WO2018133793A1

WO2018133793A1 - Blood coagulation factor xia inhibitor and uses thereof

Info

Publication number: WO2018133793A1
Application number: PCT/CN2018/072988
Authority: WO
Inventors: 左应林; 王建成; 林继华; 张英勋; 曹生田; 吴方园; 杨雯; 许娟; 王晓军; 张英俊
Original assignee: 广东东阳光药业有限公司
Priority date: 2017-01-18
Filing date: 2018-01-17
Publication date: 2018-07-26
Also published as: CN110062757B; CN110062757A

Abstract

Provided are a macrocyclic compound having inhibitory blood coagulation factor XIA and/or plasma kallikrein activity, and a pharmaceutical composition thereof. The macrocyclic compound and the pharmaceutical composition thereof can be used for treating or preventing thromboembolic diseases.

Description

Coagulation factor XIa inhibitor and its use

Field of invention

The present invention belongs to the field of medicine, relates to a blood coagulation factor XIa inhibitor and uses thereof, and particularly to a macrocyclic compound having a blood coagulation factor XIa and/or a plasma kallikrein and a pharmaceutical composition thereof; wherein the macrocyclic compound And pharmaceutical compositions thereof for use in the treatment or prevention of thromboembolic disorders.

Background technique

Procoagulant (hemostasis) and anticoagulation (antithrombotic) are two opposing mechanisms in the human blood system that contradict each other and maintain relative balance. This precise and harmonious process maintains the integrity of the circulatory system. When the function of the anticoagulant and fibrinolysis system in the body is gradually reduced, blood coagulation and anticoagulant function are out of balance, and coagulation occurs, which may cause thrombosis or embolism, which may lead to thromboembolism such as myocardial infarction, stroke, deep vein thrombosis, pulmonary embolism, etc. disease. Thromboembolic disease is the most serious disease in cardiovascular disease and the first killer of human health.

With the further elucidation of the mechanism of thrombosis, a number of new antithrombotic drugs have been researched and developed for the characteristics and causes of thrombosis, including inhibition of thrombosis (anticoagulation, for example, warfarin, heparin, low molecular weight heparin, etc.) And drugs that inhibit platelet aggregation (eg, aspirin, clopidogrel, etc.) and thrombolytic drugs. The former mainly inhibits the formation and enlargement of thrombus, and the latter mainly dissolves the formed thrombus, thereby eliminating the harm caused by thrombotic diseases to humans. At present, the use of clinically applied anticoagulant drugs is still limited by various risks (eg, bleeding), and it is increasingly important to discover and develop safe and effective oral anticoagulant drugs for the prevention and treatment of extensive thromboembolic disorders. .

The inhibition of coagulation factor XIa (FXIa) can inhibit the production of thrombin, thereby achieving the therapeutic effect of anticoagulation. Factor XIa is a plasma serine protease involved in the regulation of blood coagulation, which is initiated by the in vivo binding of tissue factor (TF) to factor VII (FVII) to produce factor VIIa (FVIIa). The TF:FVIIa complex produced therein activates Factor IX (FIX) and Factor X (FX), thereby causing the production of Factor Xa (FXa). Before this pathway is blocked by tissue factor pathway inhibitor (TFPI), the resulting FXa catalyzes the conversion of prothrombin to a small amount of thrombin, and the catalytic amount of thrombin feedbacks the activation factors V, VIII and XI, thereby further expanding the coagulation process. (Gailani, D. et al., Arterioscler. Thromb. Vasc. Biol., 2007, 27: 2507-2513). The thrombin burst caused by this process converts fibrinogen to fibrin, which polymerizes to form a structural framework for blood clots and activates platelets that are key cellular components of coagulation (Hoffman, M., Blood Reviews, 2003, 17: S1-S5). Therefore, Factor XIa plays a key role in expanding the amplification loop of the coagulation process, and thus it can serve as an attractive target for anti-thrombotic therapy.

Plasma prekallikrein is a chymase of trypsin-like serine protease which is present in plasma at a concentration of 35 μg/mL to 50 μg/mL. The gene structure of plasma kallikrein is similar to that of factor XI; in general, the amino acid sequence of plasma kallikrein (PK) has 58% homology with factor XI. Plasma kallikrein is thought to play a role in many inflammatory conditions. The major inhibitor of plasma kallikrein is a serpin C1 esterase inhibitor. Patients with genetic defects in C1 esterase inhibitors have hereditary angioedema (HAE), which causes intermittent swelling of the face, hands, throat, gastrointestinal tract, and genitals; blisters formed during acute episodes contain large amounts of plasma A peptide-releasing enzyme that cleaves a high molecular weight kininogen and releases a bradykinin, resulting in an increase in vascular permeability. Studies have shown that large protein plasma kallikrein inhibitors can effectively treat HAE by preventing the release of bradykinin, which causes an increase in vascular permeability (A. Lehmann, Ecallantide (DX-88), a plasma kallikrein inhibitor). For the treatment of hereditary angioedema and the prevention of blood loss in on-pumpcardiothoracic surgery, Expert Opin. Biol. Ther. 8, pp. 1187-99).

Kallikrein kinin system (KKS) is a complex endogenous multi-enzyme system involved in the regulation of cardiovascular, renal, nervous system and other physiological functions, and heart disease, kidney disease, inflammatory response, cancer There is a close relationship between the occurrence of diseases. In recent years, research on the cardiovascular system has progressed rapidly. Many clinical studies and basic experiments have confirmed that the occurrence of diabetes, hypertension, heart failure, myocardial infarction and left ventricular hypertrophy is associated with decreased activity of KKS. Studies have found that levels of factor XI (FXI), high molecular weight kininogen (HK), and prokallikrein (PK) are significantly elevated in the blood of patients with myocardial infarction, suggesting that they occur in the development of myocardial infarction. May play a certain role (Merlo C., et al. Elevated levels of plasma prekallikrein, high molecular weight kininoen and factor XI in coronary heart disease [J]. Atherosclerosis, 2002, 161 (2): 261-267.). Therefore, an in-depth study of the role of KKS provides a new way to study the pathogenesis and treatment of cardiovascular-related diseases.

Summary of the invention

The present invention provides a macrocyclic compound suitable for a serine protease, particularly a selective inhibitor of factor XIa and/or plasma kallikrein, an analog thereof, and a pharmaceutical composition comprising the macrocyclic compound, the compound Or a thromboembolic disease in which the pharmaceutical composition is effective for the treatment and prevention.

In one aspect, the present invention provides a compound which is a stereoisomer, a geometric isomer, a tautomer, an oxynitride of a compound of formula (I) or a compound of formula (I), a hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,

among them,

Ring A is a C _7-12 carbocyclic group, a C _8-12 aryl group, a heterocyclic group consisting of 7 to 12 atoms or a heteroaryl group of 7 to 12 atoms;

Ring B is a C _5-12 carbocyclic group, a C _6-12 aryl group, a heterocyclic group consisting of 5 to 12 atoms or a heteroaryl group of 5 to 12 atoms;

Ring C is a C _3-12 carbocyclic group, a C _6-12 aryl group, a heterocyclic group consisting of 3 to 12 atoms or a heteroaryl group of 5 to 12 atoms;

X is a C _4-8 alkylene group or a C _4-8 alkenylene group, wherein one or more carbon atoms in the alkylene group and the alkenylene group are independently selected from -O-, -S- Substituting a group of -C(=O)-, -S(=O)-, -S(=O) ₂ - or -N(R ⁵ )-; a C _4-8 alkylene group in X and The C _4-8 alkenylene group is independently optionally substituted by one or more R ⁹ ;

Y is -C(=O)N(R ⁵ )- or -N(R ⁵ )C(=O)-;

Each R ^{1 is} independently oxo (=O), H, hydrazine, halogen, -(CR ^7a R ^7b ) _r CN, C _1-6 alkyl, deuterated C _1-6 alkyl, halogenated C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -(CR ^7a R ^7b ) _r OR ⁸ , -(CR ^7a R ^7b ) _r NR ^5a R ^5b , -(CR ^7a R ^7b ) _r C(=O)R ⁶ , -(CR ^7a R ^7b ) _r C(=O)OR ⁸ , -(CR ^7a R ^7b ) _r C(=O)NR ^5a R ^5b , -(CR ^7a R ^7b ) _r S(=O)R ⁶ , -(CR ^7a R ^7b ) _r S(=O)OR ⁸ , -(CR ^7a R ^7b ) _r S(=O)NR ^5a R ^5b , -(CR ^7a R ^7b ) _r S(=O) ₂ R ⁶ , -(CR ^7a R ^7b ) _r S(=O) ₂ OR ⁸ , -(CR ^7a R ^7b ) _r S(=O) ₂ NR ^5a R ^5b , -(CR ^7a R ^7b ) _r- C _3-12 cycloalkyl, -(CR ^7a R ^7b ) _r -C _6-12 aryl, -(CR ^7a R ^7b ) _r - (heterocyclic group of 3-12 atoms) or -(CR ^7a R ^7b ) _r -(heteroaryl group of 5-12 atoms); wherein each R ^{1 is} independently optionally substituted by 1, 2, 3 or 4 R ^1a ;

Each R ^{2 is} independently H, deuterium, halogen, -(CR ^7a R ^7b ) _r CN, C _1-6 alkyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, R ⁸ OC _2-6 alkenylene, R ⁸ OC(=O)-C _2-6 alkenylene, R ⁸ OC _2-6 alkynylene, R ⁸ OC (=O)-C _2-6 alkynylene, -N=C=S, -N=C=O, -(CR ^7a R ^7b ) _r OR ⁸ , -(CR ^7a R ^7b ) _r NR ^5a R ^5b , -(CR ^7a R ^7b ) _r C(=G)R ⁶ , -(CR ^7a R ^7b ) _r N(R ^5c )C(=G)R ⁶ , -(CR ^7a R ^7b ) _r OC(=G R ⁶ , -(CR ^7a R ^7b ) _r C(=G)OR ⁸ , -(CR ^7a R ^7b ) _r N(R ^5c )C(=G)OR ⁸ , -(CR ^7a R ^7b ) _r OC (=G)OR ⁸ , -(CR ^7a R ^7b ) _r C(=G)NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c )C(=G)NR ^5a R ^5b ,-( CR ^7a R ^7b ) _r N(R ^5c )=C(R ⁷ )NR ^5a R ^5b , -(CR ^7a R ^7b ) _r S(=O)R ⁶ , -(CR ^7a R ^7b ) _r N(R ^5c )S(=O)R ⁶ , -(CR ^7a R ^7b ) _r S(=O)OR ⁸ , -(CR ^7a R ^7b ) _r N(R ^5c )S(=O)OR ⁸ ,-(CR ^7a R ^7b ) _r S(=O)NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c )S(=O)NR ^5a R ^5b , -(CR ^7a R ^7b ) _r S(=O) ₂ R ⁶ , -(CR ^7a R ^7b ) _r OS(=O) ₂ R ⁶ , -(CR ^7a R ^7b ) _r N(R ^5c )S(=O) ₂ R ⁶ , -(CR ^7a R ^7b ) _r S(=O) ₂ OR ⁸ , -(CR ^7a R ^7b ) _r N(R ^5c )S(=O) ₂ OR ⁸ , -(CR ^7a R ^7b ) _r S( =O) ₂ NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c )S(=O) ₂ NR ^5a R ^5b , -(CR ^7a R ^7b ) _r -C _3-12 cycloalkyl, -(CR ^7a R ^7b ) _r -C _6-12 aryl, -(CR ^7a R ^7b ) _r -(heterocyclic group of 3-12 atoms), -(CR ^7a R ^7b ) _r -(5- 12 atomic heteroaryl) or D-mannosyl; wherein each G is independently O, S or NR ^5d ; each R ^{2 is} independently optionally substituted by 1, 2, 3 or 4 R ^2a ;

Each R ^{3 is} independently a C _1-6 alkyl group, a C _3-12 carbocyclic group, a C _6-12 aryl group, a heterocyclic group consisting of 3 to 12 atoms, or a heteroaryl group of 5 to 12 atoms; Wherein each R ^{3 is} independently optionally substituted by 1, 2, 3, 4 or 5 R ^3a ;

Each R ^{4 is} independently H, hydrazine, halogen, hydroxy, amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _{1 -6} alkoxy, -(CR ^7a R ^7b ) _r -OR ⁸ , -(CR ^7a R ^7b ) _r -NR ^5a R ^5b , -(CR ^7a R ^7b ) _r -CN, or halogenated C _1-6 Or an alkyl group; or any two of the R ⁴ and the atom to which they are attached form a C _3-8 cycloalkyl group, a C _6-10 aryl group, a heterocyclic group of 3 to 8 atoms, or 5 to 6 atoms. Heteroaryl

Each of R ⁹ , R ^1a , R ^2a and R ^{3a is} independently oxo (=O), hydrogen, deuterium, halogen, -(CR ^7a R ^7b ) _r CN, nitro, C _1-6 alkyl, halogenated C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, R ⁸ OC _2-6 alkenylene, R ⁸ OC(=O)-C _2-6 alkenylene, R ⁸ OC _2-6 alkynylene, R ⁸ OC(=O)-C _2-6 alkynylene, -(CR ^7a R ^7b ) _r -OR ⁸ , -(CR ^7a R ^7b ) _r -NR ^5a R ^5b ,- (CR ^7a R ^7b ) _r N(R ^5c )C(=O)R ⁶ , -(CR ^7a R ^7b ) _r OC(=O)R ⁶ , -(CR ^7a R ^7b ) _r COOH,-(CR ^7a R ^7b ) _r C(=O)OC _1-6 alkyl, -(CR ^7a R ^7b ) _r C(=O)C _1-6 alkyl, -(CR ^7a R ^7b ) _r S(=O) ₂ R ⁶ , -(CR ^7a R ^7b ) _r OS(=O) ₂ R ⁶ , -(CR ^7a R ^7b ) _r N(R ^5c )S(=O) ₂ R ⁶ , -(CR ^7a R ^7b ) _r S(=O) ₂ OR ⁸ , -(CR ^7a R ^7b ) _r S(=O) ₂ NR ^5a R ^5b , -(CR ^7a R ^7b ) _r -C _3-12 cycloalkyl, -(CR ^7a R ^7b ) _r- C _6-12 aryl, -(CR ^7a R ^7b ) _r - (heterocyclic group of 3-12 atoms) or -(CR ^7a R ^7b ) _r - (5-12 atoms) Heteroaryl)

Alternatively, any two R ⁹ together with the atoms to which they are attached form a C _3-6 cycloalkyl group or a heterocyclic group consisting of 3 to 6 atoms;

Wherein each R ⁹ , R ^1a , R ^2a and R ^{3a are} independently independently substituted by 1, 2, 3, 4 or 5 R ¹⁰ ;

Each of R ⁵ , R ^5a , R ^5b , R ^5c and R ^{5d is} independently hydrogen, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy-C(=O)-, C _{6- a 10} aryl group, a C _3-10 cycloalkyl group, a heterocyclic group of 3 to 10 atoms or a heteroaryl group of 5 to 10 atoms;

Or R ⁵ , R ⁹ and the atoms attached thereto form a heterocyclic group consisting of 3-8 atoms;

Each of R ⁶ and R ^{8 is} independently hydrogen, deuterium, C _1-6 alkyl, deuterated C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxy substituted C _1-6 Alkyl, amino-substituted C _1-6 alkyl, cyano substituted C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, halo C _1-6 alkyl, C _{6- a 10} aryl group, a C _3-10 cycloalkyl group, a heterocyclic group of 3 to 10 atoms or a heteroaryl group of 5 to 10 atoms;

Each of R ⁷ , R ^7a and R ^{7b is} independently hydrogen, C _1-6 alkyl, deuterated C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or halo C _1-6 alkyl;

Each R ^{10 is} independently oxo (=O), H, D, halogen, CN, amino, hydroxy, nitro, carboxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , deuterated C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, C _1-4 alkoxy C _1-4 alkyl, hydroxy substituted C _1-4 alkyl, cyanide Substituted C _1-4 alkyl, amino substituted C _1-4 alkyl, halo C _1-4 alkyl, C _1-4 alkyl acyl, C _1-4 alkylsulfonyl, C _1-4 Alkoxyacyl group, C _1-4 alkylamino acyl group, amino acyl group, aminosulfonyl group, C _1-4 alkoxysulfonyl group, C _1-4 alkylaminosulfonyl group, C _1-4 acyloxy group, C _{6- a 10} aryl group, a C _3-6 cycloalkyl group, a heterocyclic group of 3 to 6 atoms or a heteroaryl group of 5 to 10 atoms;

Each m, n and t are independently 0, 1, 2, 3 or 4;

p is 1, 2, 3 or 4;

Each r is independently 0, 1, 2, 3 or 4.

In some embodiments, Ring C is a heterocyclic group consisting of 5-7 atoms or a heteroaryl group consisting of 5-6 atoms.

In other embodiments, Ring C is of the following substructure:

Wherein ring C passes through the N atom and

Connected

each

with

Independently representing a single or double bond;

when

or

When it is a single bond, each of Z, Z ¹ and Z ^{2 is} independently CH ₂ or NH;

when

or

When it is a double bond, each of Z, Z ¹ and Z ^{2 is} independently CH or N;

Z ⁴ is CH ₂ or NH;

Each Z ³ and Z ^{5 are} independently CH ₂ , NH, S or O;

q is 0, 1, or 2.

In still other embodiments, ring C is

Wherein ring C passes through the N atom and

Connected.

In some embodiments, the compound of formula (I) of the present invention is a stereoisomer, geometric isomer, tautomer, oxynitride of a compound of formula (II) or a compound of formula (II). a hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,

Among them, each

with

Independently a single bond or a double bond;

when

or

When it is a single bond, each Z and Z ^{1 are} independently CH ₂ or NH;

or

When it is a double bond, each Z and Z ^{1 are} independently CH or N;

Ring A, Ring B, R ¹ , R ² , R ³ , R ⁴ , X, Y, n, m, p and t all have the meanings as described in the present invention.

In some embodiments, each R ^{3 is} independently C _1-4 alkyl, C _3-8 carbocyclyl, C _6-10 aryl, heterocyclyl consisting of 3-8 atoms, or 5-10 atoms. a heteroaryl group;

Wherein each R ^{3 is} independently optionally substituted by 1, 2, 3, 4 or 5 R ^3a .

In other embodiments, each R ^{3 is} independently methyl, ethyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, imidazolinyl, triazolyl, pyridyl, pyrimidinyl, fluorenyl, Carbazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, quinolyl, isoquinolinyl or quinazolinyl ;

In some embodiments, the compound of formula (I) of the present invention is a stereoisomer, geometric isomer, tautomer, oxynitride of a compound of formula (III) or a compound of formula (III). a hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,

Among them, each

with

Independently a single bond or a double bond;

when

or When it is a single bond, Z is CH ₂ or NH;

or

When it is a double bond, Z is CH or N;

f is 0, 1, 2, 3, 4 or 5;

g is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

Ring A, Ring B, R ¹ , R ² , R ^3a , R ⁴ , R ⁵ , R ⁹ , n, m and t all have the meanings as described in the present invention.

In some embodiments, Ring A is a C _7-12 bicyclic carbocyclyl, a C _8-12 bicyclic aryl, a bicyclic heterocyclyl consisting of 7-12 atoms, or a bicyclic heteroaryl consisting of 7-12 atoms.

In some embodiments, Ring A is of the following substructure:

Wherein each of T ¹ , T ² , T ³ , T ⁴ , T ⁵ , T ⁶ , T ⁷ and T ^{8 are} independently -CH- or -N-;

Each of V ¹ , V ² , V ³ and V ^{4 is} independently -CH ₂ -, -NH-, -O-, -S-, -S(=O)-, -S(=O) ₂ - or - C(=O)-;

Each k and j are independently 0, 1, 2, 3 or 4.

In some embodiments, Ring A is

In some embodiments, Ring B is C _5-8 carbocyclyl, C _6-10 aryl, heterocyclyl consisting of 5-8 atoms, or heteroaryl consisting of 5-10 atoms;

Each R ^{2 is} independently H, hydrazine, F, Cl, Br, I, -(CR ^7a R ^7b ) _r CN, C _1-4 alkyl, deuterated C _1-4 alkyl, halogenated C _1-4 Alkyl, C _2-4 alkenyl, C _2-4 alkynyl, R ⁸ OC _2-4 alkenylene, R ⁸ OC(=O)-C _2-4 alkenylene, R ⁸ OC _2-4 Alkynyl, R ⁸ OC(=O)-C _2-4 alkynylene, -N=C=S, -N=C=O, -(CR ^7a R ^7b ) _r OR ⁸ , -(CR ^7a R ^7b _r NR ^5a R ^5b , -(CR ^7a R ^7b ) _r C(=G)R ⁶ , -(CR ^7a R ^7b ) _r N(R ^5c )C(=G)R ⁶ , -(CR ^7a R ^7b _r OC(=G)R ⁶ , -(CR ^7a R ^7b ) _r C(=G)OR ⁸ , -(CR ^7a R ^7b ) _r N(R ^5c )C(=G)OR ⁸ ,-(CR ^7a R ^7b ) _r OC(=G)OR ⁸ , -(CR ^7a R ^7b ) _r C(=G)NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c )C(=G)NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c )=C(R ⁷ )NR ^5a R ^5b , -(CR ^7a R ^7b ) _r S(=O)R ⁶ , -(CR ^7a R ^7b _r N(R ^5c )S(=O)R ⁶ , -(CR ^7a R ^7b ) _r S(=O)OR ⁸ , -(CR ^7a R ^7b ) _r N(R ^5c )S(=O)OR ⁸ , -(CR ^7a R ^7b ) _r S(=O)NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c )S(=O)NR ^5a R ^5b , -(CR ^7a R ^7b ) _{_{r S (= O) 2 R}} 6, - (CR 7a R 7b) r OS (= O) 2 R 6, - (CR 7a R 7b) r N (R 5c) S ( _{^{O) 2 R 6, - (}} CR 7a R 7b) r S (= O) 2 OR 8, - (CR 7a R 7b) r N (R 5c) S (= O) 2 OR 8, - (CR 7a R ^7b ) _r S(=O) ₂ NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c )S(=O) ₂ NR ^5a R ^5b , -(CR ^7a R ^7b ) _r -C _{3- 8} -cycloalkyl, -(CR ^7a R ^7b ) _r -C _6-10 aryl, -(CR ^7a R ^7b ) _r - (heterocyclic group of 3-8 atoms), -(CR ^7a R ^7b ) _r - (5-10 atomic heteroaryl) or D-mannosyl; wherein each G is independently O, S or NR ^5d ;

Each R ^{2 is} independently optionally substituted by 1, 2, 3 or 4 R ^2a ;

Wherein R ^2a , R ^5a , R ^5b , R ^5c , R ^5d , R ⁶ , R ⁷ , R ^7a , R ^7b , R ⁸ and r all have the meanings as described in the present invention.

In other embodiments, Ring B is of the following substructure:

Wherein each of Q ¹ , Q ⁶ and Q ^{9 is} independently CH ₂ , NH, O, S, C(=O), S(=O) or S(=O) ₂ ;

Each of Q ² , Q ³ , Q ⁴ , Q ⁵ , Q ⁷ and Q ^{8 is} independently CH or N;

s is 0, 1, 2 or 3;

Each R ^{2 is} independently H, hydrazine, F, Cl, Br, I, -(CR ^7a R ^7b ) _r CN, C _1-3 alkyl, deuterated C _1-3 alkyl, halogenated C _1-3 Alkyl, C _2-4 alkenyl, R ⁸ OC _2-6 alkenylene, R ⁸ OC(=O)-C _2-6 alkenylene, R ⁸ OC _2-6 alkynylene, R ⁸ OC ( =O)-C _2-6 alkynylene, -N=C=S, -(CR ^7a R ^7b ) _r OR ⁸ , -(CR ^7a R ^7b ) _r NR ^5a R ^5b , -(CR ^7a R ^7b ) _r C(=O)R ⁶ , -(CR ^7a R ^7b ) _r OC(=G)R ⁶ , -(CR ^7a R ^7b ) _r N(R ^5c )C(=O)R ⁶ ,-(CR ^7a R ^7b ) _r C(=O)OR ⁸ , -(CR ^7a R ^7b ) _r N(R ^5c )C(=O)OR ⁸ , -(CR ^7a R ^7b ) _r C(=O)NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c )C(=O)NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c )C(=S)NR ^5a R ^5b ,-(CR ^7a R ^7b ) _r N(R ^5c )C(=NR ^5d )NR ^5a R ^5b , -(CR ^7a R ^7b ) _r S(=O) ₂ R ⁶ , -(CR ^7a R ^7b ) _r OS(=O ₂ R ⁶ , -(CR ^7a R ^7b ) _r N(R ^5c )S(=O) ₂ R ⁶ , -(CR ^7a R ^7b ) _r S(=O) ₂ OR ⁸ , -(CR ^7a R ^7b _r N(R ^5c )S(=O) ₂ OR ⁸ , -(CR ^7a R ^7b ) _r S(=O) ₂ NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c )S( =O) ₂ NR ^5a R ^5b , -(CR ^7a R ^7b ) _r -C _3-6 cycloalkyl, -(CR ^7a R ^7b ) _r -C _{6- 10} aryl, -(CR ^7a R ^7b ) _r - (heterocyclic group of 3-6 atoms) or -(CR ^7a R ^7b ) _r - (heteroaryl group of 5-10 atoms); Each R ^{2 is} independently optionally substituted by 1, 2, 3 or 4 R ^2a ;

R ^2a , R ^5a , R ^5b , R ^5c , R ^5d , R ⁶ , R ⁷ , R ^7a , R ^7b , R ⁸ and r all have the meanings as described in the present invention.

In still other embodiments, Ring B is

Each R ^{2 is} independently H, 氘, F, Cl, Br, I, CN, -CH ₂ -CN, -CH ₂ CH ₂ -CN, methyl, ethyl, propyl, butyl, deuterated methyl , di-deuterated methyl, mono-deuterated methyl, trifluoromethyl, difluoromethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl Base, vinyl, propenyl, allyl, HO-vinyl, MeO-vinyl, HOC(=O)-vinyl, MeOC(=O)-vinyl, -N=C=S, -OH, -OMe, -O(i-Pr), -O(t-Bu), -CH ₂ -OH, -CH ₂ CH ₂ -OH, -CH ₂ -OMe, -CH ₂ CH ₂ -OMe, -CH ₂ -O(i-Pr), -CH ₂ -O(t-Bu), phenyl-O-, pyridyl-O-, pyrimidinyl-O-, pyrazinyl-O-, pyridazinyl-O- , pyrrolyl-O-, pyrazolyl-O-, thiazolyl-O-, oxazolyl-O-, oxadiazolyl-O-, imidazolyl-O-, thiadiazolyl-O-, - NH ₂ , -NHMe, -N(Me) ₂ , -CH ₂ -NH ₂ , -CH ₂ CH ₂ -NH ₂ , -CH ₂ -NHMe, -CH ₂ -N(Me) ₂ , phenyl-NH- , pyridyl-NH-, pyrimidinyl-NH-, pyrazinyl-NH-, pyridazinyl-NH-, pyrrolyl-NH-, pyrazolyl-NH-, thiazolyl-NH-, oxazolyl- NH-, oxadiazolyl-NH-, imidazolyl-NH-, thiadiazolyl-NH-, -C(=O)Me, -C( =O)Et, -CH ₂ -C(=O)Me, -CH ₂ -C(=O)Et, -NHC(=O)Me, -C(=O)OH, -C(=O)OMe , -NHC(=O)OMe, -NHC(=O)OH, -NHC(=O)OEt, -NHC(=O)O(t-Bu), -C(=O)NH ₂ , -C( =O)NHMe, -NHC(=O)NH ₂ , -NHC(=S)NH ₂ , -NHC(=NH)NH ₂ , -S(=O) ₂ Me, -NHS(=O) ₂ Me, -S(=O) ₂ OH, -S(=O) ₂ OMe, -NHS(=O) ₂ OH, -NHS(=O) ₂ OMe, -S(=O) ₂ NH ₂ , -NHS(= O) ₂ NH ₂ , cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, dioxolane, piperidinyl, piperazinyl, morpholinyl , tetrahydrofuranyl, tetrahydropyrrolyl, epoxypropyl, epoxybutyl, azetidinyl, dihydropyridyl, dihydropyranyl, phenyl, benzyl, pyridyl, pyrimidinyl, pyrazine , pyridazinyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, thiadiazolyl, triazolyl or tetrazolyl;

Wherein each R ^{2 is} independently optionally substituted by 1, 2, 3 or 4 R ^2a ; R ^2a has the meanings as described herein.

In some embodiments, each R ^{1 is} independently oxo (=O), H, hydrazine, F, Cl, Br, I, -CN, methyl, ethyl, propyl, butyl, trifluoromethyl , -OH, -OMe, -CH ₂ OMe, -CH ₂ OH, -NH ₂ , -NHMe, -N(Me) ₂ , -C(=O)Me, -C(=O)OH, -C( =O)OMe, -C(=O)NH ₂ , -S(=O) ₂ Me, -S(=O) ₂ OH, -S(=O) ₂ OMe, -S(=O) ₂ NH ₂ , cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclobutyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, Triazolyl, tetrazolyl, alkylene oxide, epoxybutyl, azetidinyl, tetrahydrofuranyl, piperidinyl, pyrrolidinyl, piperazinyl or morpholinyl; wherein each R ^{1 is} independently The ground is replaced by 1, 2, 3 or 4 R ^1a ;

Each R ^{4 is} independently H, hydrazine, F, Cl, Br, I, hydroxy, amino, methyl, ethyl, propyl, butyl, trifluoromethyl, difluoromethyl, 1,2-difluoro Ethyl, trifluoromethoxy, difluoromethoxy, -OMe, -OEt, -O(t-Bu), -CH ₂ OH, -CH ₂ CH ₂ OH, -CN, -CH ₂ CN, - CH ₂ NH ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ OMe, -CH ₂ CH ₂ OMe, -NHMe or -N(Me) ₂ ; alternatively, any two R ⁴ and the atoms to which they are attached form a C _3-6 cycloalkyl group or a heterocyclic group consisting of 3 to 6 atoms;

Each of R ⁹ , R ^1a , R ^2a and R ^{3a is} independently oxo (=O), hydrogen, hydrazine, F, Cl, Br, I, -(CR ^7a R ^7b ) _r CN, nitro, C _{1- 4-} alkyl, halo C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, R ⁸ OC _2-4 alkenylene, R ⁸ OC(=O)-C _2-4 Alkenyl, R ⁸ OC _2-4 alkynylene, R ⁸ OC(=O)-C _2-4 alkynylene, -(CR ^7a R ^7b ) _r -OR ⁸ , -(CR ^7a R ^7b ) _r - NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c )C(=O)R ⁶ , -(CR ^7a R ^7b ) _r OC(=O)R ⁶ , -(CR ^7a R ^7b ) _r COOH, -(CR ^7a R ^7b ) _r C(=O)OC _1-4 alkyl, -(CR ^7a R ^7b ) _r C(=O)C _1-4 alkyl, -(CR ^7a R ^7b ) _r S(=O) ₂ R ⁶ , -(CR ^7a R ^7b ) _r OS(=O) ₂ R ⁶ , -(CR ^7a R ^7b ) _r N(R ^5c )S(=O) ₂ R ⁶ ,-( CR ^7a R ^7b ) _r S(=O) ₂ OR ⁸ , -(CR ^7a R ^7b ) _r S(=O) ₂ NR ^5a R ^5b , -(CR ^7a R ^7b ) _r -C _3-6 cycloalkyl , -(CR ^7a R ^7b ) _r -C _6-10 aryl, -(CR ^7a R ^7b ) _r - (heterocyclic group of 3-6 atoms) or -(CR ^7a R ^7b ) _r -(5 a heteroaryl group of -6 atoms);

R ^5a , R ^5b , R ^5c , R ⁶ , R ^7a , R ^7b , R ⁸ , R ¹⁰ and r all have the meanings as described in the present invention.

In other embodiments, each R ^{1 is} independently oxo (=O), H, hydrazine, F, Cl, Br, I, cyano, methyl, ethyl, propyl, butyl, -OH, -OMe, -CH ₂ OMe, -CH ₂ OH, -NH ₂ , -NHMe, -N(Me) ₂ , -C(=O)Me, -C(=O)OH, -C(=O)OMe , -C(=O)NH ₂ , -S(=O) ₂ Me, -S(=O) ₂ OH, -S(=O) ₂ OMe or -S(=O) ₂ NH ₂ ; R ^{1 is} independently optionally substituted by 1, 2, 3 or 4 R ^1a ;

Each R ^{4 is} independently H, hydrazine, F, Cl, Br, I, hydroxy, amino, methyl, ethyl, propyl, butyl, vinyl, propenyl, allyl, deuterated methyl, three Fluoromethyl, difluoromethyl, 1,2-difluoroethyl, -OMe, -OEt, -CH ₂ OH, -CH ₂ CH ₂ OH, -CN, -CH ₂ CN, -CH ₂ NH ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ OMe, -CH ₂ CH ₂ OMe, -NHMe or -N(Me) ₂ ; alternatively, any two R ⁴ and the atoms to which they are attached form a cyclopropyl group, a ring Butyl, epoxyalkyl or azetidinyl;

Each of R ⁹ , R ^1a , R ^2a and R ^{3a is} independently oxo (=O), hydrogen, hydrazine, F, Cl, Br, I, -CN, methyl, ethyl, propyl, butyl, tri Fluoromethyl, difluoromethyl, 2,2-difluoroethyl, -CH ₂ CN, -CH ₂ CH ₂ CN, vinyl, propenyl, allyl, ethynyl, propynyl, -OH, -OMe, -O(i-Pr), -O(t-Bu), -CH ₂ -OH, -CH ₂ CH ₂ -OH, -CH ₂ -OMe, -CH ₂ CH ₂ -OMe, -CH ₂ -O(i-Pr), -CH ₂ -O(t-Bu), -NH ₂ , -NHMe, -N(Me) ₂ , -CH ₂ -NH ₂ , -CH ₂ CH ₂ -NH ₂ ,- CH ₂ -NHMe, -CH ₂ -N(Me) ₂ , -NHC(=O)Me, -CH ₂ COOH, -COOH, -C(=O)OMe, -CH ₂ C(=O)OMe, - C(=O)Me, -CH ₂ C(=O)Me, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, alkylene oxide, epoxybutyl, azetidinyl, pyrrolidine Base, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dihydropyranyl, phenyl, benzyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl , pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, triazolyl or tetrazolyl;

Alternatively, any two R ⁹ together with the atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, alkylene oxide, epoxybutyl, azetidinyl, tetrahydrofuranyl, pyrrole An alkyl group, a piperidinyl group or a piperazinyl group;

R ¹⁰ has the meanings as described in the present invention.

In some embodiments, wherein each R ⁵ , R ^5a , R ^5b , R ^{5c ,} and R ^{5d are,} independently, hydrogen, cyano, hydroxy, C _1-4 alkyl, C _1-4 alkoxy-C ( =O)-, C _6-10 aryl, C _3-6 cycloalkyl, heterocyclic group consisting of 3-6 atoms or heteroaryl group of 5-6 atoms;

Each of R ⁶ and R ^{8 is} independently hydrogen, deuterium, C _1-4 alkyl, deuterated C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, hydroxy substituted C _1-4 Alkyl, amino substituted C _1-4 alkyl, cyano substituted C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, halo C _1-4 alkyl, C _{6- a 10} aryl group, a C _3-6 cycloalkyl group, a heterocyclic group of 3 to 6 atoms or a heteroaryl group of 5 to 6 atoms;

Each of R ⁷ , R ^7a and R ^{7b is} independently hydrogen, C _1-4 alkyl, deuterated C _1-4 alkyl or halo C _1-4 alkyl;

Each R ^{10 is} independently oxo (=O), H, D, F, Cl, Br, I, CN, amino, hydroxy, nitro, carboxy, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, C _1-4 alkoxy C _1-4 alkyl, hydroxy substituted C _{1 -4} alkyl, cyano substituted C _1-4 alkyl, amino substituted C _1-4 alkyl, halo C _1-4 alkyl, C _1-4 alkyl acyl, C _1-4 alkyl sulfonate An acyl group, a C _1-4 alkoxy group, a C _1-4 alkylamino group, a phenyl group, a C _3-6 cycloalkyl group, a heterocyclic group consisting of 3 to 6 atoms or a heteroaryl group of 5 to 6 atoms base.

In other embodiments, each R ⁵ , R ^5a , R ^5b , R ^{5c ,} and R ^{5d are,} independently, hydrogen, cyano, hydroxy, methyl, ethyl, propyl, butyl, methoxy-C ( =O)-,ethoxy-C(=O)-, isopropoxy-C(=O)-, tert-butoxy-C(=O)-, phenyl, cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, epoxyalkyl, epoxybutyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, two Hydropyranyl, phenyl, benzyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thia A oxazolyl, triazolyl or tetrazolyl group;

Each of R ⁶ and R ^{8 is} independently hydrogen, deuterium, methyl, ethyl, propyl, butyl, deuterated methyl, vinyl, propynyl, hydroxymethyl, hydroxyethyl, methoxymethyl , methoxyethyl, ethoxymethyl, tert-butoxymethyl, tert-butoxyethyl, ethoxyethyl, isopropoxyethyl, trifluoromethyl, difluoromethyl, 1,2-difluoroethyl, 2,2-difluoroethyl, phenyl, cyclopropyl, cyclohexyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, pyridine , pyrrolyl, pyrimidinyl, pyrazolyl, pyrazinyl, furyl, thiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl or tetrazolyl;

Each of R ⁷ , R ^7a and R ^{7b is} independently hydrogen, methyl, ethyl, propyl, butyl, deuterated methyl, trifluoromethyl, difluoromethyl, 1,2-difluoroethyl or 2,2-difluoroethyl;

Each R ^{10 is} independently oxo (=O), H, D, F, Cl, Br, I, CN, amino, hydroxy, nitro, carboxy, methyl, ethyl, propyl, butyl, deuterated Methyl, methoxy, methylamino, dimethylamino, methoxymethyl, methoxyethyl, tert-butoxymethyl, tert-butoxyethyl, hydroxymethyl, hydroxyethyl, CN substituted Methyl, CN substituted ethyl, aminomethyl, aminoethyl, trifluoromethyl, difluoromethyl, 1,2-difluoroethyl or 2,2-difluoroethyl, methylacyl, Ethyl acyl, methylsulfonyl, methoxy acyl, tert-butoxy acyl, methylamino acyl, dimethylamino acyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, propylene oxide Base, epoxybutyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxadi Azolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl or pyrazinyl.

In one aspect, the invention relates to a pharmaceutical composition comprising a compound of any of the invention. In some embodiments, the pharmaceutical compositions of the present invention further comprise at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, and vehicle.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition for the manufacture of a medicament for the prevention, treatment or alleviation of a thromboembolic disorder.

In some embodiments, the use of the invention, wherein the thromboembolic disease is an arterial cardiovascular thromboembolic disease, a venous cardiovascular thromboembolic disease, and a thromboembolic disease in the ventricular or peripheral circulation.

In other embodiments, the use of the invention, wherein the thromboembolic disease is angina pectoris, acute coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral Occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and due to medical implants, instruments, or The blood in the procedure is exposed to the artificial surface to promote thrombosis caused by thrombosis.

In one aspect, the invention relates to the use of a compound or pharmaceutical composition for the manufacture of a medicament for the treatment of disseminated intravascular coagulation (DIC) disease.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition for the preparation of a medicament, wherein the medicament is for inhibiting the activity of Factor XIa and/or plasma kallikrein.

In one aspect, the compounds or pharmaceutical compositions of the invention are used to prevent, treat or ameliorate thromboembolic disorders.

In some embodiments, the compound or pharmaceutical composition of the present invention is for use in preventing, treating or ameliorating a thromboembolic disease, wherein the thromboembolic disease is an arterial cardiovascular thromboembolic disease, venous cardiovascular thromboembolism Sexual disease, and thromboembolic disease in the ventricular or peripheral circulation.

In other embodiments, the compounds or pharmaceutical compositions of the invention are used to prevent, treat or ameliorate a thromboembolic disease, wherein the thromboembolic disease is angina pectoris, acute coronary syndrome, atrial fibrillation, myocardium Infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism , renal embolism, pulmonary embolism, and thrombosis caused by exposure of blood in a medical implant, device, or procedure to an artificial surface to promote thrombosis.

In another aspect, the compounds or pharmaceutical compositions of the invention are useful for inhibiting the activity of Factor XIa and/or plasma kallikrein.

In one aspect, the invention also relates to a method of preventing, treating or ameliorating a thromboembolic disease using a compound or pharmaceutical composition of the invention.

In some embodiments, the method of the present invention, wherein the thromboembolic disease is an arterial cardiovascular thromboembolic disease, a venous cardiovascular thromboembolic disease, and a thromboembolic disease in the ventricular or peripheral circulation.

In still another embodiment, the method of the present invention, wherein the thromboembolic disease is angina pectoris, acute coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, Peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and medical implants, instruments Or blood in the procedure is exposed to an artificial surface to promote thrombosis caused by thrombosis.

In another aspect, the invention also relates to a method of inhibiting the activity of Factor XIa and/or plasma kallikrein using a compound or pharmaceutical composition of the invention.

The foregoing description merely summarizes certain aspects of the invention, but is not limited thereto. These and other aspects are described in more detail below.

Detailed specification

Definitions and general terms

Some embodiments of the invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and formulas. The invention is intended to cover all alternatives, modifications, and equivalents, which are within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the invention. The invention is in no way limited to the methods and materials described herein. Where one or more of the incorporated literature, patents, and similar materials are different or inconsistent with the present application (including but not limited to defined terms, terminology applications, described techniques, etc.), The application shall prevail.

It will be further appreciated that certain features of the invention are described in the various embodiments of the invention, and may be described in combination in a single embodiment. On the contrary, the various features of the invention are described in a single embodiment for the sake of brevity, but may be provided separately or in any suitable sub-combination.

Unless otherwise stated, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art. All patents and publications related to the present invention are hereby incorporated by reference in their entirety.

The following definitions used herein should be applied unless otherwise stated. For the purposes of the present invention, chemical elements are consistent with the CAS version of the Periodic Table of the Elements, and the Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, the general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007. , the entire contents of which is incorporated herein by reference.

The articles "a", "an" and "the" Therefore, the articles used herein are used to refer to the articles of one or more than one (ie, at least one). For example, "a component" refers to one or more components, i.e., more than one component may be considered for use or use in embodiments of the embodiments.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, for example, also refer to primates (eg, humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to a person (including adults and children) or other animal. In some embodiments, "patient" refers to a human.

The term "comprising" is an open-ended expression that includes the subject matter of the invention, but does not exclude other aspects.

"Stereoisomer" refers to a compound that has the same chemical structure but differs in the way the atoms or groups are spatially aligned. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotomers), geometric isomers (cis/trans) isomers, atropisomers, etc. .

"Chirality" is a molecule that has properties that cannot overlap with its mirror image; "non-chiral" refers to a molecule that can overlap with its mirror image.

"Enantiomer" refers to two isomers of a compound that are not superimposable but are mirror images of each other.

"Diastereomer" refers to a stereoisomer that has two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. The mixture of diastereomers can be separated by high resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.

The stereochemical definitions and rules used in the present invention generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry Of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

Many organic compounds exist in optically active forms, i.e., they have the ability to rotate a plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light caused by the compound, wherein (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as the (R)-, (S)- or (R, S)-configuration presence. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess in the (R)- or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

Depending on the choice of starting materials and methods, the compounds of the invention may be one of the possible isomers or mixtures thereof, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms) The form exists. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have a cis or trans configuration.

The resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography, depending on the difference in physicochemical properties of the components. Method and / or step crystallization.

The racemate of any of the resulting end products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art by known methods, for example, by obtaining the diastereomeric salts thereof. Separation. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 ^nd Ed. Robert) E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p. 268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that are interconvertible by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton transfer, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversions by recombination of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion of a pentane-2,4-dione and a 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridine-4(1H)-one tautomers. All tautomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.

The term "optional" or "optionally" means that the subsequently described event or circumstance may, but does not necessarily, occur, that is, the description includes instances in which the event or circumstance occurs and instances where it does not. For example, "optionally substituted by 1, 2, 3 or 4" includes the case where the group is substituted by 1, 2, or 3, or 4 of the substituents described, and The case where the group is not substituted by the substituent. Further, when the group is substituted by one or more of the substituents, the substituents are independent of each other, that is, the one or more substituents may be different from each other or may be the same. of.

As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the above formula, or specific examples, subclasses, and inclusions of the present invention. A class of compounds. It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" are used interchangeably. In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a particular substituent. Unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group. When more than one position in the given formula can be substituted by one or more substituents selected from a particular group, the substituents may be substituted at the various positions, either identically or differently. Here, the "one or more substituents" mean one or more substituents, and the number of specific substituents is determined by the number of positions at which the substituent group can be substituted. For example, the present invention is described in the "C ₄ alkylene group optionally substituted independently with one or more identical or different R ⁹ substituted" indicates that the group may be an alkylene or substituted with one or more R ^9, particularly Said alkylene group may be independently and optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R ⁹ ; when said alkylene group is more than one R ⁹ When substituted, the R ⁹ may be the same or different.

In the present invention, the substituent may be, but not limited to, hydrogen, hydrazine, oxo (=O), halogen, cyano, nitro, hydroxy, decyl, amino, arylamino, aminoalkyl, alkane. Base, alkylthio, hydroxyalkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -C(=O)R, -OR ^a , -COOR ^a , -SO ₂ R ^a , -NR ^b R ^c , -CONR ^b R ^c , -SO ₂ NR ^b R ^c , -C(NR ^b R ^c )=NR ^d or =NR ^d ; wherein R, R ^a , R ^b , R ^c and R ^{d is} independently hydrogen, cyano, amino, alkylamino, arylamino, alkylthio, alkoxy, aryloxy, hydroxy, decyl, alkyl, haloalkyl, carbocyclyl, heterocyclyl, Aryl, heteroaryl, alkylsulfonyl, aminosulfonyl, hydroxyalkyl, aminoalkyl, alkylacyl or aminoacyl. Wherein each alkylamino group, arylamino group, alkoxy group, aryloxy group, hydroxyl group, mercapto group, alkyl group, haloalkyl group, carbocyclic group, heterocyclic group, aryl group, heteroaryl group, alkyl group in the substituent Sulfonyl, aminosulfonyl, hydroxyalkyl, aminoalkyl, alkylacyl, aminoacyl and alkylthio have the meanings as described herein and may be further monosubstituted or identical by the substituents described herein Or different multiple substitutions.

In addition, it should be noted that the descriptions of the "individually" and "individually" and "independently" are interchangeable, unless otherwise explicitly indicated in the present invention. It should be understood in a broad sense, which can mean that the specific options expressed between the same symbols in different groups do not affect each other, and can also represent specific options expressed in the same group and between the same symbols. There is no influence between each other. For example, the description "each of R ⁹ , R ^1a , R ^2a and R ^{3a is} independently ..." means that R ⁹ , R ^1a , R ^2a and R ^3a are each independently independent of their specifically selected group. It does not affect each other. For example, "each R ⁹ , R ^1a , R ^2a and R ^{3a are} independently hydrogen, deuterium, nitro or C _1-6 alkyl" means that R ⁹ may be hydrogen, deuterium, nitro or C _1-6 alkyl, R ^1a may also be hydrogen, deuterium, nitro or C _1-6 alkyl. Similarly, R ^2a and R ^3a may also be hydrogen, deuterium, nitro or C _1-6 alkane. base.

In each part of the specification, the substituents of the compounds disclosed herein are disclosed in terms of the type or range of groups. In particular, the invention includes each individual sub-combination of each member of the group and range of such groups. For example, the term "C ₁ - _6-alkyl" refers particularly disclosed independently methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ and C ₆ alkyl group. "C _1-4 alkyl" specifically refers to independently disclosed methyl, ethyl, C ₃ alkyl (ie propyl, including n-propyl and isopropyl), C ₄ alkyl (ie butyl, including n-butyl) Base, isobutyl, sec-butyl and tert-butyl).

In various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable recited for that group is understood to be a linking group. For example, if the structure requires a linking group and the definition of the Markush group for the variable is "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represent the attached An alkylene group or an arylene group. For example, the ring A in the structure of the formula (I) of the present invention may be a heteroaryl group, and the heteroaryl group herein represents an arylene group having two linking sites attached to the rest of the molecule, more specifically, for example And ring A is a quinolyl group, and the quinolyl group here represents a quinolinyl group. As another example, "C _1-6 alkoxy C _1-6 alkyl" C _1-6 alkyl represents a C _1-6 alkylene group, including but not limited to, methylene, ethylene and the like.

The term "alkyl" or "alkyl group" as used herein, denotes a saturated straight or branched chain monovalent hydrocarbon group containing from 1 to 20 carbon atoms, wherein the alkyl group may be any Optionally, it is substituted with one or more substituents described herein. Unless otherwise specified, an alkyl group contains from 1 to 20 carbon atoms. In some embodiments, the alkyl group contains from 1 to 12 carbon atoms; in other embodiments, the alkyl group contains from 1 to 6 carbon atoms; in still other embodiments, the alkyl group contains 1 - 4 carbon atoms; in other embodiments, the alkyl group contains 1-3 carbon atoms. The term "C ₁ - ₆ alkyl" denotes an alkyl group containing 1 to 6 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH ₂ CH) (CH ₃ ) ₂ ), sec-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu, -C(CH ₃ ) ₃ ), n-pentyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl -2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1- Butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), n-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) _2), 2-methyl-3-pentyl _{_{(-CH (CH 2 CH 3)}} CH (CH 3) 2), 2,3- dimethyl 2-butyl _{_{(-C (CH 3) 2 CH}} (CH 3) 2), 3,3- dimethyl-2-butyl _{(-CH (CH 3) C (} CH 3) 3), n-heptyl Base, just octyl, and so on.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing from 2 to 12 carbon atoms, wherein there is at least one carbon-carbon sp ² double bond, wherein the alkenyl group may be optionally one or Substituted by a plurality of substituents described herein, which include the positioning of "cis" and "tans", or the positioning of "E" and "Z". In some embodiments, the alkenyl group contains 2-8 carbon atoms; in other embodiments, the alkenyl group contains 2-6 carbon atoms; in still other embodiments, the alkenyl group comprises 2 - 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH ₂ ), allyl (-CH ₂ CH=CH ₂ ), allyl (-CH=CHCH ₃ ), and the like.

The term "alkynyl" means a straight or branched chain monovalent hydrocarbon radical containing from 2 to 12 carbon atoms, wherein at least one carbon-carbon sp triple bond, wherein the alkynyl group may be optionally one or more Substituted by the substituents described in the present invention. In some embodiments, the alkynyl group contains 2-8 carbon atoms; in other embodiments, the alkynyl group contains 2-6 carbon atoms; in still other embodiments, the alkynyl group comprises 2 - 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.

The term "alkylene" means a saturated divalent hydrocarbon group derived by removing two hydrogen atoms from a saturated linear or branched hydrocarbon group. Unless otherwise specified, an alkylene group contains from 1 to 12 carbon atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms; in other embodiments, the alkylene group contains 1-4 carbon atoms; in still other embodiments, the alkylene group The group contains 1-3 carbon atoms; in other embodiments, the alkylene group contains 1-2 carbon atoms. Such examples include methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), isopropylidene (-CH(CH ₃ )CH ₂ -), n-butylene (-CH _{2 )} CH ₂ CH ₂ CH ₂ -) and so on.

The term "alkenylene" means a divalent hydrocarbyl group derived by removing two hydrogen atoms from an alkenyl group. Unless otherwise specified, an alkenylene group contains from 1 to 12 carbon atoms. In some embodiments, the alkenylene group contains 1-6 carbon atoms; in other embodiments, the alkenylene group contains 1-4 carbon atoms; in still other embodiments, the alkenylene group The group contains 1-3 carbon atoms. Examples of such include propenylene, butenylene, and the like.

The term "alkoxy" denotes an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. In some embodiments, the alkoxy group contains from 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains from 1 to 4 carbon atoms; in still other embodiments, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy group can be optionally substituted with one or more substituents described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH ₃ ), ethoxy (EtO, -OCH ₂ CH ₃ ), 1-propoxy (n-PrO, n- Propyloxy, -OCH ₂ CH ₂ CH ₃ ), and the like.

The term "alkoxyalkyl" denotes an alkyl group substituted by one or more alkoxy groups, wherein alkyl and alkoxy have the meanings as described herein. The alkoxyalkyl group can be optionally substituted with one or more substituents described herein. In some embodiments, the alkoxyalkyl group is a C _1-4 alkoxy C _1-4 alkyl group; in other embodiments, the alkoxyalkyl group is a C _1-2 alkoxy group C _1-3 Alkyl; In still other embodiments, the alkoxyalkyl group is a _C1-3 alkoxy _C1-3 alkyl group. Such examples include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl, tert-butoxymethyl, tert-butoxyethyl, and the like.

The term "alkanoyl", "alkyl acyl" or "alkylformyl" denotes an alkyl group attached to the remainder of the molecule via a carbonyl group (-C(=O)-), wherein the alkyl group has the invention The meaning of the meaning. The alkanoyl group can be optionally substituted with one or more substituents described herein. Examples of alkanoyl groups include, but are not limited to, acetyl (-C(=O)CH ₃ ), propionyl (-C(=O)CH ₂ CH ₃ ), butyryl (-C(=O) CH ₂ CH ₂ CH ₃ ) and so on.

The term "alkoxy group", "alkylamino group", "amino group" represents an alkoxy group, an alkylamino group or an amino group (-NH ₂₎ group by a carbonyl group (-C (= O) -) is connected to the rest of the molecule Wherein the alkoxy and alkylamino groups have the meanings as described herein. The alkoxyacyl, alkanoyl, or aminoacyl group may be optionally substituted with one or more substituents described herein. Examples of alkoxyacyl and alkanoyl groups include, but are not limited to, methoxyacyl (-C(=O)OCH ₃ ), ethoxyacyl (-C(=O)OCH ₂ CH ₃ ), A Aminoacyl (-C(=O)NHCH ₃ ), dimethylaminoacyl (-C(=O)N(CH ₃ ) ₂ ), and the like.

The term "alkyl sulfonyl", "alkoxy sulfonyl group,""alkylaminosulfonylgroup","aminosulfonyl" denotes an alkyl group, an alkoxy group, an alkylamino group or an amino group (-NH ₂₎ group bonded through a sulfonyl group (-SO ₂ -) is attached to the remainder of the molecule wherein the alkyl, alkoxy, alkylamino group has the meaning as described herein. The alkylsulfonyl, alkoxysulfonyl, alkylaminosulfonyl, aminosulfonyl group may be optionally substituted with one or more substituents described herein. Examples of alkylsulfonyl groups include, but are not limited to, methylsulfonyl (-SO ₂ CH ₃ ), ethylsulfonyl (-SO ₂ CH ₂ CH ₃ ), and the like.

The term "haloalkyl", "haloalkenyl" or "haloalkoxy" denotes an alkyl, alkenyl or alkoxy group substituted by one or more halogen atoms, examples of which include, but are not limited to, Trifluoromethyl, difluoromethyl 2,2-difluoroethyl, trifluoromethoxy, and the like.

The term "haloalkyl" or "deuterated alkoxy" denotes an alkyl or alkoxy group substituted by one or more deuterium atoms, examples of which include, but are not limited to, deuterated methyl (- CD ₃ ), deuterated methoxy (-OCD ₃ ), and the like.

The term "carbocyclic" or "carbocyclyl" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring carbon atoms. In some embodiments, the carbocycle comprises from 3 to 10 ring carbon atoms; in other embodiments, the carbocycle comprises from 3 to 8 ring carbon atoms; in still other embodiments, the carbocycle comprises from 3 to 6 rings. Carbon atom; in some embodiments, the carbocycle comprises from 7 to 12 ring carbon atoms; in other embodiments, the carbocycle comprises from 5 to 8 ring carbon atoms. Examples of carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl , cyclooctyl, cyclodecyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. Wherein the carbocyclic group may be optionally substituted by one or more substituents described herein.

The term "cycloalkyl" refers to a monovalent or polyvalent, non-aromatic, saturated monocyclic, bicyclic or tricyclic system containing from 3 to 12 ring carbon atoms. In some embodiments, the cycloalkyl group contains 3-10 ring carbon atoms; in other embodiments, the cycloalkyl group contains 3-8 ring carbon atoms; in still other embodiments, the cycloalkyl group comprises 3- 6 ring carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group can be optionally substituted with one or more substituents described herein.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein to refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring atoms, wherein at least one ring atom is selected. From nitrogen, sulfur and oxygen atoms, and any one of the heterocyclic ring systems is non-aromatic. Unless otherwise stated, a heterocyclic group can be a carbon or a nitrogen group, and a -CH ₂ - group can be optionally substituted with -C(=O)-. The sulfur atom of the ring can be optionally oxidized to an S-oxide. The nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound. In some embodiments, the heterocyclic group is a heterocyclic group consisting of 5 to 12 atoms; in other embodiments, the heterocyclic group is a heterocyclic group of 5 to 8 atoms; in still other embodiments, The heterocyclic group is a heterocyclic group consisting of 5 to 7 atoms; and in some embodiments, the heterocyclic group is a heterocyclic group of 5 to 6 atoms. The heterocyclic group may also be a bicyclic heterocyclic group; in some embodiments, the heterocyclic group is a bicyclic heterocyclic group consisting of 7 to 12 atoms; in other embodiments, the heterocyclic group is composed of 7 to 10 atoms. Bicyclic heterocyclic groups; In still other embodiments, the heterocyclic group is a bicyclic heterocyclic group consisting of 8-10 atoms.

Examples of heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, dihydrothienyl, 1,3-dioxo Pentyl, dithiocyclopentyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,2-dihydropyridyl, morpholinyl, thiomorpholinyl, hexahydropyrimidinyl, 1 , 6-dihydropyrimidinyl, 1,2-dihydropyrimidinyl, 1,2-dihydropyrazinyl, 1,3-oxazinyl, piperazinyl, oxazolidinyl, dioxoalkyl, Dithiaalkyl, thiamethane, homopiperazinyl, homopiperidinyl, oxetanyl, thiecycloheptyl, porphyrin, 1,2,3,4-tetrahydroiso Quinolinyl, 1,3-benzodioxanyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. Examples of the -CH ₂ - group in the heterocyclic group substituted by -C(=O)- include, but are not limited to, 2-oxopyrrolidin-1-yl, oxo-1,3-thiazolidinyl, 2 -oxooxazolidin-3-yl, 2-oxopiperidin-1-yl, 3-oxomorpholinyl, 2-oxopiperazine-1-yl, 2-oxopyridine-1 (2H ,-,3,5-dioxopiperidinyl, 6-oxopyrimidine-1(6H)-yl, 2-oxopyrimidine-1(2H)-yl, 2-oxotetrahydropyrimidine-1 (2H)-yl, 2-oxopyrazine-2(1H)-yl and pyrimidindione. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, a sulfolane group, a 1,1-dioxothiomorpholinyl group, and a 1,1-dioxo-1,2-thiomorpholinyl group. The heterocyclyl group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, fluorine, chlorine, bromine, oxo (=O), cyano, nitro, carboxyl, hydroxyl, Amino, aminomethyl, aminoacyl, methylamino, phenylamino, hydroxymethyl, methylsulfonyl, aminosulfonyl, acetyl, methoxy, phenoxy, trifluoromethoxy, methyl, ethyl , propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolyl, imidazolyl, imidazolinyl, piperidinyl , piperazinyl, morpholinyl, thienyl, thiazolyl, furyl, pyrrolyl, phenyl, pyridyl, pyrimidinyl, -C(=NH)NH ₂ or trifluoromethyl, and the like.

In some embodiments, a heterocyclic group is a heterocyclic group consisting of 5-6 atoms, and refers to a saturated or partially unsaturated monocyclic ring containing 5 or 6 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen and sulfur. And oxygen atoms. Examples of the heterocyclic group of 5-6 atoms include, but are not limited to, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuran. Base, tetrahydrothiophenyl, oxazolidinyl, piperidinyl, 1,2-dihydropyridyl, morpholinyl, thiomorpholinyl, hexahydropyrimidinyl, 1,6-dihydropyrimidinyl, 1 , 2-dihydropyrimidinyl, 1,2-dihydropyrazinyl, 1,3-oxazinyl, piperazinyl, 1,2,3,6-tetrahydropyridyl, 1,2,3, 4-tetrahydropyridyl, 1,2,3,4-tetrahydropyrimidinyl, 2,5-dihydro-1H-pyrrolyl and the like. The -CH ₂ - group in the heterocyclic group of 5-6 atoms may be substituted by -C(=O)-, or the sulfur atom therein may be oxidized to S-oxide. Also, the heterocyclic group consisting of 5-6 atoms may be optionally substituted by one or more substituents described in the present invention.

The term "unsaturated" as used in the present invention means that the group contains one or more unsaturations.

The term "heteroatom" refers to O, S, N, P, and Si, including any form of oxidation states of N, S, and P; forms of primary, secondary, tertiary, and quaternary ammonium salts; or nitrogen atoms in heterocycles. a form in which hydrogen is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like in N-substituted pyrrolidinyl) NR).

The term "halogen" means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "aryl" denotes monocyclic, bicyclic and tricyclic hydrocarbyl groups containing from 6 to 14 ring atoms, or from 6 to 12 ring atoms, or from 8 to 12 ring atoms, or from 6 to 10 ring atoms, Wherein at least one ring is aromatic and one or more attachment points in the aromatic system are attached to the remainder of the molecule. The term "aryl" can be used interchangeably with the terms "aromatic ring" or "aromatic ring". The aryl group includes an aromatic ring and an aromatic ring, or a ring system in which an aromatic ring is fused with a non-aromatic carbocyclic ring. Examples of the aryl group may include phenyl, naphthyl, anthracenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, bicyclo[4,2,0 ] 辛-1(6), 2,4-trienyl. The aryl group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, fluorine, chlorine, bromine, oxo (=O), cyano, nitro, carboxyl, hydroxy, amino, Aminomethyl, aminoacyl, methylamino, phenylamino, hydroxymethyl, methylsulfonyl, aminosulfonyl, acetyl, methoxy, phenoxy, trifluoromethoxy, methyl, ethyl, propyl Base, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolyl, imidazolyl, imidazolinyl, piperidinyl, piperidine Azinyl, morpholinyl, thienyl, thiazolyl, furyl, pyrrolyl, phenyl, pyridyl, pyrimidinyl, -C(=NH)NH ₂ or trifluoromethyl, and the like.

The term "heteroaryl" denotes a monocyclic, bicyclic, and tricyclic ring system having 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring is aromatic, and At least one ring contains one or more heteroatoms wherein one or more attachment points in the heteroaryl system are attached to the remainder of the molecule. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring" or "heteroaromatic compound". The heteroaryl group includes a heteroaryl ring and an aromatic ring, a heteroaryl ring and a heteroaryl ring, or a ring system in which a heteroaryl ring is fused with a non-aromatic carbocyclic or heterocyclic ring. In some embodiments, a heteroaryl group of 5-10 atoms comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In some embodiments, the heteroaryl is a heteroaryl group of 7 to 12 atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N; The heteroaryl group may be a single ring system or a bicyclic system containing two rings. In other embodiments, the heteroaryl is a heteroaryl group of 7-10 atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N; 7-10 atoms The heteroaryl group may be a single ring system or a bicyclic system containing two rings. The heteroaryl group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, fluorine, chlorine, bromine, oxo (=O), cyano, nitro, carboxyl, hydroxy, amino , aminomethyl, aminoacyl, methylamino, phenylamino, hydroxymethyl, methylsulfonyl, aminosulfonyl, acetyl, methoxy, phenoxy, trifluoromethoxy, methyl, ethyl, Propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolyl, imidazolyl, imidazolinyl, piperidinyl, Piperazinyl, morpholinyl, thienyl, thiazolyl, furyl, pyrrolyl, phenyl, pyridyl, pyrimidinyl, fluorenyl (-NHC(=NH)NH ₂ ), -N=C=S, - C(=NH)NH ₂ or a trifluoromethyl group or the like.

Examples of heteroaryl groups include, but are not limited to, furyl, imidazolyl (eg, 1H-imidazol-1-yl), isoxazolyl, oxazolyl, pyrrolyl, 1,3,4-oxo Azyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (eg 3-pyridazinyl), thiazolyl, 2- Thienyl, 3-thienyl, pyrazolyl (eg 2-pyrazolyl, 1H-pyrazol-1-yl), pyrazinyl, 1,3,5-triazinyl, triazolyl, tetrazolyl Etc.; also includes the following bicyclic rings, but is by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, fluorenyl (eg 2-indenyl), iso Porphyrin group, carbazolyl (such as 1H-carbazol-1-yl, etc.), quinolinyl (such as 2-quinolyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl ( Such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 3,4-dihydro-2H-pyrano[ 3,2-b]pyridyl, 2,3-dihydro-[1,4]dioxine[2,3-b]pyridyl, 2,3-dihydrobenzo[b][1,4 Dioxinyl, 6,7-dihydro-5H-cyclopenta[3,2-b]pyridyl, 2,3-dihydrofuran[3,2-b]pyridine, quinolinone, two Quinolinone-yl, and the like.

The term "i atoms", where i is an integer, typically describes the number of ring atoms in the molecule in which the number of ring atoms is i. For example, a piperidinyl group is a heterocyclic alkyl group composed of 6 atoms, and a quinolyl group or a 5,6,7,8-tetrahydroquinolyl group is a heteroaryl group composed of 10 atoms.

The terms "bicyclic carbocyclyl", "bicyclic aryl", "bicyclic heteroaryl", "bicyclic heterocyclyl" denote carbocyclyl, aryl, heteroaryl and heterocyclyl consisting of two rings, The carbocyclic, aryl, heteroaryl and heterocyclic groups described have the meanings as described herein. Among them, the bicyclic carbocyclic group and the bicyclic heterocyclic group include a fused ring, a spiro ring and a bridged ring composed of two rings. In some embodiments, the bicyclic aryl, bicyclic heteroaryl is a ring system in which an aromatic ring (aryl or heteroaryl) and a non-aromatic ring (carbocyclic or heterocyclic) are fused, wherein The non-aromatic ring may be saturated or unsaturated, for example, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, 5,6,7,8 -tetrahydroquinolinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, 2,3-dihydro-[1,4]dioxin[2,3- b] pyridyl, 2,3-dihydrobenzo[b][1,4]dioxin, 6,7-dihydro-5H-cyclopenta[3,2-b]pyridinyl, 2, 3-dihydrofuran [3,2-b]pyridine, etc.; in other embodiments, the bicyclic aryl or bicyclic heteroaryl is a ring of two aromatic rings (aryl or heteroaryl) fused. The system is, for example, a naphthyl group, a quinolyl group, an oxazolyl group or the like. Further examples of bicyclic aryl or bicyclic heteroaryl groups can be found in the foregoing examples of aryl and heteroaryl definitions.

The term "carboxy", whether used alone or in conjunction with other terms, such as "carboxyalkyl", means -CO ₂ H; the term "carbonyl", whether used alone or in conjunction with other terms, such as "aminoacyl" or "Acyloxy" means -(C=O)-.

The term "acyloxy", whether used alone or in conjunction with other terms, such as "alkyl acyloxy", means -(C=O)O-; the term "alkyl acyloxy" means alkyl through an acyloxy group. The group (-(C=O)O-) is attached to the rest of the molecule, wherein the alkyl group has the meaning as described herein. The alkyl acyloxy group can be optionally substituted with one or more substituents described herein.

The term "alkylamino", "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino groups are each independently substituted with one or two alkyl groups. The alkyl group having a suitable meaning as described in the present invention may be a monoalkylamino group or a dialkylamino group, and examples thereof include, but are not limited to, N-methylamino group, N- Ethylamino, N,N-dimethylamino, N,N-diethylamino and the like.

The term "amino-substituted alkyl" includes C _1-10 straight or branched alkyl groups substituted with one or more amino groups. In some embodiments, the aminoalkyl group is a _C1-6 "lower aminoalkyl group" substituted with one or more amino groups, examples of which include, but are not limited to, aminomethyl, ammonia Ethyl, aminopropyl, aminobutyl and aminohexyl groups.

The term "hydroxy substituted alkyl" includes C _1-10 straight or branched alkyl groups substituted with one or more hydroxy groups. In some embodiments, the hydroxyalkyl group is a C _1-6 "lower hydroxyalkyl group" substituted with one or more hydroxy groups, examples of which include, but are not limited to, hydroxymethyl, hydroxy Ethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl, and the like.

The term "cyano-substituted alkyl" includes _C1-10 straight or branched alkyl groups substituted by one or more cyano groups. In some embodiments, the hydroxyalkyl group is a C _1-6 "lower cyanoalkyl group" substituted with one or more cyano groups, examples of which include, but are not limited to, cyano Base, cyanoethyl and the like.

As described in the present invention, the ring system formed by the substituent (R ^e ) _n1 bonded to the central ring by a bond represents that n1 substituents R ^e may be substituted at any substitutable position on the ring, wherein n1 is at most The sum of the number of sites on the ring that can be replaced. For example, when ring A ^{a in} formula a is ^a quinoline ring (as shown in formula a1), any position on the A ¹ ring or B ¹ ring that may be substituted may be substituted by n1 R ^e , where n1 may It is 1, 2, 3, 4, 5, 6, or 7; wherein, when n1 is greater than 1, each of the R ^e may be the same or different.

As described in the present invention, the system in which the substituent (R ⁹ ) _g is bonded to the macrocycle by a bond represents that the substituents R ⁹ may be substituted at any substitutable position on the alkylene group. For example, R ⁹ in formula d can be a butylene group in the ring

Substituting at any position that can be substituted, including but not limited to the case shown by formula d1; wherein g, R ⁹ , A, B, R ¹ , R ² , R ⁵ , m and n in formula d, d1 have The meaning of the invention.

As described herein, the attachment point can be attached to the remainder of the molecule at any attachable position on the ring. For example, when ring A ^a in formula b is ^a quinoline ring (as shown in formula b1), any position on the A ² ring or B ² ring that may be attached may serve as a point of attachment.

As described herein, when a group is attached to the remainder of the molecule through two attachment sites, the remainder of the molecule attached to the linkage is interchangeable. For example, when the A ^a ring in formula c is a quinoline ring represented by formula c1, the quinoline ring may be attached to the remainder of the molecule through the E ¹ and E ² ends, and the E ¹ and E ² ends are linked. The moieties can be interchanged; for example, the -C(=O)NH- group in formula c4 is linked to the rest of the molecule through the E ³ and E ⁴ ends, and the portions to which the E ³ and E ⁴ ends are interchangeable . More specific example is that, when in the formula c1 quinoline ring and ring B ^a is connected to the quinoline ring by E E ² is connected to the end or ring B ^{^a. 1} (c2 and c3 shown in the formula) .

The term "protecting group" or "PG" refers to a class of substituents which, when reacted with other functional groups, are generally used to block or protect the particular functionality of the functional group. For example, "protecting group of an amino group" refers to a substituent attached to an amino group to block or protect the functionality of an amino group in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl. (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent used to block or protect a hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "Carboxy protecting group" means a substituent of a carboxy group used to block or protect the functionality of a carboxy group. Typical carboxy protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilane Ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(diphenyl Phosphine) ethyl, nitroethyl, and the like. A general description of protecting groups can be found in the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

As used herein, the term "prodrug" means that a compound can be converted to a compound of the invention in vivo. Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug-like compound of the present invention may be an ester. In the prior invention, the ester may be used as a prodrug such as a phenyl ester, an aliphatic (C _1-24 ) ester, an acyloxymethyl ester, or a carbonate. , carbamates and amino acid esters. For example, a compound of the invention comprises a hydroxyl group, i.e., it can be acylated to give a compound in the form of a prodrug. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxy group on the parent. For a discussion of the completeness of prodrugs, refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

"Metabolic product" refers to a product obtained by metabolism of a specific compound or a salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and the activity can be characterized by experimental methods as described herein. Such a product may be obtained by administering a compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage and the like. Accordingly, the invention includes metabolites of a compound, including metabolites produced by intimate contact of a compound of the invention with a mammal for a period of time.

"Solvate" as used herein refers to an association of one or more solvent molecules with a compound of the invention. Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" means that the solvent molecule is an association formed by water.

"Room temperature" in the present invention means that the temperature is from 10 ° C to 40 ° C. In some embodiments, "room temperature" refers to a temperature of from 20 °C to 30 °C; in other embodiments, "room temperature" refers to 25 °C.

As used herein, "treating" any disease or condition, in some embodiments thereof, refers to ameliorating a disease or condition (i.e., slowing or preventing or alleviating the progression of a disease or at least one of its clinical symptoms). In other embodiments, "treating" refers to alleviating or ameliorating at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or condition from the body (eg, stabilizing a detectable symptom) or physiologically (eg, stabilizing the body's parameters) or both. In other embodiments, "treating" refers to preventing or delaying the onset, onset, or exacerbation of a disease or condition.

The "thromboembolic disease" as used in the present invention refers to a disease caused by two pathological processes of thrombosis and thromboembolism, which is also called a thrombotic disease. Thrombosis refers to a pathological process in which blood forms a part of an embolus in the blood vessel or in the inner membrane of the heart under certain conditions, causing partial or complete occlusion of the blood vessel and a blood supply disorder at the corresponding site. Thromboembolism is a pathological process in which blood clots fall off from the site of formation and partially or completely block blood vessels during blood flow, causing ischemia or ischemia, hypoxia, necrosis, congestion and edema. Examples of thromboembolic diseases include, but are not limited to, arterial cardiovascular thromboembolic disease, venous cardiovascular thromboembolic disease, and thromboembolic disease in the chamber of the heart. More specific examples of such diseases include, but are not limited to, myocardial infarction, angina pectoris (including unstable colic), acute coronary syndrome, reocclusion, and angioplasty or restenosis after aortic coronary venous shunt , stroke, transient ischemic attack, peripheral arterial occlusive disease, arterial thrombosis, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, thrombophlebitis, venous thrombosis or deep vein thrombosis Form, and so on.

As used herein, "diffuse intravascular coagulation (DIC)" refers to activation of the coagulation system that occurs on a variety of diseases, resulting in extensive microthrombus formation in small blood vessels, consuming large amounts of clotting factors and secondary fibrinolysis, and further Clinical syndrome that causes systemic bleeding and microcirculatory failure. The formation of extensive microthrombus leads to multiple organ failure, activates the fibrinolytic system and depletes the clotting factor, which in turn elicits blood. Therefore, disseminated intravascular coagulation is a syndrome of coagulation and hemorrhage. At present, the main treatment method is anticoagulation, replacement, anti-platelet aggregation and symptomatic supportive treatment based on active control of the primary disease. Thus, the disclosed compounds can be used to treat disseminated intravascular coagulation.

The "pharmaceutically acceptable salts" of the present invention, i.e., the pharmaceutically acceptable salts, can be synthesized from the parent compound, basic or acidic moiety by conventional chemical methods. In general, such salts can be obtained by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base such as a hydroxide, carbonate, bicarbonate, or the like of Na, Ca, Mg or K. The free base form of these compounds is prepared by reaction with a stoichiometric amount of a suitable acid. This type of reaction is usually carried out in water or an organic solvent or a mixture of the two. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. For example, "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and A list of additional suitable salts can be found in Use), Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

The pharmaceutically acceptable salt may be a pharmaceutically acceptable acid addition salt which may be formed by the action of a compound of the invention with an inorganic acid and/or an organic acid, for example, with a mineral acid such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid or sulfuric acid. Salt formed; and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, malonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, stearic acid a salt formed of acid, succinic acid, sulfosalicylic acid, lactic acid, benzoic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid or naphthalene disulfonic acid.

The pharmaceutically acceptable salt can be a pharmaceutically acceptable base addition salt formed by the action of a compound of the invention with an inorganic base and/or an organic base. Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of Groups I to XII of the Periodic Table. In certain embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include the ammonium, potassium, sodium, calcium, and magnesium salts. Organic bases from which salts can be derived include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins and the like. Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine. .

Further, the compounds disclosed in the present invention, including their salts, may also exist in the form of their hydrates or in the form of their solvents (e.g., ethanol, DMSO, etc.), and may be used for crystallization. The compounds disclosed herein may form solvates either intrinsically or by design with pharmaceutically acceptable solvents, including water; thus, the compounds of the invention include both solvated and unsolvated forms.

Any structural formula given by the present invention is also intended to indicate that these compounds are not isotopically enriched and isotopically enriched. Isotopically enriched compounds have the structure depicted by the general formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O , ¹⁸ O, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I.

In another aspect, the compounds of the invention include isotopically enriched compounds of the invention, for example, those in which a radioisotope such as ³ H, ¹⁴ C and ¹⁸ F is present, or in which a non-radioactive isotope is present, such as ² H and ¹³ C. Such isotopically enriched compounds can be used for metabolic studies (using ¹⁴ C), reaction kinetic studies (using, for example, ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or including drugs or Single photon emission computed tomography (SPECT) of substrate tissue distribution assays, or may be used in patient radiation therapy. ¹⁸ F enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of the invention can be prepared by conventional techniques familiar to those skilled in the art or by the use of suitable isotopically labeled reagents in place of the previously used unlabeled reagents as described in the Examples and Preparations of the present invention.

In addition, substitution of heavier isotopes, particularly deuterium (i.e., ² H or D), may provide certain therapeutic advantages resulting from higher metabolic stability. For example, increased in vivo half-life or reduced dose requirements or improved therapeutic index. It will be understood that the indole in the present invention is considered to be a substituent of the compound of the present invention. Isotopic enrichment factors can be used to define the concentration of such heavier isotopes, particularly ruthenium. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotope abundance and the natural abundance of a given isotope. If a substituent of a compound of the invention is designated as hydrazine, the compound has at least 3500 for each of the specified hydrazine atoms (52.5% of ruthenium incorporation at each of the specified ruthenium atoms), at least 4,000 (60% of ruthenium incorporation), At least 4,500 (67.5% of cerium incorporation), at least 5,000 (75% of cerium incorporation), at least 5,500 (82.5% of cerium incorporation), at least 6,000 (90% of cerium incorporation), at least 6333.3 (95%) Iridium enrichment factor with at least 6466.7 (97% cerium incorporation), at least 6600 (99% cerium incorporation) or at least 6633.3 (99.5% cerium incorporation). The present invention can include pharmaceutically acceptable solvates wherein the solvent of crystallization may be isotopically substituted, for example D ₂ O, acetone -d _6, DMSO-d ₆ solvate of those.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. Additionally, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.

Description of the compounds of the invention

The inventors of the present application have extensively studied and synthesized a series of macrocyclic compounds, and first discovered the following through FXIa enzyme inhibition activity screening, plasma kallikrein inhibition activity screening, metabolic screening, anticoagulant activity experiments, and other experiments. The compound represented by the formula (I) has strong anti-FXIa activity and/or plasma kallikrein inhibitory activity, excellent drug metabolism properties and physicochemical properties, and is particularly suitable as an anticoagulant drug for treating thromboembolic diseases.

The present invention provides a macrocyclic compound represented by the formula (I), wherein the ring A is a bicyclic system, preferably, the ring A is a heterocyclic ring-containing fused bicyclic ring (including a fused bicyclic hetero ring and a fused bicyclic heteroaryl) Ring); At present, there is no related literature reported in this class of compounds, and the compounds involved in the ring A ring have good pharmacological activity data, and can effectively treat thromboembolic diseases.

The present invention relates to a compound which is a stereoisomer, a geometric isomer, a tautomer, an oxynitride, a hydrate, or a compound of the formula (I). a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug,

Wherein ring A, ring B, ring C, X, Y, R ¹ , R ² , R ³ , R ⁴ , n, m, p and t all have the meanings as described in the present invention.

In some embodiments, X is C _4-8 alkylene or C _4-8 alkenylene, wherein one or more carbon atoms of the alkylene and alkenylene are independently selected from - Substitution of O-, -S-, -C(=O)-, -S(=O)-, -S(=O) ₂ - or -N(R ⁵ )-; C _{4 in} X _{The -8} alkylene group and the C _4-8 alkenylene group are each independently optionally substituted by one or more of the same or different R ⁹ ; wherein R ⁵ and R ⁹ have the meanings as described in the present invention.

In some embodiments, X is C ₄ alkylene or C ₄ alkenylene, wherein one or more carbon atoms of the C ₄ alkylene and C ₄ alkenylene are independently selected from - Substitution of O-, -S-, -C(=O)-, -S(=O)-, -S(=O) ₂ - or -NH-; C ₄ alkylene in X and The C ₄ alkenylene group is independently optionally substituted by one or more of the same or different R ⁹ ; wherein R ⁹ has the meanings described in the present invention.

In other embodiments, X is n-n-butyl (-CH ₂ CH ₂ CH ₂ CH ₂ -) or butylene-2-alkenyl (-CH ₂ CH=CHCH ₂ -), wherein the sub-n-butyl One or more carbon atoms in the group and the butylene-2-alkenyl group are optionally independently selected from the group consisting of -O-, -S-, -C(=O)-, -S(=O)-, -S(= Substituting O) a group of _2- or -NH-; the n-butylene and butylene-2-alkenyl groups in X are each independently optionally substituted by one or more identical or different R ⁹ ; wherein R ⁹ It has the meaning of the description of the present invention.

In some embodiments, Y is -C (= O) N (R 5) - or ^{-N (R 5) C (=} O) -; wherein, R ⁵ and R ⁹ have the meaning of the present invention will be described.

In some embodiments, the compound of formula (I) of the present invention is a compound of formula (Ia) or a stereoisomer, geometric isomer, tautomer, oxynitride of a compound of formula (Ia). a hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,

Wherein ring A, ring B, ring C, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁹ , g, n, m, p and t all have the meanings as described in the present invention.

In some embodiments, Ring C is carbocyclyl, aryl, heterocyclyl or heteroaryl.

In some embodiments, Ring C is a C _3-12 carbocyclyl, a C _6-12 aryl, a heterocyclic group consisting of 3-12 atoms, or a heteroaryl group of 5-12 atoms.

In other embodiments, Ring C is a C _5-6 carbocyclic group, a C ₆ aryl group, a heterocyclic group consisting of 5-7 atoms, or a heteroaryl group consisting of 5-6 atoms.

In some embodiments, Ring C is of the following substructure:

Where ring C passes through the N atom and structure

Connected

each

with

Independently a single bond or a double bond;

when

or

when

or

When it is a double bond, each of Z, Z ¹ and Z ^{2 is} independently CH or N;

Z ⁴ is CH ₂ or NH;

Each Z ³ and Z ^{5 are} independently CH ₂ , NH, S or O;

q is 0, 1, or 2.

In other embodiments, the substructure

for

or

More specifically, the formula (C1) is

Wherein each of the above substructures C1, C1-a, C1-b, C1-c, C1-d, C1-e, C1-f or C1-g passes through an N atom and structure

Connected

with

Independently a single bond or a double bond; Z has the meanings described herein.

In some embodiments, ring C is

Where ring C passes through the N atom and structure

Connected.

In some embodiments, the compound of formula (I) according to the invention may be a stereoisomer, a geometric isomer, a tautomer of a compound of formula (II) or a compound of formula (II). Body, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

Among them, each

with

Independently a single bond or a double bond;

when

or

When it is a single bond, each Z and Z ^{1 are} independently CH ₂ or NH;

or

When it is a double bond, each Z and Z ^{1 are} independently CH or N;

Ring A, Ring B, X, Y, R ¹ , R ² , R ³ , R ⁴ , n, m, p and t all have the meanings as described herein.

In some embodiments, the compound of formula (I) according to the invention may be a compound of formula (IIa), or a stereoisomer, geometric isomer, tautomer of a compound of formula (IIa) a construct, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug,

Among them, each

with

Independently a single bond or a double bond;

when

or

When it is a single bond, each Z and Z ^{1 are} independently CH ₂ or NH;

or

When it is a double bond, each Z and Z ^{1 are} independently CH or N; ring A, ring B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁹ , g, n, m, p and t All have the meanings described in the present invention.

In some embodiments, each R ^{3 is} independently halo, C _1-6 alkyl, C _3-12 carbocyclyl, C _6-12 aryl, heterocyclyl consisting of 3-12 atoms, or 5-12 A heteroaryl group consisting of atoms; wherein each R ^{3 is} independently optionally substituted by 1, 2, 3, 4 or 5 identical or different R ^3a ; wherein R ^3a has the meanings as described herein.

In some embodiments, each R ^{3 is} independently C _1-4 alkyl, C _3-8 carbocyclyl, C _6-10 aryl, heterocyclyl consisting of 3-8 atoms, or 5-10 atoms. a heteroaryl group; wherein each R ^{3 is} independently optionally substituted by 1, 2, 3, 4 or 5 R ^3a ; R ^3a has the meanings as described herein.

In some embodiments, each R ^{3 is} independently

Wherein each of E ¹ , E ² and E ^{3 is} independently CH or N;

Each of E ⁴ and E ^{5 is} independently CH ₂ , O, S or NH;

Each e is independently 0, 1, 2 or 3;

Wherein each R ^{3 is} independently optionally substituted by 1, 2, 3, 4 or 5 R ^3a ; R ^3a has the meanings as described herein.

In some embodiments, each R ^{3 is} independently methyl, ethyl, F, Cl, Br, phenyl, pyrrolyl, pyrazolyl, imidazolyl, imidazolinyl, triazolyl, pyridyl, pyrimidinyl , mercapto, carbazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, quinolyl, isoquinolyl Or quinazolinyl;

In some embodiments, the compound of formula (I) according to the invention may be a stereoisomer, a geometric isomer, a tautomer of a compound of formula (IIIa) or a compound of formula (IIIa). Body, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

Among them, each

with

Independently a single bond or a double bond;

when

or

When it is a single bond, each Z and Z ^{1 are} independently CH ₂ or NH;

or

When it is a double bond, each Z and Z ^{1 are} independently CH or N; ring A, ring B, R ¹ , R ² , R ⁴ , R ⁵ , R ⁹ , R ^3a , E ¹ , E ² , E ³ , n, m, f, g, and t all have the meanings described herein.

In some embodiments, the compound of formula (I) according to the invention may be a stereoisomer, a geometric isomer, a tautomer of a compound of formula (IIIb) or a compound of formula (IIIb). Body, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

Among them, each

with

Independently a single bond or a double bond;

when

or

When it is a single bond, each Z and Z ^{1 are} independently CH ₂ or NH;

or

In some embodiments, the compound of formula (I) according to the invention may be a stereoisomer, a geometric isomer, a tautomer of a compound of formula (III) or a compound of formula (III). Body, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

Among them, each

with

Independently a single bond or a double bond;

when

or

When it is a single bond, each Z and Z ^{2 are} independently CH ₂ or NH;

or

When it is a double bond, each Z and Z ^{2 is} independently CH or N; ring A, ring B, R ¹ , R ² , R ⁴ , R ⁵ , R ⁹ , R ^3a , n, m, f, g and t All have the meanings described in the present invention.

In some embodiments, the compound of formula (I) according to the invention may be a compound of formula (IIIc), or a stereoisomer, geometric isomer, tautomer of a compound of formula (IIIc) a construct, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug,

Among them, each

with

Independently a single bond or a double bond;

when

or

When it is a single bond, each Z and Z ^{2 are} independently CH ₂ or NH;

or

In some embodiments, the substructure

for

among them,

Through N atoms and structures

Connected.

In some embodiments, the substructure

for

among them,

Through N atoms and structures

Connected.

In some embodiments, Ring A is a C _7-12 carbocyclyl, a C _8-12 aryl, a heterocyclic group consisting of 7-12 atoms, or a heteroaryl group of 7-12 atoms.

In some embodiments, Ring A is of the following substructure:

Each k and j are independently 0, 1, 2, 3 or 4.

In some embodiments, Ring A is

In some embodiments, Ring B is carbocyclyl, aryl, heterocyclyl or heteroaryl.

In some embodiments, Ring B is a C _5-8 carbocyclic group, a C _6-10 aryl group, a heterocyclic group consisting of 5-8 atoms, or a heteroaryl group consisting of 5-10 atoms.

In some embodiments, Ring B is of the following substructure:

s is 0, 1, 2 or 3.

In some embodiments, Ring B is

In some embodiments, each R ^{1 is} independently oxo (=O), H, hydrazine, halogen, -(CR ^7a R ^7b ) _r CN, C _1-6 alkyl, deuterated C _1-6 alkyl , halogenated C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -(CR ^7a R ^7b ) _r OR ⁸ , -(CR ^7a R ^7b ) _r NR ^5a R ^5b , -( CR ^7a R ^7b ) _r C(=O)R ⁶ , -(CR ^7a R ^7b ) _r C(=O)OR ⁸ , -(CR ^7a R ^7b ) _r C(=O)NR ^5a R ^5b ,-( CR ^7a R ^7b ) _r S(=O)R ⁶ , -(CR ^7a R ^7b ) _r S(=O)OR ⁸ , -(CR ^7a R ^7b ) _r S(=O)NR ^5a R ^5b ,-( CR ^7a R ^7b ) _r S(=O) ₂ R ⁶ , -(CR ^7a R ^7b ) _r S(=O) ₂ OR ⁸ , -(CR ^7a R ^7b ) _r S(=O) ₂ NR ^5a R ^5b , -(CR ^7a R ^7b ) _r -C _3-12 cycloalkyl, -(CR ^7a R ^7b ) _r -C _6-12 aryl, -(CR ^7a R ^7b ) _r -(3-12 atoms Heterocyclic group) or -(CR ^7a R ^7b ) _r -(heteroaryl group of 5-12 atoms);

Wherein each R ^{1 is} independently optionally substituted by 1, 2, 3 or 4 identical or different R ^1a ;

R ^1a , R ^5a , R ^5b , R ⁶ , R ^7a , R ^7b , R ⁸ and r all have the meanings as described in the present invention.

In other embodiments, each R ^{1 is} independently oxo (=O), H, hydrazine, halogen, -(CR ^7a R ^7b ) _r CN, C _1-3 alkyl, deuterated C _1-3 alkane , halo C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, -(CR ^7a R ^7b ) _r OR ⁸ , -(CR ^7a R ^7b ) _r NR ^5a R ^5b ,- (CR ^7a R ^7b ) _r C(=O)R ⁶ , -(CR ^7a R ^7b ) _r C(=O)OR ⁸ , -(CR ^7a R ^7b ) _r C(=O)NR ^5a R ^5b ,- (CR ^7a R ^7b ) _r S(=O) ₂ R ⁶ , -(CR ^7a R ^7b ) _r S(=O) ₂ OR ⁸ , -(CR ^7a R ^7b ) _r S(=O) ₂ NR ^5a R ^5b , -(CR ^7a R ^7b ) _r -C _3-6 cycloalkyl, -(CR ^7a R ^7b ) _r -C _6-10 aryl, -(CR ^7a R ^7b ) _r -(3-6 atoms a heterocyclic group consisting of or -(CR ^7a R ^7b ) _r -(heteroaryl group of 5-10 atoms);

In other embodiments, each R ^{1 is} independently oxo (=O), H, hydrazine, F, Cl, Br, I, -CN, -CH ₂ -CN, -CH ₂ CH ₂ -CN, A Base, ethyl, propyl, butyl, trifluoromethyl, -OH, -OMe, -CH ₂ OMe, -CH ₂ OH, -NH ₂ , -CH ₂ NH ₂ , -CH(NH ₂ ) ₂ , -NHMe, -N(Me) ₂ , -C(=O)Me, -C(=O)OH, -C(=O)OMe, -C(=O)NH ₂ , -S(=O) ₂ Me, -S(=O) ₂ OH, -S(=O) ₂ OMe, -S(=O) ₂ NH ₂ , cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclobutane Base, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, alkylene oxide, epoxybutyl, nitrogen heterocycle Butyl, tetrahydrofuranyl, piperidinyl, pyrrolidinyl, piperazinyl or morpholinyl; wherein each R ^{1 is} independently optionally substituted by 1, 2, 3 or 4 identical or different R ^1a ; ^1a has the meanings described in the present invention.

In some embodiments, each R ^{2 is} independently H, deuterium, halogen, -(CR ^7a R ^7b ) _r CN, C _1-6 alkyl, deuterated C _1-6 alkyl, halo C _1-6 Alkyl, C _2-6 alkenyl, C _2-6 alkynyl, R ⁸ OC _2-6 alkenylene, R ⁸ OC(=O)-C _2-6 alkenylene, R ⁸ OC _2-6 Alkynyl, R ⁸ OC(=O)-C _2-6 alkynylene, -N=C=S, -N=C=O, -(CR ^7a R ^7b ) _r OR ⁸ , -(CR ^7a R ^7b _r NR ^5a R ^5b , -(CR ^7a R ^7b ) _r C(=G)R ⁶ , -(CR ^7a R ^7b ) _r N(R ^5c )C(=G)R ⁶ , -(CR ^7a R ^7b _r OC(=G)R ⁶ , -(CR ^7a R ^7b ) _r C(=G)OR ⁸ , -(CR ^7a R ^7b ) _r N(R ^5c )C(=G)OR ⁸ ,-(CR ^7a R ^7b ) _r OC(=G)OR ⁸ , -(CR ^7a R ^7b ) _r C(=G)NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c )C(=G)NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c )=C(R ⁷ )NR ^5a R ^5b , -(CR ^7a R ^7b ) _r S(=O)R ⁶ , -(CR ^7a R ^7b _r N(R ^5c )S(=O)R ⁶ , -(CR ^7a R ^7b ) _r S(=O)OR ⁸ , -(CR ^7a R ^7b ) _r N(R ^5c )S(=O)OR ⁸ , -(CR ^7a R ^7b ) _r S(=O)NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c )S(=O)NR ^5a R ^5b , -(CR ^7a R ^7b ) _r S(=O) ₂ R ⁶ , -(CR ^7a R ^7b ) _r OS(=O) ₂ R ⁶ , -(CR ^7a R ^{7 b} ) _r N(R ^5c )S(=O) ₂ R ⁶ , -(CR ^7a R ^7b ) _r S(=O) ₂ OR ⁸ , -(CR ^7a R ^7b ) _r N(R ^5c )S(= O) ₂ OR ⁸ , -(CR ^7a R ^7b ) _r S(=O) ₂ NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c )S(=O) ₂ NR ^5a R ^5b ,- (CR ^7a R ^7b ) _r -C _3-12 cycloalkyl, -(CR ^7a R ^7b ) _r -C _6-12 aryl, -(CR ^7a R ^7b ) _r -(3-12 atomic hetero a cyclic group), -(CR ^7a R ^7b ) _r -(heteroaryl group of 5-12 atoms) or a D-mannosyl group; wherein each G is independently O, S or NR ^5d ;

Each R ^{2 is} independently optionally substituted by 1, 2, 3 or 4 identical or different R ^2a ;

In other embodiments, each R ^{2 is} independently H, hydrazine, F, Cl, Br, I, -(CR ^7a R ^7b ) _r CN, C _1-4 alkyl, deuterated C _1-4 alkyl , halogenated C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, R ⁸ OC _2-4 alkenylene, R ⁸ OC(=O)-C _2-4 alkenylene, R ⁸ OC _2-4 alkynylene, R ⁸ OC(=O)-C _2-4 alkynylene, -N=C=S, -N=C=O, -(CR ^7a R ^7b ) _r OR ⁸ , -(CR ^7a R ^7b ) _r NR ^5a R ^5b , -(CR ^7a R ^7b ) _r C(=G)R ⁶ , -(CR ^7a R ^7b ) _r N(R ^5c )C(=G)R ⁶ , -(CR ^7a R ^7b ) _r OC(=G)R ⁶ , -(CR ^7a R ^7b ) _r C(=G)OR ⁸ , -(CR ^7a R ^7b ) _r N(R ^5c )C(=G )OR ⁸ , -(CR ^7a R ^7b ) _r OC(=G)OR ⁸ , -(CR ^7a R ^7b ) _r C(=G)NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c C(=G)NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c )=C(R ⁷ )NR ^5a R ^5b , -(CR ^7a R ^7b ) _r S(=O)R ⁶ , -(CR ^7a R ^7b ) _r N(R ^5c )S(=O)R ⁶ , -(CR ^7a R ^7b ) _r S(=O)OR ⁸ , -(CR ^7a R ^7b ) _r N(R ^5c S(=O)OR ⁸ , -(CR ^7a R ^7b ) _r S(=O)NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c )S(=O)NR ^5a R ^5b , ^{^{_{- (CR 7a R 7b) r}}} S (= O) 2 R 6, - (CR 7a R 7b) r OS (= O) 2 R 6 ^{^{_{- (CR 7a R 7b) r}}} N (R 5c) S (= O) 2 R 6, - (CR 7a R 7b) r S (= O) 2 OR 8, - (CR 7a R 7b) r N (R ^5c )S(=O) ₂ OR ⁸ , -(CR ^7a R ^7b ) _r S(=O) ₂ NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c )S(=O) ₂ NR ^5a R ^5b , -(CR ^7a R ^7b ) _r -C _3-8 cycloalkyl, -(CR ^7a R ^7b ) _r -C _6-10 aryl, -(CR ^7a R ^7b ) _r -(3-8 a heterocyclic group consisting of one atom), -(CR ^7a R ^7b ) _r - (heteroaryl group of 5-10 atoms) or D-mannosyl group; wherein each G is independently O, S or NR ^5d ;

In still other embodiments, each R ^{2 is} independently H, hydrazine, F, Cl, Br, I, -(CR ^7a R ^7b ) _r CN, C _1-3 alkyl, deuterated C _1-3 alkyl , halogenated C _1-3 alkyl, C _2-4 alkenyl, R ⁸ OC _2-6 alkenylene, R ⁸ OC(=O)-C _2-6 alkenylene, R ⁸ OC _2-6 Alkynyl, R ⁸ OC(=O)-C _2-6 alkynylene, -N=C=S, -(CR ^7a R ^7b ) _r OR ⁸ , -(CR ^7a R ^7b ) _r NR ^5a R ^5b , -(CR ^7a R ^7b ) _r C(=O)R ⁶ , -(CR ^7a R ^7b ) _r OC(=G)R ⁶ , -(CR ^7a R ^7b ) _r N(R ^5c )C(=O) R ⁶ , -(CR ^7a R ^7b ) _r C(=O)OR ⁸ , -(CR ^7a R ^7b ) _r N(R ^5c )C(=O)OR ⁸ , -(CR ^7a R ^7b ) _r C( =O)NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c )C(=O)NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c )C(=S)NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c )C(=NR ^5d )NR ^5a R ^5b , -(CR ^7a R ^7b ) _r S(=O) ₂ R ⁶ , -(CR ^7a R ^7b ) _r OS(=O) ₂ R ⁶ , -(CR ^7a R ^7b ) _r N(R ^5c )S(=O) ₂ R ⁶ , -(CR ^7a R ^7b ) _r S(=O) ₂ OR ⁸ , -(CR ^7a R ^7b ) _r N(R ^5c )S(=O) ₂ OR ⁸ , -(CR ^7a R ^7b ) _r S(=O) ₂ NR ^5a R ^5b , -(CR ^7a R ^7b ) _r ^{N (R 5c) S (=} O) 2 NR 5a R 5b, - (CR 7a R 7b) r -C 3-6 cycloalkyl ^{^{Group, - (CR 7a R 7b)}} r -C 6-10 ^{^{aryl, - (CR 7a R 7b)}} r - ( heterocyclic group consisting of 3-6 atoms), or ^{^{_{- (CR 7a R 7b) r}}} - ( a heteroaryl group of 5-10 atoms; wherein each R ^{2 is} independently optionally substituted by 1, 2, 3 or 4 identical or different R ^2a ; R ^2a , R ^5a , R ^5b , R ^5c R ^5d , R ⁶ , R ^7a , R ^7b , R ⁸ and r all have the meanings as described in the present invention.

In some embodiments, each R ^{2 is} independently H, 氘, F, Cl, Br, I, CN, —CH ₂ —CN, —CH ₂ CH ₂ —CN, methyl, ethyl, propyl, butyl Base, deuterated methyl, dideuterated methyl, monodecylmethyl, trifluoromethyl, difluoromethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, 2,2 , 2-trifluoroethyl, vinyl, propenyl, allyl, HO-vinyl, MeO-vinyl, HOC(=O)-vinyl, MeOC(=O)-vinyl, -N=C =S, -OH, -OMe, -O(i-Pr), -O(t-Bu), -CH ₂ -OH, -CH ₂ CH ₂ -OH, -CH ₂ -OMe, -CH ₂ CH ₂ -OMe, -CH ₂ -O(i-Pr), -CH ₂ -O(t-Bu), phenyl-O-, pyridyl-O-, pyrimidinyl-O-, pyrazinyl-O-, Pyridazinyl-O-, pyrrolyl-O-, pyrazolyl-O-, thiazolyl-O-, oxazolyl-O-, oxadiazolyl-O-, imidazolyl-O-, thiadiazole -O-, -NH ₂ , -NHMe, -N(Me) ₂ , -CH ₂ -NH ₂ , -CH ₂ CH ₂ -NH ₂ , -CH ₂ -NHMe, -CH ₂ -N(Me) ₂ , phenyl-NH-, pyridyl-NH-, pyrimidinyl-NH-, pyrazinyl-NH-, pyridazinyl-NH-, pyrrolyl-NH-, pyrazolyl-NH-, thiazolyl-NH -, oxazolyl-NH-, oxadiazolyl-NH-, imidazolyl-NH-, thiadipine Groups -NH -, - C (= O ) Me, -C (= O) Et, -CH 2 -C (= O) Me, -CH 2 -C (= O) Et, -NHC (= O) Me , -C(=O)OH, -C(=O)OMe, -NHC(=O)OMe, -NHC(=O)OH, -NHC(=O)OEt, -NHC(=O)O(t -Bu), -C(=O)NH ₂ , -C(=O)NHMe, -NHC(=O)NH ₂ , -NHC(=S)NH ₂ , -NHC(=NH)NH ₂ , -S (=O) ₂ Me, -NHS(=O) ₂ Me, -S(=O) ₂ OH, -S(=O) ₂ OMe, -NHS(=O) ₂ OH, -NHS(=O) ₂ OMe, -S(=O) ₂ NH ₂ , -NHS(=O) ₂ NH ₂ , cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, two Oxacyclyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyrrolyl, epoxypropyl, epoxybutyl, azetidinyl, dihydropyridyl, dihydropyran Base, phenyl, benzyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, thiadiazolyl, tri Azolyl or tetrazolyl;

Wherein each R ^{2 is} independently optionally substituted by 1, 2, 3 or 4 identical or different R ^2a ; R ^2a has the meanings as described herein.

In some embodiments, each R ^{4 is} independently H, deuterium, halogen, hydroxy, amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkane Base, deuterated C _1-6 alkoxy, halo C _1-6 alkoxy, -(CR ^7a R ^7b ) _r -OR ⁸ , -(CR ^7a R ^7b ) _r -NR ^5a R ^5b , -( CR ^7a R ^7b ) _r CN, or halogenated C _1-6 alkyl;

Wherein R ^5a , R ^5b , R ^7a , R ^7b , R ⁸ and r all have the meanings as described in the present invention.

In some embodiments, any two R ⁴ and the atoms to which they are attached form a C _3-8 cycloalkyl group, a C _6-10 aryl group, a heterocyclic group consisting of 3-8 atoms, or 5-6 atoms. a heteroaryl group consisting of: a C _3-8 cycloalkyl group, a C _6-10 aryl group, a heterocyclic group consisting of 3-8 atoms, and a heteroaryl group consisting of 5-6 atoms, optionally independently Substituted by one or more R ¹⁰ ; said R ¹⁰ has the meanings as described herein.

In some embodiments, each R ^{4 is} independently H, hydrazine, F, Cl, Br, I, hydroxy, amino, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, hydrazine C _1-4 alkyl, deuterated C _1-4 alkoxy, halo C _1-4 alkoxy, -(CR ^7a R ^7b ) _r -OR ⁸ , -(CR ^7a R ^7b ) _r -NR ^5a R ^5b , -(CR ^7a R ^7b ) _r CN, or halogenated C _1-4 alkyl;

In some embodiments, any two R ⁴ and the atoms to which they are attached form a C _3-6 cycloalkyl group, a C ₆ aryl group, a heterocyclic group consisting of 3-6 atoms, or 5-6 atoms. a heteroaryl group; the C _3-6 cycloalkyl group, a C ₆ aryl group, a heterocyclic group composed of 3 to 6 atoms, and a heteroaryl group composed of 5 to 6 atoms, optionally independently one or more Substituted by R ¹⁰ ; said R ¹⁰ has the meanings as described in the present invention.

In some embodiments, each R ^{4 is} independently H, hydrazine, F, Cl, Br, I, hydroxy, amino, methyl, ethyl, propyl, butyl, trifluoromethyl, difluoromethyl, 1,2-difluoroethyl, trifluoromethoxy, difluoromethoxy, -OMe, -OEt, -O(t-Bu), -CH ₂ OH, -CH ₂ CH ₂ OH, -CN, -CH ₂ CN, -CH ₂ NH ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ OMe, -CH ₂ CH ₂ OMe, -NHMe or -N(Me) ₂ .

In some embodiments, any two R ⁴ and the atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, alkylene oxide, oxetanyl, tetrahydrofuranyl, pyrrolidine , piperidinyl, piperazinyl, morpholinyl or azetidinyl; said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, alkylene oxide, oxetanyl, tetrahydrofuran The base, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and azetidinyl are optionally independently substituted by one or more R ¹⁰ ; said R ¹⁰ has the meanings as described herein.

In some embodiments, each R ⁹ , R ^1a , R ^{2a ,} and R ^{3a are} independently oxo (=O), hydrogen, deuterium, halogen, —(CR ^7a R ^7b ) _r CN, nitro, C _{1- 6} alkyl, halo C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, R ⁸ OC _2-6 alkenylene, R ⁸ OC(=O)-C _2-6 Alkenyl, R ⁸ OC _2-6 alkynylene, R ⁸ OC(=O)-C _2-6 alkynylene, -(CR ^7a R ^7b ) _r -OR ⁸ , -(CR ^7a R ^7b ) _r - NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c )C(=O)R ⁶ , -(CR ^7a R ^7b ) _r OC(=O)R ⁶ , -(CR ^7a R ^7b ) _r COOH, -(CR ^7a R ^7b ) _r C(=O)OC _1-6 alkyl, -(CR ^7a R ^7b ) _r C(=O)C _1-6 alkyl, -(CR ^7a R ^7b ) _r S(=O) ₂ R ⁶ , -(CR ^7a R ^7b ) _r OS(=O) ₂ R ⁶ , -(CR ^7a R ^7b ) _r N(R ^5c )S(=O) ₂ R ⁶ ,-( CR ^7a R ^7b ) _r S(=O) ₂ OR ⁸ , -(CR ^7a R ^7b ) _r S(=O) ₂ NR ^5a R ^5b , -(CR ^7a R ^7b ) _r -C _3-12 cycloalkyl , -(CR ^7a R ^7b ) _r -C _6-12 aryl, -(CR ^7a R ^7b ) _r - (heterocyclic group of 3-12 atoms) or -(CR ^7a R ^7b ) _r -(5 a heteroaryl group of -12 atoms);

Wherein each R ⁹ , R ^1a , R ^2a and R ^{3a are} independently independently substituted by 1, 2, 3, 4 or 5 identical or different R ¹⁰ ;

In some embodiments, each R ⁹ , R ^1a , R ^{2a ,} and R ^{3a are,} independently, oxo (=O), hydrogen, deuterium, F, Cl, Br, I, -(CR ^7a R ^7b ) _r CN, Nitro, C _1-4 alkyl, halo C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, R ⁸ OC _2-4 alkenylene, R ⁸ OC(=O) -C _2-4 alkenylene, R ⁸ OC _2-4 alkynylene, R ⁸ OC(=O)-C _2-4 alkynylene, -(CR ^7a R ^7b ) _r -OR ⁸ , -(CR ^7a R ^7b ) _r -NR ^5a R ^5b , -(CR ^7a R ^7b ) _r N(R ^5c )C(=O)R ⁶ , -(CR ^7a R ^7b ) _r OC(=O)R ⁶ ,-( CR ^7a R ^7b ) _r COOH, -(CR ^7a R ^7b ) _r C(=O)OC _1-4 alkyl, -(CR ^7a R ^7b ) _r C(=O)C _1-4 alkyl, -( CR ^7a R ^7b ) _r S(=O) ₂ R ⁶ , -(CR ^7a R ^7b ) _r OS(=O) ₂ R ⁶ , -(CR ^7a R ^7b ) _r N(R ^5c )S(=O) ₂ R ⁶ , -(CR ^7a R ^7b ) _r S(=O) ₂ OR ⁸ , -(CR ^7a R ^7b ) _r S(=O) ₂ NR ^5a R ^5b , -(CR ^7a R ^7b ) _r -C _3-6 cycloalkyl, -(CR ^7a R ^7b ) _r -C _6-10 aryl, -(CR ^7a R ^7b ) _r - (heterocyclic group of 3-6 atoms) or -(CR ^7a R ^7b ) _r - (heteroaryl group of 5-6 atoms);

In some embodiments, each R ⁹ , R ^1a , R ^{2a ,} and R ^{3a are} independently oxo (=O), hydrogen, hydrazine, F, Cl, Br, I, -CN, methyl, ethyl, propyl Base, butyl, trifluoromethyl, difluoromethyl, 2,2-difluoroethyl, -CH ₂ CN, -CH ₂ CH ₂ CN, vinyl, propenyl, allyl, ethynyl, C Alkynyl, -OH, -OMe, -O(i-Pr), -O(t-Bu), -CH ₂ -OH, -CH ₂ CH ₂ -OH, -CH ₂ -OMe, -CH ₂ CH ₂ -OMe, -CH ₂ -O(i-Pr), -CH ₂ -O(t-Bu), -NH ₂ , -NHMe, -N(Me) ₂ , -CH ₂ -NH ₂ , -CH ₂ CH ₂ -NH ₂ , -CH ₂ -NHMe, -CH ₂ -N(Me) ₂ , -NHC(=O)Me, -CH ₂ COOH, -COOH, -C(=O)OMe, -CH ₂ C( =O)OMe, -C(=O)Me, -CH ₂ C(=O)Me, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, alkylene oxide, epoxybutyl, aza Cyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dihydropyranyl, phenyl, benzyl, pyridyl, pyrimidinyl, pyrazinyl , furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, triazolyl or tetra Azolyl

Wherein each R ⁹ , R ^1a , R ^2a and R ^{3a is} independently optionally substituted by 1, 2, 3, 4 or 5 identical or different R ¹⁰ ; said R ¹⁰ has the meanings as described herein.

In some embodiments, each R ⁵ , R ^5a , R ^5b , R ^{5c ,} and R ^{5d are,} independently, hydrogen, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy-C (=O) a C _6-10 aryl group, a C _3-10 cycloalkyl group, a heterocyclic group of 3 to 10 atoms or a heteroaryl group of 5 to 10 atoms.

In some embodiments, each R ⁵ , R ^5a , R ^5b , R ^{5c ,} and R ^{5d are,} independently, hydrogen, cyano, hydroxy, C _1-4 alkyl, C _1-4 alkoxy-C (=O) -, C _6-10 aryl, C _3-6 cycloalkyl, heterocyclic group consisting of 3-6 atoms or heteroaryl group of 5-6 atoms.

In some embodiments, each R ⁵ , R ^5a , R ^5b , R ^{5c ,} and R ^{5d are,} independently, hydrogen, cyano, hydroxy, methyl, ethyl, propyl, butyl, methoxy-C (= O)-, ethoxy-C(=O)-, isopropoxy-C(=O)-, tert-butoxy-C(=O)-, phenyl, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, epoxyalkyl, epoxybutyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dihydrogen Pyranyl, phenyl, benzyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiyl Azolyl, triazolyl or tetrazolyl.

In some embodiments, R ⁵ , R ⁹ and the atoms attached thereto form a heterocyclic group consisting of 3-8 atoms.

In other embodiments, R ⁵ , R ⁹ and the atoms attached thereto form a heterocyclic group of 3 to 6 atoms.

In some embodiments, each R ⁶ and R ^{8 are} independently hydrogen, deuterium, C _1-6 alkyl, deuterated C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxy Substituted C _1-6 alkyl, amino substituted C _1-6 alkyl, cyano substituted C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, halo C _1-6 An alkyl group, a C _6-10 aryl group, a C _3-10 cycloalkyl group, a heterocyclic group of 3 to 10 atoms or a heteroaryl group of 5 to 10 atoms.

In some embodiments, each R ⁶ and R ^{8 are} independently hydrogen, deuterium, C _1-4 alkyl, deuterated C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, hydroxy Substituted C _1-4 alkyl, amino substituted C _1-4 alkyl, cyano substituted C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, halo C _1-4 An alkyl group, a C _6-10 aryl group, a C _3-6 cycloalkyl group, a heterocyclic group composed of 3 to 6 atoms or a heteroaryl group of 5 to 6 atoms.

In other embodiments, each R ⁶ and R ^{8 are} independently hydrogen, deuterium, methyl, ethyl, propyl, butyl, deuterated methyl, vinyl, propynyl, hydroxymethyl, hydroxyethyl , methoxymethyl, methoxyethyl, ethoxymethyl, tert-butoxymethyl, tert-butoxyethyl, ethoxyethyl, isopropoxyethyl, trifluoromethyl , difluoromethyl, 1,2-difluoroethyl, 2,2-difluoroethyl, phenyl, cyclopropyl, cyclohexyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidine Base, piperazinyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazolyl, pyrazinyl, furyl, thiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl or Tetrazolyl.

In some embodiments, each R ⁷ , R ^{7a ,} and R ^{7b are,} independently, hydrogen, C _1-6 alkyl, deuterated C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or Halogenated C _1-6 alkyl.

In some embodiments, each R ⁷ , R ^{7a ,} and R ^{7b is} independently hydrogen, C _1-4 alkyl, deuterated C _1-4 alkyl, or halo C _1-4 alkyl.

In other embodiments, each R ⁷ , R ^7a and R ^{7b are} independently hydrogen, methyl, ethyl, propyl, butyl, deuterated methyl, trifluoromethyl, difluoromethyl, 1, 2-difluoroethyl or 2,2-difluoroethyl.

In some embodiments, each R ^{10 is} independently oxo (=O), H, D, halogen, CN, amino, hydroxy, nitro, carboxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, C _1-4 alkoxy C _1-4 alkyl, hydroxy substituted C _{1 -4} alkyl, cyano substituted C _1-4 alkyl, amino substituted C _1-4 alkyl, halo C _1-4 alkyl, C _1-4 alkyl acyl, C _1-4 alkyl sulfonate Acyl, C _1-4 alkoxy acyl, C _1-4 alkylamino acyl, amino acyl, aminosulfonyl, C _1-4 alkoxysulfonyl, C _1-4 alkylaminosulfonyl, C _1-4 acyl An oxy group, a C _6-10 aryl group, a C _3-6 cycloalkyl group, a heterocyclic group consisting of 3 to 6 atoms or a heteroaryl group of 5 to 10 atoms.

In some embodiments, each R ^{10 is} independently oxo (=O), H, D, F, Cl, Br, I, CN, amino, hydroxy, nitro, carboxy, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, C _1-4 alkoxy C _1-4 alkyl , hydroxy-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, amino-substituted C _1-4 alkyl, halo C _1-4 alkyl, C _1-4 alkyl acyl, C _1-4 alkylsulfonyl group, C _1-4 alkoxy group, C _1-4 alkylamino group, phenyl group, C _3-6 cycloalkyl group, heterocyclic group consisting of 3-6 atoms or 5-6 A heteroaryl group consisting of atoms.

In other embodiments, each R ^{10 is} independently oxo (=O), H, D, F, Cl, Br, I, CN, amino, hydroxy, nitro, carboxy, methyl, ethyl, propyl Base, butyl, deuterated methyl, methoxy, methylamino, dimethylamino, methoxymethyl, methoxyethyl, tert-butoxymethyl, tert-butoxyethyl, hydroxymethyl , hydroxyethyl, CN substituted methyl, CN substituted ethyl, aminomethyl, aminoethyl, trifluoromethyl, difluoromethyl, 1,2-difluoroethyl or 2,2-difluoro Ethyl, methylacyl, ethylacyl, methylsulfonyl, methoxyacyl, tert-butoxyacyl, methylaminoacyl, dimethylaminoacyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, propylene oxide, epoxybutyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, furyl, thienyl, pyrrolyl, pyrazole Base, imidazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl or pyrazinyl.

In some embodiments, each m, n, and t are independently 0, 1, 2, 3, or 4.

In some embodiments, p is 1, 2, 3 or 4.

In some embodiments, each r is independently 0, 1, 2, 3 or 4.

In some embodiments, f is 0, 1, 2, 3, 4 or 5;

In some embodiments, g is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

The present invention relates to a compound which is one of the following structures:

Or a stereoisomer, geometric isomer, tautomer, oxynitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the above structure.

In another aspect, the invention also relates to a method of using a compound or pharmaceutical composition of the invention to prevent, treat or ameliorate a thromboembolic disorder.

In some embodiments, the thromboembolic disease of the invention is an arterial cardiovascular thromboembolic disease, a venous cardiovascular thromboembolic disease, and a thromboembolic disease in the ventricular or peripheral circulation.

In other embodiments, the thromboembolic disease is angina pectoris, acute coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis , deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and exposure to blood from artificial surfaces in medical implants, instruments, or procedures Thereby promoting thrombosis caused by thrombosis.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition for the preparation of a medicament for inhibiting the activity of factor XIa and/or plasma kallikrein.

In one aspect, the compounds or pharmaceutical compositions of the invention are used to inhibit the activity of Factor XIa and/or plasma kallikrein.

The present invention encompasses the use of the compounds and their pharmaceutically acceptable salts for the manufacture of pharmaceutical products for the treatment of thromboembolic disorders in patients, including those described herein. The invention comprises a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention in combination with at least one pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle.

The invention also encompasses a method of treating or ameliorating, or susceptibility to, a thromboembolic disease in a patient comprising treating a patient with a therapeutically effective amount of a compound of the invention.

The thromboembolic diseases of the present invention include myocardial infarction, angina pectoris, re-occlusion and angioplasty or restenosis after aortic coronary venous shunt, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism Or deep vein thrombosis.

Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are The scope of the invention.

In particular, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" includes that the substance or composition must be chemically or toxicologically relevant to the other components of the formulation and to the mammal being treated.

Salts of the compounds of the invention also include the intermediates used in the preparation or purification of the compounds of the invention or the isolated enantiomers of the compounds of the invention, but are not necessarily pharmaceutically acceptable salts.

If the compound of the present invention is basic, the desired salt can be prepared by any suitable method provided in the literature, for example, using a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or the like. Or use organic acids such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; pyranoic acid such as glucitol Acids and galacturonic acids; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, Ethane sulfonic acid, and so on.

If the compound of the present invention is acidic, the desired salt can be prepared by a suitable method, for example, using an inorganic base or an organic base such as ammonia (primary ammonia, secondary ammonia, tertiary ammonia), alkali metal hydroxide or alkaline earth. Metal hydroxide, and so on. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary ammonia, and cyclic ammonia such as piperidine, morpholine and piperazine Etc., and inorganic salts are obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

Pharmaceutical compositions, formulations, administrations and uses of the compounds of the invention

According to another aspect, the pharmaceutical composition of the present invention comprises the formula (I) or formula (Ia) or formula (II) or formula (IIa) or formula (III) or formula (IIIa) or formula (IIIb) or formula A compound represented by (IIIc), a compound listed in the present invention, or a compound of Examples 1-11, and a pharmaceutically acceptable carrier, adjuvant, or excipient. The amount of the compound in the composition of the present invention is effective for treating or alleviating a thromboembolic disease in a patient, or effectively inhibiting the activity of factor XIa and/or plasma kallikrein.

In some embodiments, the pharmaceutical composition of the present invention comprises any one of the compounds of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof; In some embodiments, the pharmaceutical compositions of the present invention comprise any combination of any of the compounds described herein.

In some embodiments, the pharmaceutical compositions of the present invention further comprise additional therapeutic agents. Wherein, the other therapeutic agent is selected from the group consisting of an antiarrhythmic agent, an antihypertensive agent, an anticoagulant, an antiplatelet agent, a thrombin inhibitor, a thrombolytic agent, a fibrinolytic agent, a calcium channel blocker, Potassium channel blockers, cholesterol/lipid lowering agents, or combinations thereof.

In other embodiments, the present invention provides a pharmaceutical composition wherein the other therapeutic agent is an antihypertensive agent selected from the group consisting of an ACE inhibitor, an AT-1 receptor antagonist, a beta adrenergic receptor antagonist, ETA receptor antagonist, dual ETA/AT-1 receptor antagonist, renin inhibitor (alliskerin) and vasopressin inhibitor), antiarrhythmic agent (selected from IKur inhibition) Anticoagulant (which is selected from the group consisting of thrombin inhibitors, antithrombin-III activators, heparin cofactor II activators, other factor XIa inhibitors, other kallikrein inhibitors, plasmin Pro-activator inhibitor (PAI-1) antagonist, thrombin-activated fibrinolysis inhibitor (TAFI) inhibitor, factor VIIa inhibitor, factor IXa inhibitor and factor Xa inhibitor) or anti-platelet agent GPIIb/IIIa blocker, GP Ib/IX blocker, protease activated receptor 1 (PAR-1) antagonist, protease activated receptor 4 (PAR-4) antagonist, prostaglandin E2 receptor EP3 antagonist, Collagen receptor antagonist, phosphodiesterase-III inhibitor, P2Y receptor antagonist, P2Y 12 antagonist, lipoprotein receptor Antagonists, cyclooxygenase-1 inhibitors, and aspirin), or any combination thereof.

In other embodiments, the other therapeutic agents included in the pharmaceutical compositions of the invention are antiplatelet agents or a combination thereof. Wherein, the anti-platelet agent includes, but is not limited to, clopidogrel and/or aspirin or a combination thereof. In still other embodiments, the pharmaceutical composition of the present invention comprises other therapeutic agents: warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, hirudin, argatroban, aspirin, bupro Fen, naproxen, sulindac, indomethacin, mefima, dipyridamol, dioxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, Tirofiban, eptifibatide, abciximab, melagatran, ximelagatran, hirudin sulfate, tissue plasminogen activator, modified tissue plasminogen activator Agent, anipase, urokinase, and streptokinase or a combination thereof.

The compounds of the invention exist in free form or, as appropriate, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, ester salts, or any other agent which can be administered, directly or indirectly, depending on the needs of the patient. An adduct or derivative, a compound described in other aspects of the invention, a metabolite thereof or a residue thereof.

As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for the particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DBTroy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999 Marcel Dekker, New York, incorporating the contents of the literature, indicates that different carriers are useful in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. In addition to any conventional carrier medium that is incompatible with the compounds of the invention, such as any undesirable biological effects produced or interactions with any other component of a pharmaceutically acceptable composition in a detrimental manner, The use is also within the scope of the invention.

Substances which may be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, sorbus Potassium acid, a partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking polymer, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Cellulose sodium, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talcum powder; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; seaweed acid Pyrogen-free water; isotonic salt; Ringer's solution; ethanol, phosphate buffer solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings Clothing, sweeteners, flavorings and fragrances, preservatives and antioxidants.

The compounds of the present invention can be administered in the form of oral preparations, such as tablets, capsules (each of which includes a sustained release or timed release formulation), pills, powders, granules, elixirs, elixirs, suspensions, syrups. , and emulsifiers. They can also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly. All dosage forms used are well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected based on the mode of administration chosen and standard pharmaceutical practice.

The dosage regimen of the compounds of the invention will vary with various factors known, such as the pharmacokinetic profile of the particular agent and its mode and route of administration; the race, age, sex, health, medical condition and weight of the recipient; The nature and extent of the symptoms; the type of treatment being treated; the frequency of treatment; the route of administration, the kidney and liver function of the patient, and the desired effect. A physician or veterinarian can make a decision and prescribe an effective amount of the drug to prevent, counteract or prevent the development of a thromboembolic disease.

According to general guidelines, in order to achieve the specified effect, the daily oral dose of each active ingredient used ranges from about 0.001 to 1000 mg/kg body weight, preferably between about 0.01 and 100 mg/kg body weight. . Moreover, most preferably, it is between about 1.0 and 20 mg/kg body weight per day. For intravenous administration, the most preferred dosage range during a conventional rate of infusion is from about 1 to about 10 mg/kg body weight per minute. The compounds of the invention may be administered once daily, or may be administered in two, three or four times daily.

The compounds of the invention may be administered in intranasal form via topical use of a suitable intranasal vehicle or by transdermal routes using transdermal patches. When administered in the form of a transdermal delivery system, the dosage administered throughout the administration is continuous rather than intermittent.

Typically, the compound is administered in admixture with a suitable pharmaceutical diluent, excipient, or carrier (herein referred to as a pharmaceutical carrier), depending on the form of administration and conventional pharmaceutical practice, in the form of an oral tablet. Capsules, tinctures, syrups, etc.

For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methylcellulose , magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc.; for oral administration in liquid form, the oral pharmaceutical component can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier Combine, such as ethanol, glycerin, water, etc. Moreover, suitable binders, lubricants, decomposition agents, and colorants can also be added to the mixture as needed or necessary. Suitable binders include starch, gelatin, natural sugars (such as glucose or beta-lactose), corn sweeteners, natural and synthetic gums (such as acacia), tragacanth, or sodium alginate, carboxymethyl fibers. , polyethylene glycol, wax and so on. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Decomposers include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds of the invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed by different phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine.

The compounds of the invention are also coupled to a soluble polymer that acts as a targeted pharmaceutical carrier. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylate-phenol, polyhydroxyethylaspartamide phenol, or polyethylene oxide substituted with palmitoyl residues-poly Amino acid. Moreover, the compounds of the invention can be coupled to a class of biodegradable polymers for accomplishable controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, Crosslinked or amphiphilic blocking copolymers of esters, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels.

Each unit dose of a dosage form (pharmaceutical composition) suitable for administration may contain from about 1 mg to about 100 mg of the active ingredient. In these pharmaceutical compositions, the weight of the active ingredient will generally comprise from about 0.5% to about 95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient as well as powder carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Compressed tablets can be made using similar diluents. Tablets and capsules can be made as a product of sustained release to provide a continuous release of the drug over a period of time. Compressed tablets may be sugar coated or coated with a film to mask any unpleasant taste and to isolate the tablet from the air, or an enteric coating for selective decomposition in the gastrointestinal tract.

Liquid dosage forms for oral administration may contain coloring and flavoring to enhance patient acceptance.

Typically, water, a suitable oil, saline, hydrated dextrose (glucose), and related sugar solutions, as well as glycols such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. The solution for parenteral administration preferably contains a water-soluble salt of the active ingredient, a suitable stabilizer, and possibly a buffer material. The antioxidant is a suitable stabilizer such as sodium hydrogen sulfite, sodium sulfite, or vitamin C, either alone or in combination, or citric acid and a salt thereof, and sodium EDTA. In addition, parenteral solutions also contain preservatives such as benzalkonium, methyl- or propyl-p-hydroxybenzoate, and chlorobutanol.

The compounds of the invention may be combined with other anticoagulant agents, for example, for a kilogram of patient body weight, a daily dose may be from about 0.1 to 100 mg of a compound of the invention and from about 1 to 7.5 mg of a second anticoagulant combination. For a tablet dosage form, the compound of the invention will generally be from about 5 to 10 mg per dosage unit, and the amount of the second anti-aggregating agent will be from about 1 to 5 mg per dosage unit. Among them, other anticoagulant reagents include, but are not limited to, apixaban, rivaroxaban, edoxaban, betrixaban, dabigatran (dabigatran), bemiparin, enoxaparin sodium, tinzaparin sodium, danaparoid sodium, pentosan sodium, nadroparin calcium, aspartame sodium, palparin sodium and the like.

The compounds of the invention may be used alone or in combination with other therapeutic agents, either sequentially or sequentially. Wherein the other therapeutic agent is selected from the group consisting of a factor Xa inhibitor (eg, apixaban, rivaroxaban, betrixaban, edoxaban), an anticoagulant, an antiplatelet agent, thrombin inhibition Agents (eg, dabigatran), thrombolytic agents, and fibrinolytic agents. Preferably, the other therapeutic agent is at least one agent selected from the group consisting of warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, hirudin, argatroban, aspirin, ibuprofen ( Ibuprofen), naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone ), piroxicam, ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab, melagatran ), desulfatohirudin, tissue plasminogen activator, modified tissue plasminogen activator, anistreplase, urokinase, and streptokinase. Preferably, the additional therapeutic agent is at least one anti-platelet agent. Preferably, the antiplatelet agent is clopidogrel and/or aspirin or a combination thereof

According to general guidelines, the compounds of the invention are administered in combination with an anti-platelet agent. A typical daily dose may be from about 0.01 to 300 mg of the compound of the invention per kg of body weight of the patient and from about 50 to 150 mg of the anti-platelet agent, preferably about 0.1 to 4 mg of a compound of the invention and about 1 to 3 mg of an anti-platelet agent.

When the compound of the present invention is administered in combination with a thrombolytic agent, the usual daily dose may be from about 0.1 to 100 mg of the compound of the present invention per kg of the patient's body weight, and in the presence of a thrombolytic agent, generally when administered alone with the thrombolytic agent. In contrast to the dosage, when the thrombolytic agent is administered with a compound of the invention, the dosage of the thrombolytic agent can be reduced by about 50-80%.

When two or more of the foregoing second therapeutic agents are administered with a compound of the invention, generally, in view of the additive or synergistic effect of the therapeutic agent in combination administration, each of the typical daily dosages and typical dosage forms The amount of one component may be decreased relative to the usual dose when administered alone.

In particular, when provided as a single dosage unit, there is a possibility of a chemical reaction between the combined active ingredients. For this reason, when the compound of the present invention and the second therapeutic agent are combined in a single dosage unit, they are formulated such that the physical contact between the active ingredients is minimized (i.e., reduced) despite the active ingredient. Combine in a single dosage unit. For example, one active ingredient can be an enteric coating. By coating an active ingredient with an enteric coating, it is possible to not only minimize contact between the combined active ingredients, but it is also possible to control the release of one of these ingredients in the gastrointestinal tract so that one of these components It is not released in the stomach but released in the small intestine. One of the active ingredients may also be coated with a material which affects its sustained release in the gastrointestinal tract and which may also be used to reduce physical contact between the combined active ingredients. Further, the sustained release component may also be additionally coated with an enteric coating. This ingredient is only released in the intestines. Still another method involves the formulation of a combination product in which one component is coated with a continuous and/or enteric release polymer and the other component is also a polymer such as a low viscosity grade hydroxyl group. Propylmethylcellulose (HPMC) or other suitable materials known in the art are coated for the purpose of further separating the active ingredients. Polymer coating creates an additional barrier to reaction with other components.

These and other methods of minimizing contact between components of the combination products of the present invention will be apparent to those skilled in the art once they are aware of the present invention, whether they are administered in a single dosage form or in separate form, But it is applied at the same time or in the same way.

The compound of the present invention or a pharmaceutically acceptable salt thereof or a hydrate thereof can be effectively used for preventing, treating or ameliorating a thromboembolic disease in a patient; the thromboembolic disorder includes an arterial cardiovascular thromboembolic disorder, venous cardiovascular thromboembolism Symptoms, arterial cerebrovascular thromboembolic disorders, and venous cerebrovascular thromboembolic disorders. Examples of thromboembolic disorders include, but are not limited to, unstable angina, acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis Hardening, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and medical implants, The blood in the device or procedure is exposed to an artificial surface to promote thrombosis caused by thrombosis.

The compounds or pharmaceutical compositions provided herein can also be used to treat, prevent or treat inflammatory diseases; including, but not limited to, sepsis, acute respiratory distress syndrome, or systemic inflammatory response syndrome.

The compound or pharmaceutical composition provided by the present invention can be used for preventing, treating or ameliorating a disease associated with plasma kallikrein; wherein the disease associated with plasma kallikrein includes, but is not limited to, visual acuity Damage, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, kidney disease, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer Adult respiratory distress syndrome, disseminated intravascular coagulation and cardiopulmonary bypass.

General synthetic process

In this specification, if there is any difference between the chemical name and the chemical structure, the structure is dominant. In general, the compounds of the present invention can be prepared by the methods described herein, unless otherwise stated, wherein the substituents are as defined in (I) or Formula (Ia) or Formula (II) or Formula (IIa) or Formula (III) or formula (IIIa) or formula (IIIb) or formula (IIIc). The following reaction schemes and Examples 1-11 are used to further illustrate the contents of the present invention.

Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare a number of other compounds of the invention, and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention. Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by modifications by those skilled in the art, such as appropriate protection of interfering groups, by utilizing other known reagents (other than that described herein), Or make some routine modifications to the reaction conditions. Additionally, the reactions or known reaction conditions disclosed herein are also recognized to be suitable for the preparation of other compounds of the invention.

The examples described below, unless otherwise indicated, all temperatures are set to degrees Celsius. The reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. The general reagents were purchased from Shantou Xiqiao Chemical Plant, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant.

Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by refluxing with sodium metal. Anhydrous dichloromethane and chloroform were obtained by reflux drying of calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were previously dried over anhydrous sodium sulfate.

The following reaction is generally carried out under a positive pressure of nitrogen or argon or on a dry solvent (unless otherwise indicated), the reaction bottle is stoppered with a suitable rubber stopper, and the substrate is driven through a syringe. The glassware is dried.

The column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. Nuclear magnetic resonance spectroscopy data was determined by Bruker Avance 400 NMR spectrometer or Bruker Avance III HD 600 NMR spectrometer with CDC1 ₃ , DMSO-d ₆ , CD ₃ OD or acetone-d ₆ as solvent (reported in ppm) TMS (0 ppm) or chloroform (7.25 ppm) was used as a reference standard. When multiple peaks appear, the following abbreviations are used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, wide) Peak), dd (doublet of doublets), dt (doublet of triplets), ddd (doublet of doublet of doublets), ddt (doublet of doublet of triplets), double triplet ), dddd (doublet of doublet of doublet of doublets). Coupling constant, expressed in Hertz (Hz).

The conditions for low resolution mass spectrometry (MS) data determination were: Agilent 6120 Quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 μm, 6 min, flow rate 0.6 mL/min, mobile phase: 5%-95) The ratio of % (CH ₃ CN with 0.1% formic acid) in (H ₂ O with 0.1% formic acid)) was detected by UV at 210/254 nm using electrospray ionization mode (ESI).

The purity of the compound is characterized by: Agilent 1260 preparative high performance liquid chromatography (Pre-HPLC) or Calesep Pump 250 preparative high performance liquid chromatography (Pre-HPLC) (column model: NOVASEP, 50/80 mm, DAC) at 210 nm /254nm with UV detection.

The following abbreviations are used throughout the invention:

Grubbs 2nd generation catalyst Grubb second generation catalyst, benzylidene-1,3-bis(2,4,6-trimethylphenyl)-2-(imidazoline carbene) (tricyclohexylphosphine) ruthenium dichloride

(dba) ₃ Pd ₂ , (dba) ₃ Pd(0) ₂ tris(dibenzylidenefluoreneacetone) dipalladium (0)

Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 1,1-bis(diphenylphosphino)ferrocene palladium chloride dichloromethane complex

Dess-Martin oxidant Dess-Martin oxidant, (1,1,1-triacetoxy)-1,1-dihydro-1,2-phenyliodo-3(1H)-one

Boc tert-butoxycarbonyl

Boc anhydride di-tert-butyl dicarbonate

EDTA-2Na disodium edetate

SEM 2-(trimethylsilyl)ethoxymethyl

PtO ₂ -3H ₂ O platinum dioxide (three water)

CDC1 ₃ deuterated chloroform

CD ₃ OD deuterated methanol

DMSO-d ₆ deuterated dimethyl sulfoxide

DMSO dimethyl sulfoxide

g g

Mg mg

Mol Moore

Mm mmol

mL ml

μL microliter

MPa MPa

Mass% mass percentage or mass fraction or mass percentage

Pd/C palladium/carbon

FXIa factor XIa

HEPES 4-hydroxyethylpiperazineethanesulfonic acid

NaCl sodium chloride

KCl potassium chloride

PEG8000 polyethylene glycol 8000

PT prothrombin time

Partial activation of prothrombin time by APTT

The following reaction schemes describe the steps of preparing the compounds disclosed herein. Wherein A, B, X, Y, Z, Z ¹ , R ¹ , R ² , R ³ , R ⁴ , R ^3a , m, n, t, f have the meanings described herein; L is Cl, Br Or I; PG represents a protecting group, and suitable protecting groups can be found in the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

Synthetic scheme 1

Compound 1c can be prepared by the method described in Synthesis Scheme 1. Compounds 1a and 1b in 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and 1,8-diazabicyclo10 The pyrimidone compound 1c is obtained by reacting in a solvent such as acetonitrile in the presence of monocarb-7-ene (DBU).

Synthetic scheme 2

Compound 2f can be prepared by the method described in Synthesis Scheme 2. Compound 2a is first subjected to a Michael addition reaction with compound 2c in a solvent such as tetrahydrofuran or the like, and then subjected to a compound 2d under basic conditions (for example, under the action of pyridine or 4-dimethylaminopyridine). Acetylation gives compound 2e. Compound 2e is subjected to ring closure under basic conditions (e.g., sodium methoxide or sodium hydride) to give compound 2f.

Among them, the intermediate compound 2e can also be produced by the following method: Compound 2a is first added in the presence of trimethylchlorosilane (TMSCl) and sodium iodide (NaI) in a solvent (for example, acetonitrile and water). The reaction gives compound 2b; compound 2b and compound 2c undergo a substitution reaction under basic conditions (for example, under the action of triethylamine), and then under basic conditions (for example, in pyridine or 4-dimethylaminopyridine) The compound 2d is acetylated to give the compound 2e.

Synthetic scheme 3

Compound 3h can be prepared by the method described in Synthetic Scheme 3. Compound 3a is reacted with a vinyl Grignard reagent (such as vinylmagnesium bromide) to obtain compound 3b; compound 3b is subjected to an oxidation reaction (such as reaction with Jones (Jone's) reagent or Dess-Martin oxidant, etc.) to obtain compound 3c. Compound 3c is first subjected to a Michael addition reaction with compound 3e in a solvent such as tetrahydrofuran or the like, and then acetylated by compound 3f under basic conditions (for example, under the action of pyridine or 4-dimethylaminopyridine). Compound 3g is obtained; compound 3g is subjected to ring closure under basic conditions (e.g., under sodium methoxide, sodium hydride, etc.) to afford compound 3h.

Wherein, the intermediate compound 3g can also be produced by the following method: the compound 3c is first subjected to an addition reaction in the presence of TMSCl and NaI in a solvent (for example, acetonitrile and water) to obtain a compound 3d; the compound 3d is further reacted with the compound 3e. The substitution reaction occurs under basic conditions (for example, under the action of triethylamine), and then acetylated by 3f under basic conditions (for example, under the action of pyridine or 4-dimethylaminopyridine) to obtain a compound 3g. .

Synthetic scheme 4

The intermediate compound 4m can be produced by the method described in Synthesis Scheme 4. The aldehyde 4a and (S)-2-methylpropyl-2-sulfinamide are condensed in a solvent such as dichloromethane in the presence of anhydrous copper sulfate to give compound 4b. Compound 4b is reacted with allyl magnesium bromide under the action of indium trichloride catalyzed to obtain compound 4c; compound 4c is subjected to acidic conditions (for example, under the action of HCl), and (S)-2-A is removed. Base propyl-2-sulfinyl group gives compound 4d; compound 4d is amino protected to give compound 4e; compound 4e and compound 4f are in a catalyst (such as Pd(dppf)Cl ₂ -CH ₂ Cl ₂ ) and a base (such as cesium carbonate) In the presence of a solution, the Suzuki coupling reaction is carried out in a solvent such as dioxane and water to obtain a compound 4g; the compound 4g is subjected to a reduction reaction (for example, a nitro group is reduced in a zinc powder-ammonium chloride system) to obtain a compound 4h. Compound 4h is substituted with compound 4i under basic conditions (such as pyridine) to obtain compound 4j; compound 4j is subjected to ring-closing metathesis reaction under the action of a catalyst (such as Grubbs 2 generation catalyst) to obtain macrocyclic compound 4k; compound 4k Hydrogenation by catalysis (e.g., Pd/C catalysis) affords compound 41; compound 41 is deprotected (e.g., the Boc protecting group is removed under acidic conditions such as trifluoroacetic acid) to afford compound 4m.

Synthetic scheme 5

The intermediate compound 5i can be produced by the method described in Synthesis Scheme 5. Compound 4e and compound 5b are subjected to Suzuki coupling reaction in a solvent such as dioxane and water in the presence of a catalyst such as Pd(dppf)Cl ₂ -CH ₂ Cl ₂ ) and a base such as cesium carbonate. Compound 5c; compound 5c is reacted by reduction (such as reduction of nitro group to amino group in zinc powder-ammonium chloride system) to obtain compound 5d; compound 5d and compound 4i are substituted under basic conditions (such as pyridine) to obtain compound 5f. Compound 5f is subjected to a ring-closing metathesis reaction in the presence of a catalyst (such as Grubbs 2nd generation catalyst) to obtain a macrocyclic compound 5g; compound 5g is catalyzed (e.g., Pd/C catalyzed) hydrogenation reduction to obtain compound 5h; compound 5h is deprotected (for example, Removal of the Boc protecting group under acidic conditions such as trifluoroacetic acid affords compound 5i.

Synthetic scheme 6

The intermediate compound 6j can be produced by the method described in Synthesis Scheme 6. Compound 4e and compound 6b are subjected to Suzuki coupling reaction in a solvent such as dioxane and water in the presence of a catalyst such as Pd(dppf)Cl ₂ -CH ₂ Cl ₂ ) and a base such as cesium carbonate. Compound 6c; compound 6c is condensed with methyl chloroformate under basic conditions (such as pyridine) to obtain compound 6d; compound 6d is reduced (for example, nitro group is reduced to amino group in zinc powder-ammonium chloride system) The reaction gives compound 6e; compound 6e and compound 4i are substituted under basic conditions (such as pyridine) to obtain compound 6g; compound 6g in the presence of a catalyst (such as Grubbs 2 generation catalyst) by ring-closing metathesis reaction to obtain macrocyclic compound 6h; Compound 6h is catalytically hydrogenated (e.g., Pd/C catalyzed) to give compound 6i; compound 6i is deprotected (e.g., the Boc protecting group is removed under acidic conditions such as trifluoroacetic acid) to afford compound 6j.

Synthetic scheme 7

The intermediate compound 7i can be produced by the method described in Synthesis Scheme 7. Compound 4e and compound 7b are in the presence of a palladium (II) catalyst (such as Pd(OAC) ₂ ), a phosphorus ligand (such as n-butylbis(1-adamantyl)phosphine), and a base (such as potassium carbonate). a coupling reaction occurs in a solvent (such as N, N-dimethylformamide) to obtain a compound 7c; a compound 7c is reduced (for example, a nitro group is reduced to an amino group in a zinc powder-ammonium chloride system) to obtain a compound 7d; Compound 7d and compound 4i are subjected to a substitution reaction in a solvent (such as dichloromethane) under basic conditions (such as pyridine) to obtain compound 7f; and compound 7f is subjected to a ring-closing metathesis reaction under the action of a catalyst (such as Grubbs 2 generation catalyst). The ring compound 7g; the compound 7g is hydrogenated by catalytic (e.g., Pd/C catalysis) reduction to give the compound 7h, and then deprotected (for example, the Boc protecting group is removed under acidic conditions such as trifluoroacetic acid) to obtain the compound 7i.

The invention is further described in the following examples, which should not be construed as limiting the scope of the invention.

Example

Example 1

N-((10R,14S)-14-(4-(6-bromo-3-chloro-4-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl ) -10-methyl-9-oxo-8,16-diaza- tetracyclo [13.7.1.0 ^2,7 .0 ^17,22] tricosa-1 (23), 2 (7), 3 ,5,15,17(22),18,20-octadec-5-yl)carbamic acid methyl ester

Step 1: 2-(phenylamino)maleic acid dimethyl ester (1A)

Dimethyl ethynedicarboxylate (15.26g, 107.40mmol) was slowly added dropwise to a solution of aniline (10.00g, 107.40mmol) in anhydrous methanol (100mL) at room temperature. After the addition was completed, the system was heated to Stir at 90 ° C for 12 hours under reflux. The reaction was quenched, cooled to EtOAc (EtOAc m. MS (ESI, pos.) m/z: 236.0 [M + 1] ⁺ .

Step 2: Methyl 4-hydroxyquinoline-2-carboxylate (1B)

Polyphosphoric acid (31.25 g, 318.82 mmol) was added to 1A (25.00 g, 106.27 mmol) at room temperature, then the system was warmed to 120 ° C and stirred for 1 hour. The reaction was quenched, cooled to room temperature, and the excess acid was quenched with 20% sodium carbonate solution (300 mL), filtered, washed with water, and then filtered and washed with dichloromethane (2000 mL). The organic phase was washed with water (100 mL×3) Drying over anhydrous sodium sulfate, EtOAc (EtOAc:EtOAc)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 12.07 (s, 1H), 8.08 (d, J = 7.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.76 - 7.65 ( m, 1H), 7.38 (t, J = 7.5 Hz, 1H), 6.66 (s, 1H), 3.96 (s, 3H).

Step 3: Methyl 4-bromoquinoline-2-carboxylate (1C)

Phosphorus oxybromide (8.9 g, 31 mmol) and sodium carbonate (4.3 g, 31 mmol) were added to a solution of 1B (2.1 g, 10 mmol) in anhydrous acetonitrile (45 mL). Stir at 92 ° C for 2 hours. Then it was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was taken up in EtOAc (EtOAc)EtOAc.

MS (ESI, pos.) m/z: 399.1 (M+1).

Step 4: 4-bromoquinoline-2-carbaldehyde (1D)

1 C (0.60 g, 2.25 mmol) of a dry tetrahydrofuran solution (15 mL) was cooled to -78 ° C under nitrogen, then diisobutylaluminum hydride (12.09 mL, 12.09 mmol, 1 mol/L in toluene) was added dropwise. The reaction was carried out at this temperature for 4 hours. 3 mol/L of dilute hydrochloric acid (20 mL) was slowly added dropwise to the system, and then the temperature was raised to room temperature. A saturated sodium bicarbonate (20 mL) solution was added, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated Purification of the ester/petroleum ether (v/v) = 1/10) gave a white solid (0.51 g, 96.2%).

Step 5: (S,E)-N-((4-bromoquinolin-2-yl)methylene)-2-methylpropane-2-sulfinamide (1E)

Copper sulfate (0.045 g, 0.28 mmol) and 1 D (0.03 g, 0.13 mmol) were added to dry dichlorochloride of (S)-(-)-tert-butylsulfinamide (0.015 g, 0.13 mmol) at room temperature. In the methane (5 mL) solution, after the addition was completed, the mixture was stirred at room temperature for 3 hours. Filtration, washing with methylene chloride, EtOAc (EtOAc:EtOAc) .

MS (ESI, pos.) m/z: 339.0 [M+1] ⁺ .

Step 6: (S)-N-((S)-1-(4-bromoquinolin-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide ( 1F)

A solution of indium trichloride (0.022 g, 0.097 mmol) in dry tetrahydrofuran (1 mL) was cooled to -5 ° C under nitrogen atmosphere, then allyl magnesium bromide (0.13 mL, 0.13 mmol, 1 mol) was slowly added dropwise into the system. /L of tetrahydrofuran solution, after completion of the dropwise addition, the mixture was heated to room temperature and stirred for 1 hour, and then a solution of 1E (0.033 g, 0.0973 mmol) in anhydrous ethanol (1 mL) was added. After the addition was completed, stirring was continued for 2-3 hours. The reaction was quenched and concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc)EtOAc. Washing with water (100 mL), EtOAc (EtOAc m. Oily product (0.0060 g, 16.0%).

MS (ESI, pos.) m/z: 383.3 [M + 1] ⁺ .

Step 7: (S)-1-(4-bromoquinolin-2-yl)but-3-en-1-amine (1G)

A 6 mol/L hydrochloric acid solution (2.7 mL, 16.32 mmol) was slowly added dropwise to a solution of 1F (0.37 g, 0.96 mmol) in methanol (6 mL) at room temperature. After the addition was completed, stirring was continued for 3 hours at room temperature. The reaction was quenched and the MeOH was evaporated (EtOAc) (EtOAc) (EtOAc) The mixture was combined and dried with anhydrous sodium sulfate.

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm) 8.18 - 8.14 (m, 1H), 8.06 - 8.03 (m, 1H), 7.84 - 7.79 (m, 1H), 7.74 (t, J = 7.4 Hz, 1H) ), 7.60 (t, J = 7.5 Hz, 1H), 5.85 - 5.76 (m, 1H), 5.19 (d, J = 17.3 Hz, 1H), 5.15 (d, J = 10.3 Hz), 4.24 (dd, J =8.1, 4.9 Hz, 1H), 2.73–2.64 (m, 1H), 2.50–2.43 (m, 1H).

Step 8: (S)-(1-(4-Bromoquinolin-2-yl)but-3-en-1-yl)carbamic acid tert-butyl ester (1H)

Di-tert-butyl dicarbonate (0.16 g, 0.17 mL, 0.72 mmol) was added dropwise to dryness in 1G (0.20 g, 0.72 mmol) and triethylamine (0.074 g, 0.10 mL, 0.72 mmol). After the dropwise addition was completed in a dichloromethane (10 mL) solution, stirring was continued for 16 hours at room temperature. The reaction was quenched, and dichloromethane (20 mL) was evaporated. /v) = 1/10) purified to give a yellow solid (0.26 g, 95.9%).

MS (ESI, pos.) m/z: 376.9 [M+1] ⁺ .

Step 9: (S)-(1-(4-(4-Amino-2-nitrophenyl)quinolin-2-yl)but-3-en-1-yl)carbamic acid tert-butyl ester (1I)

To 3-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.22 g, 0.83 mmol) at room temperature In a 1H (0.26 g, 0.69 mmol) system, ethylene glycol dimethyl ether (15 mL) and a 2 mol/L aqueous sodium carbonate solution (1.73 mL, 3.46 mmol) were added in this order, followed by tetrakis(triphenylphosphine)palladium (0). (0.080 g, 0.069 mmol), the system was heated to 90 ° C under nitrogen atmosphere for 4 hours. The reaction was quenched, cooled to EtOAc (EtOAc m.

MS (ESI, pos. ion) m/z: 435.3 [M+1] ⁺ .

Step 10: (S)-(1-(4-(4-(methoxy)amino)-2-nitrophenyl)quinolin-2-yl)but-3-en-1-yl)carbamic acid Tert-butyl ester (1J)

A solution of methyl chloroformate (0.024 g, 0.020 mL, 0.25 mmol) in dichloromethane (5 mL) was slowly added dropwise to compound 1I (0.10 g, 0.23 mmol) and pyridine (0.055 g, 0.056 mL) at -78 °C After a dropwise addition of a solution of 0.69 mmol of dichloromethane (20 mL), stirring was continued at -78 ° C for 2 hours. The reaction was stopped, and a saturated ammonium chloride solution (5 mL) was added to the mixture. After stirring for 5 minutes, the mixture was warmed to room temperature and stirred for 10 minutes. Dichloromethane (50 mL) was added, the mixture was washed with water (10 mL×2) and brine (20 mL). Purification with ether (v/v) = 1/10) gave dark red crystals (0.103 g, 90.9%).

MS (ESI, pos.) m/z: 492.9 [M+1] ⁺ .

Step 11: (S)-(1-(4-(4-(methoxy)amino)-2-aminophenyl)quinolin-2-yl)but-3-en-1-yl)carbamic acid Butyl ester (1K)

Zinc powder (4.26 g, 65.20 mmol) and ammonium chloride (3.49 g, 65.20 mmol) were added to a solution containing 1 J (3.21 g, 6.52 mmol) in methanol (65 mL) and the mixture was stirred at room temperature for 2.5 hours. . The reaction was stopped, filtered, and the filter cake was washed with methanol (10 mL×3), and the filtrate was concentrated to give residue. The residue was dissolved in dichloromethane (100mL), washed with water (30mL×2) and brine (30mL) The aqueous solution was dried with EtOAc (EtOAc m.

MS (ESI, pos.) m/z: 463.3 [M + 1] ⁺ .

Step 12: (S)-(1-(4-(4-(methoxy)amino)-2-((R)-2-methylbut-3-enoylamino)phenyl)quinoline-2 -yl)but-3-en-1-yl)carbamic acid Butyl ester (1L)

A solution of (R)-2-methylbut-3-enoyl chloride (0.95 g, 8.04 mmol) in dichloromethane (10 mL) was slowly added to dissolve 1K (0.95 g, 2.06 mmol) and A solution of pyridine (0.66 g, 0.67 mL, 8.24 mmol) in dry methylene chloride (100 mL) was then stirred at 0 ° C for 30 min. The reaction was stopped, and dichloromethane (100 mL) was further added to the mixture, and then washed with water (50 mL×2) and brine (50 mL). Purification by column chromatography (EtOAc / EtOAc (EtOAc)

MS (ESI, pos. ion) m/z: 545.9 [M+1] ⁺ .

Step 13: N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-8,16-diazatetracyclo[13.7.1.0 ^2.7 .0 ^{17, 22} ] icosane -1(23),2(3),4,6,11(12),15,17(22),18,20-nonenylene-5-yl)methyl carbamate (1M)

P-toluenesulfonic acid monohydrate (0.84 g, 4.28 mmol) was placed in a two-necked flask at room temperature, heated to 80 ° C, and dried under reduced pressure for about 1 hour. A solution of 1 L (2.12 g, 3.89 mmol) in dry methylene chloride (100 mL) was then taken and then cooled to room temperature and stirred for 45 min. A solution of Grubbs 2 Generation Catalyst (1.05 g, 1.22 mmol) in dry dichloromethane (20 mL) was then slowly taken and then warmed to reflux and stirred overnight. The reaction was quenched and cooled to room temperature. Toluene (100 mL) and saturated aqueous sodium hydrogen carbonate (50 mL) was evaporated. After drying over anhydrous sodium sulfate, EtOAc (EtOAc m.) MS (ESI, pos. ion) m/z: 517.3 [M-13] ⁺ .

Step 14: N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-8,16-diazatetracyclo[13.7.1.0 ^2.7 .0 ^{17, 22} ] icosane -1(23),2(3),4,6,15,17(22),18,20-octadec-5-yl)carbamate (1N)

10% Pd/C (0.123 g) was added to a solution of 1 M (1.15 g, 2.17 mmol) in anhydrous methanol (100 mL) at room temperature, 2-3 times with hydrogen, stirred at room temperature under hydrogen atmosphere overnight. The reaction was quenched, filtered, EtOAcqqqqqqqqqqq

MS (ESI, pos. ion) m/z: 519.5 [M-13] ⁺ .

Step 15: N - ((10R, 14S) -14- amino-10-methyl-9-oxo-8,16-diaza- tetracyclo [13.7.1.0 ^2.7 .0 ^17,22] tricosane -1(23),2(3),4,6,15,17(22),18,20-octadec-5-yl)carbamate (1O)

Trifluoroacetic acid (4.6 g, 3.0 mL, 40.00 mmol) was added to 1N (0.67 g, 1.28 mmol) in dry dichloromethane (30 mL) The reaction was quenched, EtOAc (EtOAc m. The combined organic layers were dried with EtOAc EtOAcjjjjjjjjjj

Step 16: 1-(6-Bromo-3-chloro-2-fluorophenyl)-3-iodopropan-1-one (1P)

Trimethylchlorosilane (0.78 g, 0.62 mL, 7.13 mmol) was added to a system containing sodium iodide (1.10 g, 7.3 mmol) and acetonitrile (5 mL) at room temperature, stirred for 10 min, then water was added (0.50g), after stirring for 5 minutes, adding 1-(6-bromo-3-chloro-2-fluorophenyl)prop-2-en-1-one (prepared by the synthesis method of intermediate 2 of patent WO 2014022766) (1.25 g, 4.74 mmol), stirring was continued for 2 hours. The reaction was stopped, water (5 mL) was added and the mixture was extracted with ethyl acetate (20mL×3). The organic phase was combined, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was evaporated to crystals crystals crystals crystals Liquid (1.35 g, 72.7%).

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm) 7.36 - 7.32 (m, 1H), 3.48 (t, J = 7.0 Hz, 1H), 3.41 (dd, J = 10.7, 3.8 Hz, 1H).

Step 17: N-((10R,14S)-14-(3-(6-bromo-3-chloro-2-fluorophenyl)-3-oxopropylamino)-10-methyl-9-oxo -8,16-diazatetracyclic [13.7.1.0 ^2.7 .0 ^17,22] tricosa-1 (23), 2 (3), 4,6,15,17 (22), 18,20- eight-5-yl) carbamic acid Methyl ester (1Q)

Triethylamine (0.24 g, 0.33 mL, 2.37 mmol) was added EtOAc (EtOAc m. The solution was stirred at room temperature for 5 hours after the addition. The reaction was quenched, ethyl acetate (50 mL) EtOAc (EtOAc)EtOAc. Purification by neutral alumina column chromatography (EtOAc / EtOAc (EtOAc) (EtOAc)

MS (ESI, pos. ion) m/z: 683.4 [M-13] ⁺ .

Step 18: N-((10R,14S)-14-(N-(3-(6-bromo-3-chloro-2-fluorophenyl)-3-oxopropyl)-2-(diethoxy) Phosphoryl)acetamido)-10-methyl-9- Oxo-8,16-diaza- tetracyclo [13.7.1.0 ^2.7 .0 ^17,22] tricosa-1 (23), 2 (3), 4,6,15,17 (22), 18 Methyl 20-octadec-5-yl)carbamate (1R)

Pyridine (0.021 g, 0.021 mL, 0.27 mmol) and 4-dimethylaminopyridine (0.006 g, 0.049 mmol) were added to a solution of 1Q (0.029 g, 0.042 mmol) in dichloromethane (10 mL). Further, a solution of (2-chloro-2-oxoethyl)phosphoric acid diethyl ester (0.019 g, 0.088 mmol) in dichloromethane (10 mL) was added, and after stirring, the mixture was warmed to 40 ° C under microwave for 2 hours. The reaction was quenched, cooled to rt. EtOAc (EtOAc) (EtOAc)EtOAc. Concentration gave a solid which was purified eluting elut elut elut elut elut

MS (ESI, pos. ion) m/z: 861.5 [M-13] ⁺ .

Step 19: N-((10R,14S)-14-(4-(6-Bromo-3-chloro-4-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridine- 1-yl)-10-methyl-9-oxo-8,16-diazo Oxatetracyclo [13.7.1.0 ^2,7 .0 ^17,22] tricosa-1 (23), 2 (7), 3,5,15,17 (22), 18,20- eight 5-ene Methyl carbamate

60% sodium hydride (0.015 g, 0.38 mmol) was placed in a two-necked flask at room temperature, and after being protected with nitrogen, a solution of 1R (0.078 g, 0.091 mmol) in dry tetrahydrofuran (5 mL) was poured in a syringe at room temperature. Stir for 30 minutes. The reaction was quenched, dichloromethane (50 mL) and EtOAc (EtOAc)EtOAc. Filtration and EtOAc (EtOAc:EtOAc:EtOAc)

MS (ESI, pos.): m/z: 707.4 [M + 1] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm) 8.22 (s, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.9 Hz, 1H), 7.56–7.53 (m, 1H), 7.48–7.43 (m, 1H), 7.43–7.38 (m, 2H), 7.33 (s, 1H), 7.29 (d, J = 7.7 Hz, 1H) ), 6.51 (d, J = 4.8 Hz, 1H), 4.84 - 4.77 (m, 1H), 3.02 (s, 3H), 3.00 - 2.90 (m, 2H), 2.70 - 2.64 (m, 1H), 2.46 ( Td, J = 14.8, 7.4 Hz, 2H), 2.24 - 2.18 (m, 1H), 2.03 - 1.99 (m, 2H), 1.68-1.63 (m, 2H), 0.93 (d, J = 6.9 Hz, 3H) , 0.84 (s, 2H).

Example 2

N-((10R,14S)-14-(4-(6-bromo-3-chloro-2-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl )-10-methyl-9-oxo-8,16-diazatetracyclo[13.6.1.0 ^2,7 .0 ^17,21 ]docosane-1(22),2(7),3 ,5,15,17(21)-hexaen-5-yl)carbamic acid methyl ester

Step 1: 6,7-Dihydro-5H-cyclopenta[b]pyridine 1-oxide (2A)

6,7-Dihydro-5H-cyclopenta[B]pyridine (50 g, 419.60 mmol) was weighed into a flask, dichloromethane (500 mL) was added, and m-chloroperoxybenzoic acid was added portionwise in an ice bath. (95 g, 467.93 mmol, 85 mass%), after 5 min, was stirred at room temperature overnight. The reaction was quenched, EtOAc (EtOAc)EtOAc.

Step 2: 6,7-Dihydro-5H-cyclopenta[b]pyridine-2-carbonitrile (2B)

2A (55.2 g, 408 mmol) was weighed into a four-necked flask, dichloromethane (700 mL) was added thereto, and trimethylcyanosilane (56.5 mL, 452 mmol) was added at room temperature, stirred for 20 minutes, and then added dropwise. Diethylcarbamoyl chloride (57 mL, 450 mmol) was reacted at room temperature for 64 hours. The reaction was terminated, and a 10% potassium carbonate solution (700 mL) was added to the system, and the mixture was stirred for 20 minutes. The organic phase was separated and the aqueous phase was extracted with dichloromethane (40 mL×3). The mixture was evaporated to dryness crystallite crystal crystal crystal crystal crystal crystal crystal

Step 3: (6,7-Dihydro-5H-cyclopenta[b]pyridin-2-yl)methanol (2C)

2B (28.56 g, 198.1 mmol) was weighed into an autoclave, 10% of Pd/C (4.1 g) was added thereto, and 2 mol/L hydrochloric acid solution (400 mL) and methanol (200 mL) were added thereto, and hydrogen gas was introduced thereto. The reaction was carried out at 2.6 MPa and room temperature. When the pointer on the gauge stays at 2.4 MPa no longer decreases, the reaction is stopped. The sodium carbonate solid was added to the reaction flask until no bubbles were formed, and the methanol was removed by rotary evaporation. The aqueous phase was extracted with a mixed solvent of dichloromethane and methanol (v/v = 10/1) (30 mL×6), and the organic phase was dried. The organic layer was dried (MgSO4) (mjjjjjjj

MS (ESI, pos.) m/z: 150.3 [M + 1] ⁺ .

Step 4: 2-(Hydroxymethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (2D)

2C (16.364g, 109.69mmol) was weighed into a flask, dichloromethane (400 mL) was added thereto, and m-chloroperoxybenzoic acid (24.5 g, 120.65 mmol, 85 mass%) was added portionwise at room temperature, and the system was at room temperature. Stir under 1 hour. The reaction was quenched, and the solvent was evaporated. mjjjjjjjjjjjjj

Step 5: 4-Bromo-2-(bromomethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (2E)

2D (4.18 g, 25.3 mmol) was weighed into a flask, and N,N-dimethylformamide (70 mL) and toluene (70 mL) were added thereto, and phosphorus tribromide (29.16 g, 101.7 mmol) was added portionwise at room temperature. The system was stirred at room temperature for 1 hour. The reaction was terminated, water (70 mL) was added to the system, and sodium carbonate solid was added until no bubbles were formed, ethyl acetate was extracted (50 mL×4), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and dried. This was purified by silica gel column chromatography (EtOAc(EtOAc)

Step 6: (4-Bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)methanol (2F)

2E (10.28 g, 35.33 mmol) was weighed into a flask, and sodium carbonate (60 g, 3740.2 mmol), acetone (200 mL) and water (200 mL) were added to the reaction flask at room temperature, and the mixture was heated to 75 ° C and stirred overnight. The reaction was quenched, cooled to room temperature, EtOAc (EtOAc)EtOAc. (v/v) = 20/1) gave a pale yellow solid (5.14 g, 63.8%).

MS (ESI, pos.) m/z: 229.1 [M+1] ⁺ .

Step 7: 4-Bromo-6,7-dihydro-5H-cyclopenta[b]pyridine-2-carbaldehyde (2G)

2F (5.14 g, 22.5 mmol) was weighed into a flask, and dichloromethane (200 mL) and Dess-Martin oxidizing agent (11.5 g, 27.1 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. To the system, a saturated sodium thiosulfate solution (50 mL) and a saturated sodium hydrogen carbonate solution (50 mL) were added, and the mixture was stirred to ethyl acetate (50 mL×2). The mixture was evaporated to dryness crystals crystals crystals crystals

Step 8: (S,E)-N-((4-Bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)methylene)-2-methylpropane- 2-sulfinamide (2H)

(S)-(-)-tert-butylsulfinamide (3.80 g, 31.38 mmol) and copper sulfate (6.69 g, 41.9 mmol) were added to 2G (4.73 g, 20.9 mmol) of dichloromethane at room temperature. In a (150 mL) solution, the mixed system was heated to reflux for 8 hours. The reaction was quenched, the reaction mixture was filtered with EtOAc EtOAc (EtOAc) (EtOAc) %).

MS (ESI, pos.) m/z: 330.2 [M + 1] ⁺ .

Step 9: (S)-N-((S)-1-(4-bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)but-3-ene-1 -yl)-2-methylpropane-2-sulfinamide (2I)

Allyl magnesium bromide (40 mL, 40 mmol, 1.0 mol/L tetrahydrofuran solution) was added dropwise to a solution of indium trichloride (8.73 g, 39.5 mmol) in tetrahydrofuran (150 mL) at -5 °C. After the addition was completed, the mixture was allowed to react to room temperature for 1 hour. A 2H (6.46 g, 19.6 mmol) solution of ethanol (60 mL) was added dropwise to the mixture, and stirred at room temperature for 3 hours. The reaction was quenched, the reaction mixture was filtered with EtOAc EtOAc (EtOAc) (EtOAcjjjjjjjj The residue was dried with EtOAc EtOAc EtOAcjjjjjjj

MS (ESI, pos.) m/z: 372.2 [M+1] ⁺ .

Step 10: (S)-1-(4-Bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)but-3-en-1-amine (2J)

2I (7.18 g, 19.3 mmol) was added to a flask, and methanol (75 mL) and a 6 mol/L hydrochloric acid solution (103 mL, 618.7 mmol) were further added, and the mixture was stirred at room temperature for 1 hour. The methanol was depressed under reduced pressure, and then a saturated aqueous solution of sodium hydrogen carbonate was added to the mixture, and the mixture was extracted with methylene chloride (yield: EtOAc (EtOAc) 6.6g, 100%).

Step 11: (S)-(1-(4-Bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)but-3-en-1-yl)carbamic acid Butyl ester (2K)

2 J (6.6 g, 25 mmol) was weighed into a flask, and dichloromethane (150 mL) and triethylamine (7 mL, 50.2 mmol) were added thereto. Di-tert-butyl dicarbonate (6.2 mL, 27 mmol) was added dropwise at room temperature, and the mixture was reacted at room temperature for 6 hours. The reaction was terminated, and dichloromethane (150 mL) was added to the mixture. The mixture was washed with water (300 mL×2) and brine (200 mL). Purification by chromatography (EtOAc/EtOAc (EtOAc:EtOAc) MS (ESI, pos. ion) m/z: 368.3 [M+1] ⁺ .

Step 12: (S)-(1-(4-(4-Amino-2-nitrophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)- Tert-butyl 3-en-1-yl)carbamate (2L)

Weigh 2K (7.82g, 21.3mmol), 3-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (8.59 g, 32.5 mmol) and 2 mol/L sodium carbonate solution (22 mL, 44 mmol) in a two-necked flask, to which tricyclohexylphosphine (0.92 g, 3.19 mmol) was rapidly added, and then the oxygen contained in the system was replaced with nitrogen. Then, (dba) ₃ Pd(0) ₂ (68.73 mg, 2.13 mmol) was quickly added, and then the oxygen contained in the system was replaced with nitrogen, and the reaction flask was stirred in an oil bath at 100 ° C overnight. The reaction was quenched and the mixture was cooled to room temperature. The mixture was filtered over Celite, and ethyl acetate (400 mL) was added to the filtrate. The organic phase was washed with water (200 mL×3) and brine (300 mL) The residue was purified by silica gel chromatography eluting elut elut elut elut elut

MS (ESI, pos.ion) m / z: 425.3 [M + 1] +.

Step 13: N-[4-[2-[(S)-1-(tert-Butoxycarbonylamino)but-3-enyl]-6,7-dihydro-5H-cyclopenta[b]pyridine 4-yl]-3-nitro-phenyl]amino Methyl formate (2M)

2 L (6.83 g, 16.1 mmol) and pyridine (4 mL, 49.7 mmol) were added to a two-neck flask, dichloromethane (170 mL) was added thereto, and the mixture was cooled to -78 ° C, and methyl chloroformate was slowly added dropwise to the system (1.4). A solution of mL, 18 mmol) in dichloromethane (80 mL) was stirred and stirred for 3 hr. The reaction was quenched, saturated ammonium chloride solution (16 mL) was added to the mixture and stirred for 5 min, then warmed to room temperature and stirred for 10 min. Dichloromethane (200 mL) was added to the mixture. The mixture was washed with water (300 mL) The resulting product was used directly in the next reaction.

Step 14: N-[3-Amino-4-[2-[(S)-1-(tert-butoxycarbonylamino)but-3-enyl]-6,7-dihydro-5H-cyclopentane [b]pyridin-4-yl]phenyl]carbamate Methyl ester (2N)

Zinc powder (10.03 g, 153.3 mmol) and ammonium chloride (8.36 g, 156 mmol) were added to a solution of 2M (7.32 g, 15.2 mmol) in methanol (200 mL) at room temperature overnight. The reaction was terminated, the reaction solution was suction filtered with celite, and the filter cake was washed with methanol (30mL×3), the solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (500 mL) The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated to dryness crystals

MS (ESI, pos. ion) m/z: 453.3 [M+1] ⁺ .

Step 15: N-[4-[2-[(1S)-1-(tert-Butoxycarbonylamino)but-3-enyl]-6,7-dihydro-5H-cyclopenta[b]pyridine 4-yl]-3-[[(2S)-2-methylbutyl) Methyl 3-enoyl]amino]phenyl]carbamate (2O)

2N (0.99 g, 2.2 mmol) was dissolved in dichloromethane (15 mL), pyridine (0.72 mL, 8.9 mmol) was added to the reaction flask, and (R)-2-methyl was added dropwise. A solution of but-3-enoyl chloride (0.4 g, 3 mmol) in dichloromethane (10 mL) was added dropwise, and the mixture was reacted for 1 hour under the conditions, and then the mixture was transferred to room temperature and the reaction was continued for 3 hours. The reaction was terminated, water (200 mL) was added to the reaction mixture, and the mixture was evaporated. (v/v) = 10/1) purified to give a pale-yellow solid (0.74 g, 63%).

MS (ESI, pos.) m/z: 535.4 [M + 1] ⁺ .

Step 16: N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-8,16-diazatetracyclo[13.6.1.0 ^2.7 .0 ^{17, 21} ]tetracosane -1(22),2(3),4,6,11(12),15,17(21)-hepten-5-yl)carbamic acid methyl ester (2P)

At room temperature, p-toluenesulfonic acid monohydrate (0.297 g, 1.56 mmol) was weighed into a two-necked bottle, and the two vials were placed in an 80 ° C oil bath and dried under reduced pressure for 0.5 hour. The oil bath was heated to dryness, cooled to room temperature, and a solution of EtOAc (EtOAc) A solution of Grubbs 2 generation catalyst (0.369 g, 0.435 mmol) in dry dichloromethane (50 mL) was then added dropwise to the system and the mixture was stirred at 45 ° C overnight. The reaction was quenched, the mixture was cooled to room temperature, and the mixture was transferred to a single-necked flask, and the solvent was evaporated to remove the residue (yield of petroleum ether/ethyl acetate (v/v) = 2/1). Obtained as a brown solid (0.55 g, 76%).

MS (ESI, pos. ion) m/z: 507.2 [M+1] ⁺ .

Step 17: N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-8,16-diazatetracyclo[13.6.1.0 ^2.7 .0 ^{17, 21} ]tetracosane -1(22),2(3),4,6,15,17(21)-hexaen-5-yl)carbamic acid methyl ester (2Q)

2P (0.55 g, 1.1 mmol) was weighed into the autoclave at room temperature, and methanol (50 mL) and 10% Pd/C (0.065 mg) were added thereto. Hydrogen gas was introduced, and the autoclave was pressurized to 5 MPa, and placed in a 50 ° C oil bath and heated and stirred overnight. The reaction was quenched, cooled to room temperature, and the mixture was filtered over Celite, and filtered. The filtrate was evaporated to dryness afforded crystals crystals crystals

MS (ESI, pos. ion) m/z: 509.2 [M+1] ⁺ .

Step 18: N - ((10R, 14S) -14- amino-10-methyl-9-oxo-8,16-diaza- tetracyclo [13.6.1.0 ^2.7 .0 ^17,21] behenic -1(22),2(3),4,6,15,17(21)-hexaen-5-yl)carbamic acid methyl ester (2R)

2Q (0.56 g, 1.1 mmol) was weighed into a flask at room temperature, and dry dichloromethane (30 mL) and trifluoroacetic acid (2.5 mL, 34 mmol) were added thereto, and the mixture was stirred at room temperature for 8 hours. The reaction was quenched, and the solvent was evaporated, evaporated, evaporated, evaporated. The organic phase was separated, EtOAc (EtOAc m.

MS (ESI, pos. ion) m/z: 409.2 [M+1] ⁺ .

Step 19: N-((10R,14S)-14-(3-(6-Bromo-3-chloro-4-fluorophenyl)-3-oxopropylamino)-10-methyl-9-oxo -8,16-diazatetracyclic [13.6.1.0 ^2.7 .0 ^17,21 ]Tetradane-1(22),2(3),4,6,15,17(21)-hexaen-5-yl)carbamic acid methyl ester (2S )

2R (0.383 g, 0.938 mmol) was weighed into a flask, and tetrahydrofuran (20 mL) and triethylamine (0.7 mL, 5 mmol) were added thereto, and then a solution of 1P (0.55 g, 1.41 mmol) in tetrahydrofuran (10 mL) was added. After the addition was completed, the mixture was stirred at room temperature overnight. The reaction was quenched, and the solvent was evaporated, evaporated, evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjj The organic phase was combined and dried over anhydrous sodium sulfate, filtered and evaporated to give a brown-brown solid (0.4 g, 60%).

MS (ESI, pos.) m/z: 672.7 [M + 1] ⁺ .

Step 20: N-((10R,14S)-14-(N-(3-(6-bromo-3-chloro-4-fluorophenyl)-3-oxopropyl)-2-(diethoxy) Phosphoryl)acetamido)-10-methyl-9- Oxo-8,16-diazatetracyclo[13.6.1.0 ^2.7 .0 ^17,21 ]tetracosane-1(22), 2(3), 4,6,15,17(21)-six Methyl ene-5-yl)carbamate (2T)

(2-Chloro-2-oxoethyl)phosphoric acid diethyl ester (0.652 g, 3.04 mmol), 4-dimethylaminopyridine (0.088 g, 0.72 mmol) and pyridine (0.24 mL, 2.98 mmol) It was added to a 2S (0.4 g, 0.6 mmol) solution of dichloromethane (15 mL), and the mixture was stirred at 50 ° C for 3 hours. The reaction was stopped, the reaction solution was poured into a sep. funnel, and dichloromethane (50 mL) and water (100 mL) were added, and the organic phase was separated, and the aqueous phase was extracted with dichloromethane (30 mL×5). Dry over anhydrous sodium sulfate, filtered, EtOAcqqqqq

MS (ESI, pos. ion) m/z: 851.4 [M+1] ⁺ .

Step 21: N-((10R,14S)-14-(4-(6-bromo-3-chloro-2-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridine- 1-yl)-10-methyl-9-oxo-8,16-diazo Heterotetracycline [13.6.1.0 ^2,7 .0 ^17,21 ]tetracosane-1(22), 2(7),3,5,15,17(21)-hexa-5-yl)amino Methyl formate

60% sodium hydride (0.087 g, 3.6 mmol) was weighed into a flask, and tetrahydrofuran (5.0 mL) was added to the flask under a nitrogen atmosphere, and 2T (0.5 g, 0.6 mmol) of tetrahydrofuran (20 mL) was added to the flask. The solution was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction flask to quench the reaction. The solvent was evaporated under reduced pressure. the residue was evaporated mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 5) The organic phase was combined and dried over anhydrous sodium sulfate (mjjjjjjjjj 0.278 g, 70%). MS (ESI, pos.) m/z: 695.8 [M+1] ⁺

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 7.94 (s, 1H), 7.90 (s, 1H), 7.52 (d, J = 7.9Hz, 1H), 7.37 (d, J = 8.7Hz, 1H) , 7.32-7.25 (m, 3H), 5.93 (s, 1H), 5.23 (brs, 1H), 3.92-3.86 (m, 1H), 3.71 (s, 3H), 3.40-3.32 (m, 2H), 3.19 -3.13 (m, 5H), 2.74-2.65 (m, 4H), 2.38-2.29 (m, 2H), 1.69-1.51 (m, 2H), 1.05-0.96 (m, 2H).

Example 3

N-((10R,14S)-14-(4-(6-bromo-3-chloro-4-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl ) -10-methyl-9-oxo-8,16-diaza- tetracyclo [13.7.1.0 ^2,7 .0 ^17,22] tricosa-1 (23), 2 (7), 3 ,5,15,17(22)-hexaen-5-yl)carbamic acid methyl ester

Step 1: Methyl 4-hydroxy-5,6,7,8-tetrahydroquinoline-2-carboxylate (3A)

At room temperature, concentrated hydrochloric acid (200mL) and 4-hydroxy quinoline-2-carboxylate (50.00g, 246.08mmol) was added to the autoclave, the mixed system was stirred uniformly, added PtO _₂ -3H ₂ O ( 5.00 g, 17.79 mmol), sealed system, after replacing the gas with hydrogen, charged with hydrogen, and pressurized to about 3.4 MPa, and stirred at room temperature for two days. The intermediate gas pressure will drop, and after filling about 3-4 times of hydrogen, the system pressure will remain basically unchanged and the reaction will be stopped. The organic layer was concentrated under reduced pressure.

MS (ESI, pos. ion) m/z: 208.3 [M+1] ⁺ .

Step 2: 4-Bromo-5,6,7,8-tetrahydroquinoline-2-carboxylic acid methyl ester (3B)

Potassium carbonate (102.00g, 730.63mmol) was added to a solution of 3A (50.30g, 243.00mmol) in acetonitrile (500mL) at room temperature, the system was heated to 95 ° C, and added phosphorus bromide (210.00g) , 732.52 mmol), after the addition was completed, the system was refluxed for 4 hours. The reaction was quenched, the mixture was cooled to room temperature, and the supernatant was concentrated. The residue was evaporated and evaporated. Filtration and concentrating of the filtrate gave EtOAc (EtOAc:EtOAc:EtOAc

MS (ESI, pos.) m/z: 270.2 [M + 1] ⁺ .

Step 3: (4-Bromo-5,6,7,8-tetrahydroquinolin-2-yl)methanol (3C)

Sodium borohydride (3.20 g, 83.00 mmol) was added in portions to a solution of 3B (7.40 g, 27.4 mmol) in dry ethanol (100 mL), and then warmed to reflux for 3 hours. The reaction was quenched and cooled to room temperature. EtOAc (EtOAc) (EtOAc) Purification by column chromatography (EtOAc / EtOAc (EtOAc)

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 7.29 (s, 1H), 4.65 (s, 2H), 2.90 (t, J = 5.8Hz, 2H), 2.75 (t, J = 5.8Hz, 2H) , 1.96–1.74 (m, 4H).

Step 4: 4-Bromo-5,6,7,8-tetrahydroquinoline-2-carbaldehyde (3D)

3C (5.08 g, 21.00 mmol) was dissolved in dichloromethane (100 mL), cooled in ice-cooled, and then evaporated. The reaction was stopped, filtered, and the filter cake was washed with methylene chloride (50 mL). The organic layer was combined, and then the mixture was diluted with saturated sodium thiosulfate solution (25 mL) and saturated sodium hydrogen carbonate solution (25 mL). The organic layer was combined with EtOAc (EtOAc) (EtOAc)EtOAc. The ester (v/v) = 20/1) gave a white solid (4.56 g, 90.5%). ^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 9.96 (s, 1H), 7.96 (s, 1H), 3.02 (t, J = 5.6Hz, 2H), 2.83 (t, J = 5.8Hz, 2H) , 1.94-1.87 (m, 4H).

Step 5: (S)-N-((4-Bromo-5,6,7,8-tetrahydroquinolin-2-yl)methylene)-2-methylpropane-2-sulfinamide (3E )

Anhydrous copper sulfate (6.02 g, 38.03 mmol) and (S)-(-)-tert-butylsulfinamide (2.50 g, 20.61 mmol) were added to 3D (4.52 g, 8.81 mmol) at room temperature. In a solution of methyl chloride (100 mL), the resulting mixture was stirred at room temperature overnight. The stirring was stopped, the mixture was filtered, and the filtered cake was washed with methylene chloride (50 mL × 2). Bright yellow solid (6.40 g, 99.0%).

^{1 H NMR (400MHz, DMSO-} d 6) δ (ppm) 8.37 (s, 1H), 8.06 (s, 1H), 2.91 (s, 2H), 2.75 (s, 2H), 1.91-1.67 (m, 4H ), 1.19 (s, 9H).

Step 6: (S)-N-((S)-1-(4-Bromo-5,6,7,8-tetrahydroquinolin-2-yl)but-3-en-1-yl)-2 -methylpropane-2-sulfinamide (3F)

Allyl magnesium bromide (41.0 mL, 41.0 mmol, 1.0 mol/L in tetrahydrofuran) was slowly added dropwise to a solution of indium trichloride (9.10 g, 41.12 mmol) in tetrahydrofuran (100 mL) at -5 °C. After the dropwise addition was completed, the system was heated to room temperature and stirred for 1 hour. 3E (7.06 g, 20.61 mmol) of an absolute ethanol solution (60 mL) was added dropwise to the system, and the mixture was allowed to react at room temperature overnight. It was filtered, washed with dichloromethane (150 mL×3) and evaporated. Dichloromethane (500 mL) was added to the residue, and then washed with water (100 mL×2) and brine (150 mL). Ether/ethyl acetate (v/v) = 5/1) was purified to afford white crystals (5.91 g, 74.0%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 7.29 (s, 1H), 5.78-5.65 (m, 1H), 5.07 (d, J = 4.7Hz, 1H), 5.04 (s, 1H), 4.89 ( d, J = 6.9 Hz, 1H), 4.36 (q, J = 6.6 Hz, 1H), 2.88 (d, J = 3.8 Hz, 2H), 2.71 (s, 2H), 2.54 (dd, J = 6.8 Hz, 2H), 1.84-1.82 (m, 4H), 1.25 (s, 9H).

Step 7: (S)-1-(4-Bromo-5,6,7,8-tetrahydroquinolin-2-yl)but-3-en-1-amine (3G)

A 6 mol/L hydrochloric acid solution (82.5 mL, 495.00 mmol) was added to a 3F (5.92 g, 15.41 mmol) methanol solution (60 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction was stopped, the reaction solution was concentrated to remove methanol, and the aqueous layer was extracted with ethyl acetate (15 mL × 2), and the organic phase was combined, and the mixture was diluted with a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane (100 mL×3). Drying over anhydrous sodium sulfate, filtered, EtOAcqqqqq

MS (ESI, pos.) m/z: 281.1 [M + 1] ⁺ ;

^{1 H NMR (400MHz, DMSO-} d 6) δ (ppm) 8.39 (s, 2H), 7.65 (s, 1H), 5.68-5.62 (m, 1H), 5.09 (d, J = 4.7Hz, 1H), 5.05 (s, 1H), 4.38 (t, J = 6.9 Hz, 1H), 2.87 (s, 2H), 2.70 (s, 2H), 1.80 (s, 4H).

Step 8: (S)-(1-(4-Bromo-5,6,7,8-tetrahydroquinolin-2-yl)but-3-en-1-yl)carbamic acid tert-butyl ester (3H)

Di-tert-butyl dicarbonate (4.30 g, 4.5 mL, 19.03 mmol) was slowly added dropwise to a solution of 3G (4.30 g, 15.31 mmol) and triethylamine (2.22 g, 3.0 mL, 21.03 mmol) at room temperature. After drying in a dichloromethane (100 mL) solution, the mixture was stirred at room temperature for 6 hours. Dichloromethane (100 mL) was added to the mixture, and the mixture was washed with water (50 mL×2) and brine (50 mL). Purification with ethyl acetate (v/v) = 10/1) gave white solid (5. 4 g, 100%).

MS (ESI, pos.) m/z: 381.3 [M + 1] ⁺ .

Step 9: (S)-(1-(4-(4-Amino-2-nitrophenyl)-5,6,7,8-tetrahydroquinolin-2-yl)but-3-ene-1 -yl)-tert-butyl carbamate (3I)

3-Nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (6.92 g, 26.03 mmol), 3H (7.04 g, 18.52 mmol) and tricyclohexylphosphine (0.78 g, 2.78 mmol) were dissolved in N,N-dimethylformamide (100 mL), and 2 mol/L sodium carbonate aqueous solution (19.0 mL) was added to the system. , 38.02 mmol) and (dba) ₃ Pd(0) ₂ (1.71 g, 1.91 mmol), the incoming oxygen was replaced with nitrogen, and the system was heated to 90 ° C and stirred for 14 hours. The reaction was quenched, cooled to EtOAc EtOAc (EtOAc)EtOAc. Filtration and concentrating of the filtrate gave EtOAc (EtOAc:EtOAc.

MS (ESI, pos.) m/z: 439.3 [M + 1] ⁺ .

Step 10: (S)-(1-(4-(4-(methoxy)amino)-2-nitrophenyl)-5,6,7,8-tetrahydroquinolin-2-yl) Tert-butyl 3--3-en-1-ylcarbamate (3J)

A solution of methyl chloroformate (1.00 g, 0.82 mL, 10.59 mmol) in dichloromethane (50 mL) was slowly added dropwise to 3I (4.22 g, 9.62 mmol) and pyridine (2.31 g, 2. After a dropwise addition of a solution of 29.03 mmol of dichloromethane (100 mL), stirring was continued at -78 ° C for 2 hours. The reaction was stopped, and a saturated ammonium chloride solution (10 mL) was added to the mixture. After stirring for 5 minutes, the mixture was warmed to room temperature and stirred for 10 minutes. Dichloromethane (100 mL) was added, the system was washed with water (50 mL×2) and brine (30 mL). The ester (v/v) = 5/1) was purified to give a dark red crystal (4.35 g, 91.0%).

MS (ESI, pos.) m/z: 497.5 [M + 1] ⁺ .

Step 11: (S)-(1-(4-(4-(methoxy)amino)-2-aminophenyl)-5,6,7,8-tetrahydroquinolin-2-yl)- Tert-butyl 3-en-1-yl)carbamate (3K)

Zinc powder (4.51 g, 69.03 mmol) and ammonium chloride (3.71 g, 69.0 mmol) were added to a solution containing 3J (3.41 g, 6.87 mmol) in methanol (60 mL) at room temperature. hour. The reaction was stopped, filtered, and the filter cake was washed with methanol (10 mL×3), and the filtrate was concentrated. The residue was dissolved in dichloromethane (100 mL), washed with water (30mL×2) and brine (30mL) The sodium was dried, filtered, and evaporated tolululululululululululululululululululululululululululululululu

MS (ESI, pos.) m/z: 467.3 [M + 1] ⁺ .

Step 12: (S)-(1-(4-(4-(methoxy)amino)-2-((R)-2-methylbut-3-enoylamino)phenyl)-5,6 ,7,8-tetrahydroquinolin-2-yl)but-3-en-1-yl) Tert-butyl carbamate (3L)

A solution of (R)-2-methylbut-3-enoyl chloride (1.54 g, 13.01 mmol) in dichloromethane (10 mL) was slowly added to dissolve in 3K (2.02 g, 4.33 mmol) and Pyridine (1.41 g, 1.4 mL, 17.02 mmol) in dry methylene chloride (100 mL) was stirred at 0 ° C for 30 min then warmed to room temperature and stirring was continued for 5 hr. The reaction was stopped, and dichloromethane (100 mL) was further added to the mixture, and then washed with water (50 mL×2) and brine (50 mL). Column chromatography (petroleum ether / ethyl acetate (v/v) = 3/1) eluted to afford pale yellow solid (1.15 g, 48.4%).

MS (ESI, pos. ion) m/z: 549.3 [M+1] ⁺ .

Step 13: N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-8,16-diazatetracyclo[13.7.1.0 ^2.7 .0 ^{17, 22} ] icosane -1(23),2(7),3,5,11(12),15,17(22)-hepten-5-yl)carbamic acid methyl ester (3M)

Pentyl p-toluenesulfonic acid monohydrate (0.45 g, 2.30 mmol) was placed in a two-necked flask at room temperature, heated to 80 ° C, and dried under reduced pressure for about 1 hour. After cooling to room temperature, a solution of 3 L (1.15 g, 2.10 mmol) in dry dichloromethane (100 mL) was then poured into the system and stirred for 30 min. A solution of Grubbs 2 Generation Catalyst (0.54 g, 0.63 mmol) in dry dichloromethane (20 mL) was then taken and evaporated. The reaction was quenched and cooled to room temperature. Toluene (100 mL) and saturated aqueous sodium hydrogen carbonate (50 mL) was evaporated. After drying over anhydrous sodium sulfate, EtOAc (EtOAc m.) MS (ESI, pos. ion) m/z: 521.6 [M+1] ⁺ .

Step 14: N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-8,16-diazatetracyclo[13.7.1.0 ^2.7 .0 ^{17, 22} ] icosane -1(23),2(7),3,5,15,17(22)-hexaen-5-yl)carbamic acid methyl ester (3N)

10% Pd/C (0.07g) was added to a solution of 3M (0.69g, 1.33mmol) in anhydrous methanol (20mL) at room temperature, and replaced with hydrogen for 2-3 times under hydrogen atmosphere. Stir at room temperature overnight and stop the reaction. Filtration and concentration of the filtrate gave a pale-yellow solid (0.695 g, 100.0%).

MS (ESI, pos.) m/z: 523.4 [M + 1] ⁺ .

Step 15: N - ((10R, 14S) -14- amino-10-methyl-9-oxo-8,16-diaza- tetracyclo [13.7.1.0 ^2.7 .0 ^17,22] tricosane -1(23),2(7),3,5,15,17(22)-hexaen-5-yl)carbamic acid methyl ester (3O)

Trifluoroacetic acid (4.61 g, 3.0 mL, 40.02 mmol) was added to 3N (0.69 g, 1.33 mmol) in dry dichloromethane (30 mL) The reaction was quenched, EtOAc (EtOAc m. The combined organic layers were dried with EtOAc EtOAc EtOAcjjjjjjj

MS (ESI, pos.) m/z: 423.5 [M + 1] ⁺ .

Step 16: N-((10R,14S)-14-(3-(6-Bromo-3-chloro-2-fluorophenyl)-3-oxopropylamino)-10-methyl-9-oxo -8,16-diazatetracyclic [13.7.1.0 ^2.7 .0 ^17,22] tricosa-1 (23), 2 (7), 3,5,15,17 (22) - Six-5-yl) carbamate (3P )

Triethylamine (0.73 g, 1.0 mL, 7.21 mmol) was added EtOAc (EtOAc m. The solution was stirred at room temperature overnight. Ethyl acetate (50 mL) and water (20 mL) were evaporated, evaporated, evaporated, evaporated, evaporated. Purification by neutral alumina column chromatography (EtOAc/EtOAc (EtOAc) (EtOAc)

MS (ESI, pos.) m/z: 687.0 [M + 1] ⁺ .

Step 17: N-((10R,14S)-14-(N-(3-(6-bromo-3-chloro-2-fluorophenyl)-3-oxopropyl)-2-(diethoxy) Phosphoryl)acetamido)-10-methyl-9- Oxo-8,16-diaza- tetracyclo [13.7.1.0 ^2.7 .0 ^17,22] tricosa-1 (23), 2 (7), 3,5,15,17 (22) - six Methyl ene-5-yl)carbamate (3Q)

Add pyridine (0.098 g, 0.1 mL, 1.24 mmol) and 4-dimethylaminopyridine (0.025 g, 0.20 mmol) to a solution of 3P (0.13 g, 0.19 mmol) in dichloromethane (10 mL) A solution of (2-chloro-2-oxoethyl)phosphoric acid (0.11 g, 0.47 mmol) in dichloromethane (10 mL) was evaporated. The reaction was quenched, the mixture was cooled with EtOAc EtOAc (EtOAc)EtOAc. Concentration gave a white solid (0.16 g, 99.4.

MS (ESI, pos. ion) m/z: 865.0 [M+1] ⁺ .

Step 18: N-((10R,14S)-14-(4-(6-Bromo-3-chloro-4-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridine- 1-yl)-10-methyl-9-oxo-8,16-diazo Oxatetracyclo [13.7.1.0 ^2,7 .0 ^17,22] tricosa-1 (23), 2 (7), 3,5,15,17 (22) - Six-5-yl) amino Methyl formate

60% sodium hydride (0.066 g, 1.65 mmol) was placed in a two-necked flask at room temperature. After a nitrogen atmosphere, a solution of 3Q (0.72 g, 0.83 mmol) in dry tetrahydrofuran (5 mL) was poured in a syringe and stirred at room temperature for 30 min. . The reaction was stopped, a solution of dichloromethane (50 mL) and EtOAc (EtOAc m. Purification by column chromatography (EtOAc/EtOAc (EtOAc:EtOAc)

MS (ESI, pos.) m/z: 711.6 [M + 1] ⁺ ;

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 8.00 (s, 1H), 7.44 (d, J = 5.8Hz, 2H), 7.38 (d, J = 8.5Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.80 (s, 1H), 5.95 (s, 1H), 5.62 (dd, J = 11.6, 4.3 Hz, 1H), 4.68 - 4.55 (m, 1H), 3.98-3.91 (m, 1H) ), 3.59 (s, 3H), 2.94 - 2.72 (m, 4H), 2.61-2.55 (m, 1H), 2.44 - 2.37 (m, 2H), 2.09-1.99 (m, 2H), 1.98-1.88 (m , 2H), 1.86-1.70 (m, 4H), 1.64 - 1.45 (m, 4H), 0.97 (d, J = 6.9 Hz, 3H).

Example 4

N-((10R,14S)-14-(4-(6-bromo-3-chloro-4-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl ) -21- 9-oxo-10-methyl-8,16-diaza-oxa tetracyclo [13.7.1.0 ^2,7 .0 ^17,22] tricosa-1 (23), 2 (7), 3,5,15,17(22)-hexaen-5-yl)carbamic acid methyl ester

Step 1: 6-(Hydroxymethyl)-2-vinylpyridin-3-ol (4A)

Under a nitrogen atmosphere, a 2-bromo-6-(hydroxymethyl)pyridin-3-ol (40 g, 196.1 mmol), sodium carbonate (42 g, 396.3 mmol) aqueous solution (200 mL) and a tricyclic ring were sequentially added to a four-necked flask. Hexylphosphine (8.30 g, 29.6 mmol), (dba) ₃ Pd ₂ (9.00 g, 9.83 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaboron Pentacyclo(36.0 mL, 212 mmol) and N,N-dimethylformamide (900 mL) were then stirred and stirred at 100 ° C overnight. The mixture was cooled to room temperature, filtered, and evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

MS (ESI, pos.) m/z: 152.2 [M + 1] ⁺ .

Step 2: (5-(Allyloxy)-6-vinylpyridin-2-yl)methanol (4B)

2A (28 g, 185.2 mmol) and potassium carbonate (50 g, 361.8 mmol) were added to N,N-dimethylformamide (300 mL) at 0 ° C, then allyl bromide (16.5 mL, 191 mmol), after completion of the dropwise addition, the reaction was allowed to proceed to room temperature for 2 hours. The reaction was quenched with water and extracted with EtOAc EtOAc. The combined organic layers were washed with water (200 mL×2) and brine (200 mL) Filtration and evaporation of the solvent <RTI ID=0.0>

MS (ESI, pos.) m/z: 192.2 [M+1] ⁺ .

Step 3: (2H-pyrano[3,2-b]pyridin-6-yl)methanol (4C)

4B (11g, 57.5mmol) was dissolved in anhydrous toluene (300mL) under nitrogen, and Grubbs 2nd generation catalyst (10.0g, 11.8mmol) was added, stirred at room temperature for 30 minutes, heated to 60 ° C and stirred for 3 hours. . After cooling to room temperature, the solvent was evaporated. mjjjjjjjjj

MS (ESI, pos. ion) m/z: 164.0 [M+1] ⁺ .

Step 4: (3,4-Dihydro-2H-pyrano[3,2-b]pyridin-6-yl)methanol (4D)

4C (14 g, 85.8 mmol) was dissolved in anhydrous methanol (150 mL), and then 10% Pd / C (5.0 g, 4.7 mmol). Filtration over celite, EtOAc (EtOAc) (EtOAc (EtOAc)

MS (ESI, pos.) m/z: 166.2 [M + 1] ⁺ .

Step 5: 6-(Hydroxymethyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridine 5-oxide (4E)

4D (3.50 g, 21.2 mmol) was dissolved in dichloromethane (100 mL), cooled to 0 ° C, and m-chloroperoxybenzoic acid (4.70 g, 27.2 mmol) was added, and then allowed to react at room temperature for 5 hours. The solvent was evaporated under reduced pressure. EtOAcjjjjjjjj

Step 6: 8-Bromo-6-(bromomethyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridine (4F)

4E (1.0 g, 5.5 mmol) was dissolved in N,N-dimethylformamide (60 mL) and toluene (30 mL), and tribromophosphonate (3.2 g, 11 mmol) was slowly added and stirred at room temperature for 30 min. Further, phosphorus tribromide (3.2 g, 11 mmol) was added, followed by stirring at room temperature for 2 hours. The organic layer was washed with EtOAc (EtOAc) (EtOAc) Filtration and evaporation of the solvent <RTI ID=0.0>

MS (ESI, pos. ion) m/z: 308.0 [M+1] ⁺ .

Step 7: (8-Bromo-3,4-dihydro-2H-pyrano[3,2-b]pyridin-6-yl)methanol (4G)

4F (5.0 g, 16 mmol) was dissolved in acetone (100 mL), then a 20% aqueous sodium carbonate solution (80 mL) was added, and the mixture was heated to 70 ° C and stirred for 10 hours. It was cooled to room temperature and extracted with ethyl acetate (200 mL×2). The combined organic layers were washed with water (50 mL) and brine Filtration and evaporation of EtOAc.

MS (ESI, pos.) m/z:244.1 [M+1] ⁺ .

Step 8: 8-Bromo-3,4-dihydro-2H-pyrano[3,2-b]pyridine-6-carbaldehyde (4H)

4G (5.15 g, 21.1 mmol) was dissolved in dichloromethane <RTI ID=0.0>(</RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; The solvent was evaporated under reduced pressure. EtOAcjjjjjjjj

MS (ESI, pos. ion) m/z: 242.05 [M+1] ⁺ .

Step 9: (S,E)-N-((8-Bromo-3,4-dihydro-2H-pyrano[3,2-b]pyridin-6-yl)methylene)-2-methyl Propane-2-sulfinamide (4I)

4H (6.60 g, 27.3 mmol) was dissolved in dichloromethane (150 mL), (S)-(-)-tert-butylsulfinamide (5.00 g, 41.3 mmol) and anhydrous copper sulfate (22.0 g, 138 mmol), the system was stirred at room temperature for 2 days. The reaction was stopped, the Celite was filtered, and the filter cake was washed with dichloromethane. The filtrate was collected, washed with water (100 mL×2) and brine (50 mL) and dried over anhydrous sodium sulfate. Filtration and evaporation of EtOAc.

MS (ESI, pos.) m/z: 347.0 [M + 1] ⁺ .

Step 10: (S)-N-((S)-1-(8-Bromo-3,4-dihydro-2H-pyrano[3,2-b]pyridin-6-yl)but-3- En-1-yl)-2-methylpropane-2-sulfinamide (4J)

At about -20 ° C, allyl magnesium bromide (80.0 mL, 80.0 mmol, 1.0 mol/L in tetrahydrofuran) was slowly added dropwise to anhydrous tetrahydrofuran (18.0 g, 81.4 mmol). In 100 mL), the dropwise addition was completed, and the system was heated to room temperature and stirred for 1 hour. After cooling to -20 ° C, a solution of 4I (9.50 g, 27.5 mmol) in ethanol (120 mL) was added dropwise to the mixture. After the addition was completed, the reaction was continued for 2 hours. It was filtered and extracted with ethyl acetate (300 mL×2). The combined organic layers were washed with water (200 mL×2) and brine (200 mL) Filtration and evaporation of the solvent <RTI ID=0.0>

MS (ESI, pos.) m/z: 389.15 [M+1] ⁺ .

Step 11: (S)-1-(8-Bromo-3,4-dihydro-2H-pyrano[3,2-b]pyridin-6-yl)but-3-en-1-amine (4K )

4J (10.5 g, 27.1 mmol) was dissolved in anhydrous methanol (50 mL), then a solution of 4 mol/L hydrochloric acid (60 mL, 240 mmol) was added and the mixture was stirred at room temperature for 0.5 hour. The solvent was evaporated under reduced pressure, and the mixture was evaporated, m. The combined organic layers were washed with water (200 mL) and brine (100 mL) Filtration and evaporation of the solvent <RTI ID=0.0> The crude product was used directly in the next reaction.

MS (ESI, pos.) m/z: 283.15 [M+1] ⁺ .

Step 12: (S)-(1-(8-Bromo-3,4-dihydro-2H-pyrano[3,2-b]pyridin-6-yl)but-3-en-1-yl) Tert-butyl carbamate (4L)

4K (7.60 g, 26.8 mmol) was dissolved in dichloromethane (150 mL), then triethylamine ( 8.00 mL, 57.4 mmol) and Boc anhydride (7.10 mL, 31 mmol). The organic layer was combined and washed with water (100 mL×2) and brine (100 mL) Filtration and evaporation of the solvent <RTI ID=0.0> MS (ESI, pos. ion) m/z: 381.15 [M+1] ⁺ .

Step 13: (S)-(1-(8-(4-Amino-2-nitrophenyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridine-6-yl Tert-butyl 3-buten-1-yl)carbamate (4M)

4 L (10.0 g, 26.1 mmol), sodium carbonate (6.00 g, 56.6 mmol) in water (28 mL), tricyclohexylphosphine (1.10 g, 3.92 mmol), (dba) were sequentially added to a two-necked flask. ₃ Pd ₂ (2.50 g, 2.73 mmol), 3-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (10.0 g, 37.9 mmol) and N,N-dimethylformamide (300 mL) were stirred at 90 ° C overnight. After cooling to room temperature, the mixture was extracted with EtOAc (EtOAc) (EtOAc) Filtration and evaporation of the solvent <RTI ID=0.0></RTI></RTI><RTIID=0.0></RTI><RTIgt;

MS (ESI, pos.) m/z: 441.3 [M + 1] ⁺ .

Step 14: (S)-(1-(8-(4-(methoxy)amino)-2-nitrophenyl)-3,4-dihydro-2H-pyrano[3,2-b Pyridine-6-yl)but-3-en-1-yl)carbamate Tert-butyl acid ester (4N)

Methyl chloroformate (1.55 mL, 20.1 mmol) was slowly added dropwise to a solution of 4M (7.50 g, 17.0 mmol) and pyridine (4.50 mL, 55.9 mmol) in dichloromethane (100 mL) at -70 ° C Stir at -70 ° C for 2 hours. The reaction was quenched with a saturated aqueous solution of ammonium chloride and then extracted with dichloromethane (200 <RTIgt; The combined organic layers were washed with water (100 mL), brine Filtration and evaporation of the solvent <RTI ID=0.0>

MS (ESI, pos. ion) m/z: 499.3 [M+1] ⁺ .

Step 15: (S)-(1-(8-(4-(methoxy)amino)-2-aminophenyl)-3,4-dihydro-2H-pyrano[3,2-b] Pyridin-6-yl)but-3-en-1-yl)carbamate Tert-butyl acid ester (4O)

4N (7.20 g, 14.4 mmol) was dissolved in MeOH (200 mL). EtOAc (EtOAc:EtOAc: After filtration, the solvent was evaporated under reduced pressure and dichloromethane was evaporated. The combined organic layers were washed with water (100 mL), brine brine Filtration and evaporation of the solvent <RTI ID=0.0>

MS (ESI, pos. ion) m/z: 469.3 [M+1] ⁺ .

Step 16: (S)-(1-(8-(4-(methoxy)amino)-2-((R)-2-methylbut-3-enoylamino)phenyl)-3,4 -dihydro-2H-pyrano[3,2-b]pyridine-6- Tert-butyl 3-buten-1-yl)carbamate (4P)

4O (3.0 g, 6.4 mmol) was dissolved in dichloromethane (20 mL), pyridine (2.10 mL, 26.0 mmol) and (R)-2-methylbut-3-enoyl chloride (1.0) g, 8.4 mmol), stirring was continued at 0 ° C for 1 hour, and then stirred at room temperature for 3 hours. The organic layer was combined and washed with water (50 mL×2) and brine (40 mL). After filtration, the solvent was evaporated.jjjjjjlililililililililililili

MS (ESI, pos.) m/z: 551.2 [M+1] ⁺ .

Step 17: N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-21-oxa-8,16-diazatetracyclo[13.7.1.0 ^2,7 .0 ^17,22 ]Twenty Trioxane-1(23), 2(3),5,6,11(12),15,17(22)-hepten-5-yl)carbamic acid methyl ester (4Q)

The p-toluenesulfonic acid monohydrate (650 mg, 3.42 mmol) was placed in a two-necked flask at room temperature, heated to 80 ° C, and dried under reduced pressure for about 30 minutes. A solution of 4P (1.70 g, 3.09 mmol) in dry dichloromethane (90 mL) was then taken and then cooled to 45 &lt A solution of Grubbs 2nd generation catalyst (1.05 g, 1.24 mmol) in dry dichloromethane (50 mL) was then slowly poured into the system. After the addition was completed, the mixture was stirred at 45 ° C overnight. After cooling to room temperature, the solvent was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

MS (ESI, pos. ion) m/z: 523.2 [M+1] ⁺ .

Step 18: N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-21-oxa-8,16-diazatetracyclo[13.7.1.0 ^2,7 .0 ^17,22 ]Twenty Trioxane-1(23), 2(3),5,6,15,17(22)-hexaen-5-yl)carbamic acid methyl ester (4R)

4Q (990 mg, 1.894 mmol) was dissolved in methanol (150 mL), and 10% Pd/C (200 mg, 0.188 mmol) was added and stirred overnight under a hydrogen atmosphere of 4.0 MPa. Filtration over celite and evaporation of EtOAc EtOAc.

MS (ESI, pos. ion) m/z: 525.2 [M+1] ⁺ .

Step 19: N-((10R,14S)-14-Amino-10-methyl-9-oxo-21-oxa-8,16-diazatetracyclo[13.7.1.0 ^2,7 .0 ^{17 ,22} ]tetracosane -1(23),2(3),5,6,15,17(22)-hexaen-5-yl)carbamic acid methyl ester (4S)

4R (890 mg, 1.70 mmol) was dissolved in dichloromethane (10 mL). The reaction solution was neutralized with a saturated sodium hydrogen carbonate solution, and then extracted with dichloromethane (50 mL × 3). The combined organic layers were washed with water (20 mL×2) and brine (40 mL) Filtration and evaporation of the solvent <RTI ID=0.0> MS (ESI, pos. ion) m/z: 425.0 [M+1] ⁺ .

Step 20: N-((10R,14S)-14-(3-(6-bromo-3-chloro-2-fluorophenyl)-3-oxopropylamino)-10-methyl-9-oxo -21-oxa-8,16-diazatetracyclo [13.7.1.0 ^2,7 .0 ^17,22] tricosa-1 (23), 2 (3), 5,6,15,17 (22) - Six-5-yl) carbamate (4T)

4S (700 mg, 1.65 mmol) was dissolved in tetrahydrofuran (10 mL), triethylamine (1.20 mL, 8.63 mmol) was added, and then a solution of 1P (800 mg, 2.0439 mmol) in tetrahydrofuran (10 mL) was added and then stirred at room temperature 5 hour. The organic layer was extracted with EtOAc (EtOAc) (EtOAc) Filtration and evaporation of the solvent <RTI ID=0.0>

MS (ESI, pos.) m/z: 689.8 [M + 1] ⁺ .

Step 21: N-((10R,14S)-14-(N-(3-(6-bromo-3-chloro-2-fluorophenyl)-3-oxopropyl)-2-(diethoxy) Phosphoryl)acetamido)-10-methyl-9- -21- oxo-oxa-8,16-diaza- tetracyclo [13.7.1.0 ^2,7 .0 ^17,22] tricosa-1 (23), 2 (3), 5,6,15 ,17(22)-hexaen-5-yl)carbamic acid methyl ester (4U)

4T (400 mg, 0.581 mmol), (2-chloro-2-oxoethyl)phosphate (700 mg, 3.26 mmol), pyridine (0.25 mL, 3.1 mmol), 4-dimethylamino group were added to a microwave tube. Pyridine (70 mg, 0.573 mmol) and dichloromethane (15 mL) were then warmed to 50 ° C under microwave for 3 hours. After cooling to room temperature, it was extracted with dichloromethane (50 mL × 2). Filtration and evaporation of the solvent <RTI ID=0.0>

MS (ESI, pos.) m/z: 867.5 [M + 1] ⁺ .

Step 22: N-((10R,14S)-14-(4-(6-Bromo-3-chloro-4-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridine- 1-yl)-10-methyl-9-oxo-21-oxa 8,16-diaza- tetracyclo [13.7.1.0 ^2,7 .0 ^17,22] tricosa-1 (23), 2 (7), 3,5,15,17 (22) - six Methyl ene-5-yl)carbamate

4 U (500 mg, 0.577 mmol) of tetrahydrofuran (100 mL) was added to 60% sodium hydride (140 mg, 3.50 mmol), and then stirred at room temperature for 1 hour. The reaction was quenched with water (10 mL)EtOAc. The combined organic layers were washed with water (50 mL) and brine Filtration, and the solvent was evaporated under reduced pressure. EtOAcjjjjjjjjj 41.36%).

MS (ESI, pos.) m/z: 713.4 [M+1] ⁺ ;

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 9.58 (s, 1H), 7.96 (s, 1H), 7.59 (s, 2H), 7.40 (d, J = 8.7Hz, 1H), 7.33 (d, J=7.9 Hz, 2H), 6.00 (s, 1H), 5.05 (s, 2H), 4.39 (s, 2H), 3.80 (s, 4H), 3.28 (s, 2H), 2.73 (s, 2H), 2.64–2.39 (m, 1H), 2.28 (s, 2H), 2.06-1.76 (m, 2H), 1.68-1.52 (m, 2H), 1.28 (s, 3H), 1.10-0.97 (m, 2H).

Example 5

N-((10R,14S)-14-(4-(6-bromo-3-chloro-2-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl )-10-methyl-9-oxo-20-oxa-8,16-diazatetracyclo[13.6.1.0 ^2,7 .0 ^17,21 ]tetracosane-1 (22), 2 (7), 3,5,15,17(21)-hexaen-5-yl)carbamic acid methyl ester

Step 1: 2-Bromo-6-(hydroxymethyl)pyridin-3-ol (5A)

Potassium hydroxide (38 g, 677.3 mmol) was weighed into a flask, and water (260 mL), 2-bromopyridin-3-ol (100 g, 574.71 mmol), EDTA-2Na (4.36 g, 13.0 mmol) and formaldehyde were added thereto. Aqueous solution (38%, 156 mL) was warmed to 90 ° C for 5 hours. The reaction was stopped, cooled to room temperature, neutralized with acetic acid, and extracted with ethyl acetate (100 mL×2). The organic phase was washed with water (50 mL) and brine (50 mL) Yellow solid (101 g, 86.14%).

Step 2: (2-(Trimethylsilyl)furo[3,2-b]pyridin-5-yl)methanol (5B)

Weigh 5A (1.0g, 4.9mmol), bis(triphenylphosphine)palladium(II) chloride (80mg, 0.1140mmol) and cuprous iodide (40mg, 0.21mmol) in a two-necked bottle, nitrogen replacement Three times, tetrahydrofuran (20 mL), triethylamine (3.4 mL, 25 mmol) and trimethylsilylacetylene (1.0 mL, 7 mmol) were added thereto, and the mixture was heated to 80 ° C for 24 hours. After the reaction was completed, it was cooled to room temperature, filtered over EtOAc EtOAc (EtOAc)EtOAc. g, 46%).

MS (ESI, pos.) m/z: 222.2 [M + 1] ⁺ ;

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 7.76 (d, J = 8.0Hz, 1H), 7.16 (d, J = 7.1Hz, 1H), 7.13 (s, 1H), 4.87 (s, 2H) , 0.39 (s, 9H).

Step 3: Furo[3,2-b]pyridin-5-ylmethanol (5C)

5B (10.0 g, 45.2 mmol) was weighed into a flask, and methanol (100 mL) was added thereto, and a solution of sodium hydroxide (2.17 g, 54.3 mmol) in water (100 mL) was added thereto, and the mixture was reacted at room temperature for 24 hours. The reaction was quenched by EtOAc (EtOAc)EtOAc. After filtration, the solvent was evaporated to dryness crystals crystals crystals crystals

Step 4: (2,3-dihydrofuro[3,2-b]pyridin-5-yl)methanol (5D)

5C (1.0 g, 6.71 mmol) was weighed into an autoclave, and ethanol (15 mL), glacial acetic acid (5 mL) and 10% Pd/C (0.6 g) were added thereto, and reacted under a hydrogen atmosphere (3 MPa) at room temperature. 5 hours. The reaction was quenched, filtered over EtOAc EtOAc EtOAc (EtOAc)

MS (ESI, pos. ion) m/z: 152.25 [M+1] ⁺ .

Step 5: 5-(Hydroxymethyl)-2,3-dihydrofuro[3,2-b]pyridine 4-oxide (5E)

5D (23.06 g, 152.7 mmol) was weighed into a flask, and dichloromethane (500 mL) and m-chloroperoxybenzoic acid (31 g, 152.7 mmol) were added thereto, and reacted at room temperature for 24 hours. The reaction was quenched and EtOAc (EtOAc)EtOAc.

Step 6: 7-Bromo-5-(bromomethyl)-2,3-dihydrofuro[3,2-b]pyridine (5F)

5E (27 g, 161.52 mmol) was weighed into a flask, and N,N-dimethylformamide (1 L), toluene (0.5 L) and phosphorus bromide (185 g, 645 mmol) were added thereto, and the mixture was reacted at room temperature for 2 hours. The reaction was quenched with water (500 mL), EtOAc (EtOAc (EtOAc) (EtOAc) Filter, spin dry, and use the crude product directly for the next reaction.

Step 7: (7-Bromo-2,3-dihydrofuro[3,2-b]pyridin-5-yl)methanol (5G)

5F (15 g, 51.202 mmol) was weighed into a flask, and acetone (200 mL), water (200 mL) and potassium carbonate (30 g, 217.1 mmol) were added thereto, and the mixture was heated to 70 ° C overnight. The reaction was quenched, cooled to rt, EtOAc (EtOAc)EtOAc. v/v) = 3/1) gave a white solid (11.2 g, 95.1%).

MS (ESI, pos. ion) m/z: 2321. [M+1] ⁺ .

Step 8: 7-Bromo-2,3-dihydrofuro[3,2-b]pyridine-5-carbaldehyde (5H)

5G (5.6 g, 24 mmol) was weighed into a flask, and dichloromethane (120 mL) and Dess-Martin oxidizing agent (15.5 g, 36.5 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched, and the residue was evaporated,jjjjjjjjj

MS (ESI, pos.) m/z: 228.0 [M+1] ⁺ ;

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 9.92 (d, J = 7.6Hz, 1H), 9.88 (s, 1H), 7.95 (s, 1H), 7.79 (d, J = 8.3Hz, 1H) , 7.10 (d, J = 8.3 Hz, 1H), 4.88 (t, J = 9.0 Hz, 2H), 4.79 (t, J = 8.9 Hz, 1H), 3.50 (t, J = 8.9 Hz, 2H), 3.41 (t, J = 8.9 Hz, 2H).

Step 9: (S,E)-N-((7-Bromo-2,3-dihydrofuro[3,2-b]pyridin-5-yl)methylene)-2-methylpropane-2 - sulfinamide (5I)

(S)-(-)-tert-butylsulfinamide (8.93 g, 73.7 mmol) and copper sulfate (17.81 g, 111.6 mmol) were added to 5H (8.16 g, 35.8 mmol) of dichloromethane. In a solution of 300 mL), the resulting mixed system was stirred at room temperature for 18 hours. The reaction was quenched, the reaction mixture was filtered with EtOAc (EtOAc)

Step 10: (S)-N-((S)-1-(7-Bromo-2,3-dihydrofuro[3,2-b]pyridin-5-yl)but-3-ene-1- Base)-2-methylpropane-2-sulfinamide (5J)

Allyl magnesium bromide (175 mL, 175 mmol, 1 mol/L tetrahydrofuran solution) was added dropwise to a solution of indium trichloride (25.43 g, 115.0 mmol) in tetrahydrofuran (300 mL) at -5 °C. After the addition was completed, the mixture was allowed to react to room temperature for 1 hour. A 5I (18.66 g, 56.34 mmol) solution of ethanol (170 mL) was added dropwise to the reaction mixture, and the mixture was reacted at this temperature for 2 hours. The reaction was quenched and the mixture was filtered with EtOAc EtOAc EtOAc (EtOAc) The residue was dried with EtOAc EtOAc EtOAcjjjjjjj

MS (ESI, pos.) m/z: 374.0 [M + 1] ⁺ .

Step 11: (S)-1-(7-Bromo-2,3-dihydrofuro[3,2-b]pyridin-5-yl)but-3-en-1-amine (5K)

5 J (16 g, 42.86 mmol) was weighed into a flask, and methanol (200 mL) and a 6 mol/L hydrochloric acid solution (230 mL, 1380 mmol) were added to the flask, and the mixture was stirred at room temperature for 1 hour. The reaction was stopped, the methanol was evaporated under reduced pressure, and then a saturated sodium carbonate solution was added to the mixture to the mixture, and extracted with dichloromethane (200 mL × 2), dried, filtered, and evaporated to give a brown-brown liquid (11.21 g, 97.18%).

MS (ESI, pos. ion) m/z: 270.05 [M+1] ⁺ .

Step 12: (S)-(1-(7-Bromo-2,3-dihydrofuro[3,2-b]pyridin-5-yl)but-3-en-1-yl)carbamic acid tert-butyl Ester (5L)

5K (11.21 g, 41.65 mmol) was weighed into a flask, dichloromethane (300 mL) and triethylamine (15 mL, 108 mmol) were added thereto, and then di-tert-butyl dicarbonate (17 mL) was added dropwise to the system. 73.9 mmol), and the reaction was carried out for 5 hours at room temperature after completion of the dropwise addition. Dichloromethane (200 mL) was added to the mixture. EtOAc (EtOAc m. .

MS (ESI, pos.) m/z: 370.2 [M + 1] ⁺ .

Step 13: (S)-(1-(7-(4-Amino-2-nitrophenyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)butene-3 -en-1-yl)carbamic acid tert-butyl ester (5M)

Weigh 5L (22.16g, 60.02mmol), 3-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (10g , 37.86 mmol), N,N-dimethylformamide (250 mL), and a 2 mol/L sodium carbonate solution (50 mL, 100 mmol) were added to the flask, and tricyclohexylphosphine (1.9 g, 6.8 mmol) was quickly added thereto. The oxygen contained in the system was replaced with nitrogen, and then (dba) ₃ Pd ₂ (4.3 g, 4.7 mmol) was quickly added, and the oxygen contained in the system was replaced with nitrogen, and the system was reacted at 100 ° C for 12 hours. The reaction was quenched, and the reaction mixture was filtered with EtOAc EtOAc (EtOAc)EtOAc. The residue was purified by EtOAc EtOAcjjjjjjjj

MS (ESI, pos.) m/z: 427.2 [M + 1] ⁺ .

Step 14: (S)-(1-(7-(4-(methoxy)amino)-2-nitrophenyl)-2,3-dihydrofuro[3,2-b]pyridine-5 -yl)but-3-en-1-yl)carbamic acid Butyl ester (5N)

5M (8.2 g, 19 mmol) and pyridine (4.8 mL, 60 mmol) were added to a two-necked flask, dichloromethane (200 mL) was added thereto, and the mixture was cooled to -78 ° C, and methyl chloroformate (1.7) was slowly added dropwise to the system. A solution of mL, 22 mmol) in dichloromethane (100 mL) was then stirred at -78.degree. The reaction was quenched, saturated ammonium chloride (20 mL) was added and stirred for 5 min, then warmed to room temperature and stirred for 10 min. Dichloromethane (200 mL) was added to the mixture. The mixture was washed with water (200 mL) and brine (200 mL) .

MS (ESI, pos. ion) m/z: 485.3 [M+1] ⁺ .

Step 15: (S)-(1-(7-(4-(methoxy)amino)-2-aminophenyl)-2,3-dihydrofuro[3,2-b]pyridine-5- Tert-but-3-en-1-yl)carbamic acid Butyl ester (5O)

Zinc powder (15.36 g, 234.8 mmol) and ammonium chloride (12.58 g, 784.2 mmol) were added to a solution of 5N (11.4 g, 23.5 mmol) in methanol (300 mL) at room temperature for 12 hours at room temperature. The reaction was terminated, the reaction solution was suction filtered with celite, and the filter cake was washed with methanol (50mL×3), the solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (300 mL). Washed with saturated brine (300 mL), dried over anhydrous sodium sulfate.

MS (ESI, pos. ion) m/z: 455.2 [M+1] ⁺ .

Step 16: (S)-(1-(7-(4-(methoxy)amino)-2-((S)-2-methylbut-3-enoylamino)phenyl)-2,3 -dihydrofuro[3,2-b]pyridin-5-yl) Tert-butyl 3--3-en-1-ylcarbamate (5P)

5O (5.2 g, 11 mmol) was dissolved in dichloromethane (80 mL), and pyridine (3.7 mL, 46 mmol). (R)-2-methylbut-3-enoyl chloride (2.24 g, 18.9 mmol) in dichloromethane (80 mL) was added dropwise to the reaction flask, and after the addition was completed, stirring was continued for 1 hour, and then The reaction was continued for 1 hour while moving to room temperature. The reaction was terminated, water (300 mL) was added to a reaction mixture, and the mixture was combined with methylene chloride (40 mL×10), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered and dried. Purification with ethyl acetate (v/v) = 5/1)

MS (ESI, pos.) m/z: 537.2 [M+1] ⁺ .

Step 17: N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-20-oxa-8,16-diazatetracyclo[13.6.1.0 ^2.7 .0 ^17,21 ] twenty Dioxane-1(22),2(3),4,6,11(12),15,17(21)-hepten-5-yl)carbamic acid methyl ester (5Q)

At room temperature, p-toluenesulfonic acid monohydrate (1.75 g, 9.20 mmol) was weighed into a two-necked flask, and the two vials were placed in a 60 ° C oil bath and dried under reduced pressure for 1 hour. The heating was turned off and a solution of 5P (4.5 g, 8.4 mmol) dry methylene chloride (250 mL) was then taken and cooled to room temperature and stirred for 10 min. Further, a solution of Grubbs 2nd generation catalyst (2.2 g, 2.6 mmol) in dry dichloromethane (50 mL) was added dropwise to the mixture. After the dropwise addition, the system was stirred under reflux at 45 ° C for 12 hours. The reaction was quenched, cooled to EtOAc EtOAc (EtOAc) .

MS (ESI, pos.) m/z: 509.4 [M+1] ⁺ .

Step 18: N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-20-oxa-8,16-diazatetracyclo[13.6.1.0 ^2.7 .0 ^17,21 ] twenty Dioxane-1(22),2(3),4,6,15,17(21)-hexaen-5-yl)carbamic acid methyl ester (5R)

5Q (1.38 g, 2.71 mmol) was weighed into the autoclave at room temperature, methanol (100 mL) and 10% Pd/C (0.3 g) were added thereto, and hydrogen gas was charged to 5 MPa, and stirred at room temperature for 8 hours. The reaction was quenched, and the mixture was filtered over EtOAc EtOAcjjjjjjjj

MS (ESI, pos. ion) m/z: 511.3 [M+1] ⁺ .

Step 19: N-((10R,14S)-14-Amino-10-methyl-9-oxo-20-oxa-8,16-diazatetracyclo[13.6.1.0 ^2.7 .0 ^17,21 Tetane -1(22),2(3),4,6,15,17(21)-hexaen-5-yl)carbamic acid methyl ester (5S)

5R (1.4 g, 2.7 mmol) was weighed into a flask, and dried dichloromethane (80 mL) and trifluoroacetic acid (6.2 mL, 83 mmol) were added, and the mixture was stirred at room temperature for 10 hours. The reaction was terminated, and the solvent was evaporated under reduced pressure. ethyl acetate (30mL) and saturated sodium carbonate solution (20mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The organic phase was separated, EtOAc (EtOAc m.

MS (ESI, pos.) m/z: 411.3 [M + 1] ⁺ .

Step 20: N-((10R,14S)-14-(3-(6-bromo-3-chloro-2-fluorophenyl)-3-oxopropylamino)-10-methyl-9-oxo -20-oxa-8,16-diazatetracyclo [13.6.1.0 ^2.7 .0 ^17,21 ]Tetradane-1(22),2(3),4,6,15,17(21)-hexaen-5-yl)carbamic acid methyl ester (5T )

5S (1.07 g, 2.61 mmol) was weighed into a flask, and tetrahydrofuran (60 mL) and triethylamine (2 mL, 14.4 mmol) were added thereto, and a solution of 1P (1.53 g, 3.91 mmol) in tetrahydrofuran (40 mL) was added and added. After completion, it was stirred at room temperature for 13 hours. The reaction was quenched, and the solvent was evaporated evaporated evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 4) The organic phases were combined and dried over anhydrous sodium sulfate.

MS (ESI, pos.) m/z: 674.8 [M+1] ⁺ .

Step 21: N-((10R,14S)-14-(N-(3-(6-bromo-3-chloro-2-fluorophenyl)-3-oxopropyl)-2-(diethoxy) Phosphoryl)acetamido)-10-methyl-9- Oxo-20-oxa-8,16-diazatetracyclo[13.6.1.0 ^2.7 .0 ^17,21 ]tetracosane-1 (22), 2 (3), 4, 6, 15, 17 (21)-hexaen-5-yl)carbamic acid methyl ester (5U)

Pyridine (0.36 mL, 4.5 mmol), 4-dimethylaminopyridine (0.13 g, 1.1 mmol) and diethyl (2-chloro-2-oxoethyl)phosphate (1 g, 4.6603 mmol) at rt. It was added to a solution of 5T (0.6 g, 0.9 mmol) in dichloromethane (20 mL). The reaction was quenched, cooled to rt. EtOAc (EtOAc)EtOAc. The filtrate was dried to give a tan solid (0.8 g, 100%).

MS (ESI, pos. ion) m/z: 853.6 [M+1] ⁺ .

Step 22: N-((10R,14S)-14-(4-(6-bromo-3-chloro-2-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridine- 1-yl)-10-methyl-9-oxo-20-oxa -8,16-diazatetracyclo[13.6.1.0 ^2,7 .0 ^17,21 ]docosane-1(22),2(7),3,5,15,17(21)-six Methyl ene-5-yl)carbamate

60% sodium hydride (0.05 g, 1 mmol) was weighed into a flask, and tetrahydrofuran (5 mL) was added to the flask under a nitrogen atmosphere, and a solution of 5 U (0.2 g, 0.2 mmol) in tetrahydrofuran (15 mL) was added to the flask. Stir at room temperature for 1 hour. The reaction mixture was quenched with water (15 mL), and the solvent was evaporated, evaporated, evaporated. The aqueous phase was extracted with methylene chloride (30 mL×3). EtOAc (EtOAc) = 3/1) gave a brown-red solid (0.073 g, 40%).

MS (ESI, pos.) m/z: 698.5 [M+1] ⁺

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 8.73 (s, 1H), 7.84-7.80 (s, 2H), 7.57-7.50 (m, 2H), 7.37 (d, J = 8.8Hz, 1H), 7.31(s,1H), 7.24(s,1H), 5.95(s,1H), 5.25(s,1H),5.11-4.71(m,6H),4.01(s,1H),3.81(s,1H) ), 3.69 (s, 3H), 2.87-2.81 (m, 1H), 2.70-2.61 (m, 2H), 2.51-2.45 (m, 1H), 1.97 - 1.75 (m, 2H), 1.65-1.56 (m , 1H), 1.04 (d, J = 5.0 Hz, 3H).

Example 6

N-((10R,14S)-14-(4-(6-bromo-3-chloro-4-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl ) -10-methyl-9-oxo-dioxa-8,16-diaza -18,21- tetracyclo [13.7.1.0 ^2,7 .0 ^17,22] tricosa-1 (23 ), 2(7),3,5,15,17(22)-hexaen-5-yl)carbamic acid methyl ester

Step 1: 2-((2-Bromo-6-(hydroxymethyl)-4-iodopyridin-3-yl)oxy)ethanol (6A)

2-Bromo-6-(hydroxymethyl)-4-iodopyridin-3-ol (30 g, 90.93 mmol) and potassium carbonate (25 g, 180.88 mmol) were dissolved in N,N-dimethylformamide (200 mL) Then, 2-bromoethanol (11 mL, 155 mmol) was added, and the mixture was stirred at 100 ° C for 3 hours. It was cooled to room temperature, adjusted to pH = 4 with 1 mol/L of diluted hydrochloric acid, and extracted with ethyl acetate (300 mL × 2). The combined organic layers were washed with water (200 mL) and brine After filtration, the solvent was evaporated.jjjjjjjjjjjj

MS (ESI, pos.) m/z: 374.0 [M + 1] ⁺ .

Step 2: (8-Iodo-2,3-dihydro-[1,4]dioxa[2,3-b]pyridin-6-yl)methanol (6B)

6A (650 mg, 1.74 mmol), powdered potassium hydroxide (200 mg, 3.56 mmol) and 18-crown-6 (700 mg, 2.65 mmol) were dissolved in toluene (50 mL) and then stirred to 135 ° C for 2 hours. It was adjusted to pH = 4 with 1 mol/L of diluted hydrochloric acid, and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with water (40 mL), brine Filtration and evaporation of the solvent <RTI ID=0.0></RTI>

MS (ESI, pos. ion) m/z: 294.1 [M+1] ⁺

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 7.35 (s, 1H), 4.59 (s, 2H), 4.48 (dd, J = 5.1,2.9Hz, 2H), 4.38 (dd, J = 5.1,2.9 Hz, 2H), 2.81 (s, 1H).

Step 3: 8-Iodo-2,3-dihydro-[1,4]dioxa[2,3-b]pyridine-6-carbaldehyde (6C)

6B (6.10 g, 20.8 mmol) was dissolved in dichloromethane (150 mL) then EtOAc EtOAc (EtOAc &EtOAc The solvent was evaporated under reduced pressure. EtOAcjjjjjjjj

MS (ESI, pos. ion) m/z: 2921. [M+1] ⁺ .

Step 4: (S,E)-N-((8-iodo-2,3-dihydro-[1,4]dioxa[2,3-b]pyridin-6-yl)methylene)- 2-methylpropane-2-sulfinamide (6D)

6C (6.10 g, 20.96 mmol) was dissolved in dichloromethane (100 mL), (S)-(-)-tert-butylsulfinamide (2.80 g, 23.1 mmol) and anhydrous copper sulfate (10.00 g, 62.65 mmol), then stirred at room temperature for 2 days. The reaction was quenched, filtered through celite and washed with dichloromethane. The filtrate was collected, and the solvent was evaporated to dryness to give a brown solid (8.20 g, 99.2%).

MS (ESI, pos. ion) m/z: 395.3 [M+1] ⁺ .

Step 5: (S)-N-((S)-1-(8-iodo-2,3-dihydro-[1,4]dioxa[2,3-b]pyridin-6-yl) 3--3-en-1-yl)-2-methylpropane-2-sulfinamide (6E)

Allyl magnesium bromide (2.54 mL, 2.54 mmol, 1.0 mol/L tetrahydrofuran solution) was slowly added dropwise to a solution of indium trichloride (565 mg, 2.55 mmol) in tetrahydrofuran (9.0 mL) at -20 °C. After the completion of the dropwise addition, the system was warmed to room temperature and stirred for 0.5 hours. A solution of 6D (500 mg, 1.27 mmol) in ethanol (6 mL) was added dropwise to the system at -20 ° C. After the addition was completed, stirring was continued at this temperature for 3 hours. The reaction was quenched and extracted with EtOAc (EtOAc) (EtOAc) Filtration and evaporation of the solvent <RTI ID=0.0>

MS (ESI, pos. ion) m/z: 437.3 [M+1] ⁺ .

Step 6: (S)-1-(8-iodo-2,3-dihydro-[1,4]dioxa[2,3-b]pyridin-6-yl)but-3-ene-1- Amine (6F)

6E (432 mg, 0.99 mmol) was dissolved in methanol (7 mL), and then a 6 mol/L hydrochloric acid solution (3 mL, 9.3 mmol) was added and stirred at room temperature for 0.5 hour. The solvent was evaporated under reduced pressure to give white crystals (d. The crude product was used directly in the next reaction.

MS (ESI, pos. ion) m/z: 332.9 [M+1] ⁺ .

Step 7: (S)-(1-(8-iodo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)but-3-ene-1 -yl)-tert-butyl carbamate (6G)

6F (320 mg, 0.96 mmol) was dissolved in dichloromethane (20 mL), triethylamine (0.30 mL, 2.2 mmol) and di-tert-butyl dicarbonate (0.25 mL, 1.1 mmol), then stirred at room temperature 2 hour. The reaction was stopped and extracted with dichloromethane (50 mL x 2). The combined organic layers were washed with water (20 mL×2) and brine (40 mL) Filtration and evaporation of the solvent <RTI ID=0.0>

MS (ESI, pos.) m/z: 432.9 [M+1] ⁺ .

Step 8: (S)-(1-(8-(4-Amino-2-nitrophenyl)-2,3-dihydro-[1,4]dioxa[2,3-b]pyridine- 6-yl)but-3-en-1-yl)carbamic acid tert-butyl ester (6H)

Under a nitrogen atmosphere, 3-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (410 mg, was added sequentially to a two-necked flask. 1.397 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (100 mg, 0.109 mmol), cesium carbonate (600 mg, 1.8415 mmol), 6 g (400 mg) , 0.926 mmol), 1,4-dioxane (20.0 mL) and water (5.0 mL), then heated to 50 ° C and stirred for 5 hours. The reaction was quenched, cooled to room temperature and extracted with EtOAc EtOAc. The combined organic layers were washed with water (40 mL×2) and brine (40 mL) Filtration and evaporation of EtOAc.

MS (ESI, pos.) m/z: 443.5 [M + 1] ⁺ .

Step 9: (S)-(1-(8-(4-(methoxy)amino)-2-nitrophenyl)-2,3-dihydro-[1,4]dioxin[2, 3-b]pyridin-6-yl)but-3-en-1-yl)carbamate Tert-butyl acid ester (6I)

The methyl chloroformate (0.050 mL, 0.65 mmol) was slowly added dropwise to a solution of 6H (255 mg, 0.576 mmol) and pyridine (0.14 mL, 1.7 mmol) in dichloromethane (10 mL) at -70 ° C, then Stir at -70 ° C for 1.5 hours. The reaction was quenched and the reaction was quenched with saturated aq. EtOAc. The combined organic layers were washed with water (40 mL), brine Filtration and evaporation of the solvent <RTI ID=0.0>

MS (ESI, pos. ion) m/z: 501.5 [M+1]+.

Step 10: (S)-(1-(8-(4-(methoxy)amino)-2-aminophenyl)-2,3-dihydro-[1,4]dioxo[2,3 -b]pyridine-6-yl)but-3-en-1-yl)amino Tert-butyl formate (6J)

6I (285 mg, 0.57 mmol) was dissolved in MeOH (20 mL), then EtOAc (EtOAc, EtOAc (EtOAc) The reaction was quenched, filtered, and evaporated to dryness crystals MS (ESI, pos.ion) m / z: 471.5 [M + 1] +.

Step 11: (S)-(1-(8-(4-(methoxy)amino)-2-((R)-2-methylbut-3-enoylamino)phenyl)-2,3 -dihydro-[1,4]dioxa-[2,3-b]pyridine-6- Tert-butyl 3-buten-1-yl)carbamate (6K)

6 J (3.8 g, 8.1 mmol) was dissolved in dichloromethane (5 mL) at 0 ° C then pyridine (2.6 mL, 32 mmol) and (R)-2-methylbut-3-enoyl chloride (1.1) g, 9.3 mmol), stirring was continued at 0 ° C for 1 hour and then stirred at room temperature for 3 hours. The reaction was quenched and extracted with dichloromethane (30 mL×3). Filtration, the solvent was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

MS (ESI, pos.ion) m / z: 553.1 [M + 1] +.

Step 12: N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-18,21-dioxa-8,16-diazatetracyclo[ 13.7.1.0 ^2,7 .0 ^17,22] Tridecane-1(23), 2(7),3,5,11(12),15,17(22)-hepten-5-yl)carbamic acid methyl ester (6L)

The p-toluenesulfonic acid monohydrate (155 mg, 0.815 mmol) was placed in a two-necked flask at room temperature, heated to 80 ° C, and dried under reduced pressure for about 30 minutes. A solution of 6K (1.85 g, 3.35 mmol) in dry methylene chloride (15 mL) was then taken and then cooled to room temperature and stirred for 30 min. A solution of Grubbs 2nd generation catalyst (860 mg, 1.01 mmol) in dry dichloromethane (15 mL) was then taken and taken and evaporated. The reaction was quenched, cooled to room temperature and extracted with dichloromethane (50 mL×3). The combined organic layers were washed with water (50 mL×2) and brine (50 mL) Filtration, the solvent was evaporated to dryness crystalljjjjjjjjjjjjjj

MS (ESI, pos. ion) m/z: 525.3 [M+1] ⁺ .

Step 13: N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-18,21-dioxa-8,16-diazatetracyclo[ 13.7.1.0 ^2,7 .0 ^17,22] Tridecane-1(23),2(7),3,5,15,17(22)-hexaen-5-yl)carbamic acid methyl ester (6M)

6 L (180 mg, 0.343 mmol) was dissolved in methanol (50 mL), and then 10% Pd/C (50 mg, 0.047 mmol) was added and stirred under a hydrogen atmosphere of 3 MPa for 5 hours. The reaction was quenched, EtOAc (EtOAc m. The resulting product was used directly in the next reaction.

MS (ESI, pos.) m/z: 527.3 [M + 1] ⁺ .

Step 14: N-((10R,14S)-14-Amino-10-methyl-9-oxo-18,21-dioxa-8,16-diazatetracyclo[13.7.1.0 ^2,7 .0 ^17,22 ]tetracosane -1(23),2(7),3,5,15,17(22)-hexaen-5-yl)carbamic acid methyl ester (6N)

6M (156 mg, 0.296 mmol) was dissolved in dichloromethane <RTI ID=0.0> The reaction was stopped, and the reaction solution was neutralized with a saturated sodium hydrogen carbonate solution, and then extracted with dichloromethane (50 mL × 3). The combined organic layers were washed with water (20 mL×2) and brine (40 mL) Filtration and evaporation of the solvent <RTI ID=0.0>

MS (ESI, pos.) m/z: 427.3 [M + 1] ⁺ .

Step 15: N-((10R,14S)-14-(3-(6-Bromo-3-chloro-2-fluorophenyl)-3-oxopropylamino)-10-methyl-9-oxo -18,21-dioxa-8,16-diaza Tetracyclo [13.7.1.0 ^2,7 .0 ^17,22] tricosa-1 (23), 2 (7), 3,5,15,17 (22) - Six-5-yl) carbamic acid Methyl ester (6O)

6N (110 mg, 0.258 mmol) was dissolved in tetrahydrofuran (10 mL), triethylamine (0.18 mL, 1.3 mmol). The organic layer was extracted with EtOAc (EtOAc) (EtOAc) Filtration and evaporation of the solvent in vacuo to give a brown solid (yield:

MS (ESI, pos.) m/z: 691.1 [M+1] ⁺ .

Step 16: N-((10R,14S)-14-(N-(3-(6-bromo-3-chloro-2-fluorophenyl)-3-oxopropyl)-2-(diethoxy) Phosphoryl)acetamido)-10-methyl-9- Oxo-dioxa-8,16-diaza -18,21- tetracyclo [13.7.1.0 ^2,7 .0 ^17,22] tricosa-1 (23), 2 (7), 3, 5,15,17(22)-hexaen-5-yl)carbamic acid Methyl ester (6P)

6O (90 mg, 0.1304 mmol), (2-chloro-2-oxoethyl)phosphate (200 mg, 0.932 mmol), pyridine (0.1 mL, 1.24 mmol), 4-dimethylamino group were added to a microwave tube. Pyridine (20 mg, 0.164 mmol) and dichloromethane (15 mL) were then stirred in vacuo to 50 ° C for 3 hours. The reaction was stopped, cooled to room temperature and extracted with dichloromethane (50 mL×2). The combined organic layers were washed with EtOAc EtOAc EtOAc.

MS (ESI, pos.) m/z: 869.5 [M+1] ⁺ .

Step 17: N-((10R,14S)-14-(4-(6-Bromo-3-chloro-4-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridine- 1-yl)-10-methyl-9-oxo-18,21-dioxo Heteroaryl 8,16-diaza tetracyclo [13.7.1.0 ^2,7 .0 ^17,22] tricosa-1 (23), 2 (7), 3,5,15,17 (22) - Methyl hexene-5-yl)carbamate

6P (100 mg, 0.115 mmol) in tetrahydrofuran (15 mL) was added to 60% sodium hydride (30 mg, 0.75 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction was quenched and the mixture was quenched with EtOAc (EtOAc) The combined organic layers were washed with water (50 mL) and brine Filtration, and the solvent was evaporated under reduced pressure. EtOAcjjjjjjjjj 12.2%).

MS (ESI, pos.) m/z: 715.2 [M + 1] ⁺ ;

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 8.57 (s, 1H), 7.53-7.49 (m, 2H), 7.39 (d, J = 8.6Hz, 1H), 7.32-7.28 (m, 3H), 6.06(s,1H), 5.38-5.36(m,2H),4.99(s,2H),4.66-4.56(m,2H),4.41-4.33(m,2H),4.07(s,1H),3.88( s, 1H), 3.78 (s, 3H), 2.74 - 2.64 (m, 2H), 2.38 - 2.27 (m, 1H), 1.87-1.80 (m, 2H), 1.52-1.41 (m, 2H), 1.03 ( d, J = 5.6 Hz, 3H).

Example 7

N-((10R,14S)-14-(4-(6-bromo-3-chloro-2-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl )-10-methyl-9-oxo-1,8,22-triazatetracyclo[13.6.1.0 ^2,7 .0 ^16,21 ]docosane-2(7),3,5, Methyl 15(22),16(21),17,19-hepten-5-yl)carbamate

Step 1: 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbaldehyde (7A)

1H-carbazole-3-carbaldehyde (10.0 g, 68.4 mmol) was dissolved in dichloromethane (50 mL), and tetrabutylammonium bromide (230 mg, 0.7134 mmol), 50% potassium hydroxide was added. Aqueous solution (50 mL), 2-(chloromethoxy)ethyl-trimethyl-silane (13.5 mL, 76.3 mmol). The reaction was quenched and extracted with dichloromethane (200 mL×2). Filtration and evaporation of the solvent <RTI ID=0.0>

MS (ESI, pos. ion) m/z: 277.2 [M+1] ⁺ .

Step 2: (S,E)-2-Methyl-N-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)) Propane-2-sulfinamide (7B)

7A (2.50 g, 9.04 mmol) was dissolved in dichloromethane (100 mL), (S)-(-)-tert-butylsulfinamide (1.30 g, 10.7 mmol) and anhydrous copper sulfate (5.80 g, 36.3 mmol), then stirred at room temperature overnight. The reaction was quenched, filtered through celite and washed with dichloromethane. The filtrate was collected, washed with water (20 mL×2) and brine (40 mL) Filtration and evaporation of the solvent <RTI ID=0.0>

MS (ESI, pos. ion) m/z: 380.25 [M+1] ⁺ .

Step 3: (S)-2-Methyl-N-((S)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3- Butyr-3-en-1-yl)propane-2-sulfinamide (7C)

Allyl magnesium bromide (16.5 mL, 16.5 mmol, 1.0 mol/L in tetrahydrofuran) was slowly added dropwise to tetrahydrofuran (50 mL) in which indium trichloride (3.60 g, 16.3 mmol) was dissolved at -20 °C. Then, the system was warmed to room temperature and stirred for 1 hour. After cooling to -20 ° C, a solution of 7B (3.00 g, 7.90 mmol) in ethanol (100 mL) was added dropwise to the system. After the addition was completed, the reaction was continued for 3 hours. After filtration, the mixture was extracted with EtOAc (EtOAc) (EtOAc) After filtration, the solvent was evaporated.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj MS (ESI, pos. ion) m/z: 422.3 [M+1] ⁺ .

Step 4: (S)-N-((S)-1-(1H-indazol-3-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (7D )

7C (615 mg, 1.46 mmol) was dissolved in tetrahydrofuran (20 mL), and ethylenediamine (1.00 mL) and tetrabutylammonium fluoride (15.0 mL, 15.0 mmol, 1.0 mol/L in tetrahydrofuran) were added and then heated. Stir at 60 ° C for 3 hours. Further addition of tetrabutylammonium fluoride (15.0 mL, 15.0 mmol, 1.0 mol/L in tetrahydrofuran) was continued and stirring was continued at 60 ° C overnight. The reaction was quenched, cooled to room temperature and extracted with EtOAc EtOAc. The combined organic layers were washed with water (50 mL×2) and brine (50 mL) After filtration, the solvent was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

MS (ESI, pos. ion) m/z: 292.25 [M+1] ⁺ .

Step 5: (4-(3-((S)-1-((S)-1,1-dimethylethylsulfonylamino)but-3-en-1-yl)-1H-carbazole Methyl -1-yl)-3-nitrophenyl)carbamate (7E)

Under nitrogen protection, 7D (20.8 g, 71.4 mmol), potassium phosphate (31.14 g, 146.7 mmol), cuprous iodide (1.40 g, 7.35 mmol), N-(4-iodo-3) were sequentially added to a four-necked flask. Methyl-nitro-phenyl)carbamate (32.0 g, 99.4 mmol), N,N'-dimethylethane-1,2-diamine (0.80 mL, 9.0 mmol) and N,N-dimethyl The carbachamide (20 mL) was then stirred at 130 ° C for 48 hours. After cooling to room temperature, the mixture was extracted with EtOAc (EtOAc m. After filtration, the solvent was evaporated.jjjjjjjjjjjjj

MS (ESI, pos.) m/z: 486.1 [M + 1] ⁺ .

Step 6: (S)-(4-(3-(1-Aminobut-3-en-1-yl)-1H-indazol-1-yl)-3-nitrophenyl)carbamic acid methyl ester ( 7F)

7E (500 mg, 1.03 mmol) was dissolved in methanol (10 mL), and a solution of 6 mol/L hydrochloric acid (4 mL, 24 mmol) was added and stirred at room temperature for 4 hours. The reaction was quenched, and the solvent was evaporated, evaporated, evaporated, evaporated. The combined organic layers were washed with water (50 mL) and brine Filtration and evaporation of the solvent <RTI ID=0.0>

MS (ESI, pos.) m/z: 382.2 [M + 1] ⁺ .

Step 7: (S)-(4-(3-(1-(tert-Butoxycarbonylamino)but-3-en-1-yl)-1H-indazol-1-yl)-3-nitrophenyl ) methyl carbamate (7G)

7F (390 mg, 1.023 mmol) was dissolved in anhydrous ethanol (20 mL), EtOAc (20 mg, EtOAc, EtOAc, EtOAc (EtOAc) 1 hour. The reaction was quenched, cooled to EtOAc EtOAc (EtOAc)

MS (ESI, pos. ion) m/z: 503.9 [M+23] ⁺ .

Step 8: (S)-(4-(3-(1-(tert-Butoxycarbonylamino)but-3-en-1-yl)-1H-indazol-1-yl)-3-aminophenyl) Methyl carbamate (7H)

7G (3.10 g, 6.44 mmol) was dissolved in MeOH (100 mL), then EtOAc (EtOAc, EtOAc. The reaction was quenched, filtered, and the solvent was evaporated. The combined organic layers were washed with water (100 mL) and brine Filtration and evaporation of the solvent <RTI ID=0.0>

MS (ESI, pos. ion) m/z: 452.4 [M+1] ⁺ .

Step 9: (S)-(4-(3-(1-(tert-Butoxycarbonylamino)but-3-en-1-yl)-1H-indazol-1-yl)-3-((R) -2-methylbut-3-enoylamino)phenyl)carbamate Methyl ester (7I)

7H (3.00 g, 6.64 mmol) was dissolved in dichloromethane (20 mL), pyridine (2.20 mL, 27.2 mmol) and (R)-2-methylbut-3-enoyl chloride (1.30) g, 11.0 mmol), the system was further stirred at 0 ° C for 1 hour and then stirred at room temperature for 2.5 hours. The reaction was stopped and extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with water (50 mL×2) and brine (40 mL) Filtration and evaporation of EtOAc.

MS (ESI, pos. ion) m/z: 534.2 [M+1] ⁺ .

Step 10: N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-1,8,22-triazabicyclo[13.6.1.0 ^2,7 .0 ^16,21 ]tetracosane -2(7),3,5,11(12),15(22),16(21),17,19-octadec-5-yl)carbamic acid methyl ester (7J)

The p-toluenesulfonate monohydrate (1.16 g, 6.10 mmol) was placed in a two-necked flask at room temperature, heated to 70 ° C, and dried under reduced pressure for about 2 hours. A solution of 7I (2.71 g, 5.08 mmol) in dry dichloromethane (100 mL) was then poured into a system cooled to 45 ° C and stirring was continued at 45 ° C for 2 hours. Further, a solution of Grubbs 2nd generation catalyst (1.30 g, 1.53 mmol) in dry dichloromethane (50 mL) was slowly poured into the system, and the mixture was stirred at 45 ° C overnight. After cooling to room temperature, the solvent was evaporated. mjjjjjjjjjj

MS (ESI, pos.ion) m / z: 406.1 [M-100 + 1] +.

Step 11: N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-1,8,22-triazabicyclo[13.6.1.0 ^2,7 .0 ^16,21 ]tetracosane -2(7),3,5,15(22),16(21),17,19-hepten-5-yl)carbamic acid methyl ester (7K)

7J (230 mg, 0.455 mmol) was dissolved in methanol (50 mL), and 10% Pd/C (100 mg, 0.094 mmol) was added and stirred overnight under a hydrogen atmosphere of 3.5 MPa. The reaction was quenched, filtered over EtOAc EtOAc (EtOAc) MS (ESI, pos.ion) m / z: 508.2 [M + 1] +.

Step 12: N-((10R,14S)-14-Amino-10-methyl-9-oxo-1,8,22-triazabicyclo[13.6.1.0 ^2,7 .0 ^16,21 ] Dodecane -2(7),3,5,15(22),16(21),17,19-hepten-5-yl)carbamic acid methyl ester (7L)

7K (550 mg, 1.084 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2.00 mL, 26.9 mmol). The reaction was quenched, and the solvent was evaporated to dryness to give a brown solid (440 mg, 99.7%). MS (ESI, pos.) m/z: 408.9 [M+1] ⁺ .

Step 13: N-((10R,14S)-14-(3-(6-Bromo-3-chloro-2-fluorophenyl)-3-oxopropylamino)-10-methyl-9-oxo -1,8,22-triazatetracyclic [13.6.1.0 ^2,7 .0 ^16,21 ]tetracosane-2(7),3,5,15(22),16(21),17,19-hepten-5-yl)carbamic acid Methyl ester (7M)

7 L (440 mg, 1.08 mmol) was dissolved in tetrahydrofuran (10 mL), triethylamine (2.00 mL, 14.4 mmol) was added, then a solution of 1P (500 mg, 1.278 mmol) in tetrahydrofuran (10 mL) was added and the system was stirred at room temperature. 5 hours. The organic layer was extracted with EtOAc (EtOAc) (EtOAc) Filtration and evaporation of the solvent <RTI ID=0.0>

MS (ESI, pos. ion) m/z: 6721. [M+1] ⁺ .

Step 14: N-((10R,14S)-14-(N-(3-(6-bromo-3-chloro-2-fluorophenyl)-3-oxopropyl)-2-(diethoxy) Phosphoryl)acetamido)-10-methyl-9- -1,8,22- triaza-oxo tetracyclo [13.6.1.0 ^2,7 .0 ^16,21] docosa-2 (7), 3,5,15 (22), 16 (21) ,17,19-hepten-5-yl)carbamic acid methyl ester (7N)

7M (400 mg, 0.596 mmol), (2-chloro-2-oxoethyl)phosphate (500 mg, 2.33 mmol), pyridine (0.200 mL, 2.49 mmol), 4-dimethylamino group were added to a microwave tube. Pyridine (80 mg, 0.655 mmol) and dichloromethane (15 mL) were then warmed to 50 ° C under microwave for 3 hours. The reaction was stopped and extracted with dichloromethane (50 mL x 2). The combined organic layers were washed with EtOAc EtOAc EtOAc m.

MS (ESI, pos. ion) m/z: 850.05 [M+1] ⁺ .

Step 15: N-((10R,14S)-14-(4-(6-Bromo-3-chloro-2-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridine- 1-yl)-10-methyl-9-oxo-1,8,22-triazole Heterotetracyclic [13.6.1.0 ^2,7 .0 ^16,21 ]tetracosane-2(7),3,5,15(22),16(21),17,19-heptene-5-yl Methyl carbamate

7N (400 mg, 0.471 mmol) in tetrahydrofuran (20 mL) was added to 60% sodium hydride (90 mg, 2.25 mmol) and then stirred at room temperature for one hour. Stop the reaction and add water to quench the reaction. The organic layer was extracted with EtOAc (EtOAc) (EtOAc) Filtration, and the solvent was evaporated under reduced pressure. EtOAcjjjjjjjjj %).

MS (ESI, pos.) m/z: 696.2 [M+1] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 9.95 (s, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 7.4 Hz, 1H), 7.70 (dd, J = 8.5, 5.1 Hz, 2H), 7.52 (t, J = 7.7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.35 - 7.28 (m, 2H), 7.18(s,1H), 6.37-6.33(m,1H), 6.16(s,1H), 3.78(s,3H),3.76–3.68(m,1H),3.49-3.42(m,1H) , 2.55-2.46 (m, 2H), 2.35 - 2.18 (m, 2H), 2.01 - 1.86 (m, 3H), 1.78 (s, 1H), 1.32 (d, J = 7.2 Hz, 3H).

Example 8

(9R,13S)-13-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-6-oxo-pyrimidin-1-yl)-3,9-di Methyl-17,20-dioxa-3,4,7,15-tetraazatetracyclo[12.7.1.0 ^2,6 .0 ^16,21 ]tetracosane-1 (22), 2 (6 ), 4,14,16(21)-penten-8-one

Step 1: ((1S)-1-(8-(1-Methyl-4-nitro-1H-pyrazol-5-yl)-2,3-dihydro-[1,4] dioxo[ 2,3-b]pyridin-6-yl)but-3-en-1-yl)carbamate Tert-butyl acid (8A)

1-methyl-4-nitro-1H-pyrazole (1.11 g, 8.73 mmol), pivalic acid (210 mg, 2.06 mmol), palladium (II) acetate (300 mg, 1.336 mmol), was added to the two vials. Butyl bis(1-adamantyl)phosphine (725 mg, 2.022 mmol), potassium carbonate (2.80 g, 20.3 mmol) and N,N-dimethylformamide (100 mL), then added 6 g (2.91 g, 6.73 mmol) A solution of N,N-dimethylformamide (10 mL) was added and the mixture was heated to 120 ° C and stirred for 5 hours. The reaction was quenched, cooled to room temperature and extracted with EtOAc EtOAc. The combined organic layers were washed with water (50 mL×2) and brine (40 mL) After filtration, the solvent was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

MS (ESI, pos.) m/z: 432.1 [M + 1] ⁺ .

Step 2: ((1S)-1-(8-(4-Amino-1-methyl-1H-pyrazol-5-yl)-2,3-dihydro-[1,4]dioxo[2 ,3-b]pyridin-6-yl)but-3-en-1-yl)carbamate Tert-butyl acid ester (8B)

8A (3.10 g, 7.19 mmol) was dissolved in MeOH (50 mL). EtOAc (EtOAc, EtOAc. The reaction was quenched, filtered, and the solvent was evaporated. The combined organic layers were washed with water (100 mL) and brine Filtration and evaporation of the solvent <RTI ID=0.0>

MS (ESI, pos. ion) m/z: 4021. [M+1] ⁺ .

Step 3: ((1S)-1-(8-(1-methyl-4-((R)-2-methylbut-3-enoylamino)-1H-pyrazol-5-yl)-2 ,3-dihydro-[1,4]dioxa[2,3-b]pyridine-6- Tert-butyl 3-buten-1-yl)carbamate (8C)

8B (2.534 g, 6.311 mmol) was dissolved in dichloromethane (20 mL), pyridine (2.0 mL, 25 mmol) and (R)-2-methylbut-3-enoyl chloride (1.20 g) After stirring at 0 ° C for 1 hour, the mixture was stirred at room temperature for 3 hours. The reaction was stopped and extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with water (50 mL×2) and brine (40 mL) Filtration and evaporation of the solvent <RTI ID=0.0></RTI>

MS (ESI, pos.) m/z: 484.3 [M + 1] ⁺ .

Step 4: ((9R,13S)-3,9-Dimethyl-8-oxo-17,20-dioxa-3,4,7,15-tetraazatetracyclo[12.7.1.0 ^{2, 6} .0 ^16,21 ]tetracosane -1(22),2(6),4,10(11),14,16(21)-hexaen-13-yl)carbamic acid tert-butyl ester (8D)

P-toluenesulfonic acid monohydrate (512 mg, 2.69 mmol) was placed in a two-necked flask at room temperature, heated to 70 ° C, and dried under reduced pressure for about 1.5 hours. A solution of 8C (1.085 g, 2.24 mmol) in dry methylene chloride (100 mL) was then taken and then cooled to 45 &lt Further, a solution of Grubbs 2nd generation catalyst (570 mg, 0.671 mmol) in dry dichloromethane (50 mL) was slowly poured into the system, and after completion of the dropwise addition, it was stirred and refluxed at 45 ° C overnight. The reaction was quenched, cooled to EtOAc (EtOAc m.

MS (ESI, pos. ion) m/z: 456.1 [M+1] ⁺ .

Step 5: ((9R,13S)-3,9-Dimethyl-8-oxo-17,20-dioxa-3,4,7,15-tetraazatetracyclo[12.7.1.0 ^{2, 6} .0 ^16,21 ]tetracosane -1(22),2(6),4,14,16(21)-penten-13-yl)carbamic acid tert-butyl ester (8E)

8D (140 mg, 0.307 mmol) was dissolved in methanol (10 mL), 10% Pd/C (65 mg) was added, and the mixture was heated to 50 ° C under a hydrogen atmosphere of 5.0 MPa overnight. The reaction was quenched, cooled to rt EtOAc (EtOAc)EtOAc.

MS (ESI, pos.) m/z: 458.1 [M+1] ⁺ .

Step 6: (9R,13S)-13-Amino-3,9-dimethyl-17,20-dioxa-3,4,7,15-tetraazabicyclo[12.7.1.0 ^2,6 . 0 ^16,21 ]tetracosane -1(22),2(6),4,14,16(21)-penten-8-one (8F)

8E (130 mg, 0.284 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (1 mL, 13.46 mmol). The reaction was stopped, and the reaction solution was neutralized with a saturated sodium hydrogen carbonate solution, and then extracted with dichloromethane (50 mL × 3). The combined organic layers were washed with water (20 mL×2) and brine (40 mL) Filtration and evaporation of the solvent <RTI ID=0.0>

MS (ESI, pos. ion) m/z: 358.2 [M+1] ⁺ .

Step 7: 4-Chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (8G)

2-bromo-4-chloro-aniline (30 g, 145.30 mmol), pinacol borate (41 g, 161.5 mmol), potassium acetate (43 g, 438.1 mmol), [1,1'- were sequentially added to the two vials. Bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloride complex (3.56 g, 4.36 mmol) and 1,4-dioxane (700 mL), replaced with nitrogen three times, then heated The reaction was carried out at 115 ° C for 5 hours. Cool to room temperature and filter through celite. The filtrate was evaporated to drynesshhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh

Step 8: 4-Chloro-2-(6-methoxypyrimidin-4-yl)aniline (8H)

8G (4.56g, 8.99mmol), 4-chloro-6-methoxypyrimidine (1.0g, 6.91mmol), sodium carbonate (1.47g, 13.9mmol) and [1,1'-bis ( at room temperature) Diphenylphosphine)ferrocene]palladium(II) chloride dichloride complex (0.576 g, 0.691 mmol) was charged into the reactor, the air was replaced with nitrogen, and ethylene glycol dimethyl ether was injected. (45 mL), ethanol (3 mL) and water (3 mL). After the addition was completed, the mixture was warmed to 90 ° C and stirred for 14 hours. Filtration, the filtrate was extracted with ethyl acetate (500 mL), EtOAc (EtOAc)EtOAc. Purification (petroleum ether / ethyl acetate (v / v) = 3 / 1)

MS (ESI, pos.) m/z: 236.0 [M + 1] ⁺ .

Step 9: 4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-6-methoxypyrimidine (8I)

8H (0.50 g, 2.1 mmol) was weighed into a flask, and acetic acid (5 mL) and trimethyl orthoformate (0.7 mL, 6 mmol) were added thereto, and stirred for half an hour. Sodium azide (0.41 g, 6.3 mmol) was added, followed by a reaction at room temperature for 24 hours. After completion of the reaction, ethyl acetate (20 mL) and water (20 mL) were evaporated, evaporated, evaporated, evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

Step 10: 6-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)pyrimidine-4-ol (8J)

8I (0.70 g, 2.4 mmol) was weighed into a flask, and acetonitrile (25 mL), sodium iodide (3.5 g, 23 mmol) and trimethylchlorosilane (3.0 mL, 35 mmol) were added thereto, and the mixture was reacted at room temperature for 24 hours. The reaction was quenched by the addition of saturated aqueous sodium thiosulfate (10 mL). Ethyl acetate (30 mL × 2) was evaporated, evaporated, evaporated.

MS (ESI, pos. ion) m/z: 275.0 [M+H] ⁺ .

Step 11: (9R,13S)-13-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-6-oxo-pyrimidin-1-yl)-3, 9-Dimethyl-17,20-dioxa-3,4,7,15- Tetraazatetracyclo[12.7.1.0 ^2,6 .0 ^16,21 ]docosane-1(22),2(6),4,14,16(21)-penten-8-one

8J (120 mg, 0.437 mmol), 8F (150 mg, 0.42 mmol), 1,8-diazabicycloundec-7-ene (0.10 mL, 0.67 mmol), 2-(7-) were added to a vial. Oxidized benzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (190 mg, 0.50 mmol) and acetonitrile (10 mL) were then stirred at room temperature for 2 days. The reaction was quenched and EtOAc (EtOAc m.

MS (ESI, pos.) m/z: 615.1 [M+1] ⁺ ;

^{_{1 H NMR (400MHz, CD 3}} OD) δ (ppm) 9.45 (s, 1H), 8.75 (s, 1H), 7.91 (d, J = 1.5Hz, 1H), 7.78 (d, J = 8.5Hz, 1H ), 7.69 (d, J = 8.5 Hz, 1H), 7.48 (s, 1H), 7.10 (s, 1H), 6.49 (s, 1H), 5.84 (s, 1H), 4.63 - 4.47 (m, 2H) , 4.43-4.36 (m, 2H), 3.92 (s, 3H), 2.91 (s, 1H), 2.68-2.58 (m, 1H), 2.19-2.11 (m, 1H), 2.07-2.02 (m, 1H) , 2.00–1.79 (m, 2H), 1.72–1.46 (m, 2H), 1.02 (s, 3H).

Example 9

(9R,13S)-13-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-6-oxo-pyrimidin-1-yl)-3,9-di methyl -17,20- -3,4,7- triaza-dioxa-tetracyclo [12.7.1.0 ^2,6 .0 ^16,21] docosa-1 (22), 2 (6), 4,14,16(21)-penten-8-one

Step 1: 3-Bromo-4,5-dihydroxybenzaldehyde (9A)

3,4-dihydroxybenzaldehyde (500 mg, 3.62 mmol) was dissolved in glacial acetic acid (10 mL), and then a solution of bromine (0.2 mL, 4.00 mmol) in EtOAc (1 mL) Stir at room temperature overnight. The reaction was quenched, the reaction was quenched with EtOAc (EtOAc)EtOAc.

MS (ESI, pos.) m/z: 217.0 [M+1] ⁺ , 219.0 [M+1] ⁺ .

Step 2: 8-Bromo-2,3-dihydrobenzo[b][1,4]dioxane-6-carbaldehyde (9B)

9A (27g, 124.4mmol) and potassium carbonate (43g, 311.1mmol) were dissolved in N,N-dimethylformamide (350mL), then 1,2-dibromoethane (32mL, 371mmol), system Heat to 110 ° C and stir for 4 hours. It was cooled to room temperature and extracted with ethyl acetate (300 mL×2). The combined organic layers were washed with water (200 mL×2) and brine (200 mL) Filtration and evaporation of the solvent <RTI ID=0.0>

MS (ESI, pos. ion) m/z:242.9 [M+1] ⁺ .

Step 3: (S,E)-N-((8-Bromo-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)methylene)-2-methyl Propane-2-sulfinamide (9C)

9B (555 mg, 2.28 mmol) was dissolved in dichloromethane (20 mL), (S)-(-)-tert-butylsulfinamide (300 mg, 2.48 mmol) and cesium carbonate (1.1 g, 3.4 mmol). It was then stirred at room temperature overnight. The reaction was quenched, filtered through celite and washed with dichloromethane. The filtrate was collected, washed with water (20 mL×2) and brine (40 mL) Filtration and evaporation of the solvent <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> <RTIgt;

MS (ESI, pos.) m/z: 348.0 [M + 1] ⁺ .

Step 4: (S)-N-((S)-1-(8-Bromo-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)but-3-ene -1-yl)-2-methylpropane-2-sulfinamide (9D)

9C (10.2 g, 29.5 mmol) was dissolved in saturated sodium bromide (200 mL), then EtOAc (13.5 g, 117 mmol) and allyl bromide (10.5 mL, 120 mmol). Filtration, and the solvent was evaporated under reduced pressure. EtOAcjjjjjjjjj

MS (ESI, pos.) m/z: 390.0 [M + 1] ⁺ .

Step 5: (S)-1-(8-Bromo-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)but-3-en-1-amine (9E)

9D (9.0 g, 23 mmol) was dissolved in methanol (100 mL), and 4 mol/L of diluted hydrochloric acid (17 mL, 68 mmol) was added and stirred at room temperature for 0.5 hour. The reaction was quenched, and the solvent was evaporated, evaporated, evaporated, evaporated. The combined organic layers were washed with water (100 mL) and brine Filtration and evaporation of the solvent <RTI ID=0.0>

Step 6: (S)-(1-(8-Bromo-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)but-3-en-1-yl)amino Tert-butyl formate (9F)

9E (5.0 g, 17.6 mmol) was dissolved in dichloromethane (100 mL), triethylamine (4.9 mL, 35 mmol) and di-tert-butyl dicarbonate (4.5 mL, 19 mmol). . The reaction was quenched and water (50 mL) was evaporated. The organic phase was combined, dried over anhydrous sodium sulfate EtOAcjjjjjjjjj , 44%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 7.02 (d, J = 1.6Hz, 1H), 6.75 (d, J = 1.3Hz, 1H), 5.72-5.62 (m, 1H), 5.18-5.03 ( m, 2H), 4.84 (s, 1H), 4.60 (s, 1H), 4.38 - 4.31 (m, 2H), 4.26 (dd, J = 5.1, 2.5 Hz, 2H), 2.45 (s, 2H), 1.43 (s, 9H).

Step 7: ((1S)-1-(8-(1-methyl-4-nitro-1H-pyrazol-5-yl)-2,3-dihydrobenzo[b][1,4] Dioxane-6-yl)but-3-en-1-yl)carbamic acid Butyl ester (9G)

1-methyl-4-nitro-1H-pyrazole (1.60 g, 12.6 mmol), pivalic acid (300 mg, 2.94 mmol), palladium (II) acetate (440 mg, 1.960 mmol), was added to the two vials. Butyl bis(1-adamantyl)phosphine (1.0 g, 2.8 mmol), potassium carbonate (4.0 g, 29 mmol) and N,N-dimethylformamide (30 mL), followed by 9F (3.73 g, 9.71 mmol) A solution of N,N-dimethylformamide (20 mL) was then stirred at 120 ° C for 5 hours. The reaction was quenched, cooled to room temperature and extracted with EtOAc EtOAc. The combined organic layers were washed with water (50 mL×2) and brine (40 mL) Filtration, the solvent was evaporated under reduced pressure.

^{_{1 H NMR (600MHz, CDCl 3}} ) δ (ppm) 8.18 (s, 1H), 6.97 (s, 1H), 6.74 (d, J = 12.4Hz, 1H), 5.72-5.66 (m, 1H), 5.18- 5.04 (m, 2H), 4.92 (s, 1H), 4.68 (s, 1H), 4.31 - 4.18 (m, 4H), 3.73 (d, J = 16.6 Hz, 3H), 2.51 (s, 2H), 1.41 (d, J = 7.7 Hz, 9H).

Step 8: ((1S)-1-(8-(4-Amino-1-methyl-1H-pyrazol-5-yl)-2,3-dihydrobenzo[b][1,4] Oster-6-yl)but-3-en-1-yl)carbamic acid Butyl ester (9H)

9G (3.35 g, 7.78 mmol) was dissolved in MeOH (50 mL). EtOAc (EtOAc,EtOAc. The reaction was quenched, filtered, and the solvent was evaporated. The combined organic layers were washed with water (100 mL), brine brine Filtration and evaporation of the solvent <RTI ID=0.0>

MS (ESI, pos.) m/z: 401.1 [M+1] ⁺ .

Step 9: ((1S)-1-(8-(1-methyl-4-((R)-2-methylbut-3-enoylamino)-1H-pyrazol-5-yl)-2 ,3-dihydrobenzo[b][1,4]dioxane-6-yl) Tert-butyl 3--3-en-1-ylcarbamate (9I)

9H (2.9 g, 7.2 mmol) was dissolved in dichloromethane (20 mL), pyridine (2.3 mL, 28 mmol) and (R)-2-methylbut-3-enoyl chloride (1.40 g) , 11.8 mmol), the system was further stirred at 0 ° C for 1 hour, and then stirred at room temperature for 2 hours. The reaction was stopped and extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with water (50 mL×2) and brine (40 mL) Filtration and evaporation of the solvent <RTI ID=0.0>

MS (ESI, pos.) m/z: 483.2 [M + 1] ⁺ .

Step 10: ((9R,13S)-3,9-Dimethyl-8-oxo-17,20-dioxa-3,4,7-triazatetracyclo[12.7.1.0 ^2,6 . 0 ^16,21 ]tetracosane -1(22),2(6),4,10(11),14,16(21)-hexaen-13-yl)carbamic acid tert-butyl ester (9J)

P-toluenesulfonic acid monohydrate (915 mg, 4.81 mmol) was placed in a two-necked flask at room temperature, heated to 70 ° C, and dried under reduced pressure for about 1.5 hours. A solution of 9I (1.93 g, 4.00 mmol) in dry methylene chloride (100 mL) was then taken and then cooled to 45 &lt Further, a solution of Grubbs 2nd generation catalyst (1.0 g, 1.2 mmol) in dry dichloromethane (50 mL) was slowly poured into the system, and after completion of the dropwise addition, the mixture was stirred at 45 ° C overnight. The reaction was quenched, cooled to EtOAc EtOAc (EtOAc)

MS (ESI, pos. ion) m/z: 455.2 [M+1] ⁺ .

Step 11: ((9R,13S)-3,9-Dimethyl-8-oxo-17,20-dioxa-3,4,7-triazatetracyclo[12.7.1.0 ^2,6 . 0 ^16,21 ]tetracosane -1(22),2(6),4,14,16(21)-penten-13-yl)carbamic acid tert-butyl ester (9K)

9 J (600 mg, 1.32 mmol) was dissolved in methanol (50 mL), 10% Pd/C (300 mg) was added, and the mixture was heated to 50 ° C under a hydrogen atmosphere of 5.0 MPa overnight. The reaction was quenched, cooled to rt EtOAc (EtOAc)EtOAc.

MS (ESI, pos.) m/z: 457.1 [M + 1] ⁺ .

Step 12: (9R,13S)-13-Amino-3,9-dimethyl-17,20-dioxa-3,4,7-triazatetracyclo[12.7.1.0 ^2,6 .0 ^{16 , 21} ] tetracosane -1(22),2(6),4,14,16(21)-penten-8-one (9L)

9K (500 mg, 1.095 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL, 53. The reaction was stopped, and the reaction solution was neutralized with a saturated sodium hydrogen carbonate solution, and then extracted with dichloromethane (50 mL × 3). The combined organic layers were washed with water (20 mL×2) and brine (40 mL) Filtration and evaporation of the solvent <RTI ID=0.0>

MS (ESI, pos.) m/z: 357.1 [M + 1] ⁺ .

Step 13: (9R,13S)-13-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-6-oxo-pyrimidin-1-yl)-3, 9-Dimethyl-17,20-dioxa-3,4,7- Triazatetracyclo[12.7.1.0 ^2,6 .0 ^16,21 ]docosane-1(22),2(6),4,14,16(21)-penten-8-one

8J (230 mg, 0.837 mmol), 9 L (280 mg, 0.786 mmol), 1,8-diazabicycloundec-7-ene (0.20 mL, 1.3 mmol), 2-(7-) were added to a single vial. Oxidized benzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (370 mg, 0.973 mmol) and acetonitrile (20 mL) were then stirred at room temperature for 1 day. The reaction was quenched and the solvent was evaporated. 20mg, 4.15%).

MS (ESI, pos.) m/z: 614.2 [M+1] ⁺ ;

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm) 9.46 (s, 1H), 8.45 (s, 1H), 7.93 (s, 1H), 7.78 (d, J = 7.0 Hz, 1H), 7.71 (d) , J = 7.8 Hz, 1H), 7.48 (s, 1H), 6.98 (s, 1H), 6.70 (s, 1H), 6.57 (s, 1H), 5.59 (d, J = 9.6 Hz, 1H), 4.39 -4.35 (m, 4H), 3.89 (s, 3H), 3.26-3.20 (m, 1H), 2.91 (s, 1H), 2.49 - 2.31 (m, 1H), 2.26 - 2.10 (m, 1H), 2.01 –1.90 (m, 1H), 1.85–1.70 (m, 1H), 1.16 (d, J=6.1 Hz, 3H).

Example 10

(10R,14S)-14-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-6-oxo-pyrimidin-1-yl)-4-fluoro-10 - -18,21- dioxa-8-methyl-tetracyclo [13.7.1.0 ^2,7 .0 ^17,22] tricosa-1 (23), 2 (7), 3,5, 15,17(22)-hexaen-9-one

Step 1: (S)-(1-(8-(2-Amino-5-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-6-yl) Tert-butyl 3--3-en-1-ylcarbamate (10A)

Under a nitrogen atmosphere, 9F (4.85g, 12.7mmol), sodium carbonate (2.70g, 25.5mmol) in water (10mL), tricyclohexylphosphine (530mg, 1.89mmol), (dba) ₃ were added to the two vials. Pd ₂ (580 mg, 0.633 mmol), 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (4.50 g, 19.0 Methyl) and N,N-dimethylformamide (100 mL) were then stirred at 90 ° C for 5 hours. The reaction was quenched, cooled to room temperature and extracted with EtOAc EtOAc The combined organic layers were washed with water (200 mL×2) and brine (200 mL) After filtration, the solvent was evaporated to dryness crystals crystals crystals

MS (ESI, pos.) m/z: 437.1 [M+23] ⁺ .

Step 2: ((S)-1-(8-(5-fluoro-2-((R)-2-methylbut-3-enoylamino)phenyl)-2,3-dihydrobenzo[ b][1,4]dioxane-6-yl)but-3-en-1-yl)ammonia Tert-butyl carboxylic acid (10B)

10A (2.8 g, 6.8 mmol) was dissolved in dichloromethane (20 mL), pyridine (2.2 mL, 27 mmol) and (R)-2-methylbut-3-enoyl chloride (1.15 g) , 9.70 mmol), the system was further stirred at 0 ° C for 1 hour, and then stirred at room temperature for 2 hours. The reaction was stopped and extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with water (50 mL×2) and brine (40 mL) After filtration, the solvent was evaporated.jjjjjjjjjjj

MS (ESI, pos.) m/z: 519.1 [M+23] ⁺ .

Step 3: ((10R, 14S) -4- fluoro-10-methyl-dioxa-8--18,21- tetracyclo [13.7.1.0 ^2,7 .0 ^17,22] tricosane -1(23),2(7),3,5,11(12),15,17(22)-heptene-14-yl)carbamic acid tert-butyl ester (10C)

P-toluenesulfonic acid monohydrate (770 mg, 4.05 mmol) was placed in a two-necked flask at room temperature, heated to 70 ° C, and dried under reduced pressure for about 1.5 hours. A solution of 10B (1.67 g, 3.36 mmol) in dry methylene chloride (100 mL) was then taken and then cooled to 45 &lt Further, a solution of Grubbs 2nd generation catalyst (860 mg, 1.013 mmol) in dry dichloromethane (50 mL) was slowly poured into the system. After the addition was completed, the system was stirred and refluxed at 45 ° C overnight. The reaction was quenched, cooled to EtOAc EtOAc (EtOAc m.

MS (ESI, pos. ion) m/z: 491.1 [M+23] ⁺ .

Step 4: ((10R, 14S) -4- fluoro-10-methyl-dioxa-8--18,21- tetracyclo [13.7.1.0 ^2,7 .0 ^17,22] tricosane -1(23), 2(7), 3, 5, 15, 17(22)- Hexenyl-14-yl)carbamic acid tert-butyl ester (10D)

10C (280 mg, 0.598 mmol) was dissolved in methanol (50 mL), and 10% Pd/C (150 mg, 0.141 mmol) was added and stirred overnight under a hydrogen atmosphere of 4.0 MPa. The reaction was quenched, filtered over EtOAc EtOAc (EtOAc) MS (ESI, pos.) m/z: 493.1 [M+23] ⁺ .

Step 5: (10R, 14S) -14- amino-4-fluoro-10-methyl -18,21- dioxa-8-tetracyclo [13.7.1.0 ^2,7 .0 ^17,22] two Tridecane -1(23),2(7),3,5,15,17(22)-hexaen-9-one (10E)

10D (260 mg, 0.553 mmol) was dissolved in dichloromethane (10 mL). The reaction was stopped, and the reaction solution was neutralized with a saturated sodium hydrogen carbonate solution, and then extracted with dichloromethane (50 mL × 3). The combined organic layers were washed with water (20 mL×2) and brine (40 mL) Filtration and evaporation of the solvent <RTI ID=0.0>

MS (ESI, pos. ion) m/z: 354.1 [M-17+1] ⁺ .

Step 6: (10R,14S)-14-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-6-oxo-pyrimidin-1-yl)-4- Fluoro-10-methyl-18,21-dioxa-8-nitrogen Oxatetracyclo [13.7.1.0 ^2,7 .0 ^17,22] tricosa-1 (23), 2 (7), 3,5,15,17 (22) - Six-9-one

8J (180 mg, 0.655 mmol), 10E (200 mg, 0.540 mmol), 1,8-diazabicycloundec-7-ene (0.13 mL, 0.87 mmol), 2-(7-) were added to a single vial. Oxidized benzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (250 mg, 0.658 mmol) and acetonitrile (20 mL) were then stirred at room temperature for 2 days. The reaction was quenched and the solvent was evaporated to dryness crystals crystals crystals crystals (15 mg, 4.42%).

MS (ESI, pos.) m/z: 628.0 [M + 1] ⁺ ;

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm) 8.81 (s, 1H), 8.04 (s, 1H), 7.69 (s, 1H), 7.65 (d, J = 8.4Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.43 (dd, J = 8.6, 5.4 Hz, 1H), 7.30 (d, J = 2.8 Hz, 1H), 7.16 - 7.04 (m, 1H), 6.95 (s, 1H), 6.66(s,1H), 6.55 (d, J=8.2Hz, 2H), 5.56 (d, J=9.5Hz, 1H), 4.29(s,4H), 2.53–2.41(m,1H), 2.16–2.00 (m, 2H), 1.97–1.87 (m, 1H), 1.74 (s, 2H), 1.69-1.62 (m, 2H), 1.17 (d, J = 6.9 Hz, 3H).

Example 11

(9R,13S)-13-(4-(5-chloro-2-cyanophenyl)-6-oxo-pyrimidin-1-yl)-3,9-dimethyl-17,20-dioxo Hetero-3,4,7,15-tetraazatetracyclo[12.7.1.0 ^2,6 .0 ^16,21 ]tetracosane-1 (22), 2 (6), 4, 14, 16 (21 )-penten-8-one

Step 1: (9R,13S)-13-(4-(5-Chloro-2-iodophenyl)-6-oxo-pyrimidin-1-yl)-3,9-dimethyl-17,20- Dioxa-3,4,7,15-tetraazatetracyclic [12.7.1.0 ^2,6 .0 ^16,21 ]tetracosane-1(22),2(6),4,14,16(21)-penten-8-one (11A)

Add 6-(5-chloro-2-iodophenyl)pyrimidin-4-ol to a single-mouth bottle (prepared by the synthetic method of intermediate 5 of patent WO 2015116886) (215 mg, 0.647 mmol), 8F (242.60 mg, 0.679) Ment), 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (390 mg, 1.03 mmol), acetonitrile (60 mL) and 1,8- Diazabicycloundec-7-ene (0.60 mL, 4.0 mmol) was then stirred at room temperature overnight. The solvent was evaporated under reduced pressure. EtOAcjjjjjjjj

MS (ESI, pos.) m/z: 673.0 (M+1).

Step 2: (9R,13S)-13-(4-(5-Chloro-2-cyanophenyl)-6-oxo-pyrimidin-1-yl)-3,9-dimethyl-17,20 -dioxa-3,4,7,15-tetraazatetracyclic [12.7.1.0 ^2,6 .0 ^16,21 ]tetracosane-1(22),2(6),4,14,16(21)-penten-8-one

Under a nitrogen atmosphere, copper cyanide (92 mg, 1.03 mmol) was dissolved in dimethyl sulfoxide (10 mL), heated to 150 ° C, and 11A (460 mg, 0.684 mmol) of dimethyl sulfoxide (20 mL) was added dropwise. The solution was then stirred at 150 ° C for 2 hours. Cool to room temperature and quench the reaction by adding aqueous ammonia (3 mL). It was extracted with ethyl acetate (30 mL × 3). The organic phase was combined, EtOAcjjjjjjjjjj

MS (ESI, pos.) m/z: 57.

^{1 H NMR (400MHz, DMSO-} d 6) δ (ppm) 9.11 (d, J = 21.9Hz, 1H), 8.07-7.95 (m, 2H), 7.78 (dd, J = 8.3,2.0Hz, 1H), 7.46 (d, J = 13.5 Hz, 1H), 7.13 (s, 1H), 6.97 (d, J = 10.6 Hz, 1H), 5.78 (d, J = 9.0 Hz, 1H), 4.56 - 4.14 (m, 4H) ), 3.84 (s, 3H), 2.30 (t, J = 30.7 Hz, 1H), 1.86 (d, J = 36.4 Hz, 2H), 1.72 - 1.13 (m, 4H), 0.89 (d, J = 25.3 Hz) , 3H).

Biological activity test

Example A Inhibition of Human FXIa by Compounds of the Invention

The inhibitory effect of the compound of the present invention on the activity of human coagulation factor XIa (FXIa) was determined by the following method.

The enzymatic activity of human coagulation factor XIa (FXIa) is determined by the conversion of a FXIa-specific chromogenic substrate. The assay was performed on a microtiter plate as described below.

1 experimental materials:

Enzyme: Factor XIa Protease (Source: Enzyme research laboratories, Cat. No. HFXIa 1111a)

Substrate: S-2366 (Source: Chromogenix, Cat. No. 82109039)

Buffer: 50 mM HEPES, 145 mM NaCl, 5 mM KCl, 0.1% PEG 8000, pH = 7.5

2 experimental steps:

2.1 Preparation of S-2366 substrate stock solution (10 mM): Take a bottle of S-2366 chromogenic substrate (25 mg), add 4.64 mL of sterile deionized water, mix, and store in a 4 ° C refrigerator in the dark. .

Preparation of S-2366 substrate working solution (1.875 mM): The S-2366 substrate stock solution was diluted 5.33 times with buffer before use.

2.2 Preparation of FXIa enzyme working solution (125mU/mL): The original mother liquor (102.6U/mL) was diluted to 125mU/mL with buffer before use.

2.3 Preparation of compound working solution: 10 μL of compound stock solution (20 μM DMSO solution) was added, and 90 μL of buffer solution was added to prepare a compound solution having a concentration of 2 μM and a DMSO content of 10%. Take 20 μL of the above compound solution, and dilute it to a concentration of 20000, 10000, 5000, 2500, 1250, 625, 312.5, 156.25, 78.13, 39.06 nM with a buffer containing 10% DMSO, and place it on ice. spare.

2.4 Loading and Enzymatic Reaction (Double Replica): Prepare 384-well plate, add 4 μL of compound working solution (control group added 4 μL DMSO) and 12.8 μL FXIa enzyme working solution (final concentration 80 mU/mL), seal the membrane seal Plate, micro shaker, shake, incubate at 25 ° C for 10 minutes. Add 3.2 μL of S-2366 substrate working solution (final concentration of 300 μM), kinetically test the absorbance at 405 nm at 25 ° C, make a ΔA-time curve, calculate the slope as the reaction rate, and calculate the inhibition rate according to the following formula. The inhibition activity rate was plotted on the ordinate, and the enzyme activity dose-effect curve was plotted using Graph Pad Prism 5 software to calculate the IC ₅₀ value.

Inhibition rate%=(V ₀ -V _i )/V ₀ ×1 00 (wherein V ₀ is the control hole reaction rate, and V _i is the reaction rate of the sample to be tested)

The experimental results are shown in Table 1.

Table 1 Inhibition of human FXIa activity by the compounds of the invention

实施例编号Example number	FXIa IC ₅₀(nM) FXIa IC ₅₀ (nM)
实施例5Example 5	44.744.7
实施例6Example 6	28.928.9
实施例8Example 8	10.410.4
实施例9Example 9	14.114.1
实施例10Example 10	21.721.7

Conclusion: The compounds of the present invention have a significant inhibitory effect on the activity of human coagulation factor XIa.

Example B In vitro anticoagulant test of the compound of the present invention

The in vitro anticoagulant effect of the compounds of the present invention is manifested by prolonging the clotting time of rabbit and human plasma, and can be determined by the following method.

1. Preparation of compound solutions at various concentrations

4 μL of each compound working solution (10 mM) was taken and diluted with dimethyl sulfoxide 3 times to a working solution of each concentration.

2. Preparation of plasma samples

Preparation of rabbit plasma: Several rabbits were injected with 3% pentobarbital solution (30 mg/kg) in the ear vein, and blood was collected from the abdominal aorta of vacuum blood collection tube containing 0.2 mL of 3.8% sodium citrate to 2 mL. Multi-tube, mix upside down several times, let stand for 10 minutes, centrifuge at 3000rpm for 10 minutes, pipet the plasma of each tube, mix all the plasma into the same centrifuge tube, pack according to 1.6mL per tube, and quickly put into the refrigerator at -80 °C Save spare.

Preparation of human plasma: healthy people fasting, blood collection in the middle of the elbow vein, blood collection with 0.2mL 3.8% sodium citrate to 2mL, males take 50mL whole blood, females take 30mL whole blood, vacuum mining The blood vessels were collected and mixed upside down several times, allowed to stand for 10 minutes, centrifuged at 3000 rpm for 10 minutes, and the plasma of each tube was aspirated. All male plasma was mixed into the same centrifuge tube, and the female plasma was mixed into another centrifuge tube. The male and female plasmas were mixed with 1:1 plasma, and then dispensed in 1.3 mL per tube, and quickly placed in a -80 °C refrigerator.

3. Loading and measuring clotting time PT and APTT

Prepare 1.5mL EP tubes, add 180μL plasma samples to each tube; add 4μL of the corresponding concentration to each tube blood sample, add 4μL dimethyl sulfoxide solution to the control group, mix by shaking, incubate for 5 minutes at 37°C; use Sysmex The PT and APTT were measured by a CA1500 automatic blood coagulation instrument; the dose-response curve was plotted, and the curve was fitted to calculate the concentration of the test compound (CT ₂ ) which doubled the clotting time. The test results of the anticoagulant effect of the compound of the present invention on human plasma are shown in Table 2.

Table 2 In vitro anticoagulant test of the compound of the present invention

实施例编号Example number	APTT CT ₂(μM) APTT CT ₂ (μM)
实施例8Example 8	0.200.20

Conclusion: The compound of the present invention has obvious anticoagulant effect on human plasma in vitro.

In the description of the present specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" and the like means a specific feature described in connection with the embodiment or example. A structure, material or feature is included in at least one embodiment or example of the invention. In the present specification, the schematic representation of the above terms is not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in a suitable manner in any one or more embodiments or examples. In addition, various embodiments or examples described in the specification, as well as features of various embodiments or examples, may be combined and combined.

Although the embodiments of the present invention have been shown and described, it is understood that the above-described embodiments are illustrative and are not to be construed as limiting the scope of the invention. The embodiments are subject to variations, modifications, substitutions and variations.

Claims

a compound which is a stereoisomer, a geometric isomer, a tautomer, an oxynitride, a hydrate, a solvate of a compound represented by the formula (I) or a compound of the formula (I), a metabolite, a pharmaceutically acceptable salt or a prodrug,

among them,

Ring A is a C 7-12 carbocyclic group, a C 8-12 aryl group, a heterocyclic group consisting of 7 to 12 atoms or a heteroaryl group of 7 to 12 atoms;

Ring B is a C 5-12 carbocyclic group, a C 6-12 aryl group, a heterocyclic group consisting of 5 to 12 atoms or a heteroaryl group of 5 to 12 atoms;

Ring C is a C 3-12 carbocyclic group, a C 6-12 aryl group, a heterocyclic group consisting of 3 to 12 atoms or a heteroaryl group of 5 to 12 atoms;

X is a C 4-8 alkylene group or a C 4-8 alkenylene group, wherein one or more carbon atoms in the alkylene group and the alkenylene group are independently selected from -O-, -S- Substituting a group of -C(=O)-, -S(=O)-, -S(=O) 2 - or -N(R 5 )-; a C 4-8 alkylene group in X and The C 4-8 alkenylene group is optionally substituted by one or more R 9 ;

Y is -C(=O)N(R 5 )- or -N(R 5 )C(=O)-;

Each R 1 is independently =O, H, oxime, halogen, -(CR 7a R 7b ) r CN, C 1-6 alkyl, deuterated C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CR 7a R 7b ) r OR 8 , -(CR 7a R 7b ) r NR 5a R 5b , -(CR 7a R 7b ) r C(=O R 6 , -(CR 7a R 7b ) r C(=O)OR 8 , -(CR 7a R 7b ) r C(=O)NR 5a R 5b , -(CR 7a R 7b ) r S(=O R 6 , -(CR 7a R 7b ) r S(=O)OR 8 , -(CR 7a R 7b ) r S(=O)NR 5a R 5b , -(CR 7a R 7b ) r S(=O 2 R 6 , -(CR 7a R 7b ) r S(=O) 2 OR 8 , -(CR 7a R 7b ) r S(=O) 2 NR 5a R 5b , -(CR 7a R 7b ) r - C 3-12 cycloalkyl, -(CR 7a R 7b ) r -C 6-12 aryl, -(CR 7a R 7b ) r - (heterocyclic group of 3-12 atoms) or -(CR 7a R 7b ) r —(heteroaryl group of 5 to 12 atoms); wherein each R 1 is independently optionally substituted by 1, 2, 3 or 4 R 1a ;

Each R 2 is independently H, deuterium, halogen, -(CR 7a R 7b ) r CN, C 1-6 alkyl, deuterated C 1-6 alkyl, halo C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, R 8 OC 2-6 alkenylene, R 8 OC(=O)-C 2-6 alkenylene, R 8 OC 2-6 alkynylene, R 8 OC (=O)-C 2-6 alkynylene, -N=C=S, -N=C=O, -(CR 7a R 7b ) r OR 8 , -(CR 7a R 7b ) r NR 5a R 5b , -(CR 7a R 7b ) r C(=G)R 6 , -(CR 7a R 7b ) r N(R 5c )C(=G)R 6 , -(CR 7a R 7b ) r OC(=G R 6 , -(CR 7a R 7b ) r C(=G)OR 8 , -(CR 7a R 7b ) r N(R 5c )C(=G)OR 8 , -(CR 7a R 7b ) r OC (=G)OR 8 , -(CR 7a R 7b ) r C(=G)NR 5a R 5b , -(CR 7a R 7b ) r N(R 5c )C(=G)NR 5a R 5b ,-( CR 7a R 7b ) r N(R 5c )=C(R 7 )NR 5a R 5b , -(CR 7a R 7b ) r S(=O)R 6 , -(CR 7a R 7b ) r N(R 5c )S(=O)R 6 , -(CR 7a R 7b ) r S(=O)OR 8 , -(CR 7a R 7b ) r N(R 5c )S(=O)OR 8 ,-(CR 7a R 7b ) r S(=O)NR 5a R 5b , -(CR 7a R 7b ) r N(R 5c )S(=O)NR 5a R 5b , -(CR 7a R 7b ) r S(=O) 2 R 6 , -(CR 7a R 7b ) r OS(=O) 2 R 6 , -(CR 7a R 7b ) r N(R 5c )S(=O) 2 R 6 , -(CR 7a R 7b ) r S(=O) 2 OR 8 , -(CR 7a R 7b ) r N(R 5c )S(=O) 2 OR 8 , -(CR 7a R 7b ) r S( =O) 2 NR 5a R 5b , -(CR 7a R 7b ) r N(R 5c )S(=O) 2 NR 5a R 5b , -(CR 7a R 7b ) r -C 3-12 cycloalkyl, -(CR 7a R 7b ) r -C 6-12 aryl, -(CR 7a R 7b ) r -(heterocyclic group of 3-12 atoms), -(CR 7a R 7b ) r -(5- 12 atomic heteroaryl) or D-mannosyl; wherein each G is independently O, S or NR 5d ; each R 2 is independently optionally substituted by 1, 2, 3 or 4 R 2a ;

Each R 3 is independently a C 1-6 alkyl group, a C 3-12 carbocyclic group, a C 6-12 aryl group, a heterocyclic group consisting of 3 to 12 atoms, or a heteroaryl group of 5 to 12 atoms; Wherein each R 3 is independently optionally substituted by 1, 2, 3, 4 or 5 R 3a ;

Each R 4 is independently H, hydrazine, halogen, hydroxy, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halo C 1 -6 alkoxy, -(CR 7a R 7b ) r -OR 8 , -(CR 7a R 7b ) r -NR 5a R 5b , -(CR 7a R 7b ) r -CN or halogenated C 1-6 alkane Or any two R 4 and the atoms to which they are attached form a C 3-8 cycloalkyl group, a C 6-10 aryl group, a heterocyclic group consisting of 3-8 atoms, or 5-6 atoms. Heteroaryl

Each of R 9 , R 1a , R 2a and R 3a is independently =0, hydrogen, deuterium, halogen, —(CR 7a R 7b ) r CN, nitro, C 1-6 alkyl, halo C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, R 8 OC 2-6 alkenylene, R 8 OC(=O)-C 2-6 alkenylene, R 8 OC 2-6 Alkynyl, R 8 OC(=O)-C 2-6 alkynylene, -(CR 7a R 7b ) r -OR 8 , -(CR 7a R 7b ) r -NR 5a R 5b , -(CR 7a R 7b ) r N(R 5c )C(=O)R 6 , -(CR 7a R 7b ) r OC(=O)R 6 , -(CR 7a R 7b ) r COOH, -(CR 7a R 7b ) r C(=O)OC 1-6 alkyl, -(CR 7a R 7b ) r C(=O)C 1-6 alkyl, -(CR 7a R 7b ) r S(=O) 2 R 6 ,- (CR 7a R 7b ) r OS(=O) 2 R 6 , -(CR 7a R 7b ) r N(R 5c )S(=O) 2 R 6 , -(CR 7a R 7b ) r S(=O 2 OR 8 , -(CR 7a R 7b ) r S(=O) 2 NR 5a R 5b , -(CR 7a R 7b ) r -C 3-12 cycloalkyl, -(CR 7a R 7b ) r - C 6-12 aryl, -(CR 7a R 7b ) r - (heterocyclic group of 3-12 atoms) or -(CR 7a R 7b ) r - (heteroaryl group of 5-12 atoms) ;

Alternatively, any two R 9 together with the atoms to which they are attached form a C 3-6 cycloalkyl group or a heterocyclic group consisting of 3 to 6 atoms;

Wherein each R 9 , R 1a , R 2a and R 3a are independently independently substituted by 1, 2, 3, 4 or 5 R 10 ;

Each of R 5 , R 5a , R 5b , R 5c and R 5d is independently hydrogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy-C(=O)-, C 6- a 10 aryl group, a C 3-10 cycloalkyl group, a heterocyclic group of 3 to 10 atoms or a heteroaryl group of 5 to 10 atoms;

Or R 5 , R 9 and the atoms attached thereto form a heterocyclic group consisting of 3-8 atoms;

Each of R 6 and R 8 is independently hydrogen, deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxy substituted C 1-6 Alkyl, amino-substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, halo C 1-6 alkyl, C 6- a 10 aryl group, a C 3-10 cycloalkyl group, a heterocyclic group of 3 to 10 atoms or a heteroaryl group of 5 to 10 atoms;

Each of R 7 , R 7a and R 7b is independently hydrogen, C 1-6 alkyl, deuterated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or halo C 1-6 alkyl;

Each R 10 is independently =O, H, D, halogen, CN, amino, hydroxy, nitro, carboxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkoxy C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, amino substituted C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkyl acyl, C 1-4 alkyl sulfonyl, C 1-4 alkoxy acyl , C 1-4 alkylamino acyl group, amino acyl group, aminosulfonyl group, C 1-4 alkoxysulfonyl group, C 1-4 alkylaminosulfonyl group, C 1-4 acyloxy group, C 6-10 aryl group, a C 3-6 cycloalkyl group, a heterocyclic group of 3 to 6 atoms or a heteroaryl group of 5 to 10 atoms;

Each m, n and t are independently 0, 1, 2, 3 or 4;

p is 1, 2, 3 or 4;

Each r is independently 0, 1, 2, 3 or 4.
The compound according to claim 1, wherein the ring C is a heterocyclic group of 5 to 7 atoms or a heteroaryl group of 5 to 6 atoms.
The compound according to claim 1 or 2, wherein ring C is of the following substructure:

Wherein ring C passes through the N atom and
Connected

each
with
Independently a single bond or a double bond;

when
or
When it is a single bond, each of Z, Z 1 and Z 2 is independently CH 2 or NH;

when
or
When it is a double bond, each of Z, Z 1 and Z 2 is independently CH or N;

Z 4 is CH 2 or NH;

Each Z 3 and Z 5 are independently CH 2 , NH, S or O;

q is 0, 1, or 2.
The compound according to any one of claims 1 to 3, wherein ring C is

Wherein ring C passes through the N atom and
Connected.
The compound according to any one of claims 1 to 4, which is a stereoisomer, a geometric isomer, a tautomer, or a compound of the formula (II). Nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

Among them, each
with
Independently a single bond or a double bond;

when
or
When it is a single bond, each Z and Z 1 are independently CH 2 or NH;
or
When it is a double bond, each of Z and Z 1 is independently CH or N.
The compound according to any one of claims 1 to 5, wherein each R 3 is independently a C 1-4 alkyl group, a C 3-8 carbocyclic group, a C 6-10 aryl group, and a 3-8 atomic composition. Heterocyclic group or heteroaryl group of 5-10 atoms;

Wherein each R 3 is independently optionally substituted by 1, 2, 3, 4 or 5 R 3a .
The compound according to any one of claims 1 to 6, wherein each R 3 is independently methyl, ethyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, imidazolinyl, triazolyl, pyridine , pyrimidinyl, fluorenyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, quinolyl, Isoquinolinyl or quinazolinyl;

Wherein each R 3 is independently optionally substituted by 1, 2, 3, 4 or 5 R 3a .
The compound according to any one of claims 1 to 7, which is a stereoisomer, a geometric isomer, a tautomer, or a compound of the formula (III). Nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

Among them, each
with
Independently a single bond or a double bond;

when
or
When it is a single bond, Z is CH 2 or NH;
or
When it is a double bond, Z is CH or N;

f is 0, 1, 2, 3, 4 or 5;

g is 0, 1, 2, 3, 4, 5, 6, 7, or 8.
The compound according to any one of claims 1 to 8, wherein the ring A is a C 7-12 bicyclic carbocyclyl group, a C 8-12 bicyclic aryl group, a bicyclic heterocyclic group of 7 to 12 atoms or 7- A bicyclic heteroaryl group consisting of 12 atoms.
The compound according to any one of claims 1 to 9, wherein ring A is of the following substructure:

Wherein each of T 1 , T 2 , T 3 , T 4 , T 5 , T 6 , T 7 and T 8 are independently -CH- or -N-;

Each of V 1 , V 2 , V 3 and V 4 is independently -CH 2 -, -NH-, -O-, -S-, -S(=O)-, -S(=O) 2 - or - C(=O)-;

Each k and j are independently 0, 1, 2, 3 or 4.
The compound according to any one of claims 1 to 10, wherein ring A is
The compound according to any one of claims 1 to 11, wherein the ring B is a C 5-8 carbocyclic group, a C 6-10 aryl group, a heterocyclic group of 5-8 atoms or 5-10 atoms. a heteroaryl group;

Each R 2 is independently H, hydrazine, F, Cl, Br, I, -(CR 7a R 7b ) r CN, C 1-4 alkyl, deuterated C 1-4 alkyl, halogenated C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, R 8 OC 2-4 alkenylene, R 8 OC(=O)-C 2-4 alkenylene, R 8 OC 2-4 Alkynyl, R 8 OC(=O)-C 2-4 alkynylene, -N=C=S, -N=C=O, -(CR 7a R 7b ) r OR 8 , -(CR 7a R 7b r NR 5a R 5b , -(CR 7a R 7b ) r C(=G)R 6 , -(CR 7a R 7b ) r N(R 5c )C(=G)R 6 , -(CR 7a R 7b r OC(=G)R 6 , -(CR 7a R 7b ) r C(=G)OR 8 , -(CR 7a R 7b ) r N(R 5c )C(=G)OR 8 ,-(CR 7a R 7b ) r OC(=G)OR 8 , -(CR 7a R 7b ) r C(=G)NR 5a R 5b , -(CR 7a R 7b ) r N(R 5c )C(=G)NR 5a R 5b , -(CR 7a R 7b ) r N(R 5c )=C(R 7 )NR 5a R 5b , -(CR 7a R 7b ) r S(=O)R 6 , -(CR 7a R 7b r N(R 5c )S(=O)R 6 , -(CR 7a R 7b ) r S(=O)OR 8 , -(CR 7a R 7b ) r N(R 5c )S(=O)OR 8 , -(CR 7a R 7b ) r S(=O)NR 5a R 5b , -(CR 7a R 7b ) r N(R 5c )S(=O)NR 5a R 5b , -(CR 7a R 7b ) r S (= O) 2 R 6, - (CR 7a R 7b) r OS (= O) 2 R 6, - (CR 7a R 7b) r N (R 5c) S ( O) 2 R 6, - ( CR 7a R 7b) r S (= O) 2 OR 8, - (CR 7a R 7b) r N (R 5c) S (= O) 2 OR 8, - (CR 7a R 7b ) r S(=O) 2 NR 5a R 5b , -(CR 7a R 7b ) r N(R 5c )S(=O) 2 NR 5a R 5b , -(CR 7a R 7b ) r -C 3- 8 -cycloalkyl, -(CR 7a R 7b ) r -C 6-10 aryl, -(CR 7a R 7b ) r - (heterocyclic group of 3-8 atoms), -(CR 7a R 7b ) r - (5-10 atomic heteroaryl) or D-mannosyl; wherein each G is independently O, S or NR 5d ;

Each R 2 is independently optionally substituted by 1, 2, 3 or 4 R 2a .
The compound according to any one of claims 1 to 12, wherein Ring B is of the following substructure:

Wherein each of Q 1 , Q 6 and Q 9 is independently CH 2 , NH, O, S, C(=O), S(=O) or S(=O) 2 ;

Each of Q 2 , Q 3 , Q 4 , Q 5 , Q 7 and Q 8 is independently CH or N;

s is 0, 1, 2 or 3;

Each R 2 is independently H, hydrazine, F, Cl, Br, I, -(CR 7a R 7b ) r CN, C 1-3 alkyl, deuterated C 1-3 alkyl, halogenated C 1-3 Alkyl, C 2-4 alkenyl, R 8 OC 2-6 alkenylene, R 8 OC(=O)-C 2-6 alkenylene, R 8 OC 2-6 alkynylene, R 8 OC ( =O)-C 2-6 alkynylene, -N=C=S, -(CR 7a R 7b ) r OR 8 , -(CR 7a R 7b ) r NR 5a R 5b , -(CR 7a R 7b ) r C(=O)R 6 , -(CR 7a R 7b ) r OC(=G)R 6 , -(CR 7a R 7b ) r N(R 5c )C(=O)R 6 ,-(CR 7a R 7b ) r C(=O)OR 8 , -(CR 7a R 7b ) r N(R 5c )C(=O)OR 8 , -(CR 7a R 7b ) r C(=O)NR 5a R 5b , -(CR 7a R 7b ) r N(R 5c )C(=O)NR 5a R 5b , -(CR 7a R 7b ) r N(R 5c )C(=S)NR 5a R 5b ,-(CR 7a R 7b ) r N(R 5c )C(=NR 5d )NR 5a R 5b , -(CR 7a R 7b ) r S(=O) 2 R 6 , -(CR 7a R 7b ) r OS(=O 2 R 6 , -(CR 7a R 7b ) r N(R 5c )S(=O) 2 R 6 , -(CR 7a R 7b ) r S(=O) 2 OR 8 , -(CR 7a R 7b r N(R 5c )S(=O) 2 OR 8 , -(CR 7a R 7b ) r S(=O) 2 NR 5a R 5b , -(CR 7a R 7b ) r N(R 5c )S( =O) 2 NR 5a R 5b , -(CR 7a R 7b ) r -C 3-6 cycloalkyl, -(CR 7a R 7b ) r -C 6- 10 aryl, -(CR 7a R 7b ) r - (heterocyclic group of 3-6 atoms) or -(CR 7a R 7b ) r - (heteroaryl group of 5-10 atoms); Each R 2 is independently optionally substituted by 1, 2, 3 or 4 R 2a .
The compound according to any one of claims 1 to 13, wherein ring B is

Each R 2 is independently H, 氘, F, Cl, Br, I, CN, -CH 2 -CN, -CH 2 CH 2 -CN, methyl, ethyl, propyl, butyl, deuterated methyl , di-deuterated methyl, mono-deuterated methyl, trifluoromethyl, difluoromethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl Base, vinyl, propenyl, allyl, HO-vinyl, MeO-vinyl, HOC(=O)-vinyl, MeOC(=O)-vinyl, -N=C=S, -OH, -OMe, -O(i-Pr), -O(t-Bu), -CH 2 -OH, -CH 2 CH 2 -OH, -CH 2 -OMe, -CH 2 CH 2 -OMe, -CH 2 -O(i-Pr), -CH 2 -O(t-Bu), phenyl-O-, pyridyl-O-, pyrimidinyl-O-, pyrazinyl-O-, pyridazinyl-O- , pyrrolyl-O-, pyrazolyl-O-, thiazolyl-O-, oxazolyl-O-, oxadiazolyl-O-, imidazolyl-O-, thiadiazolyl-O-, - NH 2 , -NHMe, -N(Me) 2 , -CH 2 -NH 2 , -CH 2 CH 2 -NH 2 , -CH 2 -NHMe, -CH 2 -N(Me) 2 , phenyl-NH- , pyridyl-NH-, pyrimidinyl-NH-, pyrazinyl-NH-, pyridazinyl-NH-, pyrrolyl-NH-, pyrazolyl-NH-, thiazolyl-NH-, oxazolyl- NH-, oxadiazolyl-NH-, imidazolyl-NH-, thiadiazolyl-NH-, -C(=O)Me, -C( =O)Et, -CH 2 -C(=O)Me, -CH 2 -C(=O)Et, -NHC(=O)Me, -C(=O)OH, -C(=O)OMe , -NHC(=O)OMe, -NHC(=O)OH, -NHC(=O)OEt, -NHC(=O)O(t-Bu), -C(=O)NH 2 , -C( =O)NHMe, -NHC(=O)NH 2 , -NHC(=S)NH 2 , -NHC(=NH)NH 2 , -S(=O) 2 Me, -NHS(=O) 2 Me, -S(=O) 2 OH, -S(=O) 2 OMe, -NHS(=O) 2 OH, -NHS(=O) 2 OMe, -S(=O) 2 NH 2 , -NHS(= O) 2 NH 2 , cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, dioxolane, piperidinyl, piperazinyl, morpholinyl , tetrahydrofuranyl, tetrahydropyrrolyl, epoxypropyl, epoxybutyl, azetidinyl, dihydropyridyl, dihydropyranyl, phenyl, benzyl, pyridyl, pyrimidinyl, pyrazine , pyridazinyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, thiadiazolyl, triazolyl or tetrazolyl;

Wherein each R 2 is independently optionally substituted by 1, 2, 3 or 4 R 2a .
The compound according to any one of claims 1 to 14, wherein each R 1 is independently =O, H, hydrazine, F, Cl, Br, I, -CN, methyl, ethyl, propyl, butyl, tri Fluoromethyl, -OH, -OMe, -CH 2 OMe, -CH 2 OH, -NH 2 , -NHMe, -N(Me) 2 , -C(=O)Me, -C(=O)OH, -C(=O)OMe, -C(=O)NH 2 , -S(=O) 2 Me, -S(=O) 2 OH, -S(=O) 2 OMe, -S(=O) 2 NH 2 , cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclobutyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyridyl An azolyl, triazolyl, tetrazolyl, alkylene oxide, epoxybutyl, azetidinyl, tetrahydrofuranyl, piperidinyl, pyrrolidinyl, piperazinyl or morpholinyl; wherein each R 1 independently optionally substituted by 1, 2, 3 or 4 R 1a ;

Each R 4 is independently H, hydrazine, F, Cl, Br, I, hydroxy, amino, methyl, ethyl, propyl, butyl, trifluoromethyl, difluoromethyl, 1,2-difluoro Ethyl, trifluoromethoxy, difluoromethoxy, -OMe, -OEt, -O(t-Bu), -CH 2 OH, -CH 2 CH 2 OH, -CN, -CH 2 CN, - CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 OMe, -CH 2 CH 2 OMe, -NHMe or -N(Me) 2 ; alternatively, any two R 4 and the atoms to which they are attached form a C 3-6 cycloalkyl group or a heterocyclic group consisting of 3 to 6 atoms;

Each of R 9 , R 1a , R 2a and R 3a is independently =0, hydrogen, hydrazine, F, Cl, Br, I, —(CR 7a R 7b ) r CN, nitro, C 1-4 alkyl, Halogen C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, R 8 OC 2-4 alkenylene, R 8 OC(=O)-C 2-4 alkenylene, R 8 OC 2-4 alkynylene, R 8 OC(=O)-C 2-4 alkynylene, -(CR 7a R 7b ) r -OR 8 , -(CR 7a R 7b ) r -NR 5a R 5b , -(CR 7a R 7b ) r N(R 5c )C(=O)R 6 , -(CR 7a R 7b ) r OC(=O)R 6 , -(CR 7a R 7b ) r COOH,-( CR 7a R 7b ) r C(=O)OC 1-4 alkyl, -(CR 7a R 7b ) r C(=O)C 1-4 alkyl, -(CR 7a R 7b ) r S(=O 2 R 6 , -(CR 7a R 7b ) r OS(=O) 2 R 6 , -(CR 7a R 7b ) r N(R 5c )S(=O) 2 R 6 , -(CR 7a R 7b r S(=O) 2 OR 8 , -(CR 7a R 7b ) r S(=O) 2 NR 5a R 5b , -(CR 7a R 7b ) r -C 3-6 cycloalkyl, -(CR 7a R 7b ) r -C 6-10 aryl, -(CR 7a R 7b ) r -(heterocyclic group of 3-6 atoms) or -(CR 7a R 7b ) r -(5-6 atoms Composition of heteroaryl);

Alternatively, any two R 9 together with the atoms to which they are attached form a C 3-6 cycloalkyl group or a heterocyclic group consisting of 3 to 6 atoms;

Wherein each of R 9 , R 1a , R 2a and R 3a is independently optionally substituted by 1, 2, 3, 4 or 5 R 10 .
The compound according to any one of claims 1 to 15, wherein each R 1 is independently =O, H, hydrazine, F, Cl, Br, I, cyano, methyl, ethyl, propyl, butyl Base, -OH, -OMe, -CH 2 OMe, -CH 2 OH, -NH 2 , -NHMe, -N(Me) 2 , -C(=O)Me, -C(=O)OH, -C (=O)OMe, -C(=O)NH 2 , -S(=O) 2 Me, -S(=O) 2 OH, -S(=O) 2 OMe or -S(=O) 2 NH 2 ; wherein each R 1 is independently optionally substituted by 1, 2, 3 or 4 R 1a ;

Each R 4 is independently H, hydrazine, F, Cl, Br, I, hydroxy, amino, methyl, ethyl, propyl, butyl, vinyl, propenyl, allyl, deuterated methyl, three Fluoromethyl, difluoromethyl, 1,2-difluoroethyl, -OMe, -OEt, -CH 2 OH, -CH 2 CH 2 OH, -CN, -CH 2 CN, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 OMe, -CH 2 CH 2 OMe, -NHMe or -N(Me) 2 ; alternatively, any two R 4 and the atoms to which they are attached form a cyclopropyl group, a ring Butyl, epoxyalkyl or azetidinyl;

Each of R 9 , R 1a , R 2a and R 3a is independently =0, hydrogen, hydrazine, F, Cl, Br, I, -CN, methyl, ethyl, propyl, butyl, trifluoromethyl, Difluoromethyl, 2,2-difluoroethyl, -CH 2 CN, -CH 2 CH 2 CN, vinyl, propenyl, allyl, ethynyl, propynyl, -OH, -OMe, - O(i-Pr), -O(t-Bu), -CH 2 -OH, -CH 2 CH 2 -OH, -CH 2 -OMe, -CH 2 CH 2 -OMe, -CH 2 -O(i -Pr), -CH 2 -O(t-Bu), -NH 2 , -NHMe, -N(Me) 2 , -CH 2 -NH 2 , -CH 2 CH 2 -NH 2 , -CH 2 -NHMe , -CH 2 -N(Me) 2 , -NHC(=O)Me, -CH 2 COOH, -COOH, -C(=O)OMe, -CH 2 C(=O)OMe, -C(=O Me, -CH 2 C(=O)Me, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, epoxyalkyl, epoxybutyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl , piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dihydropyranyl, phenyl, benzyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, Pyrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, triazolyl or tetrazolyl;

Alternatively, any two R 9 together with the atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, alkylene oxide, epoxybutyl, azetidinyl, tetrahydrofuranyl, pyrrole An alkyl group, a piperidinyl group or a piperazinyl group;

Wherein each of R 9 , R 1a , R 2a and R 3a is independently optionally substituted by 1, 2, 3, 4 or 5 R 10 .
The compound according to any one of claims 1 to 16, wherein each of R 5 , R 5a , R 5b , R 5c and R 5d is independently hydrogen, cyano, hydroxy, C 1-4 alkyl, C 1 -4 alkoxy-C(=O)-, C 6-10 aryl, C 3-6 cycloalkyl, heterocyclic group consisting of 3-6 atoms or heteroaryl group of 5-6 atoms;

Each of R 6 and R 8 is independently hydrogen, deuterium, C 1-4 alkyl, deuterated C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, hydroxy substituted C 1-4 Alkyl, amino substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy C 1-4 alkyl, halo C 1-4 alkyl, C 6- a 10 aryl group, a C 3-6 cycloalkyl group, a heterocyclic group of 3 to 6 atoms or a heteroaryl group of 5 to 6 atoms;

Each of R 7 , R 7a and R 7b is independently hydrogen, C 1-4 alkyl, deuterated C 1-4 alkyl or halo C 1-4 alkyl;

Each R 10 is independently =O, H, D, F, Cl, Br, I, CN, amino, hydroxy, nitro, carboxy, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkoxy C 1-4 alkyl, hydroxy substituted C 1-4 alkyl , cyano-substituted C 1-4 alkyl, amino-substituted C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkyl acyl, C 1-4 alkylsulfonyl, C 1 a 4 -alkoxyacyl group, a C 1-4 alkylamino group, a phenyl group, a C 3-6 cycloalkyl group, a heterocyclic group of 3 to 6 atoms or a heteroaryl group of 5 to 6 atoms.
The compound according to any one of claims 1 to 17, wherein each of R 5 , R 5a , R 5b , R 5c and R 5d is independently hydrogen, cyano, hydroxy, methyl, ethyl, propyl, Butyl, methoxy-C(=O)-, ethoxy-C(=O)-, isopropoxy-C(=O)-, tert-butoxy-C(=O)-, benzene , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, alkylene oxide, epoxybutyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholine , tetrahydropyranyl, dihydropyranyl, phenyl, benzyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, Thiazolyl, oxadiazolyl, thiadiazolyl, triazolyl or tetrazolyl;

Each of R 6 and R 8 is independently hydrogen, deuterium, methyl, ethyl, propyl, butyl, deuterated methyl, vinyl, propynyl, hydroxymethyl, hydroxyethyl, methoxymethyl , methoxyethyl, ethoxymethyl, tert-butoxymethyl, tert-butoxyethyl, ethoxyethyl, isopropoxyethyl, trifluoromethyl, difluoromethyl, 1,2-difluoroethyl, 2,2-difluoroethyl, phenyl, cyclopropyl, cyclohexyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, pyridine , pyrrolyl, pyrimidinyl, pyrazolyl, pyrazinyl, furyl, thiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl or tetrazolyl;

Each of R 7 , R 7a and R 7b is independently hydrogen, methyl, ethyl, propyl, butyl, deuterated methyl, trifluoromethyl, difluoromethyl, 1,2-difluoroethyl or 2,2-difluoroethyl;

Each R 10 is independently =O, H, D, F, Cl, Br, I, CN, amino, hydroxy, nitro, carboxy, methyl, ethyl, propyl, butyl, deuterated methyl, A Oxyl, methylamino, dimethylamino, methoxymethyl, methoxyethyl, tert-butoxymethyl, tert-butoxyethyl, hydroxymethyl, hydroxyethyl, CN substituted methyl, CN substituted ethyl, aminomethyl, aminoethyl, trifluoromethyl, difluoromethyl, 1,2-difluoroethyl or 2,2-difluoroethyl, methylacyl, ethylacyl, Methylsulfonyl, methoxy, tert-butoxy, methylamino, dimethylamino, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, propylene oxide, epoxy Butyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxadiazolyl, tri Azolyl, tetrazolyl, pyridyl, pyrimidinyl or pyrazinyl.
A compound that is one of the following structures:

Or a stereoisomer, geometric isomer, tautomer, oxynitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the above structure.
A pharmaceutical composition comprising the compound of any one of claims 1 to 19; wherein the pharmaceutical composition further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, and vehicle .
The use of a compound according to any one of claims 1 to 19 or a pharmaceutical composition according to claim 20 for the preparation of a medicament for the prevention, treatment or alleviation of a thromboembolic disease.
The use according to claim 21, wherein the thromboembolic disease is an arterial cardiovascular thromboembolic disease, an intravenous cardiovascular thromboembolic disease, and a thromboembolic disease in the ventricular or peripheral circulation.
The use according to claim 21, wherein the thromboembolic disease is angina pectoris, acute coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease Venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and blood in medical implants, instruments, or procedures Thrombosis caused by exposure to an artificial surface to promote thrombosis.
The use of a compound according to any one of claims 1 to 19 or a pharmaceutical composition according to claim 20 for the preparation of a medicament for inhibiting factor XIa and/or plasma kallikrein Activity.
A compound according to any one of claims 1 to 19 or a pharmaceutical composition according to claim 20 for use in the prevention, treatment or alleviation of a thromboembolic disease.
The compound or composition according to claim 25, wherein the thromboembolic disease is an arterial cardiovascular thromboembolic disease, an intravenous cardiovascular thromboembolic disease, and a thromboembolic disease in the ventricular or peripheral circulation.
The compound or composition according to claim 26, wherein the thromboembolic disease is angina pectoris, acute coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusion Arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and medical implants, instruments or procedures The blood in the body is exposed to the artificial surface to promote thrombosis caused by thrombosis.
A compound according to any one of claims 1 to 19 or a pharmaceutical composition according to claim 20 for inhibiting the activity of factor XIa and/or plasma kallikrein.
A method of preventing, treating or ameliorating a thromboembolic disease using the compound according to any one of claims 1 to 19 or the pharmaceutical composition according to claim 20.
The method according to claim 29, wherein the thromboembolic disease is an arterial cardiovascular thromboembolic disease, an intravenous cardiovascular thromboembolic disease, and a thromboembolic disease in the ventricular or peripheral circulation.
The method according to claim 30, wherein said thromboembolic disease is angina pectoris, acute coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease Venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and blood in medical implants, instruments, or procedures Thrombosis caused by exposure to an artificial surface to promote thrombosis.
A method of inhibiting the activity of Factor XIa and/or plasma kallikrein using a compound according to any one of claims 1-19 or a pharmaceutical composition according to claim 20.