Amide-substituted heteroaryl compound, preparation method thereof and application of amide-substituted heteroaryl compound in medicine

Abstract

The invention relates to an amide-substituted heteroaryl compound, a preparation method thereof and application of the amide-substituted heteroaryl compound in medicine. Specifically, the invention relates to an amide-substituted heteroaryl compound as shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the amide-substituted heteroaryl compound as a therapeutic agent, the present invention relates to the use of RXFP1 agonists, in particular as RXFP1 agonists and in the preparation of medicaments for the treatment and / or prevention of diseases or conditions mediated or dependent by RXFP1. # imgabs0 #

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine and relates to an amide-substituted heteroaryl compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and its use as a therapeutic agent, in particular, its use as an RXFP1 agonist and its use in the preparation of a drug for treating and / or preventing diseases or conditions mediated by or dependent on RXFP1. Background Art

[0002] Relaxin is a peptide hormone of about 6KDa, including 7 members: Relaxin-1, -2, -3, and insulin-like peptide (INSL) 3, 4, 5 and 6. Among them, Relaxin-2 exists in the brain as a neuropeptide and is expressed in peripheral tissues such as heart, kidney, lung, liver, pancreas and reproductive tissue. In pregnant women's plasma, the concentration of Relaxin-2 increases during pregnancy, which can induce an increase in cardiac output during pregnancy, reduce systemic vascular resistance, increase overall arterial compliance, and increase renal blood flow. Relaxin has been shown to play a variety of beneficial cardiovascular effects in pathological events such as hypertension, atrial fibrillation, heart failure and myocardial infarction. The functions of relaxin-2 in chronic heart failure include: 1) stimulating cAMP production and activating the NO-sGC pathway to dilate blood vessels; 2) anti-fibrosis and anti-inflammation; 3) enhancing atrial contractility; 4) increasing the release of atrial natriuretic peptide; 5) increasing renal blood flow and inhibiting water and sodium retention [Mol Cell Endocrinol.2019:487:45-53; Cardiovasc Res.2017;113(6):609-619; J Cardiac Fail.2011;17:158e166; Hypertension.2014;64:315-32; Hypertension.2005;46:745-750].

[0003] The structure of Serelaxin recombinant peptide is the same as human Relaxin-2. Continuous infusion of Serelaxin has been clinically proven to reduce cardiovascular and all-cause mortality in patients with heart failure, improve dyspnea, improve heart damage, increase renal blood flow, etc. However, due to the short half-life of Serelaxin and its rapid clearance from the human body, the drug concentration drops rapidly after the continuous infusion stops, limiting the efficacy, and about 1 / 3 of patients reduce the dosage or even stop taking the drug due to the side effect of lowered blood pressure (reduced by >40mmHg).

[0004] RXFP1 is a homologous receptor of human Relaxin-2. After being activated by Relaxin-2, RXFP1 produces cAMP and increases NO, thereby exerting vasodilation, anti-fibrosis and anti-inflammatory effects [Pharmacol Rev. 2015: 67(2): 389-440; Mol Genet Genomic Med. 2020; 8(4): e1194.]. Activation of RXFP1 can exert similar effects to Relaxin-2 peptide [Mol Ther. 2021; 29(8): 2499-2513. Sci Rep. 2017; 7(1): 2968. Nat Commun. 2013; 4: 1953.].

[0005] In summary, small molecule agonists of RXFP1 that can be used in clinical practice are urgently needed to be developed. The developed small molecule agonists of RXFP1 need to have good pharmacokinetic properties (such as low clearance rate and long half-life), and reduce the risk of hypotension while maintaining the cardioprotective effect to inhibit the progression of heart failure.

[0006] Disclosed patent applications for compounds of RXFP1 agonists include WO2013165606A1, WO2022122773A1, WO2023076626A1, WO2023077040A1, WO2023077041A1, WO2023077070A1, WO2023114818A1, WO2023114819A1, WO2023114822A1 and WO2023114823A1. Summary of the invention

[0007] The object of the present invention is to provide a compound represented by general formula (I), or a pharmaceutically acceptable salt thereof:

[0008]

[0009] in:

[0010] U is N or CR 2 ;

[0011] V is CR V ;

[0012] W is N or CR W ;

[0013] R V , R 2 Together with the carbon atom to which it is attached, it forms a ring D, or R V , R W Together with the carbon atom to which it is attached, it forms a ring D, or R W , R V , R2 Together with the carbon atom to which it is attached, it forms ring D;

[0014] Ring D is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; and Ring D is optionally substituted by one or more R 4 replaced by;

[0015] R 2 With R W When present, it is selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, NR 20 R 21 、C(O)R 23 , OR 23 , cycloalkyl, heterocyclic group, aryl and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently optionally replaced by one or more R 01 replace;

[0016] R 3 is selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, NR 20 R 21 、C(O)R 23 , OR 23 , cycloalkyl, heterocyclic group, aryl and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently optionally replaced by one or more R 01 replace;

[0017] R 1 Selected from COOH, C(O)NR 20 R 21 、C(O)OR 23 NR 20 R 21 、OC(O)R 23 、S(O) r R 23 、S(O) r OR 23 、OS(O) r R 23 、S(O) r NR 20 R 21 、Alkylene NR 20 R 21 、P(O)R 23 R 24 , OR 23 、C(=NR 22 )NR 20 R21 、S(=NR 22 )(O)R 23 NR 22 C(O)NR 20 R 21 NR 22 S(O) r NR 20 R 21 、C(O)NR 22 NR 20 R 21 , =CR 23 R 24 , =NR 22 , hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, hydroxyl, hydroxyalkyl, alkenyl, alkynyl, cyano, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl; the alkylene, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R 02 replace;

[0018] X is selected from a bond, an alkylene group, O, S, NR e 、C(O)、C(O)NR e NR e C(O), Oalkylene and alkyleneO;

[0019] Y is an alkylene group or a ring A, wherein the alkylene group and the ring A are each independently optionally substituted with one or more R A replace;

[0020] Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0021] Z is selected from a bond, alkylene, alkenylene, heteroalkyl, alkoxyalkyl, O, S, NR e 、C(O)、C(O)NR e NR e C(O), cycloalkyl and heterocyclyl; the alkyl, alkenylene, heteroalkyl, cycloalkyl and heterocyclyl are each independently optionally substituted by one or more R 02 replace;

[0022] R 9 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an amino group, a cycloalkyl group, and a heterocyclic group;

[0023] A is selected from

[0024] Ring B is a cycloalkyl group or a heterocyclic group; Ring Cy is an aryl group or a heteroaryl group;

[0025] R 7 is selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, NR 20 R 21 、C(O)R 23 , OR 23 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R 03 replace;

[0026] R 6 For-(CR 10 R 11 ) s R 12 ;

[0027] R 10 and R 11 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, NR 20 R 21 、C(O)R 23 , OR 23 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R 03 replace;

[0028] or R 10 , R 11 and the carbon atom to which it is attached together form a cycloalkyl or heterocyclic group; the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more R 03 replace;

[0029] R 12 is alkyl or The alkyl group is optionally substituted with one or more R 03 replace;

[0030] Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0031] Each R 4 , R 01 , R 02 , R A , R 5 , R 8 and R 03are the same or different and are each independently selected from oxo, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, alkenyl, alkynyl, cyano, nitro, NR 20 R 21 、C(O)NR 20 R 21 、Alkylene NR 20 R 21 、Alkylene C(O)NR 20 R 21 NR 22 C(O)R 23 NR 22 C(O)NR 20 R 21 、C(O)R 23 、C(O)OR 23 、OC(O)R 23 、OC(O)OR 23 、S(O) r R 24 、S(O) r OR 24 、OS(O) r R 24 、S(O) r NR 20 R 21 NR 22 S(O) r R 24 、C(=NR 22 )R 23 、C(=NR 22 )NR 20 R 21 、S(=NR 22 )(O)R 23 、P(O)R 23 R 24 , OR 23 , =CR 23 R 24 , =NR 22 , SF5, cycloalkyl, heterocyclyl, cycloalkyloxy, heterocyclyloxy, aryl, heteroaryl, aryloxy and heteroaryloxy; the alkyl, alkoxy, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, cycloalkyloxy, heterocyclyloxy, aryl, heteroaryl, aryloxy and heteroaryloxy are each independently substituted with one or more R*;

[0032] Each R e , R 20 , R 21 , R 22 , R 23 and R24 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, hydroxy, alkenyl, alkynyl, NR a R b 、C(O)NR a R b 、Alkylene NR a R b 、Alkylene C(O)NR a R b NR c C(O)R d NR c C(O)NR a R b 、C(O)R d 、C(O)OR d 、OC(O)R d 、OC(O)OR d , OR d , cycloalkyl, heterocyclyl, aryl and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently substituted by one or more R*;

[0033] or R 20 , R 21 and the nitrogen atom to which it is attached together form a heterocyclic group, which is optionally substituted by one or more R*; or R 23 , R 24 and the carbon atom to which it is attached together form a cycloalkyl group, which is optionally substituted with one or more R*;

[0034] Each R a , R b , R c and R d are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, an amino group, an NH alkyl group, an N(alkyl)2 group, an amide group, a C(O)NH alkyl group, a C(O)N(alkyl)2 group, a C(O)O alkyl group, a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, a heterocyclylalkyl group, a cycloalkyloxy group, a heterocyclyloxy group, an aryl group and a heteroaryl group; and the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the cycloalkylalkyl group, the heterocyclylalkyl group, the cycloalkyloxy group, the heterocyclyloxy group, an aryl group and a heteroaryl group are each independently optionally replaced by one or more R * or, R a , R b and the nitrogen atom to which it is attached form a heterocyclic group, the heterocyclic group is optionally substituted by one or more R * replaced by;

[0035] Each R* are the same or different and are each independently selected from oxo, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, amino, NHalkyl, N(alkyl)2, amide, C(O)NHalkyl, C(O)N(alkyl)2, C(O)alkyl, C(O)Oalkyl, alkyleneamino, alkyleneamide, nitro, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl and heteroaryl; the alkyl, alkoxy, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl and heteroaryl are each independently optionally substituted by one or more selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, amino, cycloalkyl and heterocyclyl;

[0036] Each r is the same or different and is independently 0, 1 or 2;

[0037] m is 0, 1, 2, 3, 4, 5 or 6;

[0038] s is 0, 1, 2, 3, 4, 5 or 6; and

[0039] t is 0, 1, 2, 3, 4, 5 or 6.

[0040] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ring D is selected from polycyclic cycloalkyl, polycyclic heterocyclic, polycyclic aromatic and polycyclic heteroaromatic; and Ring D is optionally replaced by one or more R 4 Replaced by; R 4 As defined in general formula (I).

[0041] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,

[0042]

[0043] in,

[0044] Ring D is a polycyclic cycloalkyl group or a polycyclic heterocyclyl group;

[0045] n is an integer from 0 to 20;

[0046] R 1 , Z, Y, X, U, R 3 , R 4 and A are as defined in the general formula (I).

[0047] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III), (IV), (V) or (VI) or a pharmaceutically acceptable salt thereof,

[0048]

[0049] in,

[0050] Q 1 and Q are the same or different and are each independently selected from a bond, O, (CR g R h ) p 、O(CR g R h ) p , (CR g R h ) p O、(CR g R h ) p O(CR g R h ) p NR i 、C(O)NR i NR i C(O) and S(O) r ;

[0051] Each R g and R h are the same or different and are each independently a hydrogen atom or R 4 ; R i is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group;

[0052] Ring E is a cycloalkyl group or a heterocyclic group; Q 3 CR 4 or N;

[0053] n1 is 0, 1, 2, 3, 4, 5 or 6; n3 is 0, 1, 2, 3 or 4;

[0054] p is 1, 2 or 3; q is 0, 1, 2, 3, 4, 5 or 6;

[0055] Ring A, R 1 , R A ,X,U,R 3 , R 4 , A and r are as defined in the general formula (I).

[0056] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III-1) or (III-2) or a pharmaceutically acceptable salt thereof,

[0057]

[0058] in,

[0059] Ring A, Ring E, R 1 , R A ,q,X,U,R 3 , Q 1 , Q, R 4 , n1 and A are as defined in the general formula (III).

[0060] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein Selected from n is an integer from 0 to 20; Ring D1 is selected from cycloalkyl, heterocyclic, aryl and heteroaryl, Ring D2 is selected from cycloalkyl, heterocyclic, aryl and heteroaryl; Ring D, U, W and R 4 As defined in general formula (I).

[0061] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein Selected from Q 1 and Q are the same or different and are each independently selected from a bond, O, (CR g R h ) p 、O(CR g R h ) p , (CR g R h ) p O、(CR g R h ) p O(CR g R h ) p NR i 、C(O)NR i NR i C(O) and S(O) r ; Each R g and R h are the same or different and are each independently a hydrogen atom or R 4 ; R iis selected from hydrogen, alkyl, cycloalkyl and heterocyclic groups; p is 1, 2 or 3; ring E is a cycloalkyl or heterocyclic group; n1 is 0, 1, 2, 3, 4, 5 or 6; n3 is 0, 1, 2, 3 or 4; Q 3 CR 4 or N; U, R 4 and r are as defined in formula (I);

[0062] In some embodiments, Selected from Q 1 is a bond or O, Q is a bond or O, u is 1, 2, 3 or 4, n5 is 0, 1, 2 or 3; n4 is 1, 2 or 3; Q 1 ,Q,Q 3 , n1 and n3 are as defined in formula (A1), (A2), (A3) or (A4); U and R 4 As defined in general formula (I);

[0063] In some embodiments, Selected from

[0064] In some embodiments, Selected from R 4a is a hydrogen atom or R 4 ; R 2 and R 4 As defined in general formula (I);

[0065] In some embodiments, Selected from R 2 As defined in general formula (I).

[0066] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein ring D is a 7- to 14-membered bicyclic cycloalkyl or a 7- to 14-membered bicyclic heterocyclic group; in some embodiments, ring D is a 7- to 14-membered bicyclic heterocyclic group; in some embodiments, ring D is a 7-, 8- or 9-membered bicyclic heterocyclic group;

[0067] In some embodiments, ring D is selected from Q 1 , Q, ring E, n3 and Q 3 As defined in formula (A1), (A2), (A3) or (A4);

[0068] In some embodiments, ring D is selected from Q 1 is a bond or O, Q is a bond or O, u is 1, 2, 3 or 4, n5 is 0, 1, 2 or 3; n4 is 1, 2 or 3; Q 1 , Q, n3 and Q 3 As defined in formula (A1), (A2), (A3) or (A4);

[0069] In some embodiments, ring D is selected from Q 1 is a bond or O, Q is a bond or O, u is 1, 2, 3 or 4, and n3 is 0, 1, 2, 3 or 4;

[0070] In some embodiments, ring D is selected from

[0071] In some embodiments, ring D is selected from * end close to C(O); In some embodiments, ring D is selected from In some embodiments, ring D is selected from

[0072] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (IV), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein Q 1 is selected from the group consisting of a bond, O, OCH2, and OCH2CH2; in some embodiments, Q 1 is selected from a bond, O and OCH2; in some embodiments, Q 1 is a bond or O; in some embodiments, Q 1 is O; in some embodiments, Q 1 is the key.

[0073] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein Q is selected from a bond, O, OCH2, CH2O, OCH2CH2, CH2CH2O and CH2OCH2; in some embodiments, Q is selected from a bond, O, OCH2 and OCH2CH2; in some embodiments, Q is a bond or O; in some embodiments, Q is a bond; in some embodiments, Q is O.

[0074] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (IV), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein Q 1is a bond or O, and / or Q is a bond or O; in some embodiments, Q 1 and Q are both 0.

[0075] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (V), (VI) or a pharmaceutically acceptable salt thereof, wherein Q 3 is CH or N; in some embodiments, Q 3 is N.

[0076] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), and (III-2) or their pharmaceutically acceptable salts, wherein ring E is a 3- to 12-membered cycloalkyl or a 3- to 12-membered heterocyclyl; in some embodiments, ring E is a 3- to 6-membered cycloalkyl or a 4- to 7-membered heterocyclyl; in some embodiments, ring E is selected from cyclopropyl, cyclobutyl, cyclopentyl and pyrrolidinyl; in some embodiments, ring E is a 3- to 6-membered cycloalkyl; in some embodiments, ring E is a cyclopropyl or cyclobutyl; in some embodiments, ring E is a cyclopropyl; in some embodiments, ring E is a cyclobutyl; in some embodiments, ring E is a cyclobutyl or cyclopentyl; in some embodiments, ring E is a 5- or 6-membered heterocyclyl; in some embodiments, ring E is a pyrrolidinyl.

[0077] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein: each R 4 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy and 3 to 6 membered cycloalkyl; in some embodiments, each R 4 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, each R 4 are the same or different and are each independently halogen; in some embodiments, R 4 For F.

[0078] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein n1 is 0, 1 or 2; in some embodiments, n1 is 0; in some embodiments, n1 is 2.

[0079] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein each R 4 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl, and / or n1 is 0, 1 or 2.

[0080] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein each R 4 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl, and / or n is 0, 1 or 2.

[0081] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein ring E is a 3- to 6-membered cycloalkyl or a 4- to 7-membered heterocyclic group, and / or each R 4 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl, and / or n1 is 0, 1 or 2; in some embodiments, ring E is selected from cyclopropyl, cyclobutyl, cyclopentyl and pyrrolidinyl, and / or each R 4 are the same or different and are each independently halogen, and / or n1 is 0, 1 or 2.

[0082] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (IV), (V), (VI) or a pharmaceutically acceptable salt thereof, wherein n3 is 0, 1 or 2; in some embodiments, n3 is 0 or 1; in some embodiments, n3 is 0; in some embodiments, n3 is 1.

[0083] In some embodiments of the present disclosure, n4 is 1 or 2; in some embodiments, n4 is 1.

[0084] In some embodiments of the present disclosure, n5 is 1 or 2; in some embodiments, n5 is 1.

[0085] In some embodiments of the present disclosure, u is 1 or 2; in some embodiments, u is 1.

[0086] In some embodiments of the present disclosure, ring D1 is a 5- or 6-membered heterocyclyl; in some embodiments, ring D1 is a morpholinyl.

[0087] In some embodiments of the present disclosure, ring D2 is a 4- to 7-membered heterocyclyl, in some embodiments, ring D2 is a 5- or 6-membered heterocyclyl; in some embodiments, ring D2 is a pyrrolidinyl.

[0088] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein A is In some embodiments, A is Ring B, R 5 , R 6 , R 7 and m are as defined in formula (I);

[0089] In some embodiments, A is Ring B, Ring Cy, R 5 , R 6 , R 7 , R 8 and m are as defined in formula (I);

[0090] In some embodiments, A is selected from

[0091] In some embodiments, A is R 5 , R 6 , R 7 and m are as defined in Formula (I); in some embodiments, A is R 6 As defined in general formula (I);

[0092] In some embodiments, A is In some embodiments, A is In some embodiments, A is R 23 , R 24 and R 6 As defined in general formula (I);

[0093] In some embodiments, A is m1 is 0, 1, 2, 3 or 4, R 6 and R 8 As defined in general formula (I).

[0094] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein ring B is a 3- to 12-membered cycloalkyl or a 3- to 12-membered heterocyclic group; in some embodiments, ring B is a 3- to 10-membered cycloalkyl; in some embodiments, ring B is a 5- to 8-membered bridged cycloalkyl;

[0095] In some embodiments, Ring B is selected from In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is selected from In some embodiments, Ring B is In some embodiments, Ring B is The * end is connected to CO and N, and the + end is connected to R 5 connect.

[0096] In some embodiments of the present disclosure, in the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, ring Cy is a 6- to 10-membered aromatic group; in some embodiments, ring Cy is a phenyl group.

[0097] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein R 6 For-(CR 10 R 11 )R 12 or R 12 , R 12 for R 10 , R 11 , Ring C, R 03 and t are as defined in Formula (I); in some embodiments, R 6 -(CH2) s R 12 , R 12 for Ring C, R 03 , s and t are as defined in the general formula (I);

[0098] In some embodiments, R 6 Selected from In some embodiments, R 6 for

[0099] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein R 10 and R 11 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; in some embodiments, R 10 and R 11 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl; in some embodiments, R 10 and R 11 are the same or different and are each independently a hydrogen atom or CH3; in some embodiments, R 10 and R 11 All are hydrogen atoms.

[0100] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein R 10 is a hydrogen atom, and / or R 11 A hydrogen atom or C 1-6 alkyl; in some embodiments, R 10 is a hydrogen atom, and / or R 11 It is a hydrogen atom or CH3.

[0101] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein R 12 for Ring C, R 03 and t are as defined in general formula (I);

[0102] In some embodiments, R 12 for x is 0, 1, 2, 3 or 4, R 6a is a hydrogen atom or R 03 , R 6b is a hydrogen atom or R 03 , R 03 and t are as defined in Formula (I); in some embodiments, R 12 Selected from In some embodiments, R 12 for

[0103] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein ring C is selected from 3-8 membered cycloalkyl, 4-7 membered heterocyclyl and phenyl; in some embodiments, ring C is 3-6 membered cycloalkyl or phenyl; in some embodiments, ring C is 3-6 membered cycloalkyl; in some embodiments, ring C is selected from cyclopropyl, cyclobutyl and phenyl; in some embodiments, ring C is cyclobutyl.

[0104] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein each R 03 are the same or different and are each independently selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy and 3 to 6 membered cycloalkyl; in some embodiments, each R 03 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, each R 03 are the same or different and are each independently selected from F, methyl and CF3; in some embodiments, each R 03 are the same or different and are each independently halogen or C 1-6 alkyl; in some embodiments, each R 03 are the same or different and are each independently F or methyl; in some embodiments, each R 03 The same or different, and each independently is C 1-6 alkyl; in some embodiments, R 03 is methyl;

[0105] In some embodiments, each R 03 The same or different, and each independently selected from F, methyl, CF3, OCF3, SF5, S(O)2CH3 and S(O)2CF3.

[0106] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein t is 0, 1, 2 or 3; in some embodiments, t is 1, 2 or 3; in some embodiments, t is 1.

[0107] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein s is 0, 1 or 2; in some embodiments, s is 0 or 1.

[0108] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein ring C is a 3- to 6-membered cycloalkyl or phenyl, and / or each R 03 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl, and / or t is 0, 1, 2 or 3; in some embodiments, ring C is a 3- to 6-membered cycloalkyl, and / or each R 03 are the same or different and are each independently halogen or C 1-6 alkyl, and / or t is 0, 1, 2 or 3.

[0109] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein X is selected from a bond, O, S, CH2, OCH2 and CH2O; in some embodiments, X is a bond or O; in some embodiments, X is O.

[0110] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein Y is q is 0, 1, 2, 3, 4, 5 or 6; Ring A and R A As defined in formula (I); in some embodiments, Y is selected from In some embodiments, Y is

[0111] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein Selected from In some embodiments, Selected from Each v is the same or different and is independently 0, 1, 2 or 3, q ​​is 0, 1, 2, 3, 4, 5 or 6; R 1A is a hydrogen atom or R A , R A As defined in formula (I); in some embodiments, for In some embodiments, for

[0112] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein ring A is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl; in some embodiments, ring A is 3- to 6-membered cycloalkyl or phenyl; in some embodiments, ring A is 3- to 6-membered cycloalkyl; in some embodiments, ring A is cyclohexyl or phenyl; in some embodiments, ring A is cyclohexyl; in some embodiments, ring A is selected from cyclohexyl, phenyl, five-membered heteroaryl, y is 0, 1 or 2, y1 is 0 or 1;

[0113] In some embodiments, Ring A is selected from cyclohexyl, phenyl, Connected to X or an aromatic ring.

[0114] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein each R A are the same or different and are each independently selected from oxo, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyl; in some embodiments, each R A are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, each R A The same or different, and each independently is C 1-6 alkyl; in some embodiments, R A C 1-6 alkyl; in some embodiments, R A is methyl;

[0115] In some embodiments, each R A are the same or different and are each independently halogen or C 1-6 alkyl; in some embodiments, each R A are the same or different and are each independently F or methyl.

[0116] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein Ring A is a 3- to 6-membered cycloalkyl or phenyl, and / or each R A are the same or different and are each independently selected from halogen, C1-6 Alkyl and C 1-6 haloalkyl, and / or q is 0, 1 or 2.

[0117] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein Z is selected from a bond, C 1-6 Alkylene and C 1-6 Heteroalkyl, the C 1-6 Alkylene and C 1-6 The heteroalkyl groups are each independently optionally substituted with one or more R 02 Replacement, R 02 As defined in Formula (I); in some embodiments, Z is a bond.

[0118] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein R 1 Selected from COOH, C(O)NR 20 R 21 、C(O)OR 23 , hydrogen atom, hydroxyl group, C 1-6 alkyl, 3 to 10 membered heterocyclic group and 5 or 6 membered heteroaryl, the C 1-6 The alkyl, 3 to 10 membered heterocyclyl and 5 or 6 membered heteroaryl groups are each independently optionally substituted by one or more R 01 Replacement, R 20 , R 21 , R 23 and R 01 As defined in Formula (I); in some embodiments, R 1 Selected from C(O)OR 23 、C(O)NR 20 R 21 , hydroxyl, C 1-6 Alkyl and hydrogen atoms, the C 1-6 The alkyl group is optionally substituted with one or more R 01 Replacement; R 20 , R 21 , R 23 and R 01 As defined in general formula (I);

[0119] In some embodiments, R 1 C(O)OR 23 or C(O)NR 20 R 21 , R 20 , R 21 and R 23 As defined in Formula (I); in some embodiments, R 1is COOH or C(O)NH2; in some embodiments, R 1 C(O)OR 23 , R 23 As defined in Formula (I); in some embodiments, R 1 is COOH.

[0120] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein for X, Y, and R 1 As defined in formula (I); in some embodiments, Selected from In some embodiments, for

[0121] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein each R 20 and R 21 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl; in some embodiments, R 20 and R 21 are the same or different and are each independently a hydrogen atom or a methyl group; in some embodiments, R 20 and R 21 All are hydrogen atoms.

[0122] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein R 23 A hydrogen atom or C 1-6 alkyl; in some embodiments, R 23 is a hydrogen atom or a methyl group; in some embodiments, R 23 A hydrogen atom.

[0123] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein each R 01 are the same or different and are each independently selected from oxo, halogen, hydroxyl, C 1-6 Alkyl and C 1-6 Alkoxy.

[0124] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein each R02 are the same or different and are each independently selected from oxo, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyl; in some embodiments, each R 02 are the same or different and are each independently selected from halogen, hydroxyl, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0125] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein U is CR 2 , R 2 As defined in Formula (I); in some embodiments, U is selected from N, CH, CF and C-CN; in some embodiments, U is CF.

[0126] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein R 2 Selected from hydrogen atoms, halogens, cyano groups, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 2 is a hydrogen atom or a halogen; in some embodiments, R 2 is selected from hydrogen atoms, F and CN; in some embodiments, R 2 is a hydrogen atom or F.

[0127] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein R 3 Selected from hydrogen atoms, halogens, cyano groups, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 3 is selected from hydrogen, halogen and cyano; in some embodiments, R 3 A hydrogen atom.

[0128] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein R 2 Selected from hydrogen atoms, halogens, cyano groups, C 1-6 Alkyl and C 1-6 haloalkyl; and / or R 3 is a hydrogen atom; in some embodiments, R 2 is a hydrogen atom or a halogen, and / or R3 A hydrogen atom.

[0129] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein: each R 5 are the same or different and are each independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and =CR 23 R 24 In some embodiments, R 5 =CR 23 R 24 , R 23 and R 24 As defined in Formula (I); in some embodiments, each R 5 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 haloalkyl and 3- to 6-membered cycloalkyl.

[0130] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein: R 7 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Alkoxy; in some embodiments, R 7 is selected from hydrogen atoms, F, CH3 and OCH3; in some embodiments, R 7 A hydrogen atom.

[0131] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein: each R 8 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy.

[0132] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein: m is 0, 1 or 2; in some embodiments, m is 0.

[0133] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 9 A hydrogen atom.

[0134] In some embodiments of the present disclosure, m1 is 0, 1 or 2; in some embodiments, m1 is 0.

[0135] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein: each R* is the same or different and is independently selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy and 3- to 6-membered cycloalkyl.

[0136] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein: R 23 and R 24 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl, 3 to 6-membered cycloalkyl, phenyl and 5 or 6-membered heteroaryl, the C 1-6 Alkyl, 3 to 6 membered cycloalkyl, phenyl and 5 or 6 membered heteroaryl are each independently optionally substituted with one or more R*, or R 23 , R 24 and the carbon atom to which it is attached together form a 3- to 6-membered cycloalkyl group, R* is as defined in the general formula (I); in some embodiments, R 23 and R 24 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl, 3 to 6 membered cycloalkyl, and 3 to 6 membered halocycloalkyl; in some embodiments, R 23 and R 24 are the same or different and are each independently selected from hydrogen, F, methyl, CF3, cyclopropyl, cyclobutyl, and cyclopentyl.

[0137] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein R 23 is a hydrogen atom or a halogen; in some embodiments, R 23 is a hydrogen atom or F; in some embodiments, R 23 A hydrogen atom.

[0138] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein R 24Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 6 membered cycloalkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are each independently optionally substituted with one or more R*;

[0139] In some embodiments, R 24 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl, 3 to 6 membered cycloalkyl, phenyl and 5 or 6 membered heteroaryl, wherein the C 1-6 Alkyl, 3 to 6 membered cycloalkyl, phenyl and 5 or 6 membered heteroaryl are each independently optionally selected from halogen, C 1-6 Alkyl and C 1-6 In some embodiments, R 24 is selected from hydrogen, F, methyl, CF3, cyclopropyl, cyclobutyl, In some embodiments, R 24 is a hydrogen atom or a 3- to 6-membered cycloalkyl group, wherein the 3- to 6-membered cycloalkyl group is optionally selected from halogen and C 1-6 In some embodiments, R 24 is a hydrogen atom or a cyclopropyl group.

[0140] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein each R * are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and 3- to 6-membered cycloalkyl.

[0141] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein: each R 22 , R a , R b and R c are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl; in some embodiments, R 22 , R a , R b and R care the same or different and are each independently a hydrogen atom or a methyl group; in some embodiments, R 22 , R a , R b and R c All are hydrogen atoms.

[0142] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein: R d A hydrogen atom or C 1-6 alkyl; in some embodiments, R d C 1-6 alkyl; in some embodiments, R d It is methyl.

[0143] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein: each R g , R h and R i are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl; in some embodiments, R g and R h is a hydrogen atom, R i A hydrogen atom or a methyl group.

[0144] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein: p is 1 or 2; in some embodiments, p is 1; in some embodiments, p is 2.

[0145] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (III-1), (III-2) or their pharmaceutically acceptable salts, wherein: r is 1 or 2; in some embodiments, r is 2.

[0146] In some embodiments of the present disclosure, the compound represented by the general formula (III), (IV), (V), (VI), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein: X is a bond or O; Ring A is a 3- to 6-membered cycloalkyl or phenyl; each R A are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; q is 0, 1 or 2; R 1 C(O)OR 23 or C(O)NR 20 R 21 , R20 and R 21 are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; R 23 A hydrogen atom or C 1-6 Alkyl; U is CR 2 , R 2 Selected from hydrogen atoms, halogens, cyano groups, C 1-6 Alkyl and C 1-6 Haloalkyl; R 3 is selected from hydrogen atom, halogen and cyano group; Q 1 is selected from a bond, O, OCH2 and OCH2CH2; Q is a bond or O; Ring E is a 3- to 6-membered cycloalkyl or a 4- to 7-membered heterocyclyl; each R 4 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; n1 is 0, 1 or 2; n3 is 0 or 1; Q 3 is CH or N; A is R 6 For-(CR 10 R 11 )R 12 or R 12 , R 12 for R 10 and R 11 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; Ring C is a 3- to 6-membered cycloalkyl or phenyl; each R 03 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; t is 0, 1, 2 or 3.

[0147] In some embodiments of the present disclosure, the compound represented by the general formula (III), (IV), (V), (VI), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein: X is a bond or O; Ring A is a 3- to 6-membered cycloalkyl or phenyl; each R A are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; q is 0, 1 or 2; R 1 C(O)OR 23 , R 23 A hydrogen atom or C 1-6 Alkyl; U is CR 2 , R 2 Selected from hydrogen atoms, halogens, cyano groups, C 1-6 Alkyl and C 1-6 Haloalkyl; R 3is selected from hydrogen atom, halogen and cyano group; Q 1 is selected from a bond, O and OCH2; Q is a bond or O; Ring E is selected from cyclopropyl, cyclobutyl, cyclopentyl and pyrrolidinyl; each R 4 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; n1 is 0, 1 or 2; n3 is 0 or 1; Q 3 is CH or N; A is R 6 For-(CR 10 R 11 )R 12 or R 12 , R 12 for R 10 and R 11 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; Ring C is a 3- to 6-membered cycloalkyl; each R 03 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; t is 0, 1, 2 or 3.

[0148] In some embodiments of the present disclosure, the compound represented by the general formula (III), (IV), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein: X is a bond or O; Ring A is a cyclohexyl group, and each R A are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; q is 0, 1 or 2; R 1 is C(O)OH; U is CR 2 , R 2 Selected from hydrogen atoms, halogens, cyano groups, C 1-6 Alkyl and C 1-6 Haloalkyl; R 3 is selected from hydrogen atom, halogen and cyano group; Q 1 is selected from a bond, O and OCH2; Q is a bond or O; Ring E is cyclopropyl or cyclobutyl; each R 4 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; n1 is 0, 1 or 2; n3 is 0 or 1; A is R 6 For-(CR 10 R 11 )R 12 or R 12 , R 12 for R10 and R 11 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; Ring C is a 3- to 6-membered cycloalkyl; each R 03 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; t is 0, 1, 2 or 3.

[0149] In some embodiments of the present disclosure, the compound represented by the general formula (III), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein: X is a bond or O; Ring A is a 3- to 6-membered cycloalkyl or phenyl; each R A are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; q is 0, 1 or 2; R 1 is C(O)OH or C(O)NH2; U is CR 2 , R 2 Selected from hydrogen atoms, halogens, cyano groups, C 1-6 Alkyl and C 1-6 Haloalkyl; R 3 is selected from hydrogen atom, halogen and cyano group; Q 1 is a bond or O; Q is a bond or O; Ring E is cyclobutyl or cyclopentyl; each R 4 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; n1 is 0, 1 or 2; A is R 6 For-(CR 10 R 11 )R 12 or R 12 , R 12 for R 10 and R 11 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; Ring C is a 3- to 6-membered cycloalkyl; each R 03 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; t is 0, 1, 2 or 3.

[0150] In some embodiments of the present disclosure, the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof, wherein: X is a bond or O; Ring A is a 3- to 6-membered cycloalkyl or phenyl; each R A are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C1-6 haloalkyl; q is 0, 1 or 2; R 1 is C(O)OH or C(O)NH2; U is CR 2 , R 2 Selected from hydrogen atoms, halogens, cyano groups, C 1-6 Alkyl and C 1-6 Haloalkyl; R 3 is selected from hydrogen atom, halogen and cyano group; Q 1 is selected from a bond, O and OCH2; Q is a bond or O; Ring E is cyclopropyl; each R 4 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; n1 is 0, 1 or 2; n3 is 0 or 1; A is R 6 For-(CR 10 R 11 )R 12 or R 12 , R 12 for R 10 and R 11 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; Ring C is a 3- to 6-membered cycloalkyl; each R 03 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; t is 0, 1, 2 or 3.

[0151] In some embodiments of the present disclosure, the compound represented by the general formula (V) or (VI) or a pharmaceutically acceptable salt thereof, wherein: X is a bond or O; Ring A is a cyclohexyl group, and each R A are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; q is 0, 1 or 2; R 1 is C(O)OH; U is CR 2 , R 2 Selected from hydrogen atoms, halogens, cyano groups, C 1-6 Alkyl and C 1-6 Haloalkyl; R 3 is selected from hydrogen atom, halogen and cyano group; Q 3 is N; Q is a bond or O; Ring E is a 5- or 6-membered heterocyclic group; n3 is 0 or 1; each R 4 are the same or different and are each independently halogen; n1 is 0, 1 or 2; A is R 6 For-(CR 10 R 11 )R12 or R 12 , R 12 for R 10 and R 11 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; Ring C is a 3- to 6-membered cycloalkyl; each R 03 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; t is 0, 1, 2 or 3.

[0152] Table A Typical compounds of the present disclosure include, but are not limited to:

[0153]

[0154]

[0155]

[0156] Table B Typical intermediate compounds or their salts disclosed herein include but are not limited to:

[0157]

[0158]

[0159]

[0160] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0161]

[0162] R 1 C(O)OR 23 The compound represented by the general formula (I) or its pharmaceutically acceptable salt undergoes a deprotection reaction to obtain R 1 A compound represented by the general formula (I) C(O)OH or a pharmaceutically acceptable salt thereof;

[0163] Among them, R 23 is alkyl or -alkylaryl;

[0164] Z, Y, X, U, V, W, R 3 , R 9 and A are as defined in the general formula (I).

[0165] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0166]

[0167] R 1 C(O)OR 23 The compound represented by the general formula (II) or its pharmaceutically acceptable salt undergoes a deprotection reaction to obtain R 1 A compound represented by the general formula (II) of C(O)OH or a pharmaceutically acceptable salt thereof;

[0168] Among them, R 23 is alkyl or -alkylaryl;

[0169] Z, Y, X, U, R 3 , Ring D, R 4 , n and A are as defined in the general formula (II).

[0170] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0171]

[0172] R 1 C(O)OR 23 The compound represented by the general formula (III) or its pharmaceutically acceptable salt undergoes a deprotection reaction to obtain R 1 A compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein the compound is C(O)OH;

[0173] Among them, R 23 is alkyl or -alkylaryl;

[0174] Ring A, R A ,q,X,U,R 3 , Q 1 ,Q,Ring E,R 4 , n1 and A are as defined in the general formula (III).

[0175] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0176]

[0177] R 1 C(O)OR 23 The compound represented by the general formula (III-1) or its pharmaceutically acceptable salt undergoes a deprotection reaction to obtain R 1 A compound represented by the general formula (III-1) C(O)OH or a pharmaceutically acceptable salt thereof;

[0178] Among them, R 23is alkyl or -alkylaryl;

[0179] Ring A, R A ,q,X,U,R 3 , Q 1 ,Q,Ring E,R 4 , n1 and A are as defined in the general formula (III-1).

[0180] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0181]

[0182] R 1 C(O)OR 23 The compound represented by the general formula (III-2) or its pharmaceutically acceptable salt undergoes a deprotection reaction to obtain R 1 A compound represented by the general formula (III-2) C(O)OH or a pharmaceutically acceptable salt thereof;

[0183] Among them, R 23 is alkyl or -alkylaryl;

[0184] Ring A, R A ,q,X,U,R 3 , Q 1 ,Q,Ring E,R 4 , n1 and A are as defined in the general formula (III-2).

[0185] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:

[0186]

[0187] R 1 C(O)OR 23 The compound represented by the general formula (IV) or its pharmaceutically acceptable salt undergoes a deprotection reaction to obtain R 1 A compound represented by the general formula (IV) of C(O)OH or a pharmaceutically acceptable salt thereof;

[0188] Among them, R 23 is alkyl or -alkylaryl;

[0189] Ring A, R A ,q,X,U,R 3 , Q 1 ,Q,Ring E,R 4 , n1, n3 and A are as defined in the general formula (IV).

[0190] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (V) or a pharmaceutically acceptable salt thereof, the method comprising:

[0191]

[0192] R 1 C(O)OR 23 The compound represented by the general formula (V) or its pharmaceutically acceptable salt undergoes a deprotection reaction to obtain R 1 A compound represented by the general formula (V) of C(O)OH or a pharmaceutically acceptable salt thereof;

[0193] Among them, R 23 is alkyl or -alkylaryl;

[0194] Ring A, R A ,q,X,U,R 3 , Q 3 ,Q,Ring E,R 4 , n1, n3 and A are as defined in the general formula (V).

[0195] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (VI) or a pharmaceutically acceptable salt thereof, the method comprising:

[0196]

[0197] R 1 C(O)OR 23 The compound represented by the general formula (VI) or its pharmaceutically acceptable salt undergoes a deprotection reaction to obtain R 1 A compound represented by the general formula (VI) C(O)OH or a pharmaceutically acceptable salt thereof;

[0198] Among them, R 23 is alkyl or -alkylaryl;

[0199] Ring A, R A ,q,X,R 3 , Q 3 ,Q,Ring E,R 4 , n1, n3 and A are as defined in the general formula (VI).

[0200] In some embodiments of the present disclosure, the method for preparing the compound represented by the general formula (I) to (VI), (III-1), (III-2) or a pharmaceutically acceptable salt thereof, wherein: R 23 is -alkylaryl; in some embodiments, R 23 Selected from C 1-6 alkyl, benzyl, and -CH2-naphthyl; in some embodiments, R 23 It is -CH2-naphthyl.

[0201] Another aspect of the present disclosure relates to a pharmaceutical composition, which contains the compounds of the present disclosure represented by general formula (I) to (VI), (III-1), (III-2) and Table A or their pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0202] The present disclosure further relates to the use of compounds of formula (I) to (VI), (III-1), (III-2) and shown in Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same in the preparation of drugs for agonizing RXFP1 activity.

[0203] The present disclosure further relates to the use of compounds of formula (I) to (VI), (III-1), (III-2) and shown in Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same in the preparation of RXFP1 agonists.

[0204] The present disclosure further relates to the use of compounds of formula (I) to (VI), (III-1), (III-2) and shown in Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same, in the preparation of drugs for treating and / or preventing diseases or conditions mediated by or dependent on RXFP1.

[0205] The present disclosure further relates to the use of the compounds shown in general formula (I) to (VI), (III-1), (III-2) and Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same in the preparation of drugs for treating and / or preventing heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, chronic kidney disease, acute kidney injury, fibrotic diseases and related diseases and inflammatory diseases; wherein the heart failure is preferably advanced heart failure, post-acute heart failure, cardiorenal syndrome, heart failure with impaired renal function, chronic heart failure, chronic heart failure with reduced ejection fraction (HFmEF), compensated heart failure, decompensated heart failure, right heart failure, left heart failure, global failure, ischemic cardiomyopathy, dilated cardiomyopathy, heart failure associated with congenital heart defects, heart valve defects, heart valve defects and heart valve defects. Related heart failure, mitral stenosis, mitral regurgitation, aortic stenosis, aortic stenosis insufficiency, tricuspid stenosis, tricuspid regurgitation, pulmonary stenosis, pulmonary regurgitation, heart failure associated with valvular heart defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, heart failure associated with valvular heart defects, cardiac storage disorder, diastolic heart failure, systolic heart failure, acute phase of worsening heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), chronic heart failure with reduced ejection fraction (HFrEF), chronic heart failure with preserved ejection fraction (HFpEF), after myocardial remodeling, angina pectoris, hypertension, pulmonary hypertension and pulmonary hypertension.

[0206] The present disclosure also relates to a method for treating and / or preventing diseases or conditions mediated by or dependent on RXFP1, comprising administering to a patient in need thereof a compound represented by the above-mentioned general formula (I) to (VI), (III-1), (III-2) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0207] The present disclosure also relates to a method for agonizing RXFP1 activity, comprising administering to a patient in need thereof a compound of the above general formula (I) to (VI), (III-1), (III-2) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0208] The present disclosure also relates to a method for treating and / or preventing heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, chronic kidney disease, acute kidney injury, fibrotic diseases and related diseases and inflammatory diseases, which comprises administering to a patient in need thereof a compound represented by the above-mentioned general formula (I) to (VI), (III-1), (III-2) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0209] The present disclosure further relates to a compound of the above general formula (I) to (VI), (III-1), (III-2) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug.

[0210] The present disclosure further relates to a compound of the above general formula (I) to (VI), (III-1), (III-2) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a RXFP1 modulator; preferably as a RXFP1 agonist.

[0211] The present disclosure further relates to a compound of the above general formula (I) to (VI), (III-1), (III-2) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug for agonizing RXFP1 activity.

[0212] The present disclosure further relates to a compound of the above-mentioned general formula (I) to (VI), (III-1), (III-2) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug for treating and / or preventing diseases or conditions mediated by or dependent on RXFP1.

[0213] The present disclosure further relates to the compounds represented by the above general formula (I) to (VI), (III-1), (III-2) or Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same, for agonizing RXFP1 activity.

[0214] The present disclosure further relates to the compounds represented by the above general formula (I) to (VI), (III-1), (III-2) or Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same, for use in treating and / or preventing diseases or conditions mediated by or dependent on RXFP1.

[0215] The present disclosure further relates to a compound shown in the above-mentioned general formula (I) to (VI), (III-1), (III-2) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for treating and / or preventing heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, chronic kidney disease, acute kidney injury, fibrotic diseases and related diseases and inflammatory diseases.

[0216] The diseases or conditions include, but are not limited to, heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, chronic kidney disease, acute kidney injury, fibrotic diseases and related diseases, and inflammatory diseases; preferably heart failure.

[0217] The compounds described in the present disclosure can be used to treat cardiovascular diseases, such as heart failure.

[0218] "Heart failure" includes acute heart failure, chronic heart failure (CHF), and acute decompensated heart failure (ADHF), and may also include more specific diagnoses such as heart failure with preserved ejection fraction (HFpEF), heart failure with intermediate ejection fraction, or heart failure with reduced ejection fraction (HFrEF).

[0219] The compounds described in the present disclosure can also be used to treat kidney disease (including chronic kidney disease), acute kidney injury, lung disease and fibrotic disorders, such as fibrotic disorders of the kidney, heart, lung and liver, and for wound healing (Sherwood OD (2004) Endocrine Reviews [Endocrine Review] 25 (2): 205-234). It can also be used to reverse insulin resistance in diabetic patients (Bonner JS et al. (2013) Diabetes [Diabetes] 62 (9): 3251-3260); It can also be used to treat various forms of pulmonary hypertension.

[0220] The compounds described in the present disclosure may also be used to treat disorders that are the result of or cause: arteriosclerosis, reduced arterial elasticity, reduced arterial compliance and distensibility (including hypertension), kidney disease, peripheral arterial disease, carotid and cerebrovascular disease (i.e., stroke and dementia), diabetes, microvascular disease leading to end-organ damage, coronary artery disease, and heart failure. The compounds described in the present disclosure may also be used to treat pre-eclampsia.

[0221] The compounds of the present disclosure can be used, for example, to treat and / or prevent heart failure, fibrotic diseases and related diseases such as lung disease (e.g., idiopathic pulmonary fibrosis), kidney disease (e.g., chronic kidney disease), or liver disease (e.g., nonalcoholic steatohepatitis and portal hypertension).

[0222] The compounds described in the present disclosure are RXFP1 receptor agonists and can be used to treat medical indications such as heart failure (e.g., HFREF and HFpEF), fibrotic diseases and related diseases such as lung diseases (e.g., idiopathic pulmonary fibrosis or pulmonary hypertension), kidney diseases (e.g., chronic kidney disease), or liver diseases (e.g., non-alcoholic steatohepatitis and portal hypertension).

[0223] "Disorders of the cardiovascular system" or "cardiovascular disorders" include, for example, the following disorders: hypertension (high blood pressure), peripheral vascular and cardiovascular disorders, coronary heart disease, stable and unstable angina, heart attack, myocardial insufficiency, abnormal heart rhythm (or arrhythmia), persistent ischemic dysfunction (hibernating myocardium), transient post-ischemic dysfunction (myocardial stunning), heart failure, peripheral blood flow disturbances, acute coronary syndrome, heart failure, myocardial disease (cardiomyopathy), myocardial infarction, and vascular disease (vascular disease).

[0224] "Heart failure" includes acute and chronic manifestations of heart failure, preferably advanced heart failure, post-acute heart failure, cardiorenal syndrome, heart failure with impaired renal function, chronic heart failure, chronic heart failure with reduced ejection fraction (HFmEF), compensated heart failure, decompensated heart failure, right heart failure, left heart failure, global failure, ischemic cardiomyopathy, dilated cardiomyopathy, heart failure associated with congenital heart defects, heart valve defects, heart failure associated with heart valve defects, mitral stenosis, mitral regurgitation, aortic stenosis, aortic stenosis insufficiency, tricuspid stenosis, tricuspid regurgitation, pulmonary stenosis, pulmonary Aortic regurgitation, heart failure associated with valvular heart defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, heart failure associated with valvular heart defects, cardiac storage disorder, diastolic heart failure, systolic heart failure, acute phase of worsening heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), chronic heart failure with reduced ejection fraction (HFrEF), chronic heart failure with preserved ejection fraction (HFpEF), after myocardial remodeling, angina pectoris, hypertension, pulmonary hypertension and pulmonary hypertension.

[0225] "Fibrotic disorders" encompass diseases and disorders characterized by fibrosis, and include, inter alia, the following: liver fibrosis, cirrhosis, NASH, pulmonary fibrosis or pulmonary fibrosis, cardiac fibrosis, endomyocardial fibrosis, kidney disease, glomerulonephritis, interstitial renal fibrosis, fibrotic lesions due to diabetes, myelofibrosis and similar fibrotic diseases, scleroderma, morphea, keloids, hypertrophic scars (also after surgical intervention), nevi, diabetic retinopathy, proliferative vitreoretinopathy, and connective tissue diseases (e.g., sarcoidosis).

[0226] Such diseases or disorders include, but are not limited to, disorders of the cardiovascular system and fibrotic disorders.

[0227] Such diseases or conditions include, but are not limited to, acute heart failure, compensated cirrhosis with portal hypertension, coronary artery disease, induction of labor, pulmonary hypertension, acute compensated heart failure, and cardiovascular disease.

[0228] The active compound may be formulated for administration by any appropriate route, preferably in a unit dosage form, or in a form in which a patient can self-administer a single dose. The unit dosage form of the disclosed compound or composition may be tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations.

[0229] As a general guide, suitable unit doses may be in the range of 0.1 to 1000 mg.

[0230] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, and the excipients are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0231] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0232] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution.

[0233] In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable excipient based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable excipient.

[0234] The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, lozenges, pastilles, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any known method for preparing pharmaceutical compositions in the art, and such compositions may contain one or more ingredients selected from the following: sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

[0235] Oral preparations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or an oily vehicle.

[0236] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, dispersants or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

[0237] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or a mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant.

[0238] The pharmaceutical composition of the present disclosure can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil, a mineral oil or a mixture thereof. A suitable emulsifier can be a naturally occurring phospholipid, and the emulsion can also contain a sweetener, a flavoring agent, a preservative and an antioxidant. Such preparations can also contain a demulcent, a preservative, a coloring agent and an antioxidant.

[0239] The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, and the injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred that the solution and microemulsion be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

[0240] Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared with suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable nontoxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils can be used. In addition, fatty acids can also be used to prepare injections.

[0241] The disclosed compounds may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0242] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the best treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0243] Terminology

[0244] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0245] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 Alkyl), preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituent is preferably selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0246] The term "heteroalkyl" refers to a saturated straight or branched aliphatic hydrocarbon group, one or more of which is replaced one or more times by one or more selected from N, NH, O, S, S(O), S(O)2, wherein the aliphatic hydrocarbon group has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 The heteroalkyl group preferably has 1 to 12 carbon atoms (i.e., C 1-12 heteroalkyl), more preferably heteroalkyl having 1 to 6 carbon atoms (i.e., C 1-6 heteroalkyl); including but not limited to -methylNHmethyl, -methylNHethyl, -methylNHpropyl, -ethylNHmethyl, -propylNHmethyl, etc.

[0247] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkylene group is preferably an alkylene group having 1 to 10 carbon atoms (i.e., C 1-10 Alkylene), preferably an alkylene group having 1 to 8 carbon atoms (i.e., C 1-8 alkylene), more preferably an alkylene group having 2 to 7 carbon atoms (i.e., C 2-7 alkylene) or an alkylene group having 1, 2 or 3 carbon atoms (i.e., C 1-6 Alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylene can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0248] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the alkyl group is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl). Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0249] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0250] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy and butoxy, etc. Alkoxy can be substituted or unsubstituted, and when substituted, it can be substituted at any usable point of attachment, and the substituent is preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0251] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3- to 20-membered cycloalkyl). The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3- to 12-membered cycloalkyl group) or a cycloalkyl group having 7 to 14 ring atoms (i.e., a 7- to 14-membered cycloalkyl group), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3- to 8-membered cycloalkyl group), most preferably a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3- to 6-membered cycloalkyl group), a cycloalkyl group having 4 to 7 ring atoms (i.e., a 4- to 7-membered cycloalkyl group) or a cycloalkyl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered cycloalkyl group); most preferably a cycloalkyl group having 5 or 6 ring atoms.

[0252] Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl.

[0253] The polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.

[0254] The term "spirocycloalkyl" refers to a polycyclic system in which one carbon atom (called spiro atom) is shared between the rings, and the rings may contain one or more double bonds, or the rings may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but not including -OO-, -OS- or -SS-), provided that at least one all-carbon ring is contained and the connection point is on the all-carbon ring, and it has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20-membered spirocycloalkyl). The spirocycloalkyl preferably has 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl). The spirocycloalkyl includes monospirocycloalkyl and polyspirocycloalkyl (such as bispirocycloalkyl, etc.), preferably monospirocycloalkyl or bispirocycloalkyl, more preferably 3-yuan / 4-yuan, 3-yuan / 5-yuan, 3-yuan / 6-yuan, 4-yuan / 4-yuan, 4-yuan / 5-yuan, 4-yuan / 6-yuan, 5-yuan / 3-yuan, 5-yuan / 4-yuan, 5-yuan / 5-yuan, 5-yuan / 6-yuan, 5-yuan / 7-yuan, 6-yuan / 3-yuan, 6-yuan / 4-yuan, 6-yuan / 5-yuan, 6-yuan / 6-yuan, 6-yuan / 7-yuan, 7-yuan / 5-yuan or 7-yuan / 6-yuan monospirocycloalkyl. Non-limiting examples include:

[0255] Its connection point can be at any position;

[0256] wait.

[0257] The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more heterocyclyls, aryls or heteroaryls, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within the ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20-membered fused cycloalkyl). The fused cycloalkyl preferably has 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl). The fused cycloalkyl includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), preferably bicyclic fused cycloalkyl or tricyclic fused cycloalkyl, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan bicyclic fused cycloalkyl. Non-limiting examples include:

[0258]

[0259] Its connection point can be at any position;

[0260]

[0261] wait.

[0262] The term "bridged cycloalkyl" refers to a full carbon polycyclic system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds in the ring and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl). The bridged cycloalkyl preferably has a bridged cycloalkyl of 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and more preferably has a bridged cycloalkyl of 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl. Non-limiting examples include:

[0263] Its connection point can be at any position.

[0264] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0265] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl), which contains at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-) in the ring, and has 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclic group) or a heterocyclic group having 7 to 14 ring atoms (i.e., a 7- to 14-membered heterocyclic group); further preferably, a heterocyclic group having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclic group); more preferably, a heterocyclic group having 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclic group), a heterocyclic group having 4 to 7 ring atoms (i.e., a 4- to 7-membered heterocyclic group) or a heterocyclic group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclic group); and most preferably, a heterocyclic group having 5 or 6 ring atoms.

[0266] Non-limiting examples of the monocyclic heterocyclic group include pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl, thiomorpholinyl and homopiperazinyl.

[0267] The polycyclic heterocyclic group includes a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group.

[0268] "Nitrogen-containing heterocyclic group" refers to a heterocyclic group containing at least one (e.g., 1, 2, 3 or 4) nitrogen atom in the ring, and the heterocyclic group is as defined above. It is preferably a 3- to 10-membered nitrogen-containing heterocyclic group, more preferably a 4- to 7-membered nitrogen-containing heterocyclic group, and most preferably a 5- or 6-membered nitrogen-containing heterocyclic group.

[0269] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), provided that it contains at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroheterocyclyl). The spiro heterocyclic radical preferably has a spiro heterocyclic radical of 6 to 14 ring atoms (i.e., a 6 to 14-membered spiro heterocyclic radical), and more preferably has a spiro heterocyclic radical of 7 to 11 ring atoms (i.e., a 7 to 11-membered spiro heterocyclic radical). The spiro heterocyclic radical includes a monospiro heterocyclic radical and a polyspiro heterocyclic radical (such as a bispiro heterocyclic radical, etc.), preferably a monospiro heterocyclic radical or a bispiro heterocyclic radical, more preferably a 3-yuan / 4-yuan, 3-yuan / 5-yuan, 3-yuan / 6-yuan, 4-yuan / 4-yuan, 4-yuan / 5-yuan, 4-yuan / 6-yuan, 5-yuan / 3-yuan, 5-yuan / 4-yuan, 5-yuan / 5-yuan, 5-yuan / 6-yuan, 5-yuan / 7-yuan, 6-yuan / 3-yuan, 6-yuan / 4-yuan, 6-yuan / 5-yuan, 6-yuan / 6-yuan, 6-yuan / 7-yuan, 7-yuan / 5-yuan or 7-yuan / 6-yuan monospiro heterocyclic radical. Non-limiting examples include:

[0270]

[0271] wait.

[0272] The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system which shares two adjacent atoms between the rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur within the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more of cycloalkyl, aryl, or heteroaryl, wherein the point of attachment is on the monocyclic heterocyclyl, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused heterocyclyl). The fused heterocyclic group preferably has a fused heterocyclic group of 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), and more preferably has a fused heterocyclic group of 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic group). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), preferably a bicyclic fused heterocyclic group or a tricyclic fused heterocyclic group, more preferably a 3-yuan / 4-yuan, 3-yuan / 5-yuan, 3-yuan / 6-yuan, 4-yuan / 4-yuan, 4-yuan / 5-yuan, 4-yuan / 6-yuan, 5-yuan / 3-yuan, 5-yuan / 4-yuan, 5-yuan / 5-yuan, 5-yuan / 6-yuan, 5-yuan / 7-yuan, 6-yuan / 3-yuan, 6-yuan / 4-yuan, 6-yuan / 5-yuan, 6-yuan / 6-yuan, 6-yuan / 7-yuan, 7-yuan / 5-yuan or 7-yuan / 6-yuan bicyclic fused heterocyclic group. Non-limiting examples include:

[0273]

[0274] wait.

[0275] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, which may contain one or more double bonds in the ring, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -OO-, -OS-, or -SS-), and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered bridged heterocyclic groups). The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., 6 to 14-membered bridged heterocyclic groups), and more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., 7 to 10-membered bridged heterocyclic groups). According to the number of constituent rings, it can be divided into bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), preferably bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include:

[0276] wait.

[0277] The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic groupoxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic group, aryl and heteroaryl.

[0278] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., polycyclic aromatic group) having a conjugated π electron system, which has 6 to 20 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 6 to 20-membered aromatic group). The aromatic group preferably has 6 to 14 ring atoms (i.e., 6 to 14-membered aromatic group), and more preferably has 6 to 10 ring atoms (i.e., 6 to 10-membered aromatic group). The monocyclic aromatic group is, for example, phenyl. Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthrenyl, etc. The polycyclic aromatic group also includes a phenyl group fused to one or more heterocyclic groups or cycloalkyl groups, or a naphthyl group fused to one or more heterocyclic groups or cycloalkyl groups, wherein the point of attachment is on the phenyl group or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include:

[0279]

[0280] wait.

[0281] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0282] The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which contains at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but does not include -OO-, -OS- or -SS-) in the ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered heteroaryl). The heteroaryl group is preferably a heteroaryl group having 5 to 14 ring atoms (i.e. a 5- to 14-membered heteroaryl group), more preferably a heteroaryl group having 5 to 10 ring atoms (i.e. a 5- to 10-membered heteroaryl group), and most preferably a heteroaryl group having 5 or 6 ring atoms (i.e. a 5- or 6-membered heteroaryl group).

[0283] The monocyclic heteroaryl group includes, but is not limited to, furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl, etc.

[0284] The polycyclic heteroaryl, non-limiting examples include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, carbazolyl, etc. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aromatic groups, wherein the connection point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more cycloalkyl or heterocyclic groups, wherein the connection point is on the monocyclic heteroaromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include:

[0285]

[0286] wait.

[0287] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0288] The term "cycloalkyloxy" refers to an -O-cycloalkyl group, wherein cycloalkyl is as defined above.

[0289] The term "heterocyclyloxy" refers to an -O-heterocyclyl group wherein the heterocyclyl group is as defined above.

[0290] The term "aryloxy" refers to an -O-aryl group in which aryl is as defined above.

[0291] The term "heteroaryloxy" refers to an -O-heteroaryl group wherein heteroaryl is as defined above.

[0292] The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.

[0293] The term "heterocyclylalkyl" refers to an alkyl group substituted by one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.

[0294] The term "arylalkyl" refers to an alkyl group substituted with one or more aryl groups, wherein aryl and alkyl are as defined above.

[0295] The term "heteroarylalkyl" refers to an alkyl group substituted with one or more heteroaryl groups, wherein heteroaryl and alkyl are as defined above.

[0296] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0297] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0298] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0299] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0300] The term "hydroxyalkoxy" refers to an alkoxy group substituted with one or more hydroxy groups, wherein alkoxy is as defined above.

[0301] The term "alkoxyalkyl" refers to an alkyl group substituted by one or more alkoxy groups, wherein alkyl and alkoxy are as defined above; preferably -alkyl-alkoxy; including but not limited to methoxymethyl, ethoxymethyl, methoxyethyl.

[0302] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0303] The term "hydroxy" refers to -OH.

[0304] The term "amino" refers to -NH2.

[0305] The term "cyano" refers to -CN.

[0306] The term "nitro" refers to -NO2.

[0307] The term "oxo" or "oxo" refers to "=0".

[0308] The term "carbonyl" refers to C=O.

[0309] TBS refers to tert-butyldimethylsilyl.

[0310] The term "amido" refers to -CONH2.

[0311] The term "acetyl" refers to C(O)CH3.

[0312] The term "alkyleneamino" refers to an -alkylene-amino group wherein alkylene and amino are as defined above.

[0313] The term "alkyleneamido" refers to an -alkylene-amide group in which the alkylene and amide groups are as defined above.

[0314] The term "amino protecting group" refers to a group that is easily removed and introduced on the amino group in order to keep the amino group unchanged when other parts of the molecule react. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl (PMB), etc.

[0315] The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers with identical structures but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). Substituents in the disclosed compounds may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers may be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomer salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art to obtain pure isomers. In addition, the separation of enantiomers and diastereoisomers is usually completed by chromatography.

[0316] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or include both For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E configurations are included.

[0317] In the chemical structure of the compounds disclosed herein, rac is the abbreviation of racemate (also known as raceme), which refers to an equimolar mixture of a pair of enantiomers. For example, when the compound has only one chiral center, rac refers to an equimolar mixture of (R) configuration and (S) configuration; when the compound has two chiral centers, rac refers to an equimolar mixture of (R,R) configuration and (S,S) configuration; or an equimolar mixture of (R,S) configuration and (S,R) configuration. Specifically, rac-(1R,2R) means that the compound is a racemate, which is an equimolar mixture of (1R,2R) configuration and (1S,2S) configuration.

[0318] In the chemical structures of the compounds described in the present disclosure, the bonds connected to the stereogenic centers of the compounds are or Indicates the relative configuration of the stereogenic center. In, two The bonds representing the two stereogenic centers are oriented in the same direction.

[0319] Cis-trans isomerism, also known as geometric isomerism, is a type of stereoisomerism. Cis-trans isomerism refers to the diastereoisomerism phenomenon that occurs when the groups in a compound molecule are arranged differently in space due to the restriction of free rotation. Organic molecules containing this type of isomerism, such as olefins, azo compounds, alicyclic hydrocarbons, etc., are considered cis-trans isomers.

[0320] cis-, also known as a cis isomer mixture, refers to two identical atoms or groups on the same side of a double bond or alicyclic ring. trans-, also known as a trans isomer mixture, refers to two identical atoms or groups on opposite sides of a double bond or alicyclic ring.

[0321] A cis isomer mixture is a mixture of a pair of cis isomers. Specific examples are as follows: for mixture.

[0322] The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is easily converted from one isomeric form to another isomeric form. It includes all possible tautomers, i.e., in the form of a single isomer or in the form of a mixture of any proportions of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc. Examples of lactam-lactim equilibrium are shown below:

[0323]

[0324] For example, when referring to pyrazolyl, it is understood to include either or a mixture of two tautomers of the following two structures:

[0325]

[0326] All tautomeric forms are within the scope of the present disclosure, and the naming of compounds does not exclude any tautomer.

[0327] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example, respectively. 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14C. 15 N. 17 O. 18 O. 32 p. 33 p. 33 S. 34 S. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I, etc., preferably deuterium.

[0328] Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending drug biological half-life. All isotopic composition changes of the compounds disclosed herein, whether radioactive or not, are included in the scope of the present disclosure. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.

[0329] When a position is specifically designated as deuterium, D, the position is understood to have an abundance of deuterium (ie, at least 15% deuterium incorporation) that is at least 1000 times greater than the natural abundance of deuterium, which is 0.015%. Examples of compounds having a greater than natural abundance of deuterium may be at least 1000 times more abundant in deuterium (i.e., at least 15% deuterium incorporation), at least 2000 times more abundant in deuterium (i.e., at least 30% deuterium incorporation), at least 3000 times more abundant in deuterium (i.e., at least 45% deuterium incorporation), at least 3340 times more abundant in deuterium (i.e., at least 50.1% deuterium incorporation), at least 3500 times more abundant in deuterium (i.e., at least 52.5% deuterium incorporation), at least 4000 times more abundant in deuterium (i.e., at least 60% deuterium incorporation), at least 4500 times more abundant in deuterium (i.e., at least 67.5% deuterium incorporation), at least 5000 times more abundant in deuterium (i.e., at least 65.6% deuterium incorporation), at least 5000 times more abundant in deuterium (i.e., at least 60% deuterium incorporation), at least 5000 times more abundant in deuterium (i.e., at least 67.5% deuterium incorporation), at least 5000 times more abundant in deuterium (i.e., at least 60 ... deuterium is incorporated at least 5000 times more abundant in deuterium (i.e., at least 75% deuterium incorporation), at least 5500 times more abundant in deuterium (i.e., at least 82.5% deuterium incorporation), at least 6000 times more abundant in deuterium (i.e., at least 90% deuterium incorporation), at least 6333.3 times more abundant in deuterium (i.e., at least 95% deuterium incorporation), at least 6466.7 times more abundant in deuterium (i.e., at least 97% deuterium incorporation), at least 6600 times more abundant in deuterium (i.e., at least 99% deuterium incorporation), at least 6633.3 times more abundant in deuterium (i.e., at least 99.5% deuterium incorporation), or more.

[0330] "Optional" or "optionally" means that the event or environment described later may but need not occur, and includes both the occurrence and non-occurrence of the event or environment. For example, "C 1-6 The term "alkyl group" includes the case where the alkyl group is substituted by halogen or cyano and the case where the alkyl group is not substituted by halogen or cyano.

[0331] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, preferably 1, 2 or 3, more preferably 1 to 3 hydrogen atoms, which are independently replaced by a corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an alkene).

[0332] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their pharmaceutically acceptable salts and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredients, and thus exert biological activity.

[0333] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and have the desired biological activity. They may be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0334] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0335] As used herein, the singular form of "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0336] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given only for illustrative purposes and not for limitation.

[0337] Synthesis method of the disclosed compound

[0338] In order to achieve the purpose of this disclosure, this disclosure adopts the following technical solutions:

[0339] Solution 1

[0340] The method for preparing the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0341]

[0342] R 1 C(O)OR 23 The compound represented by the general formula (I) or its pharmaceutically acceptable salt undergoes a deprotection reaction to obtain R 1 A compound represented by the general formula (I) C(O)OH or a pharmaceutically acceptable salt thereof;

[0343] Among them, R 23 is alkyl or -alkylaryl;

[0344] Z, Y, X, U, V, W, R 3 , R 9 and A are as defined in the general formula (I).

[0345] Solution 2

[0346] The method for preparing the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0347]

[0348] R 1 C(O)OR 23 The compound represented by the general formula (II) or its pharmaceutically acceptable salt undergoes a deprotection reaction to obtain R 1 A compound represented by the general formula (II) of C(O)OH or a pharmaceutically acceptable salt thereof;

[0349] Among them, R 23 is alkyl or -alkylaryl;

[0350] Z, Y, X, U, R 3 , Ring D, R 4 , n and A are as defined in the general formula (II).

[0351] Option 3

[0352] The method for preparing the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0353]

[0354] R 1 C(O)OR23 The compound represented by the general formula (III) or its pharmaceutically acceptable salt undergoes a deprotection reaction to obtain R 1 A compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein the compound is C(O)OH;

[0355] Among them, R 23 is alkyl or -alkylaryl;

[0356] Ring A, R A ,q,X,U,R 3 , Q 1 ,Q,Ring E,R 4 , n1 and A are as defined in the general formula (III).

[0357] Option 4

[0358] The method for preparing the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0359]

[0360] R 1 C(O)OR 23 The compound represented by the general formula (III-1) or its pharmaceutically acceptable salt undergoes a deprotection reaction to obtain R 1 A compound represented by the general formula (III-1) C(O)OH or a pharmaceutically acceptable salt thereof;

[0361] Among them, R 23 is alkyl or -alkylaryl;

[0362] Ring A, R A ,q,X,U,R 3 , Q 1 ,Q,Ring E,R 4 , n1 and A are as defined in the general formula (III-1).

[0363] Option 5

[0364] The method for preparing the compound represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0365]

[0366] R 1 C(O)OR 23 The compound represented by the general formula (III-2) or its pharmaceutically acceptable salt undergoes a deprotection reaction to obtain R 1 A compound represented by the general formula (III-2) C(O)OH or a pharmaceutically acceptable salt thereof;

[0367] Among them, R23 is alkyl or -alkylaryl;

[0368] Ring A, R A ,q,X,U,R 3 , Q 1 ,Q,Ring E,R 4 , n1 and A are as defined in the general formula (III-2).

[0369] Option 6

[0370] The method for preparing the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0371]

[0372] R 1 C(O)OR 23 The compound represented by the general formula (IV) or its pharmaceutically acceptable salt undergoes a deprotection reaction to obtain R 1 A compound represented by the general formula (IV) of C(O)OH or a pharmaceutically acceptable salt thereof;

[0373] Among them, R 23 is alkyl or -alkylaryl;

[0374] Ring A, R A ,q,X,U,R 3 , Q 1 ,Q,Ring E,R 4 , n1, n3 and A are as defined in the general formula (IV).

[0375] Option 7

[0376] The method for preparing the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0377]

[0378] R 1 C(O)OR 23 The compound represented by the general formula (V) or its pharmaceutically acceptable salt undergoes a deprotection reaction to obtain R 1 A compound represented by the general formula (V) of C(O)OH or a pharmaceutically acceptable salt thereof;

[0379] Among them, R 23 is alkyl or -alkylaryl;

[0380] Ring A, R A ,q,X,U,R 3 , Q 3 ,Q,Ring E,R 4 , n1, n3 and A are as defined in the general formula (V).

[0381] Option 8

[0382] The method for preparing the compound represented by the general formula (VI) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0383]

[0384] R 1 C(O)OR 23 The compound represented by the general formula (VI) or its pharmaceutically acceptable salt undergoes a deprotection reaction to obtain R 1 A compound represented by the general formula (VI) C(O)OH or a pharmaceutically acceptable salt thereof;

[0385] Among them, R 23 is alkyl or -alkylaryl;

[0386] Ring A, R A ,q,X,R 3 , Q 3 ,Q,Ring E,R 4 , n1, n3 and A are as defined in the general formula (VI).

[0387] The deprotection reaction in the above schemes optionally occurs in the presence of a catalyst.

[0388] The catalyst includes but is not limited to palladium carbon, dry palladium carbon, wet palladium carbon and 10% palladium carbon, preferably a 10% palladium carbon hydrogenation catalyst.

[0389] The reagents providing acidic conditions in the above scheme include but are not limited to hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a 1,4-dioxane solution of hydrochloric acid, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, concentrated sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me3SiCl and TMSOTf; preferably trifluoroacetic acid.

[0390] The reaction in the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and mixtures thereof. DETAILED DESCRIPTION

[0391] The following embodiments are used to further describe the present disclosure, but these embodiments are not intended to limit the scope of the present disclosure.

[0392] Example

[0393] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic spectrometer or a Bruker AVANCE NEO 500M, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the measurement solvent, and tetramethylsilane (TMS) as the internal standard.

[0394] MS was measured using Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid spectrometer-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0395] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity QdaDetector / waters SQ Detector)

[0396] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO QExactive)

[0397] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

[0398] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0399] High performance liquid chromatography was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

[0400] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0401] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0402] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0403] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0404] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0405] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, Shanghai Leyan, Shanghai Bid and other companies.

[0406] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0407] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0408] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0409] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0410] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0411] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0412] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0413] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0414] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of thin layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0415] Example 1

[0416] (1R,4s)-4-((cis-(2aS,8aR)-4-fluoro-7-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)formamido)bicyclo[2.2.1]hept-2-yl)formamido)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxan-5-yl)oxy)-1-methylcyclohexane-1-carboxylic acid 1 (cis isomer mixture)

[0417]

[0418] first step

[0419] Naphthalene-1-ylmethyl (1r, 4r)-1-methyl-4-((methylsulfonyl)oxy)cyclohexane-1-carboxylate 1b Naphthalene-1-ylmethyl (1r, 4r)-4-hydroxy-1-methylcyclohexane-1-carboxylate 1a (340 mg, 1.14 mmol, prepared by the method disclosed in Intermediate 11 on page 143 of the specification of patent application "WO2022122773") was dissolved in dichloromethane (3 mL) and added under ice bath. Triethylamine (230.6 mg, 2.28 mmol), methanesulfonyl chloride (195.8 mg, 1.71 mmol), keep the temperature and stir to react for 1 hour, add ammonium chloride to quench the reaction solution, extract with dichloromethane (15 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter to remove the desiccant, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography with eluent system B to obtain the title compound 1b (428 mg, yield: 99%).

[0420] Step 2

[0421] 2-(Benzyloxy)cyclobutane-1-one 1d

[0422] 1,2-Bis(trimethylsilyloxy)cyclobutene 1c (100 g, 433.9 mmol, Jiangsu Aikang) and benzyl alcohol (46.9 g, 433.9 mmol) were mixed in a 4M hydrogen chloride solution in 1,4-dioxane (300 mL), and reacted at 80° C. for 4 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system C to give the title compound 1d (43.8 g, yield: 57.3%).

[0423] Step 3

[0424] cis-(1R,2S)-2-(Benzyloxy)cyclobutane-1-ol 1e (cis isomer mixture)

[0425] Compound 1d (20.4 g, 115.7 mmol) was dissolved in tetrahydrofuran (200 mL), nitrogen was replaced three times, and the mixture was cooled to -78°C. A 1M solution of lithium tri-sec-butylborohydride in tetrahydrofuran (127.3 mL) was added dropwise. The temperature was maintained and stirred for 1 hour, and then the mixture was returned to room temperature and stirred for another 1 hour. The reaction solution was cooled to 0°C, and water (30 mL), 2M aqueous sodium hydroxide solution (30 mL) and hydrogen peroxide (30 mL) were added in sequence. After stirring for 10 minutes, a saturated sodium sulfite solution was added, and the mixture was extracted with ethyl acetate (150 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system C to obtain the title compound 1e (cis isomer mixture, 18 g, yield: 87.2%).

[0426] Step 4

[0427] 1,2,3-Trifluoro-4-(methoxymethoxy)benzene 1g

[0428] 2,3,4-Trifluorophenol 1f (5 g, 33.77 mmol, Shanghai Titan) was dissolved in dichloromethane (50 mL). N,N-diisopropylethylamine (8.72 g, 67.52 mmol) and bromomethyl methyl ether (6.33 g, 50.6 mmol) were added dropwise at 0°C under a nitrogen atmosphere. The reaction mixture was restored to room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain 1g (4.5 g, yield: 69%) of the title compound.

[0429] Step 5

[0430] 2,3,4-Trifluoro-5-(methoxymethoxy)benzoic acid 1h

[0431] Compound 1g (3.2g, 16.65mmol) was dissolved in tetrahydrofuran (30mL), and a 2M solution of lithium diisopropylamide in tetrahydrofuran (9.2mL) was added dropwise at -78°C, and the temperature was maintained and stirred for 2 hours. Dry ice was added to the reaction solution and stirred for 0.5 hours, and then water was added. The aqueous phase was separated, and the pH of the aqueous phase was adjusted to about 1 with concentrated hydrochloric acid, and extracted with dichloromethane (50mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1h (3.2g), which was directly used in the next step without purification. MS m / z (ESI): 235.0 [M-1].

[0432] Step 6

[0433] 2-(cis-(1R,2S)-2-(Benzyloxy)cyclobutyloxy)-3,4-difluoro-5-(methoxymethoxy)benzoic acid 1i (cis isomer mixture)

[0434] Compound 1e (1.6 g, 9 mmol) was dissolved in tetrahydrofuran (20 mL), and a 2M tetrahydrofuran solution of sodium bis(trimethylsilyl)amide (6 mL) was added dropwise. After stirring for 1 hour, the temperature was cooled to -78°C and a tetrahydrofuran solution (5 mL) of crude compound 1h (1.6 g, 6.77 mmol) was added. After stirring for 1 hour at 50°C, the temperature was cooled to 0°C, and the pH was adjusted to about 2 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system C to give the title compound 1i (cis isomer mixture, 2.5 g, yield: 93.5%).

[0435] MS m / z(ESI):395.3[M+1].

[0436] Step 7

[0437] 3,4-Difluoro-2-(cis-(1R,2S)-2-hydroxycyclobutyloxy)-5-(methoxymethoxy)benzoic acid 1j (cis isomer mixture)

[0438] Compound 1i (1.8 g, 4.56 mmol) was dissolved in methanol (80 mL), 10% palladium carbon hydrogenation catalyst (1.2 g) was added, hydrogen was replaced, the reaction was stirred for 16 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1j (mixture of cis isomers, 1.4 g), which was used directly in the next reaction without purification.

[0439] MS m / z(ESI):303.2[M-1].

[0440] Step 8

[0441] cis-(2aR,8aS)-7-Fluoro-6-(methoxymethoxy)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carboxylic acid 1k (cis isomer mixture)

[0442] The crude compound 1j (1.4 g, 4.60 mmol) was dissolved in dimethyl sulfoxide (60 mL), and cesium carbonate (5.6 g, 17.19 mmol) was added. The reaction was stirred at 115°C for 5 days. After the reaction solution was cooled to room temperature, water was added and extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with water and saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system A to obtain the title compound 1k (cis isomer mixture, 500 mg, yield: 38.2%).

[0443] MS m / z(ESI):285.3[M+1].

[0444] Step 9

[0445] (cis-(2aR,8aS))-7-fluoro-6-(methoxymethoxy)-N-((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)formamido)bicyclo[2.2.1]hept-2-yl)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carboxamide 1m (cis isomer mixture)

[0446] Compound 1k (110 mg, 387 μmol) and (1R,2S,3R,4S)-3-amino-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride 1l (126.7 mg, 464.4 μmol, prepared by the method disclosed in Intermediate 22 on page 149 of the specification of patent application "WO2022122773") were dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (200 mg, 1.55 mmol) was added. ), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (220.72 mg, 580.5 μmol), stirred for reaction for 1 hour, water was added to the reaction solution, extracted with ethyl acetate (15 mL×3), the organic phases were combined, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1m (cis isomer mixture, 194 mg), which was used directly in the next step without purification.

[0447] MS m / z(ESI):503.2[M+1].

[0448] Step 10

[0449] (cis-(2aR,8aS))-7-Fluoro-6-hydroxy-N-((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)formamido)bicyclo[2.2.1]hept-2-yl)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carboxamide 1n (cis isomer mixture)

[0450] The crude compound 1m (194 mg, 386 μmol) was dissolved in 4M methanol solution of hydrogen chloride (6 mL), and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and adjusted to pH>8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system C to give the title compound 1n (cis isomer mixture, 110 mg, yield: 62.1%).

[0451] MS m / z(ESI):459.2[M+1].

[0452] Step 11

[0453] Naphthalen-1-ylmethyl (1R,4s)-4-((cis-(2aS,8aR)-4-fluoro-7-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)formamido)bicyclo[2.2.1]hept-2-yl)formamido)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxin-5-yl)oxy)-1-methylcyclohexane-1-carboxylate 1o (cis isomer mixture)

[0454] Compound 1n (60 mg, 130.86 μmol) and compound 1b (73.9 mg, 196,3 μmol) were dissolved in N,N-dimethylformamide (1 mL), and anhydrous potassium carbonate (54.2 mg, 392.5 μmol) was added. The mixture was stirred at 80°C for 16 hours. After the reaction solution was cooled to room temperature, it was diluted with water and extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium bicarbonate and saturated sodium chloride solutions in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1o (cis isomer mixture, 96 mg). The product was directly used in the next step without purification.

[0455] MS m / z(ESI):739.2[M+1].

[0456] Step 12

[0457] (1R,4s)-4-((cis-(2aS,8aR)-4-fluoro-7-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)formamido)bicyclo[2.2.1]hept-2-yl)formamido)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxan-5-yl)oxy)-1-methylcyclohexane-1-carboxylic acid 1 (cis isomer mixture)

[0458] The crude compound 1o (80 mg, 108.3 μmol) was dissolved in ethanol (4 mL), and a 10% palladium carbon hydrogenation catalyst (20 mg) was added. The mixture was replaced with hydrogen and stirred for 4 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-42%, flow rate: 30 mL / min) to give the title compound 1 (cis isomer mixture, 30 mg, yield: 46.2%).

[0459] MS m / z(ESI):599.2[M+1].

[0460] 1 H NMR (500MHz, CD3OD): δ7.31(d,1H),4.78(t,1H),4.39-4.29(m,1H),4.19(d t,1H),3.25-3.15(m,1H),3.01(dd,1H),2.69(d,1H),2.39(d,1H),2.33(ddd ,2H),2.28-2.20(m,5H),2.11(d,1H),1.99(ddd,2H),1.78(ddt,3H),1.67(t t,2H),1.57(ddt,4H),1.49(d,1H),1.35(dt,6H),1.22(s,3H),0.99(s,3H).

[0461] Example 1-p1, 1-p2

[0462] (1S,4s)-4-(((2aR,8aS)-4-fluoro-7-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)formamido)bicyclo[2.2.1]hept-2-yl)formamido)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxan-5-yl)oxy)-1-methylcyclohexane-1-carboxylic acid 1-p1

[0463] (1R,4s)-4-(((2aS,8aR)-4-fluoro-7-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)formamido)bicyclo[2.2.1]hept-2-yl)formamido)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxan-5-yl)oxy)-1-methylcyclohexane-1-carboxylic acid 1-p2

[0464]

[0465] The cis isomer mixture 1 (36 mg) was separated and purified by chiral column (Gilson 281, chromatographic column: CHIRALPAK IE, 20*250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.1% formic acid), gradient ratio: A:B=80:20, flow rate: 20 mL / min) to give the title compound (15 mg, yield: 41.6%).

[0466] Chiral HPLC analysis of isomer mixture 1: retention time 3.201 minutes, 4.895 minutes (chromatographic column: CHIRALPAK AD-H, 250*4.6 mm, 5μ; mobile phase A: ethanol (+0.1% diethylamine), mobile phase B: n-hexane, gradient ratio: A:B=50.2:49.8, flow rate: 1 mL / min).

[0467] Single configuration compound (short retention time) (15 mg, yield: 41.6%)

[0468] MS m / z(ESI):599.2[M+1].

[0469] 1 H NMR (500MHz, CD3OD): δ7.31(d,1H),4.78(t,1H),4.39-4.29(m,1H),4.19(d t,1H),3.25-3.15(m,1H),3.01(dd,1H),2.69(d,1H),2.39(d,1H),2.33(ddd ,2H),2.28-2.20(m,5H),2.11(d,1H),1.99(ddd,2H),1.78(ddt,3H),1.67(t t,2H),1.57(ddt,4H),1.49(d,1H),1.35(dt,6H),1.22(s,3H),0.99(s,3H).

[0470] Single configuration compound (longer retention time) (15 mg, yield: 41.6%)

[0471] MS m / z(ESI):599.2[M+1].

[0472] 1 H NMR (500MHz, CD3OD): δ7.31(d,1H),4.80(dt,1H),4.34(d,1H),4.19(dt,1 H),3.19(dt,1H),3.07(dd,1H),2.69(d,1H),2.44-2.36(m,2H),2.31(dddd ,2H),2.26-2.16(m,4H),2.10(d,1H),2.02-1.95(m,2H),1.80(tdd,3H),1. 74-1.63(m,2H),1.61-1.52(m,5H),1.35(d,6H),1.22(s,3H),1.02(s,3H).

[0473] Example 2

[0474] (1R,4s)-1-methyl-4-((cis-(2aS,8aR)-7-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)formamido)bicyclo[2.2.1]hept-2-yl)formamido)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxan-5-yl)oxy)cyclohexane-1-carboxylic acid 2 (cis isomer mixture)

[0475]

[0476] first step

[0477] Methyl 2-(cis-(1R,2S)-2-(benzyloxy)cyclobutyloxy)-5-bromo-3-fluorobenzoate 2b (cis isomer mixture)

[0478] Compound 1e (2.9 g, 16.2 mmol) was dissolved in N,N-dimethylformamide (35 mL), sodium hydride (836.5 mg, 20.9 mmol, purity 60%) was added at 0°C, the temperature was maintained and stirred for 1 hour, 5-bromo-2,3-difluorobenzoic acid methyl ester 2a (3.5 g, 13.9 mmol, Shanghai Bid) in N,N-dimethylformamide (10 mL) was added dropwise at -70°C, the reaction mixture was returned to room temperature and stirred for 1 hour, saturated ammonium chloride solution was added to the reaction solution for quenching, and the reaction solution was extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system C to obtain the title compound 2b (cis isomer mixture, 3.8 g, yield: 64.8%).

[0479] Step 2

[0480] Methyl 5-bromo-3-fluoro-2-(cis-(1R,2S)-2-hydroxycyclobutyloxy)benzoate 2c-1 (cis isomer mixture)

[0481] and

[0482] Mixture of 5-bromo-3-fluoro-2-(cis-(1R,2S)-2-(2,2,2-trifluoroacetyloxy)cyclobutyloxy)benzoic acid methyl ester 2c-2 (cis isomer mixture)

[0483] Compound 2b (3.7 g, 9 mmol) was dissolved in trifluoroacetic acid (40 mL), heated to 80 ° C for 12 hours, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), washed with saturated sodium bicarbonate and saturated sodium chloride solutions in sequence, and the organic phase was concentrated under reduced pressure to obtain a mixture of crude title compounds 2c-1 and 2c-2 (mixture of cis isomers, 3.7 g). The product was directly used in the next step without purification.

[0484] Step 3

[0485] cis-(2aR,8aS)-6-Bromo-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carboxylic acid 2d (cis isomer mixture)

[0486] A mixture of compounds 2c-1 and 2c-2 (3.7 g) and cesium carbonate (11 g, 33.7 mmol) were dissolved in dimethyl sulfoxide (60 mL), and the mixture was stirred at 110°C for 16 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was diluted with water and extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 2d (mixture of cis isomers, 2.5 g). The product was used directly in the next step without purification.

[0487] MS m / z(ESI):285.2[M+1].

[0488] Step 4

[0489] cis-(2aR,8aS)-6-bromo-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carboxylic acid methyl ester 2e (cis isomer mixture)

[0490] The crude compound 2d (2.5 g, 8.77 mmol) was dissolved in tetrahydrofuran (25 mL) and methanol (3 mL), and a 2M trimethylsilyldiazomethane solution in n-hexane (21.9 mL) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 2e (mixture of cis isomers, 1 g, yield: 38.1%).

[0491] MS m / z(ESI):298.9[M+1].

[0492] Step 5

[0493] cis-(2aR,8aS)-6-hydroxy-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carboxylic acid methyl ester 2f (cis isomer mixture)

[0494] Compound 2e (500 mg, 1.67 mmol), α-benzaldehyde oxime (303.7 mg, 2.5 mmol, TCI), methanesulfonyl (2-(di-tert-butylphosphino)-3-methoxy-6-methyl, 2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (280.3 mg, 334.31 μmol, Shanghai Titan), cesium carbonate (1.63 g, 5 mmol) were mixed in N,N-dimethylformamide (5 mL), heated to 100° C. and stirred for 16 hours. 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 with elution system C to give the title compound 2f (cis isomer mixture, 100 mg, yield: 25.3%).

[0495] MS m / z(ESI):237.0[M+1].

[0496] Step 6

[0497] (cis-(2aR,8aS))-6-(((1s,4R)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carboxylic acid methyl ester 2g (cis isomer mixture)

[0498] Compound 2f (68 mg, 287.8 μmol) and compound 1b (260 mg, 690.6 μmol) were dissolved in N,N-dimethylformamide (2 mL), and anhydrous potassium carbonate (130 mg, 940.6 μmol) was added. The mixture was stirred at 85°C for 16 hours. After the reaction solution was cooled to room temperature, it was diluted with water and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated sodium bicarbonate and saturated sodium chloride solutions in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude title compound 2g (cis isomer mixture, 140 mg). The product was directly used in the next step without purification.

[0499] MS m / z(ESI):517.2[M+1].

[0500] Step 7

[0501] (cis-(2aR,8aS))-6-(((1s,4R)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carboxylic acid 2h (cis isomer mixture)

[0502] The crude compound 2g (148 mg, 287.8 μmol) was dissolved in water (0.5 mL) and tetrahydrofuran (2 mL), and lithium hydroxide monohydrate (4.3 g, 102 mmol) was added. The reaction was stirred for 16 hours, and the pH of the reaction solution was adjusted to 6 with 2M hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 2h (cis-isomer mixture, 140 mg).

[0503] MS m / z(ESI):501.2[M-1].

[0504] Step 8

[0505] Naphthalen-1-ylmethyl (1R,4s)-1-methyl-4-((cis-(2aS,8aR)-7-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)formamido)bicyclo[2.2.1]hept-2-yl)formamido)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxin-5-yl)oxy)cyclohexane-1-carboxylate 2i (cis isomer mixture)

[0506] The crude compound 2h (50 mg, 99.5 μmol) and compound 11 (30.6 mg, 112.1 μmol) were dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (38.6 mg, 298.5 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (56.7 mg, 149.2 μmol) were added. The reaction mixture was stirred for 1 hour, and the reaction solution was diluted with water and extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium bicarbonate and saturated sodium chloride solutions in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2i (cis isomer mixture, 34 mg, yield: 47.4%).

[0507] MS m / z(ESI):721.2[M+1].

[0508] Step 9

[0509] (1R,4s)-1-methyl-4-(((cis-2aS,8aR)-7-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)formamido)bicyclo[2.2.1]hept-2-yl)formamido)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxan-5-yl)oxy)cyclohexane-1-carboxylic acid 2 (cis isomer mixture)

[0510] Compound 2i (34 mg, 47.1 μmol) was dissolved in ethanol (2 mL), and a 10% palladium-carbon hydrogenation catalyst (30 mg) was added. The mixture was replaced with hydrogen and stirred for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-42%, flow rate: 30 mL / min) to give the title compound 2 (cis isomer mixture, 20 mg, yield: 73%).

[0511] MS m / z(ESI):581.2[M+1].

[0512] 1H NMR (500MHz, CDCl3): δ8.53(dd,1H),6.60(dd,1H),5.60(d,1H),4.84-4.73(m,1H),4.66(dd,1H),4.44(dt,1H),4.17(dt,1H),3.19 (ddd,1H),2.90(ddd,1H),2.52(d,1H),2.47(d,1H),2.29-2.21(m,6H),2.00(t,3H),1.62-1.56(m,10H),1.25(d,8H),0.98(d,3H).

[0513] Example 3

[0514] (1S,4s)-4-((4-fluoro-7-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)aminocarbonyl)bicyclo[2.2.1]hept-2-yl)aminocarbonyl)-2H-spiro[benzofuran-3,1'-cyclopropane]-5-yl)oxy)-1-methylcyclohexane-1-carboxylic acid 3

[0515]

[0516]

[0517] first step

[0518] 2-(3-Bromo-6-fluoro-2-methoxyphenyl)-2-oxoacetic acid ethyl ester 3b

[0519] 2-Bromo-5-fluoroanisole 3a (10 g, 48.77 mmol) was dissolved in tetrahydrofuran (100 mL). A 2 M solution of lithium diisopropylamide in tetrahydrofuran (30 mL) was added at -78°C. The temperature was maintained and stirred for 1 hour. Diethyl oxalate (10 g, 68.43 mmol) was added dropwise. The temperature was maintained and stirred for 1 hour. Saturated ammonium chloride solution was added to the reaction solution for quenching. The reaction solution was extracted with ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system C to give the title compound 3b (13 g, yield: 87.3%).

[0520] Step 2

[0521] Ethyl 2-(3-bromo-6-fluoro-2-methoxyphenyl)-2-hydroxypropanoate 3c

[0522] Compound 3b (11 g, 36.05 mmol) was dissolved in tetrahydrofuran (70 mL), protected by nitrogen, cooled to -5°C, and 1 M methylmagnesium bromide solution in tetrahydrofuran (50.5 mL) was slowly added dropwise. The temperature was maintained and stirred for 1 hour. Saturated ammonium chloride solution was added dropwise to the reaction solution for quenching. The layers were separated, and the aqueous phase was extracted with ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 3c (11 g). The product was directly used in the next reaction without purification.

[0523] Step 3

[0524] Ethyl 2-(3-bromo-6-fluoro-2-methoxyphenyl)acrylate 3d

[0525] The crude compound 3c (11 g, 34.25 mmol) was dissolved in toluene (50 mL), and 4-p-toluenesulfonic acid (1.18 g, 6.85 mmol) was added under nitrogen protection. The mixture was stirred at 120° C. for 16 hours. The reaction solution was cooled to room temperature, diluted with methyl tert-butyl ether, and washed with saturated sodium bicarbonate solution and saturated sodium chloride in sequence. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 3d (11 g). The product was directly used in the next step without purification.

[0526] MS m / z(ESI):302.9[M+1].

[0527] Step 4

[0528] 1-(3-Bromo-6-fluoro-2-methoxyphenyl)cyclopropane-1-carboxylic acid ethyl ester 3e

[0529] Trimethyl sulfoxide chloride (7 g, 54.43 mmol) was dissolved in tetrahydrofuran (150 mL), potassium tert-butoxide (5.29 g, 47.17 mmol) was added under ice bath, and the reaction was stirred for 3 hours. A tetrahydrofuran solution (50 mL) of compound 3d (11 g, 36.29 mmol) was added dropwise, and the mixture was stirred for 30 minutes. The reaction solution was slowly poured into 300 mL of ice saturated ammonium chloride solution to quench, and stirred for 5 minutes. The liquid was separated, and the aqueous phase was extracted with methyl tert-butyl ether (80 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system C to give the title compound 3e (6.4 g, yield: 55.6%).

[0530] MS m / z(ESI):317.2[M+1].

[0531] Step 5

[0532] 6-Bromo-3-fluoro-2-(1-(hydroxymethyl)cyclopropyl)phenol 3f

[0533] Compound 3e (3.8 g, 12.53 mmol) was dissolved in tetrahydrofuran (60 mL), sodium borohydride (1.42 g, 37.59 mmol) was added under ice bath, and boron trifluoride etherate (1.78 g, 12.5 mmol) was slowly added. The mixture was naturally stirred at room temperature for 1.5 hours. The reaction solution was slowly added into 0.4 M hydrochloric acid solution for quenching, stirred for 15 minutes, and extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 3f (11 g). The product was used directly in the next step without purification.

[0534] MS m / z(ESI):259.1[M-1].

[0535] Step 6

[0536] 7-Bromo-4-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane] 3g

[0537] The crude compound 3f (1.7 g, 6.51 mmol) and potassium tert-butoxide (1.46 g, 13.02 mmol) were mixed in dimethyl carbonate (20 mL), and the mixture was stirred at 85°C for 4 hours. The reaction solution was cooled to room temperature, poured into water for quenching, and the pH was adjusted to 6-7 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 3g (800 mg). The product was used directly in the next step without purification.

[0538] Step 7

[0539] 4-Fluoro-2H-spiro[benzofuran-3,1'-cyclopropane]-7-carboxylic acid methyl ester 3h

[0540] The crude compound 3g (600 mg, 2.47 mmol) was dissolved in methanol (6 mL), N,N-dimethylacetamide (6 mL), and 1,3-bis(diphenylphosphino)propane (203.6 mg, 493.7 μmol), palladium acetate (110.8 mg, 493.7 μmol), N,N-diisopropylethylamine (638 mg, 4.93 mmol) were added, and carbon monoxide was replaced. The reaction was carried out at 80°C for 16 hours. After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system D (petroleum ether / dichloromethane) to give the title compound 3h (500 mg, yield: 91.1%).

[0541] MS m / z(ESI):223.2[M+1].

[0542] Step 8

[0543] 5-(1,3,6,2-Dioxazaboroctane-2-yl)-4-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane]-7-carboxylic acid methyl ester 3i

[0544] Dissolve pinacol diboron (240 mg, 945 μmol) in 2-methyltetrahydrofuran (4 mL), add compound 3h (200 mg, 900 μmol), 4,4'-di-tert-butyl-2,2'-bipyridine (6 mg, 54 μmol), methoxy(cyclooctadiene)iridium dimer (17.8 mg, 27 μmol), replace with nitrogen, react with stirring at 85 ° C for 2 hours, cool the reaction solution to 0 ° C, slowly add diethanolamine (284 mg, 2., mmol) in isopropanol solution (0.5 mL), keep stirring and react for 2.5 hours at the same temperature, filter, wash the filter cake with 2-methyltetrahydrofuran, and dry to obtain the crude title compound 3i (300 mg), which is used directly in the next step without purification.

[0545] Step 9

[0546] 4-Fluoro-5-hydroxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-carboxylic acid methyl ester 3j

[0547] The crude compound 3i (300 mg, 895.2 μmol) and acetic acid (161.3 mg, 2.6 mmol) were mixed in 2-methyltetrahydrofuran (1.5 mL), and 30% hydrogen peroxide (121.7 mg, 1.07 mmol) was added under ice bath. The mixture was returned to room temperature and stirred for 2 hours. Ethyl acetate was added to the reaction solution to dilute it, and it was quenched with saturated sodium sulfite solution. The layers were separated, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to give the title compound 3j (120 mg, yield: 56.2%).

[0548] MS m / z(ESI):239.2[M+1].

[0549] Step 10

[0550] 4-Fluoro-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)-2H-spiro[benzofuran-3,1'-cyclopropane]-7-carboxylic acid methyl ester 3k

[0551] Naphthalene-1-ylmethyl (1r, 4r)-4-hydroxy-1-methylcyclohexane-1-carboxylate 1a (125.2 mg, 419.8 μmol, prepared by the method disclosed in Intermediate 11 on page 143 of the specification of patent application "WO2022122773"), compound 3j (100 mg, 419.8 μmol), triphenylphosphine (275 mg, 1.05 mmol) were dissolved in tetrahydrofuran (2 mL), and diisopropyl azodicarboxylate (212.2 mg, 1.05 mmol) was added, replaced with nitrogen, and stirred for 16 hours. The reaction solution was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound 3k (217 mg, yield: 99.6%).

[0552] MS m / z(ESI):519.6[M+1].

[0553] Step 11

[0554] 4-Fluoro-5-(((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)-2H-spiro[benzofuran-3,1'-cyclopropane]-7-carboxylic acid 3l

[0555] Compound 3k (300 mg, 578.5 μmol) was dissolved in tetrahydrofuran (3 mL) and water (1 mL), lithium hydroxide monohydrate (60 mg, 1.43 mmol) was added, and the reaction was stirred for 16 hours. The reaction solution was adjusted to pH = 6-7 with dilute hydrochloric acid, extracted with ethyl acetate (10 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 3l (290 mg), which was used directly in the next step without purification.

[0556] MS m / z(ESI):505.6[M+1].

[0557] Step 12

[0558] Naphthalen-1-ylmethyl (1S,4s)-4-((4-fluoro-7-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)aminocarbonyl)bicyclo[2.2.1]hept-2-yl)aminocarbonyl)-2H-spiro[benzofuran-3,1'-cyclopropane]-5-yl)oxy)-1-methylcyclohexane-1-carboxylate 3m

[0559] Compound 31 (290 mg, 574.7 μmol), (1R,2S,3R,4S)-3-amino-N-((1-methylcyclobutyl)methyl)bicyclo[2.2.1]heptane-2-carboxamide hydrochloride (156.8 mg, 574.7 μmol, prepared by the method disclosed in Intermediate 22 on page 149 of the specification of patent application "WO2022122773") were dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (288 mg, 2.23 mmol), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (327.8 mg, 862.1 μmol), stirred for 0.5 hour, water was added to the reaction solution, extracted with ethyl acetate (15 mL×3), the organic phases were combined, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 3m (400 mg), which was used directly in the next step without purification.

[0560] MS m / z(ESI):723.5[M+1].

[0561] Step 13

[0562] (1S,4s)-4-((4-fluoro-7-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)aminocarbonyl)bicyclo[2.2.1]hept-2-yl)aminocarbonyl)-2H-spiro[benzofuran-3,1'-cyclopropane]-5-yl)oxy)-1-methylcyclohexane-1-carboxylic acid 3

[0563] The crude compound 3m (400 mg, 553.3 μmol) was dissolved in ethanol (10 mL), and a 10% palladium carbon hydrogenation catalyst (50 mg) was added. The mixture was replaced with hydrogen and stirred for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, Boston phlex prep C18, 30×150 mm; 5 um; mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-60%, flow rate: 30 mL / min) to give the title compound 3 (40 mg, yield: 12.4%).

[0564] MS m / z(ESI):583.7[M+1].

[0565] 1H NMR (500MHz, DMSO-d6): δ8.21(d,1H),7.87(t,1H),7.24(d,1H),4.62(d,1H),4.54(d,1H),4.18(t,1H),4.07(s,1H),3.10(dd,1H),2.88(dd,1H) ),2.63(d,1H),2.24(d,1H),2.09-1.99(m,5H),1.90-1.82(m,2H),1.76 -1.50(m,6H),1.49-1.30(m,9H),1.17(d,2H),1.10(s,5H),0.92(s,3H).

[0566] Example 4

[0567] (1R,4S)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)aminocarbonyl)bicyclo[2.2.1]hept-2-yl)aminocarbonyl)-4-(((S)-tetrahydrofuran-3-yl)oxy)phenoxy)-1-methylcyclohexane-1-carboxylic acid 4

[0568]

[0569] first step

[0570] (S)-4-Fluoro-2-(tetrahydrofuran-3-yl)oxy)benzoic acid methyl ester 4b

[0571] Methyl 4-fluoro-2-hydroxybenzoate 4a (5 g, 29.39 mmol, Shanghai Titan) (125.3 mg, 419.7 μmol), (R)-(-)-3-hydroxytetrahydrofuran (3.89 g, 44.15 mmol), triphenylphosphine (11.55 g, 44.08 mmol) were dissolved in tetrahydrofuran (60 mL), diisopropyl azodicarboxylate (8.92 g, 44.11 mmol) was added, nitrogen was replaced, and the reaction was stirred at 45 ° C for 1 hour. After the reaction solution was cooled to room temperature, saturated ammonium chloride solution was added, and it was extracted with ethyl acetate (50 mL×3), the organic phase was collected, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to give the title compound 4b (7 g, yield: 99.1%).

[0572] MS m / z(ESI):241.2[M+1].

[0573] Step 2

[0574] Naphthalen-1-ylmethyl (1R,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)aminocarbonyl)bicyclo[2.2.1]hept-2-yl)aminocarbonyl)-4-(((S)-tetrahydrofuran-3-yl)oxy)phenoxy)-1-methylcyclohexane-1-carboxylate 4c

[0575] Using the synthetic route in Example 3, the eighth step compound 3h was replaced by compound 4b to obtain the crude title compound 4c (450 mg).

[0576] MS m / z(ESI):739.5[M-1].

[0577] Step 3

[0578] (1R,4S)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)aminocarbonyl)bicyclo[2.2.1]hept-2-yl)aminocarbonyl)-4-(((S)-tetrahydrofuran-3-yl)oxy)phenoxy)-1-methylcyclohexane-1-carboxylic acid 4

[0579] The crude compound 4c (200 mg, 269.9 μmol) was dissolved in trifluoroacetic acid (2 mL), and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by HPLC (Waters-2545, Boston phlex prep C18, 30×150 mm; 5 um; mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-60%, flow rate: 30 mL / min) to give the title compound 4 (50 mg, yield: 30.8%).

[0580] MS m / z(ESI):601.6[M+1].

[0581] 1H NMR (500MHz, CDCl3): δ8.18(d,1H),7.85(d,1H),6.66(d,1H),5.68(t,1H),4.96(t,1H), 4.45(t,1H),4.28(d,1H),4.18-4.13(m,1H),4.04-4.00(m,1H),3.94-3.90(m,1H),3.14 (dd,1H),2.82(dd,1H),2.58(d,1H),2.55(d,1H),2.29-2.12(m,4H),2.08-1.91(m,4H), 1.77-1.69(m,5H),1.54-1.45(m,5H),1.38-1.28(m,5H),1.25-1.18(m,5H),0.94(s,3H).

[0582] Example 5

[0583] (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)aminocarbonyl)bicyclo[2.2.1]hept-2-yl)aminocarbonyl)-4-(((R)-tetrahydrofuran-3-yl)oxy)phenoxy)-1-methylcyclohexane-1-carboxylic acid 5

[0584]

[0585] The synthetic route in Example 4 was used to replace the first step raw material (R)-(-)-3-hydroxytetrahydrofuran with (S)-(+)-3-hydroxytetrahydrofuran (Shanghai Titan) to obtain the title compound 5 (40 mg, yield: 16.9%).

[0586] MS m / z(ESI):601.7[M+1].

[0587] 1 H NMR (500MHz, CDCl3): δ8.14(d,1H),7.85(d,1H),6.61(d,1H),5.76(t,1H),4.9 6(t,1H),4.45(t,1H),4.11-4.09(m,2H),4.01-3.95(m,2H),3.12(dd,1H),2.8 2(dd,1H),2.57-2.54(m,2H),2.45-2.38(m,2H),2.32-2.21(m,4H),2.05-1.91 (m,4H),1.75-1.60(m,7H),1.56-1.46(m,3H),1.31-1.20(m,8H),0.94(s,3H).

[0588] Example 6

[0589] (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)aminocarbonyl)bicyclo[2.2.1]hept-2-yl)aminocarbonyl)-4-(oxetan-3-yloxy)phenoxy)-1-methylcyclohexane-1-carboxylic acid 6

[0590]

[0591]

[0592] first step

[0593] Methyl 4-fluoro-2-(oxetan-3-yloxy)benzoate 6a

[0594] Methyl 4-fluoro-2-hydroxybenzoate 4a (5 g, 29.39 mmol, Shanghai Titan), oxetan-3-ol (3.27 g, 44.14 mmol), and triphenylphosphine (11.55 g, 44.08 mmol) were dissolved in tetrahydrofuran (60 mL), and diisopropyl azodicarboxylate (8.92 g, 44.11 mmol) was added. The mixture was replaced with nitrogen and stirred at 45°C for 16 hours. After the reaction solution was cooled to room temperature, saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phase was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to give the title compound 6a (6.5 g, yield: 97.8%).

[0595] MS m / z(ESI):227.0[M+1].

[0596] Step 2

[0597] (1S,4s)-4-(2-fluoro-5-(((1S,2R,3S,4R)-3-(((1-methylcyclobutyl)methyl)aminocarbonyl)bicyclo[2.2.1]hept-2-yl)aminocarbonyl)-4-(oxetan-3-yloxy)phenoxy)-1-methylcyclohexane-1-carboxylic acid 6

[0598] The synthetic route in Example 3 was used to replace the compound 3h in the eighth step with compound 6a to obtain the title compound 6 (30 mg, yield: 32.3%).

[0599] MS m / z(ESI):587.5[M+1].

[0600] 1H NMR (500MHz, CDCl3): δ8.37(d,1H),7.87(d,1H),6.20(d,1H),5.67(t,1H),5.2 2-5.18(m,1H),5.05(t,1H),5.00-4.93(m,2H),4.47(t,1H),4.20-4.15(m,1H), 3.12(dd,1H),2.95(dd,1H),2.50(dd,2H),2.28-2.25(m,3H),2.08(d,1H),1.99 (dd,2H),1.78-1.60(m,8H),1.58-1.47(m,4H),1.37-1.22(m,8H),0.94(s,3H).

[0601] Biological evaluation

[0602] Test Example 1: Stimulating effect of the compounds of the present invention on cAMP production in CHO-K1 cells overexpressing hRXFP1

[0603] 1. Experimental materials and instruments

[0604] hRXFP1-CHO-K1 (Beijing Tuojie Biopharmaceutical Co., Ltd., NA)

[0605] cAMP dynamic 2kit-20,000tests (cisbio, 62AM4PEC)

[0606] 384-well plate (Corning, 4513)

[0607] U-bottom 96-well plate (Corning, 3795)

[0608] Ham's F-12K (Kaighn's) medium (Gibco, 21127022)

[0609] 500mL fetal bovine serum (FBS), Regular (Corning, 35-081-CV)

[0610] Penicillin-Streptomycin (P / S, Gibco, 15140122)

[0611] 0.25% Trypsin-EDTA (1x), phenol red (Gibco, 25200072)

[0612] 3-Isobutyl-1-methylxanthine (IBMX) (sigma, I7018-1G)

[0613] Hygromycin B (Thermo, 10687-010)

[0614] Microplate reader (BMG, PHERAstar FS)

[0615] Cell counter (Shanghai Ruiyu Biotechnology Co., Ltd., IC1000)

[0616] 2. Experimental steps

[0617] hRXFP1-CHO-K1 monoclonal cells were cultured in complete medium (F-12K+10% FBS+1% P / S+1mg / ml hygromycin B) and passaged every 3 days at a passage density of about 1:10. During passage, the cells were digested with trypsin and transferred to a centrifuge tube, centrifuged at 1000rpm for 3 minutes, the supernatant medium was discarded, and the cells were resuspended in complete medium.

[0618] Preparation of compounds: 1) Preparation of polypeptide compounds: Dilute the polypeptide compound (Relaxin-2) to 2 μM with the experimental buffer (5x stimulation buffer 1 is diluted to 1x with ddH2O, and then add IBMX with a final concentration of 0.5 mM), and then dilute it 4 times with the experimental buffer to 10 concentrations, and set a blank well. 2) Preparation of compounds of the present disclosure: Dilute the sample to be tested to 2 mM with DMSO, and then dilute it 4 times with DMSO to 10 concentrations, and set a blank well. Take 2 μL of the compound solution prepared in gradient concentrations and add it to 198 μL of the experimental buffer to prepare the experimental buffer containing the compound.

[0619] During the experiment, trypsin was used to digest the cells, and the supernatant was discarded after centrifugation. The cells were washed once with the experimental buffer, the residual liquid was discarded after centrifugation, and the cells were resuspended with the experimental buffer. The density was adjusted to 1×10 after counting with a cell counter. 6 cells / mL, 5 μL / well was added to a 384-well plate, 5000 cells per well. 5 μL of the above experimental buffer containing the compound was added to the 384-well plate and incubated in a 37°C incubator for 30 minutes. Then the experiment was performed according to the instructions of the cAMP kit. The signal value was read using the HTRF program of the microplate reader.

[0620] Use Graphpad prism 10 to draw the cAMP standard curve, calculate the cAMP value, fit the log(agonist) vs.response--Variable slope curve, and calculate the compound EC 50 The data are shown in Table 1.

[0621] Table 1 hRXFP1 cAMP EC 50 and Emax fold

[0622]

[0623] Conclusion: The disclosed compounds have a significant activating effect on the production of cAMP in CHO-K1 cells overexpressing hRXFP1.

Claims

1. A compound represented by general formula (I), or a pharmaceutically acceptable salt thereof: in: U is N or CR 2 ; V is CR V ; W is N or CR W ; R V , R 2 Together with the carbon atom to which it is attached, it forms a ring D, or R V , R W Together with the carbon atom to which it is attached, it forms a ring D, or R W , R V , R 2 Together with the carbon atom to which it is attached, it forms ring D; Ring D is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; and Ring D is optionally substituted by one or more R 4 replaced by; R 2 With R W When present, it is selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, NR 20 R 21 、C(O)R 23 , OR 23 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R 01 replace; R 3 is selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, NR 20 R 21 、C(O)R 23 , OR 23 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R 01 replace; R 1 Selected from COOH, C(O)NR 20 R 21 、C(O)OR 23 NR 20 R 21 、OC(O)R 23 、S(O) r R 23 、S(O) r OR 23 、OS(O) r R 23 、S(O) r NR 20 R 21 、Alkylene NR 20 R 21 、P(O)R 23 R 24 , OR 23 、C(=NR 22 )NR 20 R 21 、S(=NR 22 )(O)R 23 NR 22 C(O)NR 20 R 21 NR 22 S(O) r NR 20 R 21 、C(O)NR 22 NR 20 R 21 , =CR 23 R 24 , =NR 22 , hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, hydroxyl, hydroxyalkyl, alkenyl, alkynyl, cyano, nitro, cycloalkyl, heterocyclic group, aryl and heteroaryl; the alkylene, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently optionally replaced by one or more R 02 replace; X is selected from a bond, an alkylene group, O, S, NR e 、C(O)、C(O)NR e NR e C(O), Oalkylene and alkyleneO; Y is an alkylene group or a ring A, wherein the alkylene group and the ring A are each independently optionally substituted with one or more R A replace; Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Z is selected from a bond, alkylene, alkenylene, heteroalkyl, alkoxyalkyl, O, S, NR e 、C(O)、C(O)NR e NR e C(O), cycloalkyl and heterocyclyl; the alkyl, alkenylene, heteroalkyl, cycloalkyl and heterocyclyl are each independently optionally substituted by one or more R 02 replace; R 9 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an amino group, a cycloalkyl group, and a heterocyclic group; A is selected from Ring B is a cycloalkyl group or a heterocyclic group; Ring Cy is an aryl group or a heteroaryl group; R 7 is selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, NR 20 R 21 、C(O)R 23 , OR 23 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R 03 replace; R 6 is -(CR 10 R 11 ) s R 12 ; R 10 and R 11 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, NR 20 R 21 、C(O)R 23 , OR 23 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R 03 replace; or R 10 , R 11 and the carbon atom to which it is attached together form a cycloalkyl or heterocyclic group; the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more R 03 replace; R 12 is alkyl or The alkyl group is optionally substituted with one or more R 03 replace; Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Each R 4 , R 01 , R 02 , R A , R 5 , R 8 and R 03 are the same or different and are each independently selected from oxo, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, alkenyl, alkynyl, cyano, nitro, NR 20 R 21 、C(O)NR 20 R 21 、Alkylene NR 20 R 21 、Alkylene C(O)NR 20 R 21 NR 22 C(O)R 23 NR 22 C(O)NR 20 R 21 、C(O)R 23 、C(O)OR 23 、OC(O)R 23 、OC(O)OR 23 、S(O) r R 24 、S(O) r OR 24 、OS(O) r R 24 、S(O) r NR 20 R 21 NR 22 S(O) r R 24 、C(=NR 22 )R 23 、C(=NR 22 )NR 20 R 21 、S(=NR 22 )(O)R 23 、P(O)R 23 R 24 , OR 23 , =CR 23 R 24 , =NR 22 , SF5, cycloalkyl, heterocyclyl, cycloalkyloxy, heterocyclyloxy, aryl, heteroaryl, aryloxy and heteroaryloxy; the alkyl, alkoxy, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, cycloalkyloxy, heterocyclyloxy, aryl, heteroaryl, aryloxy and heteroaryloxy are each independently substituted with one or more R*; Each R e , R 20 , R 21 , R 22 , R 23 and R 24 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, hydroxy, alkenyl, alkynyl, NR a R b 、C(O)NR a R b 、Alkylene NR a R b 、Alkylene C(O)NR a R b NR c C(O)R d NR c C(O)NR a R b 、C(O)R d 、C(O)OR d 、OC(O)R d 、OC(O)OR d , OR d , cycloalkyl, heterocyclyl, aryl and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently substituted by one or more R*; or R 20 , R 21 and the nitrogen atom to which it is attached together form a heterocyclic group, which is optionally substituted by one or more R*; or R 23 , R 24 and the carbon atom to which it is attached together form a cycloalkyl group, which is optionally substituted with one or more R*; Each R a , R b , R c and R d are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, an amino group, an NH alkyl group, an N(alkyl)2 group, an amide group, a C(O)NH alkyl group, a C(O)N(alkyl)2 group, a C(O)O alkyl group, a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, a heterocyclylalkyl group, a cycloalkyloxy group, a heterocyclyloxy group, an aryl group and a heteroaryl group; and the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the cycloalkylalkyl group, the heterocyclylalkyl group, the cycloalkyloxy group, the heterocyclyloxy group, an aryl group and a heteroaryl group are each independently optionally replaced by one or more R * or, R a , R b and the nitrogen atom to which it is attached form a heterocyclic group, the heterocyclic group is optionally substituted by one or more R * replaced by; Each R * are the same or different and are each independently selected from oxo, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, amino, NHalkyl, N(alkyl)2, amide, C(O)NHalkyl, C(O)N(alkyl)2, C(O)alkyl, C(O)Oalkyl, alkyleneamino, alkyleneamide, nitro, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl and heteroaryl; the alkyl, alkoxy, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl and heteroaryl are each independently optionally substituted by one or more selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, amino, cycloalkyl and heterocyclyl; Each r is the same or different and is independently 0, 1 or 2; m is 0, 1, 2, 3, 4, 5 or 6; s is 0, 1, 2, 3, 4, 5 or 6; and t is 0, 1, 2, 3, 4, 5 or 6.

2. The compound represented by the general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II), or a pharmaceutically acceptable salt thereof: in, Ring D is a polycyclic cycloalkyl group or a polycyclic heterocyclyl group; n is an integer from 0 to 20; R 1 , Z, Y, X, U, R 3 , R 4 and A as defined in claim 1.

3. The compound represented by the general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (III), or a pharmaceutically acceptable salt thereof: in, Ring E is a cycloalkyl group or a heterocyclic group; Q 1 and Q are the same or different and are each independently selected from a bond, O, (CR g R h ) p 、O(CR g R h ) p , (CR g R h ) p O、(CR g R h ) p O(CR g R h ) p NR i 、C(O)NR i NR i C(O) and S(O) r ; Each R g and R h are the same or different and are each independently a hydrogen atom or R 4 ; R i is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group; n1 is 0, 1, 2, 3, 4, 5 or 6; q is 0, 1, 2, 3, 4, 5 or 6; p is 1, 2 or 3; Ring A, R 1 , R A ,X,U,R 3 , R 4 , A and r are as defined in claim 1.

4. The compound represented by the general formula (I) according to claim 3, or a pharmaceutically acceptable salt thereof, wherein: Q 1 is a bond or O, and / or Q is a bond or O.

5. The compound represented by the general formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, wherein: In some embodiments, ring D is selected from Q 1 is a bond or O, Q is a bond or O, u is 1, 2, 3 or 4, n3 is 0, 1, 2, 3 or 4; preferably, ring D is selected from * end is close to C(O).

6. The compound of general formula (I) according to any one of claims 3 to 5, or a pharmaceutically acceptable salt thereof, wherein: Ring E is a 3- to 6-membered cycloalkyl group or a 4- to 7-membered heterocyclic group, and / or each R 4 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl, and / or n1 is 0, 1 or 2; preferably, ring E is cyclobutyl.

7. A compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein: A is Ring B, R 5 , R 6 , R 7 and m as defined in claim 1; preferably, A is R 5 , R 6 , R 7 and m as defined in claim 1.

8. The compound of general formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein: Ring B is a 3- to 10-membered cycloalkyl group; preferably, ring B is a 5- to 8-membered bridged cycloalkyl group.

9. The compound represented by general formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein: R 6 -(CH2) s R 12 , R 12 for Ring C, R 03 , s and t as defined in claim 1; preferably, R 6 for 10. The compound represented by general formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein: R 1 is COOH.

11. The compound represented by general formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein: X is a bond or O; preferably, X is O.

12. The compound of general formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 3- to 6-membered cycloalkyl group or a phenyl group; preferably, Ring A is a cyclohexyl group.

13. A compound of general formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein: R 2 Selected from hydrogen atoms, halogens, cyano groups, C 1-6 Alkyl and C 1-6 haloalkyl; and / or R 3 is a hydrogen atom; preferably, R 2 It is a halogen.

14. A compound represented by the general formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, selected from any of the following compounds:

15. The compound represented by the general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, which is selected from any of the following structures:

16. A method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising: R 1 C(O)OR 23 The compound represented by the general formula (II) or its pharmaceutically acceptable salt undergoes a deprotection reaction to obtain R 1 A compound represented by the general formula (II) of C(O)OH or a pharmaceutically acceptable salt thereof; Among them, R 23 is alkyl or -alkylaryl; Z, Y, X, U, R 3 , Ring D, R 4 , n and A are as defined in claim 2.

17. A pharmaceutical composition comprising a compound represented by general formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

18. Use of the compound represented by general formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 17 in the preparation of an RXFP1 agonist.

19. Use of a compound of formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 17 in the preparation of a medicament for treating and / or preventing diseases or conditions mediated by or dependent on RXFP1.

20. Use of a compound of formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 17 in the preparation of a medicament for treating and / or preventing heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, chronic kidney disease, acute kidney injury, fibrotic diseases and related diseases and inflammatory diseases; wherein the heart failure is preferably advanced heart failure, post-acute heart failure, cardiorenal syndrome, heart failure with impaired renal function, chronic heart failure, chronic heart failure with reduced ejection fraction (HFmEF), compensated heart failure, decompensated heart failure, right heart failure, left heart failure, global failure, ischemic cardiomyopathy, dilated cardiomyopathy, heart failure associated with congenital heart defects, heart valve defects, heart failure associated with heart valve defects Heart failure, mitral stenosis, mitral regurgitation, aortic stenosis, aortic stenosis insufficiency, tricuspid stenosis, tricuspid regurgitation, pulmonary stenosis, pulmonary regurgitation, heart failure associated with valvular heart defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, heart failure associated with valvular heart defects, cardiac storage disorder, diastolic heart failure, systolic heart failure, acute phase of worsening heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), chronic heart failure with reduced ejection fraction (HFrEF), chronic heart failure with preserved ejection fraction (HFpEF), after myocardial remodeling, angina pectoris, hypertension, pulmonary hypertension and pulmonary hypertension.

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