmaceutically acceptable salts thereof, wherein the ring C is selected from phenyl, 5- to 6-membered heteroaryl, benzo5- to 6-membered heterocyclic, benzo5- to 6-membered heteroaryl, pyrido5- to 6-membered heterocyclic, and pyrido5- to 6-membered heteroaryl.

[0078] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein Selected from

[0079] When ring C is a multi-ring, R 5 It can replace H on any ring, and H on NH in the ring can be replaced by R. 5 replace;

[0080] R 5 p is as defined in equation (I).

[0081] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein Selected from

[0082] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein Selected from

[0083] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein R 1 Selected from C 1-3 Alkyl, C 1-3 Alkoxy, cyano, -C(O)C 1-3 Alkyl and 5-membered heteroaryl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy and 5-membered heteroaryl groups are optionally surrounded by one or more R 1A Replaced;

[0084] R 1A Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl, cyano, and carboxyl groups.

[0085] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein R 1 Selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups and cyano groups.

[0086] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein R 1 It is a cyano group.

[0087] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein R 1 C 1-3 Alkyl group.

[0088] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein R 1 -C(O)C 1-3 alkyl.

[0089] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein R 1 It is a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally coupled with one or more R groups. 1A Replaced; R 1A Selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl, cyano, and carboxyl groups.

[0090] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein R 1 for R 1A1 Selected from H, halogens, C1-3 Alkyl, C 1-3 Halogenated alkyl, cyano, and carboxyl groups.

[0091] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein R 1 Acetyl, propionyl, difluoromethyl, trifluoromethoxy,

[0092] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein R 2 It can be H or F.

[0093] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein X is N.

[0094] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein X is a compound. 6 ;R 6 It is H or halogen.

[0095] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein X is CH.

[0096] In some embodiments, this disclosure provides a compound of formula (I), formula (I-1), or formula (I-2) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, tetrahydrofuranyl, azacyclobutyl, and tetrahydropyrroleyl; ring B is... R 4a and R 4b They may be the same or different, and each is independently H, F or Cl; the a-terminus is connected to the spirocyclic moiety; the ring C is selected from phenyl, 5- to 6-membered heteroaryl, benzo5-6-membered heterocyclic, benzo5-6-membered heteroaryl, pyrido5-6-membered heterocyclic and pyrido5-6-membered heteroaryl.

[0097] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein R 3 It is F.

[0098] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein R 3 For H.

[0099] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), and formula (II-2), or pharmaceutically acceptable salts thereof, wherein R 4 It can be F or Cl.

[0100] In some embodiments, this disclosure provides compounds of formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein for R 4a and R 4b They may be the same or different, and each is independently H or F; the a-terminus is connected to the spirocyclic moiety; the ring C is selected from phenyl, 5- to 6-membered heteroaryl, benzo5-6-membered heterocyclic, benzo5-6-membered heteroaryl, pyrido5-6-membered heterocyclic and pyrido5-6-membered heteroaryl.

[0101] In some embodiments, this disclosure provides compounds of formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein for R 4a and R 4b They may be the same or different, and each is independently H or F; end a is connected to the helical part; Selected from

[0102] When ring C is a multi-ring, R 5 It can replace H on any ring, and H on NH in the ring can be replaced by R. 5 replace;

[0103] R 5 p is as defined in equation (I).

[0104] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein each R 5 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, oxo, cyano, hydroxyl, -NR 7 R 8 and 3 to 8-membered cycloalkyl groups, wherein the C 1-6 Alkyl groups are optionally surrounded by one or more R 5A Replaced;

[0105] R 5A Selected from halogens, hydroxyl groups, and -NR 7 R 8 and 3- to 8-membered cycloalkyl groups;

[0106] R 7 and R 8 They are the same or different, and each is independently H or C. 1-6 alkyl.

[0107] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein each R5 They may be the same or different, and each is independently selected from halogens, hydroxyl groups, and C. 1-6 Alkyl, oxo, and -NH2.

[0108] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein each R 5 They may be the same or different, and each is independently selected from F, hydroxyl, methyl, oxo and -NH2.

[0109] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein p is selected from 0, 1, and 2.

[0110] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), or formula (IV-2), or pharmaceutically acceptable salts thereof, wherein m is selected from 0 and 1.

[0111] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (IV), formula (IV-1) or formula (IV-2) or pharmaceutically acceptable salts thereof, wherein n is selected from 0, 1 and 2.

[0112] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (IV), formula (IV-1) or formula (IV-2) or pharmaceutically acceptable salts thereof, wherein n is 0.

[0113] In some embodiments, this disclosure provides compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (IV), formula (IV-1) or formula (IV-2) or pharmaceutically acceptable salts thereof, wherein n is 2.

[0114] Specific compounds exemplified in this disclosure include, but are not limited to, the structures in Table A below:

[0115] Table A

[0116]

[0117]

[0118]

[0119]

[0120]

[0121] The specific compounds exemplified by this disclosure also include, but are not limited to, the structures in Table B below:

[0122] Table B

[0123]

[0124]

[0125] In another aspect of this disclosure, isotopic labels of compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), and Table A or Table B are provided.

[0126] In another aspect of this disclosure, isotope labels for compounds of formulas (I), (I-1), (I-2), (IM), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), or those shown in Table A or Table B are provided, wherein the isotope label is deuterium (D or 2 H) replaces hydrogen ( 1 H).

[0127] In another aspect of this disclosure, compounds of formula (IA) or salts thereof are provided.

[0128]

[0129] Among them: ring A, ring C, R 1 R 2 R 3 R 5 X, n, and p are defined as in equation (IM).

[0130] In another aspect of this disclosure, compounds of formula (IIA) or salts thereof are provided.

[0131]

[0132] Among them: rings C and R 1 R 2 R 3 R 5 X, n and p are as defined in equation (II).

[0133] In another aspect of this disclosure, compounds of formula (IIIA) or salts thereof are provided.

[0134]

[0135] Among them: rings C and R 1 R 2 R 3a R 3b R 3c R 3d R 5 X, Y and p are as defined in equation (III).

[0136] In another aspect of this disclosure, compounds of formula (IVA) or salts thereof are provided.

[0137]

[0138] Among them: rings C and R 1 R 2 R 3 R 5 X, n, and p are as defined in equation (IV).

[0139] In another aspect of this disclosure, compounds of formula (IB) or salts thereof are provided.

[0140]

[0141] Where: R G It is a leaving group; preferably, R G Selected from Cl, Br, OTs, OTf and OMs;

[0142] Rings A and R 1 R 2 R 3 X and n are as defined in equation (I).

[0143] In another aspect of this disclosure, compounds of formula (IIB) or salts thereof are provided.

[0144]

[0145] in:

[0146] R G It is a leaving group; preferably, R G Selected from Cl, Br, OTs, OTf and OMs;

[0147] R 1 R 2 R 3 X and n are as defined in equation (II).

[0148] In another aspect of this disclosure, compounds of formula (IIIB) or salts thereof are provided.

[0149]

[0150] in:

[0151] R G It is a leaving group; preferably, R G Selected from Cl, Br, OTs, OTf and OMs;

[0152] R 1 R 2 R 3a R 3b R 3c R 3d X and Y are as defined in equation (III).

[0153] In another aspect of this disclosure, compounds of formula (IVB) or salts thereof are provided.

[0154]

[0155] in:

[0156] R G It is a leaving group; preferably, R G Selected from Cl, Br, OTs, OTf and OMs;

[0157] R 1 R 2 R 3 X and n are as defined in equation (IV).

[0158] In another aspect of this disclosure, a method is provided for preparing a compound of formula (ID) or a pharmaceutically acceptable salt thereof, comprising the following steps,

[0159]

[0160] The compound represented by formula (IA) or its salt reacts with ammonium acetate to undergo cyclization, yielding the compound represented by formula (ID) or its pharmaceutically acceptable salt.

[0161] Among them: ring A, ring C, R 1 R 2 R 3 R 5 X, n, and p are defined as in equation (I).

[0162] In another aspect of this disclosure, a method for preparing a compound of formula (IE) or a pharmaceutically acceptable salt thereof is provided, comprising the following steps,

[0163]

[0164] The compound represented by formula (IB) or its salt reacts with formula (IC) in a ring-closure reaction to give the compound represented by formula (IE) or its pharmaceutically acceptable salt.

[0165] Among them: ring A, ring C, R 1 R 2 R 3 R 5 X, n, and p are defined as in equation (I).

[0166] In another aspect of this disclosure, a method is provided for preparing a compound of formula (IM) or a pharmaceutically acceptable salt thereof, when R 4a or R 4b When H is not present, the compound represented by formula (IM) can be obtained by conversion using formula (ID) or formula (IE).

[0167] The compounds represented by formula (II), formula (III) or formula (IV), or their pharmaceutically acceptable salts, can be prepared by referring to the preparation method of the compounds represented by formula (IM).

[0168] In another aspect of this disclosure, a pharmaceutical composition is provided comprising at least one therapeutically effective amount of the compound provided herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0169] In another aspect of this disclosure, use is also provided for the use of compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), the compounds shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, for the preparation of a medicament for inhibiting factor XIa.

[0170] This disclosure also provides the use of compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), the compounds shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions comprising them, in the preparation of medicaments for the prevention and / or treatment of XIa factor-mediated diseases or conditions.

[0171] This disclosure also provides the use of compounds of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), the compounds shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions comprising them, in the preparation of medicaments for the prevention and / or treatment of blood coagulation-related diseases; preferably, the blood coagulation-related diseases are thrombosis or thromboembolic diseases or cardiovascular and cerebrovascular diseases.

[0172] This disclosure also provides a method for inhibiting factor XIa, comprising administering to a desired patient a therapeutically effective amount of a compound of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the aforementioned compounds.

[0173] This disclosure also provides a method for preventing and / or treating XIa factor-mediated diseases or conditions, comprising administering to a desired patient a therapeutically effective amount of a compound of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the aforementioned compounds.

[0174] This disclosure also provides a method for preventing and / or treating blood coagulation-related diseases, comprising administering to a desired patient a therapeutically effective amount of a compound of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing; preferably, the blood coagulation-related disease is thrombosis or thromboembolic disease or cardiovascular disease.

[0175] This disclosure also provides a compound of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament.

[0176] This disclosure also provides a compound of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, which is used as an FXIa inhibitor.

[0177] This disclosure also provides a compound of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing, for use as a medicament for the prevention and / or treatment of XIa factor-mediated diseases or conditions.

[0178] This disclosure also provides the use of a compound of formula (I), formula (I-1), formula (I-2), formula (IM), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing, as a medicament for the prevention and / or treatment of blood clotting-related diseases; preferably, the blood clotting-related diseases are thrombosis or thromboembolic diseases or cardiovascular and cerebrovascular diseases.

[0179] The diseases or conditions mediated by factor XIa described in this disclosure are blood coagulation-related diseases, preferably thrombotic or thromboembolic diseases or cardiovascular and cerebrovascular diseases.

[0180] This disclosure of “thrombotic or thromboembolic conditions” includes conditions occurring in the arterial and venous vascular systems and treatable with the compounds of this disclosure, particularly conditions in the coronary arteries of the heart, such as acute coronary syndrome (ACS), myocardial infarction with and without ST-segment elevation (STEMI), stable angina, unstable angina, restenosis and re-occlusion after coronary interventions such as angioplasty, stenting, or aortocoronary artery bypass grafting, and other thrombotic or thromboembolic conditions in the blood vessels that lead to peripheral artery occlusive disease, pulmonary embolism, venous thromboembolism, venous thrombosis, particularly in the deep veins of the lower extremities and renal veins, transient ischemic attack, and thrombotic stroke and thromboembolic stroke.

[0181] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0182] In some embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compounds of formula (I), (I-1), (I-2), (IM), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), or those shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or isotopic labels thereof. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compounds of formula (I), (I-1), (I-2), (IM), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), or those shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or isotopic labels thereof. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% of the aforementioned compounds of formula (I), (I-1), (I-2), (IM), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), or those shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or isotopic labels thereof. In some embodiments, the pharmaceutical composition contains 1% to 99% of the aforementioned compounds of formula (I), (I-1), (I-2), (IM), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), or those shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or isotopic labels thereof.

[0183] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable one or more excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable one or more excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable one or more excipients.

[0184] When administered as a medicine, the disclosed compounds may be given in the form of pharmaceutical compositions. These compositions may be prepared in a manner well known in the pharmaceutical art and may be administered via a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. Administration may be local (e.g., transdermal, skin, eye, and mucous membrane delivery, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or blowing of powders or aerosols, including via nebulizers; intratracheal, intranasal), oral, or parenteral administration. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration may be in the form of a single large dose or via, for example, a continuous infusion pump.

[0185] In preparing the compositions disclosed herein, the active ingredient is typically mixed with an excipient, and the compositions may be in the following forms: tablets, pills, powders, lozenges, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or soluble in liquid solvents), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0186] The term "excipient" as used in this disclosure refers to components other than the active ingredient, such as diluents, fillers, absorbents, wetting agents, binders, disintegrants, and lubricants.

[0187] On the other hand, pharmaceutically acceptable salts of the compounds described in this disclosure may be inorganic or organic salts, and if these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form base addition salts; and if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form inner salts.

[0188] On the other hand, the compounds disclosed herein may exist in specific geometric or stereoisomeric forms. For example, cis and trans isomers, (D) or (+) isomers (“(D)” or “(+)” indicates dextrorotatory), (L) or (-) isomers (“(L)” or “(-)” indicates levorotatory), (R)- and (S)- enantiomers, diastereomers, racemic mixtures and other mixtures, as well as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure.

[0189] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that no configuration has been specified. The absolute configuration of a stereocenter, i.e., if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations.

[0190] key This indicates that the configuration is not specified, including cis (E) or trans (Z) configurations.

[0191] Furthermore, the compounds and intermediates of this disclosure may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. "Tautomer" refers to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactamimide isomerization. All tautomer forms of the compounds in this disclosure are within the scope of this disclosure. The name of a compound named in a single manner does not exclude any tautomer. For example... Specifically, regarding the compounds in this disclosure, for example Interconvertible If such a situation exists, it should be understood that either the individual forms of the two tautomers or the mixture of the two tautomers are within the scope of this disclosure.

[0192] This disclosure also includes compounds of this disclosure with the same structure as those described herein, but with one or more atoms replaced by isotopes of atoms having atomic weights or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this disclosure include isotopes of H, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure.

[0193] The "therapeutic effective amount" of this disclosure refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians seek in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) inhibition of disease: e.g., inhibition of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms). For the purposes of this disclosure, "therapeutic effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect. The determination of an effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate effective amount in a particular case can be determined by a person skilled in the art based on routine testing.

[0194] "Pharmaceutical acceptable" in this disclosure means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0195] In this disclosure, "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with human being being the most preferred.

[0196] Terminology Explanation

[0197] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0198] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms (C 1-6Alkyl groups. Non-limiting examples of alkyl groups 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, and their various branched isomers. Alkyl groups can be substituted or unsubstituted.

[0199] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described herein. Preferably, alkoxy groups (C-) contain 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms. 1-12 Alkoxy groups, more preferably alkoxy groups containing 1 to 6 carbon atoms (C 1-6 Alkoxy groups. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be substituted or unsubstituted.

[0200] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) carbon atoms or 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably 3 to 6 carbon atoms, wherein the ring atoms may optionally be oxidized, and the oxidizing group (=O) on the ring is part of the ring. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes spirocyclic, fused-ring, and bridged-ring cycloalkyl.

[0201] The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group in which each monocyclic ring in the system shares a carbon atom (called a spiro atom), and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it is a 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, or 5 / 6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

[0202]

[0203] The term "fused cycloalkyl" refers to a 5- to 20-membered polycyclic aromatic hydrocarbon 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 rings may contain one or more double bonds. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3 / 4-membered, 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 4-membered, 5 / 5-membered, 5 / 6-membered, 6 / 3-membered, 6 / 4-membered, 6 / 5-membered, and 6 / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0204]

[0205] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0206]

[0207] The cycloalkyl ring comprises a cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described herein, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include... etc.; preferred The cycloalkyl group may be substituted or unsubstituted.

[0208] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon, wherein the ring carbon atoms may optionally be oxidized, and the oxidized group (=O) on the ring is part of the ring. Preferably, it contains 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) ring atoms, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it contains 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), of which 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; even more preferably, it contains 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0209] The term "spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each monocyclic ring in the system shares one atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups according to the number of shared spiro atoms between rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, it is a 3- / 5-membered, 3- / 6-membered, 4- / 4-membered, 4- / 5-membered, 4- / 6-membered, 5- / 5-membered, or 5- / 6-membered monospirocyclic group. Non-limiting examples of spirocyclic groups include:

[0210]

[0211] 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, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0212]

[0213] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly connected atoms. It may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0214]

[0215] The heterocyclic ring comprises a heterocyclic group (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic rings) fused to an aryl, heteroaryl, or cycloalkyl ring as described herein, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0216] The heterocyclic group may be substituted or unsubstituted.

[0217] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl group comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described herein, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0218] And. The aryl group can be substituted or unsubstituted.

[0219] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl group fused to an aryl, heterocyclic, or cycloalkyl ring as described herein, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0220] The heteroaryl group can be substituted or unsubstituted.

[0221] The terms “alkyl,” “alkoxy,” “cycloalkyl,” “heterocyclic,” “aryl,” and “heteroaryl” used herein may be substituted or unsubstituted; when substituted, they may be substituted at any usable linking point, and the substituents are preferably independently selected independently from one or more of the same or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0222] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one H from a parent ring atom, or residues derived from removing two H from the same or two different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "arylene", and "heteroarylene".

[0223] The term “cycloalkyloxy” refers to cycloalkyl-O-, where the cycloalkyl group is as defined herein.

[0224] The term “heterocyclic oxy group” refers to a heterocyclic group -O-, wherein the heterocyclic group is as defined herein.

[0225] The term “halogenated alkyl” refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined herein.

[0226] The term “haloalkoxy” refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined herein.

[0227] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups, wherein the alkyl group is as defined herein.

[0228] The term "halogen" refers to F, Cl, Br, or I.

[0229] The term "hydroxyl group" refers to -OH.

[0230] The term "amino" refers to -NH2.

[0231] The term "cyano" refers to -CN.

[0232] The term "nitro" refers to -NO2.

[0233] The term "oxo" or "oxo" refers to "=O".

[0234] The term "carbonyl" refers to C=O.

[0235] The term "carboxyl group" refers to -C(O)OH.

[0236] The term “carboxylic acid ester group” refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined herein.

[0237] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes situations in which the event or environment may or may not occur. For example, "optionally alkyl-substituted heterocyclic alkyl group" means that an alkyl group may but does not have to be present, and the description includes cases where the heterocyclic alkyl group is substituted with an alkyl group and cases where the heterocyclic alkyl group is not substituted with an alkyl group.

[0238] "Substituted" refers to one or more H atoms in a group, preferably up to five, more preferably one to three atoms, that are independently substituted by the corresponding number of substituents. 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 much effort. For example, an amino or hydroxyl group with free H atoms may be unstable when bonded to a carbon atom with an unsaturated bond (such as an alkene).

[0239] Beneficial effects of this disclosure

[0240] This disclosure provides compounds of formulas (I), (I-1), (I-2), (IM), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), or those shown in Table A or Table B, which exhibit good FXIa inhibitory activity and can be used for the effective treatment or prevention of cardiovascular and cerebrovascular diseases and thromboembolic diseases. Furthermore, compared with previously disclosed FXIa inhibitor patent compounds, these aromatic / heteroaromatic spirocyclic compounds possess superior anticoagulant activity against human blood and good pharmacokinetic absorption activity. Detailed Implementation

[0241] The technical solutions of this disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of this disclosure and should not be construed as limiting the scope of protection of this disclosure. All technologies implemented based on the above content of this disclosure are covered within the scope of protection intended by this disclosure.

[0242] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0243] For experimental methods in the following examples where specific conditions are not specified, follow conventional methods and conditions, or select according to the product instructions.

[0244] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400MHz NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0245] Mass spectrometry (MS) was performed using a Waters 2767HPLC / Waters SQD, Waters H-class UPLC-SQD2, and Agilent HPLC / Waters liquid chromatography-mass spectrometry system.

[0246] Chiral HPLC analysis was performed using Shimadzu LC-20AD.

[0247] The silica gel plates used in thin-layer chromatography are GF254 silica gel plates from Cheng Chemical (Shanghai) Co., Ltd. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.2–0.25 mm, while those used for separating and purifying products by thin-layer chromatography have a diameter of 0.4–0.5 mm.

[0248] Column chromatography typically uses 100-200 mesh silica gel as a carrier, as provided by Chenghua Chemical (Shanghai) Co., Ltd.

[0249] High-performance liquid chromatography (HPLC) was performed using Waters HPLC, Gilson HPLC, and Biotage MPLC preparative chromatographs.

[0250] Chiral separation column chromatography was performed using a preparative HPLC model, Gilson GX-281.

[0251] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0252] A nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon with a volume of approximately 1 liter.

[0253] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1 liter.

[0254] Unless otherwise specified in the examples, the reaction temperature is room temperature, and the temperature range is 20℃-30℃.

[0255] Those skilled in the art should understand that chiral compounds can be distinguished by their retention times in a chiral chromatographic column. Therefore, chiral compounds separated according to their retention times are distinguished by the suffixes P1 and P2. That is, suffix P1 corresponds to the chiral structure separated first, and suffix P2 corresponds to the chiral structure separated later. If the chemical formula lists the absolute configuration of a compound, it does not mean that it corresponds one-to-one with the compounds numbered with suffixes P1 and P2, but only indicates different forms of absolute configuration. The absolute configuration of the compounds numbered with suffixes P1 and P2 is based on the absolute configuration objectively corresponding to a specific retention time.

[0256] Reagent names corresponding to English abbreviations:

[0257]

[0258]

[0259] Synthesis of intermediate compound A1

[0260]

[0261] Step 1: Synthesis of compound A1-2

[0262] At room temperature, BPO (7.70 g, 0.032 mol) and NBS (31.00 g, 0.18 mol) were added sequentially to a CCl4 (450 mL) solution of compound A1-1 (25.00 g, 0.16 mol). The reaction mixture was heated to 90 °C and stirred at this temperature for 20 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The residue was added to ethyl acetate (1000 mL) and washed with sodium sulfite aqueous solution (800 mL) and water (800 mL × 3), respectively. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE) to give compound A1-2 (20.83 g, yield 56%). 1 H NMR (400MHz, CDCl3): δ7.88-7.84 (m, 1H), 7.53-7.37 (m, 2H), 4.83 (d, J = 1.6Hz, 2H).

[0263] Step 2: Synthesis of compound A1-3

[0264] At 0°C, a 20 mL solution of diethyl malonate (2.07 g, 12.93 mmol) in DMF was slowly added to a 12 mL solution of NaH (0.65 g, 12.93 mmol) in DMF. The reaction mixture was stirred at 0°C for 15 minutes. An 8 mL solution of compound A1-2 (2.50 g, 10.78 mmol) in DMF was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was slowly poured into a 250 mL solution of saturated ammonium chloride at 0°C, extracted with ethyl acetate (200 mL × 3), and the combined organic phases were washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 20 / 1 to 5 / 1) to give compound A1-3 (2.20 g, yield 65%). 1 H NMR (400MHz, CDCl3): δ7.76 (d, J = 8.0 Hz, 1H), 7.44-7.30 (m, 2H), 4.21-4.13 (m, 4H), 3.79-3.73 (m, 1H), 3.54 (d, J = 8Hz, 2H), 1.22 (t, J = 7.2Hz, 6H).

[0265] Step 3: Synthesis of compound A1-4

[0266] At room temperature, Pd(OH)₂ / C (2.0 g) was added to a solution of compound A1-3 (20.0 g, 0.59 mmol) in 200 mL of EtOH. The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give compound A1-4 (16.0 g, crude product). MS m / z (ESI): 284.3 [M+1] + .

[0267] Step 4: Synthesis of compound A1-5

[0268] Compound A1-4 (14.00 g, crude) was added to a mixed solution of hydrochloric acid and acetic acid (4 mL / 32 mL) at room temperature. The reaction mixture was heated to 90 °C and stirred at this temperature for 4 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was adjusted to pH 7 with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (150 mL × 3). The combined organic phases were concentrated under reduced pressure to give compound A1-5 (8.75 g, 91% yield). MS m / z (ESI): 166.2 [M+1] + .

[0269] Step 5: Synthesis of compound A1-6

[0270] At room temperature, NBS (10.70 g, 60.00 mmol) was added to a DMF (150 mL) solution of compound A1-5 (9.0 g, 54.55 mmol), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with water (1500 mL), extracted with ethyl acetate (500 mL × 4), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 20 / 1 to 4 / 1) to give compound A1-6 (9.90 g, yield 73%). 1 H NMR (400MHz, CDCl3): δ9.42 (s, 1H), 7.41-7.33 (m, 1H), 6.61 (d, J = 10.8Hz, 1H), 3.11-3.03 (m, 2H), 2.73-2.65 (m, 2H).

[0271] Step 6: Synthesis of compound A1-7

[0272] At room temperature, Pd(PPh3)4 (0.43 g, 0.37 mmol) was added to a DMF (100 mL) solution of tributyl(1-ethoxyethylene)tin (CAS: 97674-02-7, 4.90 g, 13.58 mmol) and compound A1-6 (3.00 g, 12.35 mmol). The reaction mixture was heated to 125 °C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and diluted with water (1000 mL). Extraction was performed with ethyl acetate (400 mL × 4). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1 to 5 / 1) to give compound A1-7 (1.60 g, yield 55%). 1 H NMR (400MHz, CDCl3): δ8.86(s,1H),7.48-7.41(m,1H),6.65-6.63(m,1H),4.66(s,1H),4. 44(s,1H),3.99-3.90(m,2H),3.06(t,J=10Hz,2H),2.72-2.62(m,2H),1.48-1.29(m,3H).

[0273] Step 7: Synthesis of Compound A1

[0274] At room temperature, NBS (0.38 g, 2.13 mmol) was added to a mixed solution of compound A1-7 (0.50 g, 2.13 mmol) in tetrahydrofuran and water (16 mL / 2 mL). The reaction mixture was stirred at 0 °C for 30 minutes. After the reaction was complete, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (60 mL × 4), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 20 / 1 to 6 / 1) to give compound A1 (0.25 g, yield 41%). 1 H NMR (400MHz, CDCl3): δ8.85 (s, 1H), 7.91-7.83 (m, 1H), 6.75 (d, J = 11.2Hz, 1H), 4.51 (s, 2H), 3.11 (t, J = 10Hz, 2H), 2.78-2.70 (m, 2H).

[0275] Synthesis of intermediate compound A2

[0276]

[0277] Step 1: Synthesis of compound A2-2

[0278] At 0 °C, NIS (48.56 g, 0.21 mol) was added in three portions to a DMF (300 mL) solution of compound A2-1 (22 g, 0.20 mol). The reaction mixture was slowly heated to room temperature and stirred for 3 hours. After the reaction was complete, the reaction solution was diluted with water (600 mL), extracted with ethyl acetate (700 mL × 3), the organic phases were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 10 / 1 to 6 / 1) to give compound A2-2 (46.0 g, yield 98.1%). 1 H NMR (400MHz, CDCl3): δ7.75-7.71(m,1H), 6.19-6.16(m,1H), 4.64(s,2H).

[0279] Step 2: Synthesis of compound A2-3

[0280] At room temperature, a solution of Boc₂O (145.64 g, 0.61 mol) in acetonitrile (120 mL) was added to a solution of compound A₂-2 (51.30 g, 0.21 mol) and DMAP (1.84 g, 0.015 mol) in acetonitrile (390 mL). The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 100 / 1 to 50 / 1) to give compound A₂-3 (70.00 g, yield 74.4%). 1H NMR (400MHz, CDCl3): δ8.14 (d, J=8.0Hz, 1H), 7.04-7.02 (m, 1H), 1.43 (s, 18H).

[0281] Step 3: Synthesis of compound A2-4

[0282] At room temperature, ZnCN₂ (1.07 g, 9.13 mmol), zinc powder (170 mg, 2.74 mmol), dppf (800 mg, 1.46 mmol), and Pd(OAc)₂ (240 mg, 1.09 mmol) were added sequentially to a DMAC (50 mL) solution of compound A2-3 (8.00 g, 18.26 mmol). The reaction was heated to 90 °C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 100 / 1 to 40 / 1) to obtain compound A2-4 (6.00 g, crude product).

[0283] Step 4: Synthesis of compound A2-5

[0284] At room temperature, hydroxylamine hydrochloride (1.93 g, 27.84 mmol) and ammonium bicarbonate (2.34 g, 27.84 mmol) were added sequentially to a methanol (120 mL) solution of compound A2-4 (6 g, crude). The reaction mixture was stirred at room temperature for 20 minutes, then heated to 70 °C and stirred at that temperature for 3 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound A2-5 (5.30 g, crude). The product was used directly for the next reaction without purification. MS m / z (ESI): 271.3 [M+1] +

[0285] Step 5: Synthesis of compound A2

[0286] At 0°C, acetic anhydride (4 mL) was added to a 55 mL solution of acetic acid containing 5.30 g crude compound A2-5. The reaction mixture was stirred at room temperature for 1.5 hours, then water (2 mL) and palladium on carbon (3 g) were added, and the reaction mixture was stirred for 6 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by acetonitrile slurry to obtain 2.7 g of acetate product. The acetate product was purified by C-18 reversed-phase silica gel column chromatography (acetonitrile / water (containing 0.1% hydrochloric acid) = 5-95%) to obtain compound A2 (2.0 g, overall yield of 31.1%). 1H NMR (400MHz, DMSO-d6): δ10.59(s,1H),9.45-9.41(m,4H),9.02(d,J=22.8Hz,1H),8.20(t,J=8.8Hz,1H),7.84-7.77(m,1H),1.48(s,9H).

[0287] Synthesis of intermediate compound A3

[0288]

[0289] Under ice bath conditions, bromoacetyl bromide (4.10 g, 20.40 mmol, CAS: 598-21-0) and aluminum chloride (11.94 g, 89.76 mmol) were added sequentially to a DCE (20 mL) solution of compound A3-1 (2 g, 13.60 mmol). The reaction mixture was heated to 45 °C and stirred at this temperature for 16 hours. After the reaction was complete, the reaction solution was slowly poured into ice to quench the reaction, resulting in the precipitation of a white solid. The solid was filtered, and the filter cake was collected and purified by slurrying with ethyl acetate (200 mL) to give compound A3 (1.80 g, yield 50.1%). MS m / z (ESI): 268.0 [M+1] + .

[0290] Synthesis of intermediate compound A4

[0291]

[0292] Step 1: Synthesis of compound A4-2

[0293] At 0°C, 60 mL of an aqueous solution of sodium nitrite (11.1 g, 0.16 mol) was slowly added to a mixed solution of water and concentrated hydrochloric acid (600 mL / 180 mL) for compound A4-1 (30.0 g, 0.15 mol). The reaction mixture was stirred at 0°C for 1 hour. Then, 60 mL of an aqueous solution of NaN3 (10.5 g, 0.16 mol) was slowly added to the reaction mixture, and the reaction was stirred for another 0.5 hours. After the reaction was complete, the reaction solution was extracted with ethyl acetate (500 mL × 3). The combined organic phases were washed successively with saturated sodium bicarbonate aqueous solution (400 mL × 2), water (400 mL × 1), and saturated brine (400 mL × 1). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound A4-2 (31.0 g, 94% yield).

[0294] Step 2: Synthesis of compound A4-3

[0295] At room temperature, trimethylsilylacetylene (39.4 g, 0.40 mol, CAS: 1066-54-2) was added to a solution of compound A4-2 (31.0 g, 0.13 mol) and Cu2O (3.8 g, 0.027 mol) in acetonitrile (300 mL). The reaction mixture was heated to 90 °C and stirred at this temperature for 24 hours. After the reaction was completed, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 100 / 1 to 10 / 1) to give compound A4-3 (39.50 g, 90% yield). 1 H NMR (400MHz, CDCl3): δ7.89 (s, 1H), 7.76 (d, J = 2.0Hz, 1H), 7.47 (t, J = 2.4Hz, 2H), 0.38 (s, 9H).

[0296] Step 3: Synthesis of compound A4

[0297] At room temperature, potassium fluoride (70.0 g, 1.22 mol) and NCS (325.0 g, 2.44 mol) were added sequentially to a solution of compound A4-3 (67.0 g, 0.21 mol) in acetonitrile (1500 mL). The reaction mixture was heated to 90 °C and stirred at this temperature for 48 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and ethyl acetate (2000 mL) was added. The mixture was washed with water (800 mL × 4) and saturated sodium carbonate solution (500 mL × 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 100 / 1 to 10 / 1) to give compound A4 (78.0 g, yield 66%). 1 H NMR (400MHz, CDCl3): δ7.92 (s, 1H), 7.79 (t, J = 1.2Hz, 1H), 7.50 (d, J = 1.2Hz, 2H).

[0298] Synthesis of intermediate compound A5

[0299]

[0300] Step 1: Synthesis of compound A5-3

[0301] At room temperature, compound A5-2 (259.81 g, 0.74 mol) and benzoic acid (9.09 g, 0.074 mol) were added sequentially to a toluene (300 mL) solution of compound A5-1 (100 g, 0.57 mol). The reaction mixture was stirred at 90 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 100 / 1 to 20 / 1) to give compound A5-3 (29.0 g, 40.3%). 1HNMR (400MHz, CDCl3): δ6.03 (t, J=1.6Hz, 1H), 4.02 (q, J=7.2Hz, 2H), 1.26 (m, 2H), 1.13 (m, 5H).

[0302] Step 2: Synthesis of compound A5-5

[0303] At room temperature, a 20% sodium ethoxide solution (9.70 g, 0.024 mol) was added dropwise to an ethanol solution (300 mL) containing compound A5-3 (15 g, 0.12 mol) and compound A5-4 (23.25 g, 0.11 mol). The reaction mixture was stirred at room temperature for 20 minutes, then heated to 95 °C and stirred for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove ethanol. The residue was adjusted to pH 6–7 with 3M hydrochloric acid, diluted with water to 200 mL, and extracted with ethyl acetate (200 mL × 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1–2 / 1) to give compound A5-5 (20.2 g, 66.6%). 1 HNMR (400MHz, CDCl3): δ6.41 (s, 1H), 4.28-4.21 (q, J = 7.2Hz, 4H), 2.49 (s, 2H), 1.28 (t, J = 8.8Hz, 6H), 0.99 (t, J = 5.2Hz, 2H), 0.74 (t, J = 6.4Hz, 2H).

[0304] Step 3: Synthesis of compound A5-6

[0305] Lithium chloride (10.25 g, 0.25 mol) was added to a mixed solution of compound A5-5 (21 g, 0.082 mol) in DMSO and water (250 mL / 25 mL). Under nitrogen protection, the reaction mixture was heated to 140 °C and stirred at this temperature for 20 hours. After the reaction was completed, the reaction solution was diluted with water (200 mL), extracted with ethyl acetate (300 mL × 3), the organic phases were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 10 / 1 to 2 / 1) to give compound A5-6 (13.3 g, 88.2%). 1 HNMR (400MHz, CDCl3): δ6.17 (s, 1H), 4.25-4.19 (q, J = 7.2Hz, 2H), 3.81 (s, 1H), 2.60 (d, J = 17.2Hz, 1H), 2.18(d,J=17.2Hz,1H),1.27(t,J=5.6Hz,3H),0.86-0.82(m,2H),0.78-0.74(m,1H),0.68-0.64(m,1H).

[0306] Step 4: Synthesis of compound A5

[0307] At 0 °C, trimethyloxonium tetrafluoroboric acid (12.50 g, 0.085 mol, CAS: 420-37-1) was added to a dichloromethane (200 mL) solution of compound A5-6 (12 g, 0.065 mol). The reaction mixture was slowly heated to room temperature and stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure with triethylamine to adjust the pH to >5. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1 to 2 / 1) to give compound A5 (8.07 g, 63.0%). 1 H NMR (400MHz, CDCl3): δ

[0308] 4.21-4.14(m,3H),3.89(s,3H),2.83(d,J=15.6Hz,1H),2.36(d,J=12.4Hz,1H),1.27(t,J=7.2Hz,3H),0.77-0.66(m,4H).

[0309] Synthesis of intermediate compound A6

[0310]

[0311] Step 1: Synthesis of compound A6-1

[0312] Under nitrogen protection, a mixed solution of compound A5 (7.50 g, 0.038 mol), dimethyl 1,3-propanone dicarboxylate (8.60 g, 0.049 mol, CAS: 1830-54-2), and triethylamine (0.38 g, 0.038 mol) was heated to 120 °C, and the reaction mixture was stirred at this temperature for 4.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 10 / 1 to 2 / 1) to obtain compound A6-1 (5.70 g, yield 49.1%). MS m / z (ESI): 308.4 [M+1] + .

[0313] Step 2: Synthesis of compound A6-2

[0314] Compound A6-1 (5.70 g, 0.019 mol) was added to an aqueous sodium hydroxide solution (2 M, 80 mL) at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the pH of the reaction solution was adjusted to <7 with 6 M hydrochloric acid, and a solid precipitated. The solid was filtered, and the filter cake was collected and dried to give compound A6-2 (4.77 g, yield 97.1%). MS m / z (ESI): 266.2 [M+1] + .

[0315] Step 3: Synthesis of compound A6-3

[0316] Compound A6-2 (4.77 g, 17.9 mmol) was dissolved in a mixture of 100 mL of 6 M hydrochloric acid and 20 mL of 12 M hydrochloric acid at room temperature. The reaction mixture was heated to 140 °C and stirred at this temperature for 20 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound A6-3 (4.0 g, crude product). The product was used directly for the next reaction without purification. MS m / z (ESI): 222.1 [M+1] + .

[0317] Step 4: Synthesis of compound A6-4

[0318] Compound A6-3 (4 g, crude) was dissolved in hydrochloric acid / methanol (4 M, 200 mL) at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 100 / 1 to 50 / 1) to give compound A6-4 (4.0 g, yield 95.2%). MS m / z (ESI): 236.2 [M+1] + .

[0319] Step 5: Synthesis of compound A6

[0320] At 0 °C, triethylamine (2.22 g, 21.98 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (7.20 g, 20.17 mmol, CAS: 37595-74-7) were added sequentially to a tetrahydrofuran (100 mL) solution of compound A6-4 (4.0 g, 16.95 mmol). The reaction was slowly raised to room temperature and stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 10 / 1 to 3 / 1) to give compound A6 (5.1 g, yield 81.7%). MS m / z (ESI): 368.3 [M+1] + .

[0321] Synthesis of intermediate compound A7

[0322]

[0323] Step 1: Synthesis of compound A7-1

[0324] At room temperature, bis-pinacolborate (2.08 g, 8.17 mmol), tricyclohexylphosphine (0.15 g, 0.54 mmol), palladium acetate (61 mg, 0.27 mmol), and potassium acetate (0.40 g, 4.09 mmol) were added sequentially to a 30 mL solution of compound A6 (1.00 g, 2.72 mmol). The reaction mixture was heated to 100 °C and stirred at this temperature for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature to obtain a reaction solution containing compound A7-1. This reaction solution was used directly in the next step without further treatment. MS m / z (ESI): 264.2 [M+1] + .

[0325] Step 2: Synthesis of compound A7-2

[0326] At room temperature, compound A4 (0.79 g, 2.72 mmol), Pd(dppf)Cl2 (0.10 g, 0.14 mmol), and potassium carbonate (0.56 g, 4.08 mmol) were added sequentially to a mixture of 1,4-dioxane and water (30 mL / 6 mL) containing the reaction solution of compound A7-1. The reaction mixture was heated to 100 °C and stirred at this temperature for 2 hours. After the reaction was complete, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (40 mL × 3), and the combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1 to 1 / 1) to give compound A7-2 (1.1 g, two-step yield 97.3%). MS m / z (ESI): 431.3 [M+1] + .

[0327] Step 3: Synthesis of compound A7

[0328] At room temperature, a 2M sodium hydroxide solution (20 mL) was slowly added to an ethanol solution (40 mL) of compound A7-2 (1.1 g, 2.56 mmol). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the ethanol. The residue was adjusted to pH < 7 with 2M hydrochloric acid, and a solid precipitated. The solid was filtered, the filter cake was collected and slurried with ethyl acetate, and the solid was collected and dried to give compound A7 (0.67 g, yield 63%). MS m / z (ESI): 417.3 [M+1] + .

[0329] Synthesis of intermediate compound A8

[0330]

[0331] Step 1: Synthesis of compound A8-2

[0332] At room temperature, bis-pinacolborate (129.20 g, 0.51 mol), potassium acetate (83 g, 0.85 mol), and Pd(dppf)Cl2 (7.38 g, 0.01 mol) were added sequentially to a DMSO (700 mL) solution of compound A8-1 (70 g, 0.34 mol). The reaction mixture was heated to 80 °C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with water (1000 mL), extracted with ethyl acetate (1000 mL × 3), and the combined organic phases were washed with water (500 mL × 3) and saturated brine (500 mL × 3). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 100 / 1 to 30 / 1) to give compound A8-2 (61.00 g, yield 75.2%). 1 H NMR (400MHz, CDCl3): δ7.54 (d, J=2.8Hz, 1H), 7.14-7.11 (m, 1H), 6.53 (d, J=8.8Hz, 1H), 4.70 (s, 2H), 1.33 (s, 12H).

[0333] Step 2: Synthesis of compound A8-3

[0334] At room temperature, compound A8-2 (4.12 g, 12.22 mmol), potassium carbonate (4.20 g, 30.55 mmol), and Pd(dppf)Cl2 (0.89 g, 1.22 mmol) were added sequentially to a mixed solution of compound A6 (5.10 g, 12.22 mmol) in 1,4-dioxane and water (100 mL / 25 mL). The reaction mixture was heated to 100 °C and stirred at this temperature for 4 hours. After the reaction was completed, the reaction solution was diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), and the combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 1 to 1 / 3) to give compound A8-3 (3.50 g, yield 73.2%). 1 H NMR (400MHz, DMSO-d6): δ7.12-7.05(m,2H),6.77(d,J=8.4Hz,1H),6.31(s,1H),6.27(s,1H),5.22(s,2H), 4.61(s,1H),3.70(s,3H),3.38-3.34(m,1H),2.91(d,J=17.2Hz,1H),1.00-0.97(m,1H),0.85-0.81(m,3H).

[0335] Step 3: Synthesis of compound A8-4

[0336] Sodium hydroxide (2.03 g, 50.85 mmol) was added to a mixed solution of compound A8-3 (3.50 g, 10.17 mmol) in methanol and water (120 mL / 40 mL) at 0 °C. The reaction mixture was stirred at room temperature for 7 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 5–6 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (100 mL × 4). The combined organic phases were concentrated under reduced pressure to give compound A8-4 (3.30 g crude product). The product was used directly for the next reaction without purification. MS m / z (ESI): 331.1 [M+1] + .

[0337] Step 4: Synthesis of compound A8

[0338] At 0°C, trimethyl orthoformate (35 mL) and NaN3 (3.25 g, 50.00 mmol) were added sequentially to a solution of compound A8-4 (3.30 g, 10.00 mmol) in acetic acid (70 mL). The reaction mixture was stirred at 0°C for 15 minutes, then heated to 80°C and stirred at that temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with water (5 mL) and DMF (20 mL), and the acetic acid was removed by vacuum concentration. The residue was purified by C-18 reversed-phase silica gel column chromatography (acetonitrile / water (0.1% ammonium bicarbonate) = 5-95%) to obtain compound A8 (2.90 g, yield 75.7%). 1 H NMR (400MHz, DMSO-d6): δ9.69(s,1H),7.79-7.76(m,3H),5.86(s,2H),4.07(s,1H),3.29-3.25(m,2H),1.01-1.03(m,1H),0.67-0.58(m,3H).

[0339] Synthesis of intermediate compound A9

[0340]

[0341] Step 1: Synthesis of compound A9-1

[0342] At room temperature, ammonium chloride (990 mg, 18.7 mmol) was added to an ethanol (80 mL) solution of compound A5 (3.30 g, 16.8 mmol). Under nitrogen protection, the reaction was heated to 100 °C and stirred at this temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain A9-1 (4.30 g, crude product). The product was used directly for the next reaction without purification. MS m / z (ESI): 183.1 [M+1] + .

[0343] Step 2: Synthesis of compound A9-2

[0344] At room temperature, potassium monomethyl malonate (6.55 g, 42.0 mmol, CAS: 38330-80-2), DIPEA (10.84 g, 84.0 mmol), and EDCI (8.06 g, 42.0 mol) were added sequentially to a DMF (100 mL) solution of compound A9-1 (4.30 g, crude). Under nitrogen protection, the reaction was heated to 80 °C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 2-30%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 75 bar) to obtain compound A9-2 (1.70 g, yield 40.6%). MS m / z(ESI): 251.2 [M+1] + .

[0345] Step 3: Synthesis of compound A9

[0346] At 0 °C, triethylamine (0.20 g, 2.02 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (0.66 g, 1.85 mmol, CAS: 37595-74-7) were added sequentially to a DMF (15 mL) solution of compound A9-2 (0.42 g, 1.68 mmol). The reaction mixture was slowly heated to room temperature and stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 4), and the combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1 to 5 / 1) to give compound A9 (0.59 g, 97% yield). MS m / z (ESI): 383.4 [M+1] + .

[0347] Synthesis of intermediate compound A10

[0348]

[0349] Step 1: Synthesis of compound A10-1

[0350] At room temperature, bis(pinacolborate) (1.32 g, 5.18 mmol), tricyclohexylphosphine (97 mg, 0.35 mmol), palladium acetate (39 mg, 0.17 mmol), and potassium acetate (250 mg, 2.59 mmol) were added sequentially to a 30 mL solution of compound A9 (0.66 g, 1.73 mmol). The reaction mixture was heated to 100 °C and stirred at this temperature for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and product A10-1 was used directly in the next reaction without further treatment. MS m / z (ESI): 279.3 [M+1] + .

[0351] Step 2: Synthesis of compound A10-2

[0352] At room temperature, compound A4 (0.45 g, 1.56 mmol), potassium carbonate (0.36 g, 2.60 mmol), and Pd(dppf)Cl2 (0.063 g, 0.087 mmol) were added sequentially to a mixed solution of 1,4-dioxane and water (30 mL / 6 mL) of compound A10-1. Under nitrogen protection, the reaction mixture was heated to 100 °C and stirred at this temperature for 2 hours. After the reaction was complete, the reaction solution was diluted with water (80 mL), extracted with ethyl acetate (80 mL × 3), and the combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1 to 2 / 1) to give compound A10-2 (0.38 g, yield 35.8%). MS m / z (ESI): 446.3 [M+1] + .

[0353] Step 3: Synthesis of compound A10

[0354] At room temperature, lithium hydroxide (0.21 g, 4.92 mmol) was added to a mixture of tetrahydrofuran and water (20 mL / 5 mL) containing compound A10-2 (0.38 g, 0.85 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove tetrahydrofuran. The residue was adjusted to pH < 7 with 2 M hydrochloric acid, and a solid precipitated. The solid was filtered, and the filter cake was collected and slurried with ethyl acetate to give compound A10 (0.23 g, yield 64.6%). MS m / z (ESI): 417.9 [M+1] + .

[0355] Synthesis of intermediate compound A11

[0356]

[0357] Step 1: Synthesis of compound A11-1

[0358] At room temperature, compound A8-2 (990 mg, 3.93 mmol), potassium carbonate (1.35 g, 9.80 mmol), and Pd(dppf)Cl2 (290 mg, 0.39 mmol) were added sequentially to a mixed solution of compound A9 (1.50 g, 3.93 mmol) in 1,4-dioxane and water (50 mL / 10 mL). Under nitrogen protection, the reaction mixture was heated to 100 °C and stirred at this temperature for 2 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), the combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 5 / 1 to 1 / 1) to give compound A11-1 (1.30 g, yield 92.9%). MS m / z (ESI): 360.1 [M+1] + .

[0359] Step 2: Synthesis of compound A11-2

[0360] At room temperature, trimethyl orthoformate (10 mL) and sodium azide (1.01 g, 15.53 mol) were added to a solution of compound A11-1 (1.30 g, 3.62 mmol) in acetic acid (20 mL). Under nitrogen protection, the reaction mixture was heated to 80 °C and stirred at this temperature for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and diluted with water (50 mL). Extraction was performed with ethyl acetate (50 mL × 3). The combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1 to 1 / 1) to give compound A11-2 (1.20 g, yield 80.5%). MS m / z (ESI): 413.3 [M+1] + .

[0361] Step 3: Synthesis of compound A11

[0362] At room temperature, LiOH (41 mg, 0.97 mmol) was added to a mixture of tetrahydrofuran and water (40 mL / 10 mL) containing compound A11-2 (200 mg, 0.48 mmol). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, 1 M hydrochloric acid was added dropwise to adjust the pH to <7. The mixture was extracted with ethyl acetate (40 mL × 3), and the combined organic phases were washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound A11 (187 mg, crude product). MS m / z (ESI): 385.2 [M+1] + .

[0363] Synthesis of Example 1 (Compound 2-P1 or 2-P2, Compound 2-P2 or 2-P1)

[0364]

[0365] Step 1: Synthesis of compound 2a

[0366] At 0 °C, compound 1-chloro-N,N,2-trimethyl-1-propenylamine (1.71 g, 12.79 mmol, CAS: 26189-59-3) was added to a solution of compound A8 (2.45 g, 6.39 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at 0 °C for 2 hours, and then (trimethylsilyl)diazomethane (32.0 mL, 63.90 mmol) was slowly added dropwise. The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was completed, concentrated hydrochloric acid was slowly added dropwise to the reaction solution at 0 °C to adjust the pH to 2–3. The mixture was extracted with dichloromethane (100 mL × 3), and the organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 1 to DCM / MeOH = 10 / 1) to give compound 2a (0.87 g, yield 33.3%). 1 H NMR (400MHz, CDCl3): δ8.54(s,1H),7.64-7.54(m,3H),6.32(s,1H),5.58(s,1H),5.01(s,1H),4.33 -4.18(m,2H),3.41(d,J=17.6Hz,1H),2.67(d,J=17.6Hz,1H),1.04-0.94(m,2H),0.85-0.77(m,2H).

[0367] Step 2: Synthesis of compound 2b

[0368] At room temperature, compound A2 (1.18 g, 4.66 mmol) and potassium carbonate (0.93 g, 9.32 mmol) were added to a solution of compound 2a (0.97 g, 2.33 mmol) in acetonitrile (50 mL). Under nitrogen protection, the reaction was heated to 80 °C and stirred at this temperature for 72 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 3 / 1 to 1 / 2) to obtain crude compound 2b. The crude product was purified by preparative high performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 40-70%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 75 bar) to obtain compound 2b (0.24 g, yield 16.7%). 1H NMR (400MHz, CDCl3): δ9.63(s,1H),8.58-8.51(m,2H),7.91-7.89(m,1H),7.62-7.52(m,3H),7.21-7.19(m,2H),6.43(s, 1H),5.63(s,2H),5.35(s,1H),3.85-3.56(m,1H),2.53-2.48(m,1H),1.52(s,9H),1.31-1.13(m,2H),0.90-0.72(m,4H).

[0369] Step 3: Synthesis of compounds 2c-P1 and 2c-P2

[0370] At -30°C, pyridine (90 mg, 1.17 mmol) and Selectfluor (0.21 g, 0.58 mmol) were added sequentially to a mixed solution of compound 2b (0.24 g, 0.39 mmol) in tetrahydrofuran and acetonitrile (4 mL / 8 mL). Under nitrogen protection, the reaction mixture was stirred at -30°C for 4 hours. Selectfluor (0.21 g, 0.58 mmol) was then added, and the reaction mixture was stirred for another 4 hours. After the reaction was completed, the reaction was quenched with saturated sodium sulfite solution (10 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 40-70%; column temperature: 25℃; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 75 bar) to obtain compound 2c (80 mg, yield 32.1%). 1H NMR (400MHz, CDCl3): δ10.91(d,J=4.8Hz,1H),8.54(s,1H),8.41(t,J=7.2Hz,1H),7.91(d,J=8.4Hz,1H),7.62-7.59(m,1H),7.54-7.52(m,2H),7.1 7(s,1H),6.38(s,1H),5.67(s,1H),5.27(s,1H),3.63(d,J=17.6Hz,1H),2 .53(d,J=17.6Hz,1H),1.52(s,9H),1.16-1.07(m,2H),0.87-0.79(m,2H). Compound 2c was purified by chiral preparative chromatography [equipment: Gilson GX-281, column: chiralpark IB 250mm×30mm 10um; mobile phase: Hex / EtOH=50 / 50; flow rate: 25mL / min] to obtain compound 2c-P1 (retention time 18.50min, 40mg) and compound 2c-P2 (retention time 23.00min, 40mg).

[0371] Step 4: Synthesis of compounds 2-P1 and 2-P2

[0372] Compound 2-P1:

[0373] At 0 °C, TFA (2.2 mL) was slowly added dropwise to a solution of compound 2c-P1 (40 mg, 0.06 mmol) in dichloromethane (15 mL), and the reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 40-70%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 75 bar) to give compound 2-P1 (19 mg, yield 56.7%). MS m / z (ESI): 534.1 [M+1] + Chiral HPLC: retention time 9.56 min, UV = 254 nm. 1H NMR (400MHz, CDCl3): δ10.67(s,1H),8.54(s,1H),8.19-8.15(m,1H),7.62-7.59(m,1H),7.55-7.52(m,2H),6.41-6.39(m,2H) ,5.64(s,1H),5.25(s,1H),4.72(s,2H),3.62(d,J=17.2Hz,1H),2.52(d,J=17.2Hz,1H),1.14-1.06(m,2H),0.88-0.76(m,2H).

[0374] Compound 2-P2:

[0375] At 0 °C, TFA (2.2 mL) was slowly added dropwise to a solution of compound 2c-P2 (40 mg, 0.06 mmol) in dichloromethane (15 mL), and the reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 40-70%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 75 bar) to give 2-P2 (19 mg, yield 56.7%). MS m / z (ESI): 534.1 [M+1] + Chiral HPLC: retention time 11.63 min, UV = 254 nm. 1 H NMR (400MHz, CDCl3): δ10.67(s,1H),8.54(s,1H),8.20-8.15(m,1H),7.62-7.59(m,1H),7.55-7.52(m,2H),6.41-6.39(m,2H) ,5.64(s,1H),5.25(s,1H),4.71(s,2H),3.62(d,J=17.2Hz,1H),2.52(d,J=17.2Hz,1H),1.14-1.06(m,2H),0.87-0.78(m,2H).

[0376] Synthesis of Example 2 (Compounds 13 and 14)

[0377]

[0378] Step 1: Synthesis of compound 13a

[0379] Compound A3 (243 mg, 0.91 mmol) and potassium carbonate (189 mg, 1.37 mmol) were added sequentially to a DMF (20 mL) solution of compound A8 (350 mg, 0.91 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with water (100 mL), extracted with ethyl acetate (150 mL × 3), and the combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 100 / 1 to 13 / 1) to give compound 13a (390 mg, yield: 75.0%). 1 H NMR (400MHz, CDCl3): δ8.57(s,1H),8.31(s,1H),7.75-7.70(m,2H),7.62-7.56(m,3H),6.84(d,J=8.4Hz,1H),6.38(s,1H),5.60(s,1H),5.44-5.2 9(m,2H),4.71(s,1H),3.52(d,J=17.2Hz,1H),3.03(t,J=8.0Hz,2H),2.6 9-2.58(m,3H),1.44-1.13(m,1H),0.95-0.93(m,2H),0.82-0.81(m,1H).

[0380] Step 2: Synthesis of Compound 13

[0381] Ammonium acetate (1.05 g, 13.68 mmol) was added to a mixed solution of compound 13a (390 mg, 0.68 mmol) in toluene and acetic acid (50 mL / 5 mL). The reaction mixture was heated to 90 °C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1 to 10 / 1) to give compound 13 (200 mg, yield: 53.0%). 1 H NMR (400MHz, CD3OD): δ9.37(s,1H),7.74-7.67(m,3H),7.48-7.43(m,2H),7.23(br s,1H),6.87(d,J=8.0Hz,1H),6.14(d,J=11.6Hz,2H),5.23(s,1H),3.71(d,J=17.6Hz,1H),2.98(t,J=7.2H z,2H),2.80(d,J=17.2Hz,1H),2.59-2.55(m,2H),0.98-0.93(m,1H),0.88-0.83(m,1H),0.77-0.67(m,2H)

[0382] Step 3: Synthesis of Compound 14

[0383] At -20°C, pyridine (103 mg, 1.31 mmol) and Selectfluor (154 mg, 0.43 mmol) were added sequentially to a DMF (24 mL) solution of compound 13 (120 mg, 0.22 mmol). The reaction mixture was stirred at -15°C to -20°C for 30 minutes. After the reaction was complete, the reaction solution was quenched with 20 mL of saturated sodium sulfite solution, extracted with ethyl acetate (20 mL × 3), and the combined organic phases were concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-70%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 75 bar) to give compound 14 (30 mg, yield: 24.2%). MS m / z (ESI): 569.1 [M+1] + . 1 H NMR (400MHz, CD3OD): δ9.37(s,1H),7.76-7.67(m,3H),7.37-7.33(m,2H),6.91(d,J=8.0Hz,1H),6.13(d,J=7.2Hz,2H),5 .11(s,1H),3.68(d,J=17.6Hz,1H),2.99(t,J=7.2Hz,2H),2.75(d,J=17.2Hz,1H),2.61-2.57(m,2H),0.88-0.63(m,4H).

[0384] Synthesis of Example 3 (Compound 15, Compound 15-P1 or 15-P2, Compound 15-P2 or 15-P1)

[0385]

[0386] Step 1: Synthesis of Compound 15a

[0387] At room temperature, compound A1 (190 mg, 0.67 mmol) and potassium carbonate (108 mg, 0.78 mmol) were added sequentially to a DMF (10 mL) solution of compound A8 (200 mg, 0.52 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 100 / 1 to 50 / 1) to give compound 15a (174 mg, yield 56.9%). MS m / z (ESI): 589.2 [M+1] + .

[0388] Step 2: Synthesis of compounds 15-P1 and 15-P2

[0389] At room temperature, ammonium acetate (367 mg, 4.76 mmol) was added to a mixed solution of compound 15a (140 mg, 0.24 mmol) in toluene and acetic acid (20 mL / 2 mL). Under nitrogen protection, the reaction mixture was heated to 90 °C and stirred at this temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 10-50%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 75 bar) to give compound 15 (80 mg, yield 59.3%). MS m / z (ESI): 569.2 [M+1] + .

[0390] Compound 15 (80 mg) was purified by chiral preparative chromatography [equipment: Gilson GX-281, column: chiralpark IE250mm×30mm10um; mobile phase: MeOH / DCM=70 / 30; flow rate: 25mL / min] to give 15-P1 (22.1 mg, yield 27.5%) and 15-P2 (21.7 mg, yield 27.1%).

[0391] 15-P1:

[0392] MS m / z(ESI): 569.0 [M+1] + Chiral HPLC: retention time 5.07 min, UV = 254 nm. 1 H NMR (400MHz, DMSO-d6): 12.22 (d, J=90.0Hz, 1H), 10.22 (d, J=37.6Hz, 1H), 9.71 (d, J= 11.6Hz,1H),7.82(s,3H),7.69(t,J=8.4Hz,1H),7.28(d,J=3.6Hz,1H),6.75(d,J=8.0 Hz,1H),5.99(d,J=2.4Hz,2H),5.08(s,1H),3.55(d,J=17.2Hz,1H),2.92(t,J=8.0Hz, 2H), 2.63 (d, J = 17.2Hz, 1H), 0.89-0.85 (m, 1H), 0.77-0.72 (m, 1H), 0.68-0.61 (m, 2H).

[0393] 15-P2:

[0394] MS m / z(ESI): 569.0 [M+1] + Chiral HPLC: retention time 7.55 min, UV = 254 nm. 1 H NMR (400MHz, DMSO-d6): 12.22 (d, J=90.0Hz, 1H), 10.26 (d, J=37.6Hz, 1H), 9.72 (d, J= 12.0Hz,1H),7.82(s,3H),7.69(t,J=8.4Hz,1H),7.28(d,J=3.6Hz,1H),6.75(d,J=8.8 Hz,1H),5.99(d,J=7.2Hz,2H),5.08(s,1H),3.55(d,J=16.8Hz,1H),2.92(t,J=8.0Hz, 2H), 2.63 (d, J = 17.2Hz, 1H), 0.89-0.86 (m, 1H), 0.75-0.73 (m, 1H), 0.67-0.62 (m, 2H).

[0395] Synthesis of Example 4 (Compound 18, Compound 18-P1 or 18-P2, Compound 18-P2 or 18-P1)

[0396]

[0397] Step 1: Synthesis of compound 18a

[0398] Compound A1 (0.090 g, 0.32 mmol) and potassium carbonate (0.059 g, 0.43 mmol) were added sequentially to a DMF (10 mL) solution of compound A7 (0.12 g, 0.29 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 100 / 1 to 50 / 1) to give compound 18a (0.17 g, yield 95.0%). MS m / z (ESI): 622.5 [M+1] + .

[0399] Step 2: Synthesis of compounds 18-P1 and 18-P2

[0400] At room temperature, ammonium acetate (0.50 g, 6.44 mmol) was added to a mixed solution of compound 18a (0.20 g, 0.32 mmol) in toluene and acetic acid (20 mL / 2 mL). Under nitrogen protection, the reaction mixture was heated to 110 °C and stirred overnight. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 40-75%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 75 bar) to give compound 18 (130 mg, yield 52%). MS m / z (ESI): 602.3 [M+1] + .

[0401] Compound 18 (130 mg) was purified by chiral preparative chromatography (equipment: Gilson GX-281, column: chiralpark IC 250 mm × 30 mm 10 μm; mobile phase: MeOH / DCM = 60 / 40; flow rate: 25 mL / min) to obtain compound 18-P1 (54 mg, 41.5%) and compound 18-P2 (52 mg, 40.0%).

[0402] Compound 18-P1:

[0403] MS m / z(ESI): 602.2 [M+1] + Chiral HPLC: retention time 4.59 min, UV = 254 nm. 1 H NMR (400MHz, CD3OD): 8.30(s,1H),7.72-7.63(m,4H),7.32(s,1H),6.72(d,J=6.0Hz,1H),6.15(d,J=11.6Hz,2H),5.27(s,1H),3.72(d,J=17.2H z, 1H), 3.03 (t, J = 7.2Hz, 2H), 2.80 (d, J = 17.6Hz, 1H), 2.60 (t, J = 8.0Hz, 2H), 0.99-0.95 (m, 1H), 0.89-0.83 (m, J = 7.2Hz, 1H), 0.73-0.69 (m, 2H).

[0404] Compound 18-P2:

[0405] MS m / z(ESI): 602.2 [M+1] + Chiral HPLC: retention time 7.40 min, UV = 254 nm. 1H NMR (400MHz, CDCl3): 11.10 (d, J = 108.4Hz, 1H), 9.06-8.69 (m, 1H), 7.61-7.54 (m, 5H), 7.23-7.08 (m, 1H), 6.59-6.44 (m, 1H), 6.35 (s, 1H), 5. 82(d,J=15.2Hz,1H),5.41(d,J=89.2Hz,1H),3.97-3.81(m,1H),3.02- 2.85(m,2H),2.72-2.51(m,3H),1.05-0.97(m,2H),0.89-0.86(m,2H).

[0406] Synthesis of Example 5 (Compound 19, Compound 19-P1 or 19-P2, Compound 19-P2 or 19-P1)

[0407]

[0408] Synthesis of compounds 19-P1 and 19-P2

[0409] At -20°C, pyridine (72 mg, 0.92 mmol) and Selectfluor (162 mg, 0.46 mmol) were added sequentially to a DMF (26 mL) solution of compound 15 (130 mg, 0.23 mmol). The reaction mixture was stirred at -15°C to -20°C for 4 hours. After the reaction was complete, the reaction solution was quenched with 20 mL of saturated sodium sulfite solution, extracted with ethyl acetate (20 mL × 3), and the combined organic phases were concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-65%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 75 bar) to give compound 19 (90 mg, yield: 69.2%). MS m / z (ESI): 587.0 [M+1] + . 1 H NMR(400MHz,DMSO-d6):11.35(br s,1H),10.35(s,1H),9.72(s,1H),7.84-7.81(m,3H),7.29(t,J=8.4Hz,1H),6.77(d,J=8.4Hz,1H),6.03(s,1H),5.94(s,1H),5.06(s ,1H),3.48(d,J=17.2Hz,1H),2.94(t,J=8.0Hz,2H),2.64(d,J=17.2Hz,1H),0.88-0.85(m,1H),0.78-0.76(m,1H),0.70-0.62(m,2H).

[0410] Compound 19 (90 mg) was purified by chiral preparative chromatography (equipment: Gilson GX-281, column: chiralpark IE250 mm × 30 mm 10 μm; mobile phase: MeOH / EtOH = 50 / 50; flow rate: 25 mL / min) to obtain compound 19-P1 (32.1 mg, 35.7%) and compound 19-P2 (37.4 mg, 41.6%).

[0411] 19-P1:

[0412] MS m / z (ESI): 587.2 [M+1] + Chiral HPLC: retention time 5.59 min, UV = 254 nm. 1 H NMR(400MHz,DMSO-d6):12.37(br s,1H),10.35(s,1H),9.72(s,1H),7.84-7.81(m,3H),7.29(t,J=8.4Hz,1H),6.77(d,J=8.4Hz,1H),6.03(s,1H),5.94(s,1H),5.06(s ,1H),3.48(d,J=17.2Hz,1H),2.94(t,J=8.0Hz,2H),2.64(d,J=17.2Hz,1H),0.88-0.85(m,1H),0.78-0.76(m,1H),0.70-0.62(m,2H).

[0413] 19-P2:

[0414] MS m / z (ESI): 587.2 [M+1] + Chiral HPLC: retention time 9.55 min, UV = 254 nm. 1 H NMR(400MHz,DMSO-d6):12.37(br s,1H),10.35(s,1H),9.72(s,1H),7.84-7.81(m,3H),7.29(t,J=8.4Hz,1H),6.77(d,J=8.4Hz,1H),6.03(s,1H),5.94(s,1H),5.06(s ,1H),3.48(d,J=17.2Hz,1H),2.94(t,J=8.0Hz,2H),2.64(d,J=17.2Hz,1H),0.88-0.85(m,1H),0.78-0.76(m,1H),0.70-0.62(m,2H).

[0415] Synthesis of Example 6 (Compound 20, Compound 20-P1 or 20-P2, Compound 20-P2 or 20-P1)

[0416]

[0417] Step 1: Synthesis of compound 20a

[0418] Compound A3 (200 mg, 0.75 mmol) and potassium carbonate (156 mg, 1.13 mmol) were added to a DMF (20 mL) solution of compound A11 (290 mg, 0.75 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 100 / 1 to 15 / 1) to give compound 20a (320 mg, yield 74.2%). MS m / z (ESI): 572.1 [M+1] + .

[0419] Step 2: Synthesis of compound 20b

[0420] At room temperature, ammonium acetate (647 mg, 8.40 mmol) was added to a mixed solution of compound 20a (240 mg, 0.42 mmol) in toluene and acetic acid (30 mL / 3 mL). Under nitrogen protection, the reaction mixture was heated to 90 °C and stirred at this temperature for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and diluted with water (50 mL). The solution was extracted with ethyl acetate (50 mL × 3), and the combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to give compound 20b (180 mg, yield 77.9%). MS m / z (ESI): 552.1 [M+1] + .

[0421] Step 3: Synthesis of compounds 20-P1 and 20-P2

[0422] At -30°C, Selectfluor (193 mg, 0.54 mmol) was added to a mixture of tetrahydrofuran and acetonitrile (8 mL / 16 mL) containing compound 20b (200 mg, 0.36 mmol) and pyridine (86 mg, 1.09 mmol). The reaction mixture was stirred at -30°C for 2 hours. After the reaction was completed, the reaction was quenched at -30°C with saturated sodium sulfite solution (20 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 30-70%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 75 bar) to give compound 20 (80 mg, yield 38.8%). Compound 20 (80 mg) was purified by chiral preparative chromatography [equipment: Gilson GX-281, column: chiralpark IE 250 mm × 30 mm 10 μm; mobile phase: Hex / EtOH = 30 / 70; flow rate: 25 mL / min] to give compound 20-P1 (30.7 mg, yield 38.4%) and compound 20-P2 (27.7 mg, yield 34.6%).

[0423] 20-P1:

[0424] MS m / z(ESI): 570.1 [M+1] + Chiral HPLC: retention time 7.95 min, UV = 254 nm. 1 H NMR (400MHz, CD3OD): δ9.45(s,1H),7.94(d,J=2.4Hz,1H),7.79-7.76(m,1H),7.70(d,J=8.4Hz,1H),7.37-7.34(m,2H),6.91(d,J=8.4Hz,1H),6.3 9(s,1H),5.15(s,1H),3.52(d,J=18.4Hz,1H),2.99(t,J=7.6Hz,2H),2.6 7-2.57(m,3H),0.99-0.89(m,2H),0.83-0.79(m,1H),0.66-0.62(m,1H).

[0425] 20-P2:

[0426] MS m / z(ESI): 570.1 [M+1] + Chiral HPLC: retention time 11.77 min, UV = 254 nm. 1H NMR (400MHz, CD3OD): δ9.46(s,1H),7.95(d,J=2.0Hz,1H),7.80-7.77(m,1H),7.71(d,J=8.8Hz,1H),7.39-7.35(m,2H),6.92(d,J=8.4Hz,1H),6.4 0(s,1H),5.15(s,1H),3.52(d,J=18.4Hz,1H),3.00(t,J=7.6Hz,2H),2.6 9-2.58(m,3H),1.00-0.90(m,2H),0.84-0.80(m,1H),0.65-0.63(m,1H).

[0427] Synthesis of Example 7 (Compound 21, Compound 21-P1 or 21-P2, Compound 21-P2 or 21-P1)

[0428]

[0429] Step 1: Synthesis of compound 21a

[0430] Compound A1 (190 mg, 0.66 mmol) and potassium carbonate (120 mg, 0.89 mmol) were added to a DMF (10 mL) solution of compound A11 (230 mg, 0.60 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 100 / 1 to 50 / 1) to give compound 21a (340 mg, yield 97.1%). MS m / z (ESI): 590.0 [M+1] + .

[0431] Step 2: Synthesis of compounds 21-P1 and 21-P2

[0432] At room temperature, ammonium acetate (840 mg, 10.87 mmol) was added to a mixed solution of compound 21a (320 mg, 0.54 mmol) in toluene and acetic acid (20 mL / 2 mL). Under nitrogen protection, the reaction mixture was heated to 110 °C and stirred at this temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 15-50%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 75 bar) to give compound 21 (140 mg, yield 43.7%). MS m / z (ESI): 570.3 [M+1] + .

[0433] Compound 21 (140 mg) was purified by chiral preparative chromatography [equipment: Gilson GX-281, column: chiralpark ID 250 mm × 30 mm 10 μm; mobile phase: ACN / IPA = 80 / 20; flow rate: 25 mL / min] to give compound 21-P1 (57 mg, 40.7%) and compound 21-P2 (49 mg, 35.0%).

[0434] 21-P1:

[0435] MS m / z(ESI): 570.2 [M+1] + Chiral HPLC: retention time 7.86 min, UV = 254 nm. 1 H NMR (400MHz, CD3OD): 9.46 (s, 1H), 7.93 (d, J = 2.0Hz, 1H), 7.79-7.76 (m, 1H), 7.70 (d, J = 8.8Hz, 1H), 7.31 (br s,1H),6.74(d,J=8.4Hz,1H),6.40(s,1H),5.29(s,1H),4.80(s,1H),3.53(d,J=18.0Hz,1H),3.02(t,J=7.6Hz,2H),2.6 7(d,J=18.4Hz,1H),2.60(t,J=1.6Hz,2H),0.99-0.97(m,1H),0.91-0.88(m,1H),0.77-0.74(m,1H),0.61-0.59(m,1H).

[0436] 21-P2:

[0437] MS m / z(ESI): 570.2 [M+1] + Chiral HPLC: retention time 9.92 min, UV = 254 nm. 1H NMR (400MHz, CD3OD): 9.46 (s, 1H), 7.93 (d, J = 2.0Hz, 1H), 7.79-7.76 (m, 1H), 7.70 (d, J = 8.8Hz, 1H), 7.31 (br s,1H),6.74(d,J=8.4Hz,1H),6.40(s,1H),5.29(s,1H),4.80(s,1H),3.53(d,J=18.0Hz,1H),3.02(t,J=7.6Hz,2H),2.6 7(d,J=18.4Hz,1H),2.60(t,J=1.6Hz,2H),0.99-0.97(m,1H),0.91-0.88(m,1H),0.77-0.74(m,1H),0.61-0.59(m,1H).

[0438] Synthesis of Example 8 (Compound 24, Compound 24-P1 or 24-P2, Compound 24-P2 or 24-P1)

[0439]

[0440] Step 1: Synthesis of compound 24a

[0441] Compound A1 (0.12 g, 0.42 mmol) and potassium carbonate (0.079 g, 0.58 mmol) were added to a DMF (10 mL) solution of compound A10 (0.16 g, 0.38 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with water (100 mL), extracted with ethyl acetate (40 mL × 3), and the combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 100 / 1 to 50 / 1) to give compound 24a (0.22 g, yield 92.1%). MS m / z (ESI): 623.0 [M+1] + .

[0442] Step 2: Synthesis of Compound 24

[0443] Ammonium acetate (0.50 g, 6.44 mmol) was added to a mixed solution of compound 24a (0.20 g, 0.32 mmol) in toluene and acetic acid (20 mL / 2 mL). Under nitrogen protection, the reaction was heated to 110 °C and stirred overnight. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 25-50%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 75 bar) to give compound 24 (0.17 g, yield 87.6%). MS m / z (ESI): 603.4 [M+1] + .

[0444] Compound 24 (130 mg) was purified by chiral preparative chromatography (equipment: Gilson GX-281, column: chiralpark IA 250 mm × 30 mm 10 μm; mobile phase: Hex / EtOH = 30 / 70; flow rate: 25 mL / min) to obtain compound 24-P1 (55 mg, 42.3%) and compound 24-P2 (64 mg, 49.2%).

[0445] Compound 24-P1:

[0446] MS m / z (ESI): 603.2 [M+1] + Chiral HPLC: retention time 5.73 min, UV = 254 nm. 1 H NMR (400MHz, CD3OD): 8.42 (s, 1H), 7.96 (d, J = 2.4Hz, 1H), 7.79-7.76 (m, 1H), 7.70 (d, J = 8.4Hz, 1H), 7.45 (br s,1H),6.78(d,J=6.0Hz,1H),6.27(s,1H),5.34(s,1H),4.60(s,1H),3.66(d,J=18.4Hz,1H),3.07(t,J=7.6Hz,2H),2.8 1(d,J=18.0Hz,1H),2.64(t,J=8.0Hz,2H),1.12-1.03(m,1H),1.01-0.89(m,1H),0.81-0.76(m,1H),0.66-0.62(m,1H).

[0447] Compound 24-P2:

[0448] MS m / z (ESI): 603.2 [M+1] +Chiral HPLC: retention time 7.31 min, UV = 254 nm. 1 H NMR (400MHz, CD3OD): 8.40 (s, 1H), 7.94 (d, J = 2.4Hz, 1H), 7.77-7.75 (m, 1H), 7.68 (d, J = 8.4Hz, 1H), 7.34 (br s,1H),6.75(d,J=6.0Hz,1H),6.25(s,1H),5.32(s,1H),4.58(s,1H),3.64(d,J=18.4Hz,1H),3.05(t,J=7.6Hz,2H),2.7 9(d,J=18.0Hz,1H),2.62(t,J=8.0Hz,2H),1.04-1.01(m,1H),0.97-0.90(m,1H),0.82-0.78(m,1H),0.66-0.62(m,1H).

[0449] Biological evaluation

[0450] Test Example 1: Determination of in vitro FXIa enzyme activity

[0451] Experimental objective:

[0452] Detection of the inhibitory activity of the disclosed compounds against human FXIa factor.

[0453] Experimental plan:

[0454] The test compound was initially diluted 10 μM, serially diluted 5-fold, resulting in 10 concentrations, with two replicates for each concentration. For each compound, the intermediate dilution was prepared by shaking at 1000 rpm for 1 min, then 8 μL of each solution was added to 32 μL of 100% DMSO for a 5-fold dilution, and shaken at 1000 rpm for 1 min. This method was repeated for each compound, serially diluting it 5-fold. Ten intermediate dilutions of different concentrations were prepared for each compound. The initial concentration, serial dilution factor, number of concentration gradients, and number of replicates can be adjusted according to the actual situation of compound screening. The final concentration of Human Factor XIa (Haematologic Technologies Inc., HCXIA-0160) in the reaction system was 0.08 nM, and the final concentration of substrate D-LPR-ANSNH-C3H7 (Haematologic Technologies Inc., SN-13A) was 75 μM. After pre-incubating the reaction system in a 384-well plate at 25 °C for 10 min, 4 μL of 2.5× substrate D-LPR-ANSNH-C3H7 working solution was added to each well. The positive control wells contained enzyme, substrate, 0.5% DMSO, and buffer, but no compound; the negative control wells contained substrate, 0.5% DMSO, and buffer, but no enzyme or compound; the compound wells contained enzyme, substrate, compound, 0.5% DMSO, and buffer. The 384-well plate (PerkinElmer, 6007270) was centrifuged at 1000 rpm for 30 seconds, gently mixed, and the reaction was started. The excitation light was set to 352 nm and the emission light to 470 nm on the microplate reader, and kinetic readings were taken at 25°C for 1 hour. Raw data were collected at 20 minutes for data processing and analysis. Concentration-response curves were then fitted using GraphPad Prism 7 software, and the IC50 concentration of the compound with 50% inhibition was calculated. 50 First, the percentage inhibition rate corresponding to each compound concentration was calculated. After obtaining the inhibition rate for each compound concentration, the concentration-response curve was fitted using the "log(inhibitor) vs. response -- Variable slope (four parameters)" equation in GraphPad Prism 7 software to obtain the IC50. 50The relevant calculation formulas are as follows: Mean: Calculated using the AVERAGE formula in Excel. Standard deviation: Calculated using the STDEV formula in Excel. Z-factor = 1 - (3 × standard deviation of fluorescence intensity readings in positive control wells + 3 × standard deviation of fluorescence intensity readings in negative control wells) / (mean fluorescence intensity of positive control wells - mean fluorescence intensity of negative control wells), S / B = mean fluorescence intensity of positive control wells / mean fluorescence intensity of negative control wells, Inhibition rate (%) = (mean fluorescence intensity of positive control wells - fluorescence intensity of compound wells) / (mean fluorescence intensity of positive control wells - mean fluorescence intensity of negative control wells) × 100. The results are shown in Table 1 below:

[0455] Table 1 IC50 of the disclosed compounds on the enzyme inhibition of human factor XIa 50 value

[0456] Compound 2-P1 0.9853 Compound 15-P1 1.632 Compound 20-P1 0.9802 Compound 21-P2 0.7825

[0457] Conclusion: The compound disclosed herein has a good inhibitory effect on human factor XIa enzymes.

[0458] Test Example 2: Determination of human plasma aPTT (activated partial thromboplastin time) in vitro

[0459] Experimental objective: To detect the anticoagulant effect of the disclosed compound on human plasma in vitro.

[0460] Experimental plan:

[0461] The in vitro aPTT assay of human plasma was performed using an activated partial thromboplastin time assay kit (MDC, Cat: 300025) and a dual-channel coagulation analyzer (Mc-2000, German brand).

[0462] Dissolve the test compound in DMSO to a 10 mM stock solution and store at -20°C until use. Thaw the stock solution before use. The final concentrations of the test compound were 60 μM, 12 μM, 2.4 μM, 0.48 μM, and 0.096 μM, for a total of five concentration gradients. DMSO was used as a negative control instead of the compound. The compound and plasma (venous whole blood collected under non-fasting conditions, mixed with 3.2% sodium citrate anticoagulant at a 9:1 ratio (v / v), centrifuged at 1560 g for 8 min at room temperature, and the supernatant was collected to prepare plasma) were mixed at a 1:49 ratio to prepare a sample mixture. Take 30 μL of the sample mixture and incubate at room temperature for 3 min, then place it in a dual-channel coagulation analyzer and incubate at 37°C for 2 min. Add 30 μL of aPTT reagent, continue incubation for 5 min, and then add 30 μL of 0.025 M CaCl₂. 2,Read the displayed values. Calculate the aPTT Ratio (aPTT Ratio = aPTT(sample) / aPTT(negative control)); plot the existing data using GraphPad Prism7 (working concentration / aPTT Ratio); calculate EC150 and EC200 using OriginPro 2018SR1 version 9.5.1. Calculation method: After fitting the lg concentration and aPTT Ratio with an exponential equation, calculate the drug concentrations at Ratios of 1.5, 2.0, and 3.0, i.e., EC150 and EC200.

[0463] Test Example 3: Determination of Human Plasma Kalliliren Enzyme Activity in Vitro

[0464] Experimental objective:

[0465] Detection of the inhibitory activity of the disclosed compounds against Human Plasma Kalliliren

[0466] Experimental plan:

[0467] Dissolve the test compound in DMSO to a 10 mM stock solution and store at -20°C until use. The initial compound concentration was 10 μM, serially diluted 5-fold, resulting in 10 concentrations, 2 μL / well, with a final DMSO concentration of 0.5%. Buffer preparation: 50 mM triaminomethane hydrochloride (tris-HCl), 150 mM NaCl, 0.01% Triton X-100, pH 7.4, sterilized by 0.22 μM filtration. 2.5× human kallikrein protein (Natural human plasma kallikrein, Abcam, Cat#:ab77870, lot#:GR251157-8) reaction solution: kallikrein final concentration 1 nM, diluted with buffer to 2.5 nM, 4 μL / well. Preparation of 2.5× substrate reaction solution: The final concentration of substrate Z-FR-AMC (Jier Biochemical, 208708) was 40 μM. The 10 mM stock solution of the substrate was diluted to 100 μM with buffer, 4 μL / well. Add 4 μL of 2.5× kallikrein reaction solution to each well of a 384 plate, replacing the negative control wells with buffer. Then, add 2 μL / well of the diluted 5× compound working solution to the corresponding wells, replacing the negative and positive control wells with 2.5% DMSO. Mix well and pre-incubate at 37°C for 10 min. Finally, add 4 μL of 2.5× substrate reaction solution to each well and vortex to mix for at least 30 s. Incubate at 37°C for 30 min, using excitation light at 342 nm and emission light at 440 nm. Measure the fluorescence intensity, analyze the prism curve, and calculate the IC50. 50 value.

[0468] Test Example 4: Pharmacokinetic Evaluation in Rats

[0469] Experimental objective:

[0470] Detection of pharmacokinetic parameters of the disclosed compound in rats

[0471] Experimental plan:

[0472] The solvent used in the experiment was: DMAC:Solutol:PBS (V / V) = 10%:10%:80% (v / v / v). Preparation method: Accurately weigh the required compound, add a certain volume of DMAC according to the ratio, vortex to mix and dissolve completely, then add Solutol and PBS in the above ratio and mix well. The same solvent was used in both the intravenous (iv) and oral (po) administration groups. The intravenous dose was 0.5 mpk, and the oral dose was 3 mpk. Blood collection time points: IV group: 0.083, 0.25, 0.5, 1, 2, 4, 7, 24h. PO group: 0.25, 0.5, 1, 2, 4, 7, 24h. At each time point, 200 μL of whole blood was collected from the jugular vein, anticoagulated with EDTA-K2, and immediately centrifuged at 4000 rpm for 5 min at 4℃. The supernatant was collected, and the sample was frozen at -80℃. Plasma sample processing: After precipitation with CH3CN / MeOH (1:1, v / v) precipitant containing internal standard, the samples were centrifuged at 14000 rpm for 5 min. The supernatant was then analyzed by LC-MS / MS (AB Triple Quard 5500) to obtain the blood drug concentration. Parameters were calculated using the non-compartmental model in Winnolin version 8.1. The results are shown in Table 2.

[0473] Table 2

[0474]

[0475] Conclusion: The compound disclosed herein exhibits favorable pharmacokinetic properties in rats.

[0476] Test Example 5: Rabbit's AV-SHUNT Method

[0477] Experimental objective:

[0478] The inhibitory effect of the compound on arterial and venous thrombosis in vivo was detected.

[0479] Experimental plan:

[0480] Healthy male New Zealand rabbits, weighing 2.0-3.0 kg, were allowed unrestricted food and water before the experiment. Sodium pentobarbital was prepared as a 1.5% (w / v) solution with physiological saline. Straight-tipped surgical scissors, ophthalmic scissors, ophthalmic forceps, microvascular forceps, microsurgical scissors, microsurgical forceps, arterial clamps, and a Shimadzu AUW220D balance were prepared. Modeling began 20 minutes after compound infusion and ended 60 minutes after infusion, at which point the infusion was stopped. The modeling method was as follows: New Zealand white rabbits were retrieved from the supplier and, after one day of acclimatization, were randomly assigned to groups. After anesthesia, the rabbits were shaved and their skin prepared. The right external jugular vein, common jugular vein, and left carotid artery were surgically exposed. A 10cm suture was inserted into a central cannula connecting the common jugular artery and jugular vein. The access was opened 20 minutes after infusion to begin thrombus induction and timing was started. After 40 minutes of induction, the access was closed, the central cannula was removed, and the suture was taken out. Blood was repeatedly removed 8 times by dabbing the thrombus onto qualitative filter paper (medium speed 18cm, Hangzhou Special Paper Co., Ltd.). Weighing paper was placed on a balance and tare it. A cotton thread soaked in blood was placed on the weighing paper, and the wet weight of the thrombus was weighed and recorded. The experimental animals were euthanized after thrombus removal. The thrombus weight of each animal was recorded, and graphs were plotted using GraphPadPrism7 software. One-way ANOVA was used for statistical analysis, and multiple comparisons (Dunnett's test) were performed to compare with the control group. The ED of the compound was calculated using OriginPro 2018SR1 version 9.5.1. 50 .

[0481] Test Example 6: BT Test

[0482] Experimental objective: To test the duration of bleeding in experimental rabbits caused by the compound.

[0483] Experimental protocol: Healthy male New Zealand rabbits, weighing 2.0-3.0 kg, were allowed to eat and drink freely before the experiment. Sodium pentobarbital and physiological saline were prepared into a 1.5% (w / v) solution and a 0.9% (w / v) NaCl solution. A timer was used.

[0484] Method 1: Prepare a 0.9% NaCl solution and preheat it to 37°C. Anesthetize the animal by injecting 1.5% sodium pentobarbital solution (2 mL / kg) into the marginal ear vein, and shave the hair off the hind paws. Trim the nail at the visible blood vessel (approximately 1 / 3 of the way down the fingertip). Once bleeding is confirmed, start timing and immerse the paw in 37°C physiological saline. Observe the bleeding; stop timing when bleeding stops and record the duration. Use GraphPad Prism 7 software for plotting, perform one-way ANOVA for statistical analysis, and compare with the control group using multiple comparison analysis (Dunnett's test).

[0485] Method 2: The animal was restrained with a restraint device, the hair on the ear was shaved, and the rabbit's ear was wiped with physiological saline. A wound was made on the marginal ear vein using a standard incision instrument. A timer was started after bleeding began, and filter paper was placed over the wound. The bleeding was observed and the duration was recorded. GraphPad Prism 7 software was used for plotting, and one-way ANOVA was used for statistical analysis. The animal was compared with the control group using multiple comparison analysis (Dunnett's test).

[0486] The embodiments of this disclosure have been described above. However, this disclosure is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this disclosure should be included within the protection scope of this disclosure.

Claims

1. A compound as shown in formula (II) or a pharmaceutically acceptable salt thereof, in: R 1 Selected from or ;R 1A1 Selected from H, halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and cyano groups; R 2 It is H or halogen; X is N or CR 6 ; R 6 Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, cyano; Each R 3 They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyl and cyano groups; Z 1 For N or CR 4a Z 2 For N or CR 4b ;R 4a and R 4b They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Cyclic C is selected from 6-membered heteroaryl and ; Each R 5 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, hydroxy, -NR 7 R 8 ; R 7 and R 8 They are the same or different, and each is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; n is selected from 0, 1, 2, 3, and 4; p is selected from 0, 1, 2, 3, 4, and 5.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein it is a compound of formula (II-1) or formula (II-2) or a pharmaceutically acceptable salt thereof. or in: Ring C, R 1 R 2 R 3 R 5 Z 1 Z 2 X and p are as defined in claim 1.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from , , , , .

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 5 They may be the same or different, and each is independently selected from halogens, hydroxyl groups, and C. 1-6 Alkyl groups and -NH2.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein... for or ;R 4a and R 4b They may be the same or different, and each is independently H or halogen; the a end is connected to the spiro ring portion.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein... Selected from , , , , ; R 5 p as defined in claim 1.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein... Selected from , , .

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is selected from 0, 1 and 2.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any of the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any of the following compounds: , , , , , , , , , , , , , , and .

11. A pharmaceutical composition comprising at least one therapeutically effective amount of the compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

12. Use of the compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 11 in the preparation of a medicament for inhibiting factor XIa.

13. The use according to claim 12, characterized in that, The intended use is in the preparation of medicaments for the prevention and / or treatment of XIa factor-mediated diseases.

14. The use according to claim 12, characterized in that, The intended use is for the preparation of medicaments for the prevention and / or treatment of diseases related to blood clotting.

15. The use according to claim 14, characterized in that, The blood clotting-related diseases are thrombosis, thromboembolic diseases, or cardiovascular and cerebrovascular diseases.

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