WO2019134680A1 - Inhibitor of apoptosis signal-regulating kinase-1 and application thereof - Google Patents

Abstract

The present invention relates to a fused ring compound having the structure represented by formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, or a prodrug molecule thereof. The novel fused ring compound provided by the present invention may effectively bind to apoptosis signal-regulating kinase 1 (ASK1) and act as an ASK1 inhibitor, thereby being capable of blocking a downstream pathway controlled by ASK1 and alleviating or curing ASK1-mediated related diseases.

Description

Apoptosis signal-regulated kinase-1 inhibitor and its application Technical field

The present invention relates to the field of medicinal chemistry, and in particular to an apoptosis signal-regulating kinase-1 inhibitor and its use.

Background technique

The mitogen-activated protein kinase (MAPK) pathway is a critical signaling pathway regulating cellular stress responses, including three classes of protein kinases, MAPK, MAPK kinase (MAP2K) and MAPK kinase kinase (MAP3K). The relationship between the three is: MAP3K phosphorylates and activates MAP2K, which activates MAPK after phosphorylation. Multiple subtypes of MAPK regulate many cellular functions through multiple downstream pathways, including cell proliferation, differentiation, migration, and apoptosis. Apoptosis Signaling Regulatory Kinase 1 (ASK1), also known as MAP3K5, belongs to the MAP3K family and directly activates MAP2K, a variety of downstream specific subtypes, including MAP2K3, MAP2K4 and MAP2K6, which in turn activates the more downstream c-Jun N-terminal kinase ( The JNK) pathway and the p38 pathway play an important role in the MAPK pathway.

Apoptosis Signaling Regulatory Kinase-1 (ASK1) is a 1374 amino acid polypeptide with 9 alpha-helix regions and 11 beta-sheet regions with a serine/threonine as the central region of action for the kinase. There is a coiled-coil structure at the N-terminus and the C-terminus, respectively, and the catalytic region has 2 α-helices and 5 β-sheets. ASK1 forms a stable homodimer through the coiled-coil structure at the C-terminus and then forms a heterologous complex with ASK2. ASK1 acts as a stabilizing agent in the complex, and the two can activate each other. Under normal conditions, the N-terminus of ASK1 binds to reduced thioredoxin (Trx), which is used to block the activation of ASK1. Under oxidative stress, Trx detaches and the conformation of ASK1 changes, allowing the phosphorylation site to autophosphorylate or phosphorylate. ASK1 has three autophosphorylation sites, Thr813, Thr838 and Thr842. Thr813 is located in the loop region between β8 and β9, away from the substrate binding site, which phosphorylates and changes the surrounding conformation, indirectly affecting the catalytic function of ASK1. Thr838 is located in the catalytic region, and this site is phosphorylated to stabilize the catalytic region. At the same time, Thr838 plays an important role in oxidative stress-induced ASK1 activation. The third phosphorylation site Thr842 is near the catalytic region amino acid residue Asp803.

ASK1 is in an unactivated state under normal conditions and has no phosphorylation function and cannot regulate downstream pathways. However, once the body has immune stress, including oxidative stress, endoplasmic reticulum stress, calcium influx, DNA damage, viral infection, and some inflammatory factors (such as tumor necrosis factor alpha (TNFα) and lipopolysaccharide (LPS) ), etc., ASK1 will respond. Activation of ASK1 is regulated by a number of proteins that are in contact with it, of which the role of reduced thioredoxin (Trx) is critical. Trx is a redox protein that changes its structure depending on the redox state of the cell. Only the reduced Trx[Trx-(SH)2] binds to the N-terminal coiled-coil structure of the ASK1 oligomer, inhibiting the activation of ASK1 by inhibiting the homophilic interaction under non-stimulated conditions. Once high concentrations of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), are generated and stimulated, Trx will be converted to an oxidized state (Trx-S2), detached from ASK1, causing the N-terminal coiled-coil structure to be closely oligomerized, forming The ASK1 signalling body will attract TNF receptor-associated factor 1 and (TRAF2 and 6) to form a complex, which triggers ASK1 autophosphorylation site and activates by autophosphorylation. TRAF2 and 6 can also be directly used as activating factor of ASK1 to depolymerize Trx from ASK1. In addition, calmodulin kinase (CaMKII), angiotensin (Ang) II receptor type 1 (AT1) and Toll-like receptors TLR 4, 7 and 8 can also act as direct ASK1 activators. Therefore, when the body is infected with bacteria or DNA, or when TNFα and LPS signals are generated, ROS is produced, resulting in ASK1 activation; or under conditions of endoplasmic reticulum stress or virus infection, TRAF2 and 6 will be reduced in Trx [Trx] -(SH)2] Depolymerization from ASK1 triggers Thr838 phosphorylation to activate ASK1; or in the influx of calcium ions, CaMKII acts directly on ASK1 to activate it. Activation of the ASK1 protein phosphorylates downstream MKK4/7 or MKK3/6, which in turn activates the relevant JNK (JNK1, 2, and 3) pathways or the associated p38 (p38α, β, γ, and δ) pathways, triggering downstream A range of biological effects, such as apoptosis, immune response, secretion of cytokines, etc. Under oxidative stress, ASK1 is activated in a large amount, which increases the release of cytokines in mitochondria and decreases the consumption of caspase-9, which leads to mitochondria-dependent apoptosis. ASK1 can also participate in the process of cytokine release and inflammation in vivo under the regulation of Toll-like receptor-4 (TLR4) signaling. TLR4 specifically recognizes lipopolysaccharide on the surface of Gram-negative bacteria, and the resulting complex produces reactive oxygen species, triggers ASK1 activation, and activates p38 through the MAPK pathway, resulting in the release of a series of cytokines and inflammation. Therefore, the ASK1-MAPK pathway is closely related to the occurrence of many diseases. The diseases involved in the ASK1-MAPK pathway are: (1) cardiovascular disease, including ischemia/reperfusion injury, cardiac remodeling, and endothelial dysfunction; (2) neurodegenerative diseases, including polyglutamine (PolyQ) Diseases (such as Huntington's disease, spinal cord muscle atrophy, certain types of spinal cerebellar ataxia), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), normal Intraocular pressure glaucoma, etc.; (3) inflammatory diseases, including multiple sclerosis (MS), rheumatoid arthritis (RA); (4) infectious diseases, including influenza virus, HIV-1, Japanese encephalitis virus (JEV) , sepsis, hepatitis C virus (HCV), etc.; (5) tumors, including skin cancer, colon cancer, stomach cancer, liver cancer, melanoma; (6) other diseases, including Fanconi anemia, asthma, hepatic steatosis (such as Nonalcoholic fatty liver disease (NAFLD), diabetes, liver damage, aging, etc.

In view of the important role of ASK1 in the pathogenesis of various diseases, inhibition of ASK1 protein activity can block the downstream pathway controlled by ASK1, thereby alleviating or curing related diseases. Therefore, it is of great scientific significance to find and discover highly effective ASK1 inhibitors. And good clinical application prospects.

Summary of the invention

Based on this, the present invention provides a new class of fused ring compounds which bind to ASK1 and act as ASK1 inhibitors.

The specific technical solutions are as follows:

A fused ring compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a solvate thereof or a prodrug molecule thereof:

Wherein V ₁ and V ₆ are each independently selected from: N or C;

V ₂ , V ₃ , V ₄ and V ₅ are each independently selected from: O, S, N, -N(R ₁ )-, -C(R ₂ )- or none;

Each R _{1 is} independently selected from the group consisting of: H, D, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₂ -C ₄ alkenyl, substituted or unsubstituted C ₂ -C ₄ alkyne a substituted or unsubstituted C ₃ -C ₇ cycloalkyl group, or a substituted or unsubstituted heterocycloalkyl group of 3-7 atoms;

Each R _{2 is} independently selected from the group consisting of: H, D, oxo, thio, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₂ -C ₄ alkenyl, substituted or unsubstituted a C ₂ -C ₄ alkynyl group, a substituted or unsubstituted C ₃ -C ₇ cycloalkyl group, or a substituted or unsubstituted heterocycloalkyl group of 3-7 atoms;

X, Y and Z are each independently selected from: O, -N(R ₃ )-, -(CR ₄ R ₅ ) _a -, -C(=O)-, -S(=O)-, -S( =O) ₂ -, -P(=O)N(R ₇ )-, -P(=O)(OR ₈ )- or none, and X, Y and Z cannot be simultaneously;

Each R _{3 is} independently selected from: H, D, -(CR ₄ R ₅ ) _a R ₉ , -C(=O)R ₉ , -C(=O)OR ₉ , -C(=O)-NR ₉ R ₁₀ , -(CH ₂ ) _a -C(=O)-NR ₉ R ₁₀ , -N(R ₉ )-C(=O)-NR ₉ R ₁₀ , -S(=O) _0-2 NR ₉ R ₁₀ , -S(=O) _0-2 R ₁₀ , 1 or more R ₁₆ substituted or unsubstituted C ₁ -C ₆ alkyl, 1 or more R ₁₆ substituted or unsubstituted C ₃ -C ₆ cycloalkyl, 1 or more R ₁₆ substituted or unsubstituted C ₂ -C ₆ alkenyl, 1 or more R ₁₆ substituted or unsubstituted C ₂ -C ₆ alkynyl, 1 or a plurality of R ₁₆ substituted or unsubstituted monocyclic aryl groups, 1 or more R ₁₆ substituted or unsubstituted monocyclic heteroaryl groups, 1 or more R ₁₆ substituted or unsubstituted fused cycloalkyl groups, 1 or more R ₁₆ substituted or unsubstituted bridged cycloalkyl groups, 1 or more R ₁₆ substituted or unsubstituted spirocycloalkyl groups, 1 or more R ₁₆ substituted or unsubstituted fused aryl groups, Or one or more R ₁₆ substituted or unsubstituted fused heteroaryl groups;

Each of R ₄ and R _{5 is} independently selected from the group consisting of: H, D, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ a -C ₆ alkenyl group, a substituted or unsubstituted C ₂ -C ₆ alkynyl group, a substituted or unsubstituted C ₆ -C ₁₀ aryl group, or a substituted or unsubstituted heteroaryl group of 5-10 atoms, or R ₄ and R ₅ together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring of 3 to 6 atoms;

a is 1, 2 or 3;

Each of R ₇ and R _{8 is} independently selected from the group consisting of: H, D, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ a -C ₆ alkenyl group, a substituted or unsubstituted C ₂ -C ₆ alkynyl group, a substituted or unsubstituted C ₆ -C ₁₀ aryl group, or a substituted or unsubstituted heteroaryl group of 5-10 atoms;

Each of R ₉ and R _{10 is} independently selected from the group consisting of: H, D, -P(=O)(OR ₈ )(OR ₈ ), cyano, carboxy, 1 or more R ₁₆ substituted or unsubstituted C ₁ -C ₆ alkyl, 1 or more R ₁₆ substituted or unsubstituted C ₃ -C ₆ cycloalkyl, 1 or more R ₁₆ substituted or unsubstituted C ₂ -C ₆ alkenyl, 1 or a plurality of R ₁₆ substituted or unsubstituted C ₂ -C ₆ alkynyl groups, 1 or more R ₁₆ substituted or unsubstituted C ₃ -C ₇ heterocycloalkyl groups, 1 or more R ₁₆ substituted or unsubstituted Monocyclic aryl, 1 or more R ₁₆ substituted or unsubstituted monocyclic heteroaryl, or 1 or more R ₁₆ substituted or unsubstituted fused aryl, 1 or more R ₁₆ substituted or Unsubstituted fused heteroaryl; or R ₉ , R ₁₀ together with the nitrogen to which they are attached form one or more R ₁₆ substituted or unsubstituted heterocycloalkyl groups of 3 to 6 atoms; or, R ₉ , R ₁₀ together with the nitrogen to which it is bonded form one or more R ₁₆ substituted or unsubstituted spiroheterocycloalkyl groups of 6 to 12 atoms;

W ₁ , W ₂ and W ₃ are each independently selected from: N or -C(R ₁₁ )-;

Each R _{11 is} independently selected from the group consisting of: H, D, halogen, -CN, substituted or unsubstituted C ₁ -C ₃ alkyl, substituted or unsubstituted ester, amide, amino, ether, sulfonamide, Or a phosphoramide group;

A ₁ and A ₂ are each independently selected from: -C(=O)-, -S(=O) _1-2 -, -N(R ₁₂ )-, or -P(=O)(OR ₁₂ )- Or A ₁ and A _{2 are} connected to form

Each R _{12 is} independently selected from the group consisting of: H, D, substituted or unsubstituted C ₁ -C ₃ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkyne a group, or a C ₃ -C ₆ cycloalkyl group;

b is 1, 2, 3 or 4;

Ar ₁ and Ar ₂ are each independently selected from: 1 or more R ₁₆ substituted or unsubstituted aryl groups of 6-10 atoms, or 1 or more R ₁₆ substituted or unsubstituted 5-6 a heteroaryl group composed of atoms;

Each R _{16 is} independently selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, one or more R ₁₇ substituted or unsubstituted C ₁ -C ₆ alkyl, one or more R ₁₇ substituted or unsubstituted C ₂ -C ₄ alkenyl, 1 or more R ₁₇ substituted or unsubstituted C ₂ -C ₄ alkynyl, 1 or more R ₁₇ substituted or unsubstituted C ₃ -C ₆ cycloalkyl, 1 One or more R ₁₇ substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl groups, one or more R ₁₇ substituted or unsubstituted C ₁ -C ₆ alkoxy groups, substituted by one or more R ₁₇ Or an unsubstituted C ₆ -C ₁₀ aryl group, one or more R ₁₇ substituted or unsubstituted heteroaryl groups of 5-10 atoms, or -COOR ₁₈ ;

Each R _{17 is} independently selected from the group consisting of: H, halogen, hydroxy, or cyano;

R _{18 is} selected from the group consisting of: H, or a C ₁ -C ₄ alkyl group.

In some of these embodiments, V ₁ , V ₂ , V ₃ , V ₄ , V _{5 ,} and V ₆ together comprise the following cyclic structure:

Wherein R ₁ and R _{2 are} as described above.

In some of these embodiments, the fused ring compound has the structure of Formula II:

Wherein V ₃ and V ₄ are each independently selected from -C(R ₂ )- or N;

R ₂ , X, Y, Z, W ₁ , W ₂ , W ₃ , Ar ₁ and Ar _{2 are} as described above.

In some of these embodiments, the fused ring compound has the structure of Formula III:

Wherein V ₃ is -C(R ₂ )- and V ₄ is N, or V ₃ is N and V ₄ is -C(R ₂ )-;

W _{2 is} selected from: N or -C(R ₁₁ )-;

B ₁ , B ₂ , B ₃ and B ₄ are each independently selected from: O, N, S, -C(R ₁₅ )- or none;

E ₁ and E ₂ are each independently selected from: N or -C(R ₁₅ )-;

R _{13 is} selected from the group consisting of: H, 1 or more R ₁₇ -substituted C ₁ -C ₄ alkyl groups, or 1 or more R ₁₇ -substituted or unsubstituted C ₃ -C ₆ cycloalkyl groups;

R _{14 is} selected from the group consisting of: H, D, 1 or more R ₁₇ substituted or unsubstituted C ₁ -C ₄ alkyl, 1 or more R ₁₇ substituted or unsubstituted C ₂ -C ₄ alkenyl, 1 One or more R ₁₇ substituted or unsubstituted C ₂ -C ₄ alkynyl groups, or one or more R ₁₇ substituted or unsubstituted C ₃ -C ₆ cycloalkyl groups; or, R ₁₃ , R ₁₄ and The linked N and C together form a heterocyclic group consisting of 5-8 atoms;

Each R _{15 is} independently selected from: H, D, 1 or more R ₁₇ substituted or unsubstituted C ₁ -C ₄ alkyl, 1 or more R ₁₇ substituted or unsubstituted C ₂ -C ₄ Alkenyl, 1 or more R ₁₇ substituted or unsubstituted C ₂ -C ₄ alkynyl, or 1 or more R ₁₇ substituted or unsubstituted C ₃ -C ₆ cycloalkyl;

R ₂ , X, Y, Z, R ₁₁ and R _{17 are} as defined in claim 1.

In some of these embodiments, the fused ring compound has the structure of Formula IV:

Among them, V ₃ , V ₄ , X, Y, Z, W ₂ and R _{13 are} as described above.

In some of these embodiments, the fused ring compound has the structure of Formula V:

Among them, V ₃ , V ₄ , X, Y, Z, W ₂ and R _{13 are} as described above.

In some of these embodiments, X, Y, and Z are joined to form the following structure:

In some of these embodiments, X, Y, and Z are joined to form the following structure:

In some of these embodiments, each R _{2 is} independently selected from: C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, or C ₃ -C ₆ cycloalkyl.

In some of these embodiments, each R _{2 is} independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, or ring. Amyl.

In some of these embodiments, each R _{11 is} independently selected from the group consisting of: H, halo, or C ₁ -C ₃ alkyl.

In some of these embodiments, R _{11 is} selected from the group consisting of F, Cl, Br, I, methyl, ethyl, propyl, or isopropyl.

In some of these embodiments, R _{13 is} selected from the group consisting of: H, C ₁ -C ₄ alkyl, hydroxy-substituted C ₁ -C ₄ alkyl, or C ₃ -C ₆ cycloalkyl.

In some of these embodiments, R _{13 is} selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, or hydroxy-substituted isopropyl.

In some of these embodiments, R ₄ and R ₅ are each independently selected from: H, C ₁ -C ₃ alkyl, or C ₃ -C ₆ cycloalkyl, or a carbon to which R ₄ and R ₅ are attached The atoms together form a carbocyclic or heterocyclic ring of 3-6 atoms.

In some of these embodiments, R ₄ and R ₅ are each independently selected from the group consisting of: H, methyl, ethyl, or propyl.

In some of these embodiments, R _{3 is} selected from the group consisting of: H, -(CH ₂ ) _a R ₉ , -S(=O) ₂ R ₁₀ , -C(=O)R ₉ , -C(=O)OR ₉ , -C(=O)-NR ₉ R ₁₀ , -(CH ₂ ) _a -C(=O)-NR ₉ R ₁₀ , -N(R ₉ )-C(=O)-NR ₉ R ₁₀ ,- S(=O) _0-2 NR ₉ R ₁₀ , -S(=O) _0-2 R ₁₀ , 1 or more R ₁₆ substituted or unsubstituted C ₁ -C ₆ alkyl groups, 1 or more R ₁₆ substituted or unsubstituted C ₃ -C ₆ cycloalkyl, 1 or more R ₁₆ substituted or unsubstituted C ₆ -C ₁₀ aryl, or 1 or more R ₁₆ substituted or unsubstituted 5 a heteroaryl group consisting of -6 atoms; wherein a is 1 or 2.

In some of these embodiments, R _{3 is} selected from the group consisting of: H, -(CH ₂ ) _a R ₉ , -C(=O)R ₉ , -C(=O)OR ₉ , -C(=O)-NR ₉ R ₁₀ , -(CH ₂ ) _a -C(=O)-NR ₉ R ₁₀ , -N(R ₉ )-C(=O)-NR ₉ R ₁₀ , -S(=O) _0-2 NR ₉ R ₁₀ , -S(=O) _0-2 R ₁₀ , 1 or more R ₁₆ substituted or unsubstituted C ₆ -C ₁₀ aryl groups, or 1 or more R ₁₆ substituted or unsubstituted 5- a heteroaryl group of 6 atoms; wherein a is 1 or 2;

R _{16 is} selected from the group consisting of hydrogen, halogen, hydroxy, cyano, halogen substituted C ₁ -C ₆ alkyl, hydroxy substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₃ -C ₆ ring Alkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, halogen substituted C ₆ -C ₁₀ aryl, or -C(=O)OR ₁₈ ; R _{18 is} selected from: H, or C _1- C ₄ alkyl.

In some of these embodiments, R ₉ and R ₁₀ are each independently selected from: H, -P(=O)(OR ₈ )(OR ₈ ), cyano, carboxy, 1 or more R ₁₆ substituted or not Substituted C ₁ -C ₆ alkyl, 1 or more R ₁₆ substituted or unsubstituted C ₃ -C ₆ cycloalkyl, 1 or more R ₁₆ substituted or unsubstituted C ₂ -C ₆ alkynyl , 1 or more R ₁₆ substituted or unsubstituted C ₃ -C ₆ heterocycloalkyl, 1 or more R ₁₆ substituted or unsubstituted C ₆ -C ₁₀ aryl, 1 or more R ₁₆ a substituted or unsubstituted heteroaryl group of 5-6 atoms, 1 or more R ₁₆ substituted or unsubstituted C ₈ -C ₁₂ fused aryl groups, or 1 or more R ₁₆ substituted or unsubstituted a fused heteroaryl group of 8 to 12 atoms; or, R ₉ and R ₁₀ together with the nitrogen to which they are attached form one or more R ₁₆ substituted or unsubstituted heterocyclic alkyl groups of 3 to 6 atoms Or R ₉ , R ₁₀ together with the nitrogen to which they are attached form one or more R ₁₆ substituted or unsubstituted spiroheterocycloalkyl groups of 6 to 12 atoms;

R _{16 is} selected from the group consisting of: hydrogen, halogen, halogen-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, halogen-substituted C ₆ -C ₁₀ aryl, hydroxy, cyano, or -C(=O)OR ₁₈ ; R _{18 is} selected from: H, or C ₁ -C ₄ alkyl.

In some of these embodiments, the fused ring compound has the structure of Formula VI:

Wherein W _{2 is} selected from the group consisting of: N or -C(R ₁₁ )-;

R _{2 is} selected from the group consisting of: C ₃ -C ₆ cycloalkyl;

R _{3 is} selected from the group consisting of: H, -(CH ₂ ) _a R ₉ , one or more R ₁₆ substituted or unsubstituted heteroaryl groups of 5-6 atoms, -C(=O)R ₉ , -C (=O)-NR ₉ R ₁₀ , -(CH ₂ ) _a -C(=O)-NR ₉ R ₁₀ , -N(R ₉ )-C(=O)-NR ₉ R ₁₀ ,-S(= O) _0-2 R ₁₀ , or 1 or more R ₁₆ substituted or unsubstituted C ₆ -C ₁₀ aryl, wherein a is 1 or 2;

Each R ₉ and R ₁₀ are independently selected from: H, 1 or more R ₁₆ substituted or unsubstituted C ₂ -C ₆ alkynyl groups, 1 or more R ₁₆ substituted or unsubstituted C ₁ -C _{a 6} alkyl group, one or more R ₁₆ substituted or unsubstituted C ₆ -C ₁₀ aryl groups, one or more R ₁₆ substituted or unsubstituted heteroaryl groups of 5-6 atoms, 1 or a plurality of R ₁₆ substituted or unsubstituted C _3-7 heterocyclic groups, or one or more R ₁₆ substituted or unsubstituted C ₃ -C ₆ cycloalkyl groups;

R _{11 is} selected from the group consisting of halogen;

R _{13 is} selected from the group consisting of: C ₁ -C ₄ alkyl;

Each R _{16 is} independently selected from the group consisting of: hydrogen, -CN, -OH, carboxyl, -COOMe, halogen-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C _1-6 alkyl or halogen .

In some of these embodiments, R _{3 is} selected from the group consisting of: H, -(CH ₂ )R ₉ , trifluoromethyl substituted pyridyl, -C(=O)R ₉ , -C(=O)-NR ₉ R ₁₀ , -(CH ₂ )-C(=O)-NR ₉ R ₁₀ , -N(R ₉ )-C(=O)-NR ₉ R ₁₀ , or -S(=O) _0-2 -C _{1 -4} alkyl;

Each of R ₉ and R _{10 is} independently selected from the group consisting of: H, ethynyl, C ₁ -C ₆ alkyl, phenyl, C ₃ -C ₆ cycloalkyl, heteroaryl of 5-6 atoms, naphthyl Or a C _3-7 heterocyclic group; wherein the C ₁ -C ₆ alkyl group, phenyl group, C ₃ -C ₆ cycloalkyl group, heteroaryl group composed of 5-6 atoms, naphthyl group and C _{3- The 7} heterocyclic group may be optionally selected from one or more independently selected from the group consisting of F, Cl, Br, I, CH ₃ O-, CH ₃ CH ₂ O-, -CF ₃ , -CH ₂ CF ₃ , C _1-4 Substituted by alkyl, -CN, -OH, C _1-4 haloalkyl, carboxy, and -COOMe substituents.

In some of these embodiments, the fused ring compound is selected from the group consisting of:

The invention also provides the use of the above fused ring compounds.

The specific technical solutions are as follows:

Use of the above fused ring compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a solvate thereof or a prodrug molecule thereof for the preparation of an ASK1 inhibitor.

Use of the above fused ring compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a solvate thereof or a prodrug molecule thereof for the preparation of a medicament for preventing and treating a disease mediated by ASK1.

In some of these embodiments, the ASK1-mediated disease comprises: renal fibrosis, liver fibrosis, pulmonary fibrosis, chronic kidney disease, diabetic nephropathy, pulmonary hypertension, tumor.

The invention also provides a pharmaceutical composition for the prevention and treatment of a disease mediated by ASK1.

The specific technical solutions are as follows:

A pharmaceutical composition for preventing and treating a disease mediated by ASK1, which comprises the above fused ring compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a solvate thereof or a prodrug molecule thereof. The compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof can be prepared with a pharmaceutically acceptable adjuvant or carrier to obtain a pharmaceutical composition for preventing and treating ASK1-mediated diseases. . The pharmaceutically acceptable excipient or carrier may be an excipient or a sustained release agent or the like. The pharmaceutical compositions of the present invention may be in a variety of forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and may be presented in a suitable solid or liquid carrier or diluent. The pharmaceutical compositions of the invention may also be stored in a suitable injectable or drip sterilizing device. Further, an odorant, a fragrance, or the like may be contained in the pharmaceutical composition of the present invention.

The present invention demonstrates by experiments that a series of novel fused ring compounds provided by the present invention can effectively bind to ASK1 and act as ASK1 inhibitors, thereby blocking the downstream pathway of ASK1 control, and alleviating or curing ASK1-mediated related diseases. The compounds of the invention have important scientific research significance and good clinical application prospects.

Detailed ways

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.

Unless otherwise expressly stated, the descriptions of the "individually" and "individually" and "independently" interchangeable in the present invention are to be understood in a broad sense. It can be said that in different groups, the specific options expressed between the same symbols do not affect each other, and it can also be said that in the same group, the specific options expressed between the same symbols do not affect each other.

The term "alkyl" or "alkyl group" as used herein, denotes a saturated straight or branched monovalent hydrocarbon group containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally selected The ground is replaced by one or more substituents described herein. Unless otherwise specified, an alkyl group contains from 1 to 20 carbon atoms. In one embodiment, the alkyl group contains from 1 to 12 carbon atoms; in another embodiment, the alkyl group contains from 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 - 4 carbon atoms; also in one embodiment, the alkyl group contains 1-3 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 at least one site of unsaturation, i.e., has a carbon-carbon sp ² double bond, wherein the alkenyl group The group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "tans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, 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₎ 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 site of unsaturation, i.e., has a carbon-carbon sp triple bond, wherein the alkynyl group It may be optionally substituted with one or more of the substituents described herein. In one embodiment, the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group comprises 2 - 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH ₂ C≡CH), 1-propynyl (-C≡C-CH ₃ ), 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. Unless otherwise specified, the alkoxy group contains from 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains from 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains from 1 to 4 carbon atoms; in yet another embodiment, 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 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH ₃ ) ₂ ), 1-butoxy (n-BuO, n- Butoxy, -OCH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH ₂ CH(CH ₃ ) ₂ ), 2-butyl Oxygen (s-BuO, s-butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) ₃ ) ₃ ), 1-pentyloxy (n-pentyloxy, -OCH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyloxy (-OCH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyloxy (-OCH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butoxy (-OC(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butoxy (-OCH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-l-butoxy (-OCH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-l-butoxy (-OCH ₂ CH(CH ₃ )CH ₂ CH ₃ ), and so on.

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, trifluoromethoxy, and the like.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic system containing from 3 to 12 carbon atoms. In one embodiment, the cycloalkyl group contains 3 to 12 carbon atoms; in another embodiment, the cycloalkyl group contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atom. The cycloalkyl group can be independently unsubstituted or substituted with one or more substituents described herein. Suitable cycloalkyl groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of the cycloalkyl group further include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a 1-cyclopentyl-1-alkenyl group, a 1-cyclopentyl-2-alkenyl group, a 1-cyclopentyl group- 3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl Base, cyclodecyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

The terms "heterocyclyl", "heterocycle" and "heterocycloalkyl" are used interchangeably herein to refer to a saturated or partially unsaturated monocyclic, bicyclic ring containing 3-12 or 3-7 ring atoms. Or a tricyclic ring wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms. 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. Examples of heterocyclic or heterocycloalkyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, 2-pyrroline, 3-pyrroline, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentane , dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholine Base, piperazinyl, dioxoalkyl, dithiaalkyl, thiamethane, homopiperazinyl, homopiperidinyl, oxetanyl, thiecycloheptyl, oxazepine

Diaza

Thioaza

, porphyrin, 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxanyl, 2-oxa-5-azabicyclo[2.2.1]hept-5 -base. Examples of the -CH ₂ - group in the heterocyclic group substituted by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidine Keto group, 3,5-dioxopiperidinyl group and pyrimidindione group. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, a sulfolane group and a 1,1-dioxothiomorpholinyl group. The heterocyclyl group can be optionally substituted with one or more substituents described herein.

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

The term "aryl" denotes a monocyclic, bicyclic and tricyclic carbocyclic ring system containing from 6 to 14 ring atoms, or from 6 to 12 ring atoms, or from 6 to 10 ring atoms, wherein at least one ring system is aromatic Of the family, wherein each ring system comprises a ring of 3-7 atoms and one or more attachment points are attached to the remainder of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of the aryl group may include a phenyl group, a naphthyl group, and an anthracene. The aryl group may be independently and optionally substituted with one or more substituents described herein.

The term "heteroaryl" denotes a monocyclic, bicyclic and tricyclic ring system containing from 5 to 12 ring atoms, or from 5 to 10 ring atoms, or from 5 to 6 ring atoms, wherein at least one ring system is aromatic, And at least one ring system comprises one or more heteroatoms, wherein each ring system comprises a ring of 5-7 atoms and one or more attachment points 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 is optionally substituted with one or more substituents described herein. In one embodiment, a heteroaryl group of 5-10 atoms comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.

Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (eg 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3- Triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5- Triazine group; also includes the following bicyclic rings, but is by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, fluorenyl (such as 2-indenyl), fluorenyl, quinolyl (eg 2-quinolyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (eg 1-isoquinolinyl, 3-isoquinoline) Or 4-isoquinolinyl), imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[ 1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl,[1,2,4]triazolo[1,5-a]pyrimidinyl , [1,2,4]triazolo[1,5-a]pyridinyl, and the like. The term "fused aryl" refers to a monovalent aromatic ring group formed by the two aromatic rings sharing two carbon atoms, such as a naphthyl group. "Condensed aryl" means a monovalent aromatic ring group in which at least one carbon atom of the ring is replaced by a hetero atom selected from nitrogen, oxygen or sulfur to share two carbon atoms.

The term "spirocycloalkyl" refers to a cyclic group formed by the two rings sharing one carbon atom, and "spiroheterocyclyl" means a ring shared by at least one hetero atom selected from nitrogen, oxygen or sulfur. a cyclic group formed by one carbon atom. Examples of spiroheterocyclyl groups include, but are not limited to:

Wait.

The term "fused cycloalkyl" refers to a cyclic group formed by the two rings sharing two carbon atoms, and "fused heterocyclic group" means two having at least one hetero atom selected from nitrogen, oxygen or sulfur. A cyclic group in which two rings share two carbon atoms. Examples of fused heterocyclic groups include, but are not limited to:

Wait.

The term "bridged cycloalkyl" refers to a cyclic group formed by two rings sharing three or more carbon atoms, and "bridge heterocyclic group" means a hetero atom containing at least one selected from nitrogen, oxygen or sulfur. The two rings share a cyclic group formed by three or more carbon atoms. Examples include but are not limited to:

Wait.

The term "substituted" refers to the replacement of a hydrogen group in a particular structure with a group of the specified substituent. Substitution on an alkyl or cycloalkyl group in the present invention, if not indicated to occur on a particular carbon atom, means that it can occur on a carbon atom whose number of substituents has not reached saturation. When a plurality of substituents are selected from the same series, they may be the same or different. Substitutions on a benzene ring, an aromatic heterocycle or a heterocycle in the present invention, if not indicated to occur on a particular atom, indicate that it can occur at any position that is not replaced by a hydrogen atom and other atoms. When a plurality of substituents are selected from the same series, they may be the same or different. The substituents include, but are not limited to, H, D, halogenated C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ - C ₆ alkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylamino, halogen, thiol, hydroxy, nitro, cyano, C ₃ -C ₈ cycloalkyl, 3-8 Heterocyclic alkyl group consisting of a hetero atom, a C ₆ -C ₁₄ aryl group, a heteroaryl group of 5-14 atoms, a C ₃ -C ₈ cycloalkoxy group, a heterocycloalkoxy group of 3-8 atoms a cycloalkylthio group of 3-8 atoms, a heterocycloalkylthio group of 3-8 atoms, -C(=O)R, -C(=O)OR, -C(=O) _m R , -NRR', -C(=O)NRR', -S(=O) _m NRR', etc., wherein R and R' may be selected from, but not limited to, C ₁ -C ₆ alkyl.

The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term "hydrate" is used when the solvent is water.

The present invention includes free forms of the compounds of Formulas I-VI, as well as pharmaceutically acceptable salts and stereoisomers thereof, and solvates and prodrugs thereof. The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods. Typically, the salt of the basic compound is prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric or excess amount of the desired salt or mixture of the inorganic or organic acid in a suitable solvent or combination of solvents. Similarly, a salt of an acidic compound is formed by reaction with a suitable inorganic or organic base.

Thus, pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention which are formed by the reaction of a basic compound of the invention with an inorganic or organic acid. For example, conventional non-toxic salts include those prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, and hard. Fatty acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl A salt prepared from oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid or the like.

If a compound of the invention is acidic, a suitable "pharmaceutically acceptable salt" refers to a salt prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts prepared from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, zinc salts, and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred. a salt prepared from a pharmaceutically acceptable organic non-toxic base, including a primary amine, a secondary amine, a tertiary amine, a substituted amine, and the like, wherein the substituted amine includes a naturally occurring substituted amine , cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- Dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxylamine, isopropylamine, lysine Acid, methyl glucosamine, morpholine, piperazine, piperidine, guanidine, polyamine resin, procaine, guanidine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

The abbreviations used in the following examples are as follows:

DMF-DMA: N,N-dimethylformamide dimethyl acetal

DMF: N,N-dimethylformamide

HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluron hexafluorophosphate

NMP: N-methylpyrrolidone

NBS: N-bromosuccinimide

AIBN: azobisisobutyronitrile

PMB: p-methoxybenzyl

PE: petroleum ether

EA: ethyl acetate.

In addition to the standard methods known in the literature or exemplified in the experimental procedures, the compounds of the invention can be prepared by the methods of the following examples. The compounds of the present invention and the synthetic methods can be better understood in conjunction with the following examples. All parameters and related descriptions in the examples are based on quality unless otherwise stated. The filler used for column chromatography separation is silica gel unless otherwise stated. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. The following examples are illustrative of the methods that can be used to prepare the compounds described in the present invention, which are merely illustrative of the illustrative examples and are not intended to limit the scope of the invention.

The following are specific examples.

Example 1

2-cyclopropyl-5-benzyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]- Preparation of 6-oxo-5,6-dihydro-4H-benzo[f]imidazo[1,2-a][1,4]diazepine-9-carboxamide (1).

1) Preparation of Intermediate 1-2.

Methyl 6-aminopyridine-2-carboxylate (5.0 g, 32.7 mmol) was dissolved in methanol (60 mL), and EtOAc (EtOAc, EtOAc (EtOAc) It was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate. The filter cake was dried to give 4.25 g of white solid. 1H NMR (500MHz, DMSO) δ: 9.17 (s, 1H), 7.51 (t, J = 7.5 Hz, 8.0 Hz, 1H), 7.10 (d, J = 7.5 Hz, 1H), 6.60 (d, J = 8.0) Hz, 1H), 6.07 (s, 2H), 4.46 (s, 2H).

2) Preparation of Intermediates 1-3.

Intermediate 1-2 (4.25 g, 27.8 mmol) was dissolved in DMF-DMA (40 mL). After the reaction of the starting material was completed, it was cooled to room temperature, vortexed, ethyl acetate (7 mL) was added, heated to 50 ° C and stirred for half an hour, filtered, and the filter cake was washed with petroleum ether, and dried to give a white solid, 6.0 g, yield 91 %.

3) Preparation of intermediates 1-4.

The intermediate 1-3 (6.0 g, 25.3 mmol) was dissolved in acetonitrile (28 mL) and acetic acid (7 mL), and then isopropylamine (11 mL, 126.6 mmol) was added, and the mixture was refluxed at 80 ° C for 3 hours. Cool to room temperature, spin dry, add water (30 mL) to dissolve, adjust the pH to about 8 with 2M NaOH solution, precipitate a white solid, filter, wash the filter cake with water, and the filter cake is dried to give a white solid 2.35 g. Yield: 46%. _{^{1 H NMR (500MHz, CDCl 3}} ) δ: 8.30 (s, 1H), 7.56 (m, 2H), 6.56 (m, 1H), 5.60 (m, 1H), 4.51 (s, 2H), 1.51 (d, J = 7.0 Hz, 6H).

4) Preparation of intermediates 1-5.

4-Bromo-3-fluorobenzoic acid (10 g, 45.7 mmol) was dissolved in concentrated sulfuric acid (35 mL), cooled to 0 ° C, and potassium nitrate (4.85 g, 47.9 mmol) was added portionwise and reacted at room temperature for 3 hours. The reaction liquid was poured into ice water, filtered, and the cake was washed with ice water, and the obtained solid was dried to obtain 10.8 g, yield: 90%. ^{1 H NMR (400MHz, DMSO)} δ: 8.48 (d, J = 6.0Hz, 1H), 7.86 (d, J = 8.4Hz, 1H).

5) Preparation of intermediates 1-6.

Intermediate 1-5 (9.9 g, 37.5 mmol) was dissolved in dichloromethane (100 mL), oxalyl chloride (6.3 mL, 75 mmol) The reaction solution was cooled to room temperature, dried, and then dichloromethane (100 mL) was then evaporated and evaporated. DCM (100 mL) was added, EtOAc m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m v After the addition was completed, the reaction was continued at 0 ° C for 3 hours, and the reaction solution was poured into water (150 mL), extracted with DCM (150 mL×3), washed with brine (150 mL×3), dried over anhydrous sodium sulfate (Petroleum ether: ethyl acetate = 8:1) gave a pale yellow solid (12.5 g, yield: 94%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.32 (d, J = 6.0Hz, 1H), 7.35 (m, 5H), 7.24 (d, J = 7.2Hz, 1H), 6.27 (m, 1H), 4.58 (d, J = 5.6 Hz, 2H).

6) Preparation of intermediates 1-7.

Intermediate 1-6 (12.5 g, 35.4 mmol) was dissolved in methanol (50 mL) and tetrahydrofurane (150 mL), and iron powder (15.9 g, 280 mmol) and acetic acid (10.1 mL, 177 mol). The reaction was heated at 65 ° C for 3 hours. The reaction solution was cooled to room temperature, and the solvent was evaporated. EtOAc (EtOAc) (EtOAc) (EtOAc) x 3) Washing, dried over anhydrous sodium sulfate, EtOAc (EtOAc:EtOAc:EtOAc.

7) Preparation of intermediates 1-8.

Intermediate 1-7 (10.1 g, 31.2 mmol) was dissolved in dichloromethane <RTI ID=0.0>(</RTI><RTIID=0.0></RTI></RTI><RTIgt; A solution of dichloromethane (50 mL) was added and the mixture was transferred to room temperature for 1 hour. The reaction solution was poured into water (200 mL), extracted with DCM (200 mL×2), washed with brine (200 mL×2), dried over anhydrous sodium sulfate :1) A gray solid 10.3 g was obtained, yield: 82%. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.91 (m, 1H), 7.38 (m, 5H), 7.23 (d, J = 8.0Hz, 1H), 6.45 (m, 1H), 4.63 (m, 2H) , 4.17 (s, 2H).

8) Preparation of intermediates 1-9.

Intermediate 1-8 (10.3 g, 25.8 mmol) was dissolved in DMF (200 mL), cooled to 0 <0>C, then sodium hydrogen (4.12 g, 103 <RTIgt; The mixture was cooled to 0 ° C, and the mixture was evaporated to dryness. EtOAc EtOAc (EtOAc) It was spin-dried and beaten with a mixed solution of petroleum ether and diisopropyl ether to obtain 7.8 g of an off-white solid. The yield was 83%. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.42 (s, 1H), 7.78 (m, 1H), 7.35 (m, 5H), 7.22 (m, 1H), 4.84 (s, 2H), 3.81 (s, 2H).

9) Preparation of intermediate 1-10.

Intermediate 1-9 (5 g, 13.8 mmol) was dissolved in DMF (50 mL) EtOAc EtOAc (EtOAc:EtOAc. Reaction for 3 hours. The reaction mixture was poured into water (150 mL), EtOAc (150 mL, EtOAc) Ethyl ester = 5:1 to 3:1) gave 5.64 g of a foamy solid. Yield: 93%.

10) Preparation of intermediates 1-11

Intermediate 1-10 (5.64 g, 12.7 mmol) was dissolved in acetic acid (80 mL). The reaction solution was cooled, and the mixture was poured into water (200 mL), EtOAc (EtOAc (EtOAc) (Petroleum ether: ethyl acetate = 5:1) gave 3.8 g of a white solid, yield 70%. ^{1 H NMR (500MHz, DMSO)} δ: 7.96 (d, J = 6.0Hz, 1H), 7.83 (d, J = 9.0Hz, 1H), 7.57 (s, 1H), 7.39-7.23 (m, 5H), 4.74 (br, 2H), 4.41 (s, 2H), 1.79 (m, 1H), 0.79 (m, 2H), 0.65 (m, 2H).

11) Preparation of intermediates 1-12.

Intermediate 1-11 (1.55 g, 3.64 mmol) was dissolved in tetrahydrofuran (20 mL). EtOAc (EtOAc m. , 1M in THF), after the addition, the reaction was carried out for 15 minutes, the reaction was quenched with ammonium chloride solution, water (50 mL) was added, extracted with ethyl acetate (50 mL×2), and brine (100 mL) The sodium was dried, dried, and purified by column chromatography (ethyl ether: ethyl acetate = 5:1 to 3:1) to yield 0.47 g of pale yellow solid. _{^{1 HNMR (500MHz, CDCl 3)}} δ: 10.42 (s, 1H), 7.96 (d, J = 10.0Hz, 1H), 7.81 (d, J = 5.5Hz, 1H), 7.34 (m, 5H), 7.08 ( s, 1H), 4.25 (br, 4H), 1.86 (m, 1H), 0.90 (m, 2H), 0.76 (m, 2H).

12) Preparation of intermediates 1-13.

Intermediate 1-12 (440 mg, 1.17 mmol) was dissolved in tert-butanol (5 mL), tetrahydrofuran (10 mL) and water (5 mL), cooled in ice-cooling, then 2-methyl-butene (0.84 mL, 11.7 mmol) An aqueous solution of sodium chlorite (530 mg, 5.86 mmol) and sodium dihydrogen phosphate (703 mg, 5.86 mmol) was added dropwise. After reacting at 0 ° C for half an hour, spin dry, add water, adjust the pH to about 5 with 1N HCl, and filter, the obtained solid is dried first, and then beaten (petroleum ether: ethyl acetate = 3:1) to obtain an off-white solid 360 mg. 79%.

13) Preparation of Compound 1.

Intermediate 1-13 (50 mg, 0.133 mmol) was dissolved in dichloroethane (3 mL). EtOAc (EtOAc, EtOAc (EtOAc) . After reacting at room temperature for 1 hour, the reaction was further heated at 75 ° C overnight. The reaction solution was cooled to room temperature, vortexed, and purified by chromatography (methylene chloride:methanol = 15:1) to yield white powder (yield: 55%). ^{1 H NMR (500MHz, DMSO)} δ: 11.13 (s, 1H), 8.86 (s, 1H), 8.22 (d, J = 8.5Hz, 1H), 8.07 (t, J = 8.5Hz, 1H), 7.93 ( m, 2H), 7.86 (d, J = 10.0 Hz, 1H), 7.63 (s, 1H), 7.30 (m, 5H), 5.65 (m, 1H), 4.77 (br, 2H), 4.44 (s, 2H) ), 1.81 (m, 1H), 1.43 (d, J = 6.5 Hz, 6H), 0.80 (m, 2H), 0.65 (m, 2H).

Example 2

2-cyclopropyl-5-benzyl-8-fluoro-N-[2-(4-isopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl]- Preparation of 6-oxo-5,6-dihydro-4H-benzo[f]imidazo[1,2-a][1,4]diazepine-9-carboxamide (2).

1) Preparation of intermediate 2-2.

4-Bromothiazole-2-carboxylic acid (4.0 g, 19.2 mmol) was dissolved in methanol (20 mL), cooled to 0 ° C, thionyl chloride (1.4 mL) was added and reacted at 70 ° C for 3 hours. It was cooled to room temperature, and dried to dryness, and then ethanol (20 mL) and hydrazine hydrate (6 mL, 98.9 mmol) were added and the mixture was refluxed for 2 hours. The crude product was quenched to dryness 4.2 g.

2) Preparation of intermediate 2-3.

Intermediate 2-2 (2.0 g, 9.05 mmol) was dissolved in toluene (20 mL), then DMF-DMA (3.3 mL, 24.8 mmol) was added and the mixture was stirred at room temperature until the starting material disappeared, solvent was evaporated, toluene (20 mL) Acetic acid (2.7 mL, 45.7 mmol) and isopropylamine (2.7 g, 45.7 mmol) were reacted at 110 °C. After the reaction was completed, it was dried and purified by column chromatography ( petroleum ether: ethyl acetate = 2:1) to afford product 2.1 g. Yield: 85%. ^{1 HNMR (400MHz, CDCl3) δ} : 8.37 (s, 1H), 7.42 (m, 2H), 7.3 (s, 1H), 5.61-5.51 (m, 1H), 1.57 (d, J = 6.8Hz, 6H) .

3) Preparation of intermediate 2-4.

In the sealed tube, intermediate 2-3 (2 g, 7.35 mmol), DMF (16 mL), Cu (acac) 2 (0.2 g, 0.76 mmol), cesium carbonate (4.8 g, 14.7 mmol), acetylacetone (0.3) were added. mL, 2.9 mmol) and aqueous ammonia (2.2 mL, 14.3 mmol) were protected with argon and reacted at 90 ° C for 4 hours. Filtration, spurt, and purified by column chromatography (DCM:MeOH = 50:1 to 20:1) ^{1 H NMR (400MHz, CDCl3)} δ: 8.36 (s, 1H), 6.0 (s, 1H), 5.61-5.57 (m, 1H), 2.95-2.88 (d, 2H), 1.54 (d, J = 6.8Hz , 6H).

4) Preparation of Compound 2.

Compound 2 was prepared in the same manner as Compound 1, except that Intermediate 2-4 was used instead of Intermediate 1-4. 1H NMR (500 MHz, DMSO) δ: 9.41 (m, 1H), 8.37 (s, 1H), 8.20 (d, J = 6.4 Hz, 1H), 8.00 (m, 2H), 7.35 (m, 5H), 7.15 (s, 1H), 5.56 (m, 1H), 4.29 (br, 2H), 1.88 (m, 1H), 1.60 (d, J = 6.8 Hz, 6H), 0.91 (m, 2H), 0.77 (m, 2H).

Example 3

2-cyclopropyl-5-benzyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]- Preparation of 5,6-dihydro-4H-benzo[f]imidazo[1,2-a][1,4]diazepine-9-carboxamide (3).

1) Preparation of Intermediate 3-1.

The intermediate 1-11 (1.2 g, 2.82 mmol) was dissolved in tetrahydrofuran (20 mL), and borane tetrahydrofuran (11.2 mL, 11.2 mmol) was added dropwise. The reaction solution was cooled to room temperature, and the reaction was quenched by dropwise addition of methanol. After the reaction was stopped, then 1N HCl (10 mL) was added and stirred at room temperature overnight. The pH was adjusted to about 8 with a saturated sodium hydrogencarbonate solution, water (30 mL) was added, and ethyl acetate (50 mL×2) was taken, and brine (50 mL×2) was washed, dried over anhydrous sodium sulfate Purification (petroleum ether: ethyl acetate = 7:1) afforded 750 mg of white solid.

2) Preparation of intermediate 3-2.

Intermediate 3-1 (0.75 g, 1.82 mmol) was dissolved in THF (10 mL), EtOAc (EtOAc, EtOAc EtOAc , 1M in THF), after the addition, the reaction was carried out for 15 minutes, the reaction was quenched with ammonium chloride solution, water (30 mL) was added, extracted with ethyl acetate (30 mL×2), and brine (50 mL) The sodium was dried, dried, and purified by column chromatography (ethyl ether: ethyl acetate = 7:1 to 3:1) to yield 0.31 g of pale yellow solid. _{^{1 H NMR (500MHz, CDCl 3}} ) δ: 10.39 (s, 1H), 7.81 (d, J = 5.5Hz, 1H), 7.37 (m, 4H), 7.29 (m, 1H), 7.20 (d, J = 10.0 Hz, 1H), 6.98 (s, 1H), 3.75 (s, 2H), 3.63 (s, 2H), 3.51 (s, 2H), 1.90 (m, 1H), 0.90 (m, 2H), 0.81 ( m, 2H).

3) Preparation of intermediate 3-3.

Intermediate 3-2 (280 mg, 0.78 mmol) was dissolved in MeOH (10 mL) EtOAc (EtOAc) The reaction was allowed to move to room temperature for 2 hours. The mixture was filtered through Celite, and brine was added to the filtrate. The white solid was completely precipitated, filtered, and the methanol was evaporated. The pH was adjusted to about 5 with 1N HCl and extracted with a mixed solution of dichloromethane and t-butanol (4:1) ( 50 mL x 3), dried over anhydrous sodium sulfate, dried, and pulverized ( petroleum ether: diethyl ether = 1:1) to give a pale yellow solid 247 mg, yield: 85%.

4) Preparation of Compound 3.

Intermediate 3-3 (100 mg, 0.265 mmol) was dissolved in dichloromethane (5 mL), oxalyl chloride (0.33mL, 0.66mmol, 2M in DCM) and DMF (5 μL) was added and allowed to react at room temperature for 4 hours. After spin-drying, additional dichloromethane (3 mL), intermediate 1-4 (50 mg, 0.244 mmol) and pyridine (79 [mu]L, 1.06 mmol). After reacting at room temperature overnight, it was dried with EtOAc (EtOAc:EtOAc) _{^{1 H NMR (500MHz, CDCl 3}} ) δ: 9.12 (d, J = 16.0Hz, 1H), 8.43 (d, J = 8.0Hz, 1H), 8.38 (s, 1H), 8.18 (d, J = 6.8Hz , 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.42-7.30 (m, 5H), 7.22 (d, J = 11.6 Hz, 1H), 7.05 (s, 1H), 5.50 (m, 1H), 3.77 (m, 2H), 3.65 (m, 2H), 3.53 (m, 2H), 1.92 (m, 1H), 1.61 (d, J = 6.8 Hz, 6H), 0.92 (m, 2H), 0.82 (m, 2H).

Example 4

2-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-5,6-di Preparation of hydrogen-4H-benzo[f]imidazo[1,2-a][1,4]diazepine-9-carboxamide (4).

The compound 3 (60 mg, 0.11 mmol) was dissolved in methanol (5 mL), then 10% Pd / C (100 mg) The mixture was dried with EtOAc (EtOAc:EtOAc) _{^{1 HNMR (500MHz, CDCl 3)}} δ: 9.12 (d, J = 16.0Hz, 1H), 8.42 (d, J = 8.0Hz, 1H), 8.38 (s, 1H), 8.18 (d, J = 7.0Hz, 1H), 8.09 (d, J = 7.5 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 11.5 Hz, 1H), 7.04 (s, 1H), 5.50 (m, 1H), 3.90 (s, 2H), 3.85 (s, 2H), 1.90 (m, 1H), 1.60 (d, J = 6.5 Hz, 6H), 0.91 (m, 2H), 0.80 (m, 2H).

Example 5

2-cyclopropyl-5-(cyclopropylmethyl)-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- Preparation of 2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,2-a][1,4]diazepine-9-carboxamide (5).

Compound 4 (35 mg, 0.074 mmol) was dissolved in acetonitrile (5 mL), bromomethylcyclopropane (14 μL, 0.15 mmol) and potassium carbonate (20 mg, 0.15 mmol) were added and reacted at 85 ° C for 4 hours. The reaction mixture was cooled, filtered, dried and evaporated, mjjjjjj _{^{1 H NMR (500MHz, CDCl 3}} ) δ: 9.12 (d, J = 16.0Hz, 1H), 8.42 (d, J = 8.0Hz, 1H), 8.37 (s, 1H), 8.16 (d, J = 7.0Hz , 1H), 8.09 (d, J = 7.5 Hz, 1H), 7.94 (t, J = 8.0 Hz, 7.5 Hz, 1H), 7.32 (d, J = 11.5 Hz, 1H), 7.04 (s, 1H), 5.50 (m, 1H), 3.73 (m, 2H), 3.64 (m, 2H), 2.54 (d, J = 6.5 Hz, 2H), 1.90 (m, 1H), 1.60 (d, J = 7.0 Hz, 6H) ), 0.95 (m, 1H), 0.90 (m, 2H), 0.80 (m, 2H), 0.59 (m, 2H), 0.21 (m, 2H).

Example 6

2-cyclopropyl-5-benzyl-8-fluoro-N-[2-(4-isopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl]- Preparation of 5,6-dihydro-4H-benzo[f]imidazo[1,2-a][1,4]diazepine-9-carboxamide (6).

Intermediate 3-3 (145 mg, 0.38 mmol) was dissolved in dichlorohexane (5 mL), EtOAc (EtOAc, EtOAc, EtOAc, EtOAc . The reaction was allowed to proceed overnight at room temperature, and the reaction was further heated at 60 ° C for 1 hour. The reaction solution was cooled to room temperature, dried, and purified by column chromatography (dichloromethane:methanol = 50:1 to 35:1) to yield a pale yellow solid (yield: 60%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.35 (d, J = 14.8Hz, 1H), 8.37 (s, 1H), 8.18 (d, J = 6.8Hz, 1H), 7.98 (s, 1H), 7.41 -7.30 (m, 5H), 7.23 (d, J = 11.2 Hz, 1H), 7.05 (s, 1H), 5.56 (m, 1H), 3.77 (m, 2H), 3.66 (m, 2H), 3.53 ( m, 2H), 1.92 (m, 1H), 1.59 (d, J = 6.8 Hz, 6H), 0.92 (m, 2H), 0.81 (m, 2H).

Example 7

2-cyclopropyl-8-fluoro-N-[2-(4-isopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl]-5,6-di Preparation of hydrogen-4H-benzo[f]imidazo[1,2-a][1,4]diazepine-9-carboxamide (7).

Compound 6 (130 mg, 0.23 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), then 10% Pd/C (100 mg) and concentrated hydrochloric acid (0.2 mL). , vortex, add dichloromethane and sodium bicarbonate solution, extract with dichloromethane (15 mL x 3), dry over anhydrous sodium sulfate, spin dry, purified by thick-purified plate (DCM: MeOH = 12:1) Light yellow solid 10 mg, yield: 9%. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.36 (d, J = 14.8Hz, 1H), 8.37 (s, 1H), 8.17 (d, J = 6.8Hz, 1H), 7.98 (s, 1H), 7.32 (d, J = 11.6 Hz, 1H), 7.04 (s, 1H), 5.56 (m, 1H), 3.90 (m, 2H), 3.85 (m, 2H), 1.90 (m, 1H), 1.59 (d, J = 6.8 Hz, 6H), 0.91 (m, 2H), 0.79 (m, 2H).

Example 8

3-cyclopropyl-5-benzyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]- Preparation of 5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide (8).

1) Preparation of Intermediate 8-1.

3-Fluoro-4-bromotoluene (11.2 g, 59.2 mmol) was dissolved in concentrated sulfuric acid (60 mL), cooled to 0 ° C, and potassium nitrate (6.0 g, 59.2mmol). After reacting for 3 hours at 0 ° C, the reaction mixture was poured into EtOAc (EtOAc) (EtOAc (EtOAc) Dry pale yellow solid 13.4 g, yield: 97%.

2) Preparation of intermediate 8-2.

Intermediate 8-1 (17 g, 73.0 mmol) was dissolved in MeOH (250 mL). EtOAc (25 mL, 436 mmol) The reaction was carried out at 65 ° C for 4.5 hours, cooled, filtered through celite, EtOAc (EtOAc) (EtOAc)EtOAc. The organic layer was combined, washed with EtOAc EtOAc m. Yield: 88%. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 6.82 (m, 2H), 3.49 (m, 2H), 2.11 (s, 3H).

3) Preparation of intermediate 8-3.

Intermediate 8-2 (13 g, 63.7 mmol) was dissolved in NMP (100 mL). EtOAc (1. The mixture was poured into water (150 mL) and concentrated aqueous ammonia (150 mL). After stirring for 30 min, celite was filtered, and the filtrate was extracted with ethyl acetate (300 mL×3). After washing with 900 mL x 3), dried over anhydrous sodium sulfate, dried, and purified by column chromatography ( petroleum ether: ethyl acetate = 5:1) to give 7.83 g of pale yellow solid.

4) Preparation of intermediate 8-4.

Sodium hydroxide (20.8 g, 0.52 mol) and potassium iodide (1.73 g, 10.4 mmol) were dissolved in water (80 mL), and intermediate 8-3 (7.8 g, 52 mmol) was added, and the mixture was heated and refluxed for 1 hour, and the reaction liquid was cooled. The pH was adjusted to about 4 with 4N HCl, filtered, and the filter cake was washed with water and dried to give a white solid 7.3 g, yield: 83%. ¹ H NMR (400 MHz, DMSO) δ: 7.08 (d,J = 6.4 Hz, 1H), 6.78 (d,J = 11.6 Hz, 1H), 5.02 (br, 2H), 2.08 (s, 3H).

5) Preparation of Intermediate 8-5.

Intermediate 8-4 (7.3 g, 43.2 mmol) was dissolved in ethanol (100 mL). The reaction solution was cooled, and the mixture was evaporated to dryness. EtOAc was evaporated, evaporated, evaporated, evaporated. Column chromatography (petroleum ether: ethyl acetate = 5:1) afforded 8.5 g of pale yellow oil. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 7.18 (d, J = 6.4Hz, 1H), 6.83 (d, J = 11.2Hz, 1H), 4.35 (q, J = 7.2Hz, 2H), 3.57 (br , 2H), 2.17 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H).

6) Preparation of intermediate 8-6.

Copper bromide (19.2 g, 86.2 mmol) and tert-butyl nitrite (10.2 mL, 86.2 mmol) were added to acetonitrile (60 mL), stirred at 50 ° C for 15 min, then the intermediate 8-5 (8.5 g) , 43.1 mmol) in acetonitrile (40 mL). After the completion of the reaction, the reaction was continued for 1 hour, cooled, filtered over Celite, dried, and purified by column chromatography (ethyl ether: ethyl acetate = 30:1) to afford 9.1 g of colorless transparent liquid.

7) Preparation of intermediates 8-7.

Intermediate 8-6 (2.61 g, 10.0 mmol) was dissolved in carbon tetrachloride (50 mL), and NBS (1.78 g, 10.0 mmol) and AIBN (164 mg, 1.0 mmol) were added and the mixture was refluxed for 4 hours. The mixture was cooled, dried with EtOAc EtOAcjjjjjjj _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.13 (d, J = 6.8Hz, 1H), 7.27 (d, J = 10.4Hz, 1H), 4.53 (s, 2H), 4.40 (q, J = 7.2Hz , 2H), 1.40 (t, J = 7.2 Hz, 3H).

8) Preparation of intermediates 8-8.

Ethyl 3-cyclopropyl-3-oxopropanoate (10.3 g, 61 mmol) was dissolved in chloroform (40 mL), cooled to 0 ° C, sulfonyl chloride (5.7 mL, 70 mmol) was added and reacted at 65 ° C for 1.5 hours. The mixture was cooled, dried, and purified by column chromatography. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 4.90 (s, 1H), 4.28 (m, 2H), 2.27 (m, 1H), 1.29 (m, 3H), 1.16 (m, 2H), 1.06 (m, 2H).

9) Preparation of intermediates 8-9.

Intermediate 8-8 (10.5 g, 54.9 mmol) was dissolved in EtOAc (EtOAc (EtOAc:EtOAc) The mixture was cooled to dryness with EtOAc EtOAc (EtOAc) Column chromatography purification (petroleum ether: ethyl acetate = 3:1 to 1:1) yielded s. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 7.54 (s, 1H), 4.36 (q, J = 7.2Hz, 2H), 2.59 (m, 1H), 1.36 (t, J = 7.2Hz, 3H), 0.99 (m, 4H).

10) Preparation of intermediates 8-10.

Intermediate 8-9 (80 mg, 0.44 mmol) was dissolved in THF (5 mL), EtOAc evaporated, EtOAc EtOAc. The reaction was quenched by dropwise addition of water (100 mL), and then sodium sulfate (1.0 g) was added and stirred for half an hour, filtered, and the filtrate was evaporated to give a white solid. The white solid was dissolved in tetrahydrofuran (5 mL). EtOAc (116 mg, 1. The mixture was filtered through Celite, dried, and then purified from petroleum ether. ¹ H NMR (500 MHz, DMSO) δ: 11.66 (br, 1H), 7.32 (s, 1H), 1.83 (m, 1H), 0.75 (m, 2H), 0.66 (m, 2H).

11) Preparation of intermediates 8-11.

Intermediate 8-10 (550 mg, 4.04 mmol) was dissolved in ethanol (20 mL), EtOAc (EtOAc (EtOAc) The mixture was cooled, dried, and purified by column chromatography (methylene chloride:methanol = 25:1)

12) Preparation of intermediates 8-12.

Intermediate 8-11 (700 mg, 3.1 mmol) was dissolved in MeOH (20 mL). EtOAc. The reaction was quenched by EtOAc (EtOAc)EtOAc.

13) Preparation of intermediates 8-13.

Intermediate 8-12 (540 mg, 2.39 mmol) was dissolved in tetrahydrofuran (15 mL). Intermediate 8-7 (1. <RTI ID=0.0></RTI></RTI><RTIgt; It was spin-dried and purified by column chromatography to give a pale yellow thick product (yield: 69%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ: 8.10 (d, J = 6.4Hz, 1H), 8.03 (s, 1H), 7.61 (m, 1H), 7.44 (m, 1H), 7.30 (m, 5H) , 4.38 (q, J = 7.0 Hz, 2H), 3.69 - 3.65 (m, 6H), 1.73 (m, 1H), 1.38 (t, J = 7.0 Hz, 3H), 0.84 - 0.74 (m, 4H).

14) Preparation of intermediates 8-14.

Intermediate 8-13 (800 mg, 1.65 mmol) was dissolved in DMF (20 mL). EtOAc (EtOAc, EtOAc (EtOAc) hour. After cooling to room temperature, water (50 mL) was added, EtOAc (EtOAc) (Petroleum ether: ethyl acetate = 4:1) gave a brown solid: 400 mg, yield: 60%. _{^{1 H NMR (500MHz, CDCl 3}} ) δ: 8.01 (s, 1H), 7.92 (d, J = 6.0Hz, 1H), 7.67 (s, 1H), 7.41 (m, 2H), 7.37 (m, 2H) , 7.31 (m, 1H), 7.17 (m, J = 10.0 Hz, 1H), 4.43 (q, J = 7.0 Hz, 2H), 3.70 (s, 2H), 3.59 (s, 2H), 3.53 (s, 2H), 1.79 (m, 2H), 1.41 (t, J = 7.0 Hz, 3H), 0.94 (m, 2H), 0.89 (m, 2H).

15) Preparation of intermediates 8-15.

Intermediate 8-14 (390 mg, 0.96 mmol) was dissolved in methanol (10 mL) and water (5 mL). Part of the solvent was removed, water (10 mL) was added, the pH was adjusted to about 5 with 1N HCl, filtered, and the filter cake was the product. The filtrate was extracted with a mixture of dichloromethane and isopropyl alcohol (4:1). The sodium is dried and spin dried to give the product. A total of 345 mg of product was obtained, yield: 95%. Ms: m/z = 378.6 [M+H].

16) Preparation of Compound 8.

Intermediate 8-15 (150 mg, 0.40 mmol) was dissolved in dichloromethane <RTI ID=0.0>(5</RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI></RTI></RTI></RTI></RTI> DMF (2 drops) and oxalyl chloride (400 μL, 0.80 mmol, 2M in DCM). The mixture was dried and the oil was pumped for 20 minutes. Intermediate 1-4 (73 mg, 0.36 mmol) and pyridine (103 μL, 1.40 mmol) were added and allowed to react overnight at room temperature. The mixture was dried with EtOAc (EtOAc m. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.11 (d, J = 16.0Hz, 1H), 8.43 (d, J = 8.0Hz, 1H), 8.38 (s, 1H), 8.22 (d, J = 6.8Hz , 1H), 8.10 (d, J = 7.2 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.45 - 7.31 (m, 5H), 7.29 (m, 1H) , 5.50 (m, 1H), 3.74 (s, 2H), 3.64 (s, 2H), 3.58 (s, 2H), 1.81 (m, 1H), 1.61 (d, J = 6.8 Hz, 6H), 0.98- 091 (m, 4H).

Example 9

3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-5,6-di Preparation of hydrogen-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide hydrochloride (9).

Compound 8 (115 mg, 0.2 mmol) was dissolved in methanol (5 mL) and THF (5 mL). EtOAc (EtOAc) The mixture was filtered through celite, dried and evaporated to ethyl ether. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 11.25 (s, 1H), 10.61 (br, 1H), 8.87 (s, 1H), 8.22 (m, 2H), 8.05 (m, 2H), 7.92 (m, 1H) ), 7.71 (m, 1H), 5.71 (m, 1H), 4.19 (s, 2H), 4.09 (s, 2H), 2.07 (m, 1H), 1.42 (d, J = 6.4 Hz, 6H), 0.85 (m, 4H).

Example 10

3-cyclopropyl-5-(cyclopropylmethyl)-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- Preparation of 2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide (10).

Compound 9 (45 mg, 0.1 mmol) was dissolved in acetonitrile (3 mL), bromomethylcyclopropane (20 μL, 0.2 mmol) and potassium carbonate (41 mg, 0.3 mmol) were added, and the reaction was heated at 80 ° C for 2 hours. The mixture was cooled, dried, evaporated, evaporated, evaporated, evaporated. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.11 (d, J = 16.0Hz, 1H), 8.42 (d, J = 8.4Hz, 1H), 8.38 (s, 1H), 8.20 (d, J = 6.8Hz , 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.31 (d, J = 11.6 Hz, 1H), 5.50 (m) , 1H), 3.73 (s, 2H), 3.70 (s, 2H), 2.51 (d, J = 6.8 Hz, 2H), 1.87 (m, 1H), 1.60 (d, J = 6.4 Hz, 6H), 1.00 (m, 1H), 0.94 (m, 4H), 0.64 (m, 2H), 0.22 (m, 2H).

Example 11

3-cyclopropyl-8-fluoro-N-[2-(4-isopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl]-5-(4- Methoxybenzyl)-6-oxo-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide (11 Preparation of).

1) Preparation of Intermediate 11-1.

Intermediate 8-6 (0.78 g, 3.0 mmol) was dissolved in carbon tetrachloride (30 mL), and NBS (1.07 g, 6.0 mmol) and AIBN (50 mg, 0.3 mmol) were added and reacted at 80 ° C for 5 hours. The mixture was dried with EtOAc (EtOAc:EtOAc:EtOAc. Yield: 86%.

2) Preparation of intermediate 11-2.

Intermediate 11-1 (1.08 g, 2.57 mmol) was dissolved in EtOAc (20 mL) and water (5 mL). It was cooled to room temperature, filtered, and the filtrate was evaporated to dryness with ethyl acetate (50 mL). Petroleum ether: ethyl acetate = 100:1) yielded a pale yellow solid, 600 mg, yield: 85%. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 10.32 (d, J = 2.8Hz, 1H), 8.21 (d, J = 6.4Hz, 1H), 7.67 (q, J = 10.0Hz, 2H), 4.43 (q , J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H).

3) Preparation of Intermediate 11-3.

Intermediate 11-2 (600 mg, 2.17 mmol) was dissolved in tetrahydrofuran (15 mL) and water (5 mL), then 2-methyl-2-butene (2.3mL, 21.7mmol), sodium chlorite (590mg) , 6.52 mmol) and sodium dihydrogen phosphate (1.02 g, 6.52 mmol) were reacted at room temperature for 1 hour. The solvent was evaporated, water (10 mL) was added, and pH was adjusted to about 3 with 1N HCl, and a white solid was precipitated, filtered, and dried in vacuo to yield 370 mg, yield: 58%. ^{1 H NMR (400MHz, DMSO)} δ: 8.09 (d, J = 6.4Hz, 1H), 7.72 (q, J = 10.8Hz, 2H), 4.34 (q, J = 7.2Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H).

4) Preparation of intermediate 11-4.

Intermediate 8-10 (600 mg, 4.41 mmol) was dissolved in EtOAc (20 mL) EtOAc (EtOAc:EtOAc: It was cooled to room temperature, spin-dried, and purified by column chromatography to give the product 1.2 g. _{1H NMR (400MHz, CDCl 3)} δ: 8.39 (s, 1H), 7.24 (m, 2H), 6.87 (m, 2H), 4.68 (s, 2H), 3.49 (s, 3H), 2.00 (m, 1H ), 0.99 (m, 2H), 0.93 (m, 2H).

5) Preparation of intermediate 11-5.

Intermediate 11-4 (1.12 g, 4.41 mmol) was dissolved in MeOH (20 mL)EtOAc. The reaction was quenched with water, EtOAc EtOAc (EtOAc)EtOAc. 1) 0.49 g of a pale yellow oil was obtained. Yield: 49%. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 7.36 (s, 1H), 7.22 (m, 2H), 6.85 (m, 2H), 3.80 (s, 2H), 3.79 (s, 3H), 3.73 (s, 2H), 1.71 (m, 1H), 0.81 (m, 2H), 0.75 (m, 2H).

6) Preparation of intermediate 11-6.

Intermediate 11-5 (220 mg, 0.75 mmol) was dissolved in dichloromethane <RTI ID=0.0>(</RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt; Methyl), reacted at room temperature overnight. The reaction mixture was poured into water (20 mL), EtOAc (EtOAc m. : 1) A white foamy solid, 310 mg, yield: 78%. _{^{1 HNMR (400MHz, CDCl 3)}} δ: 8.12 (d, J = 6.0Hz, 1H), 7.47 (s, 1H), 7.12 (d, J = 9.6Hz, 1H), 7.08 (m, 2H), 6.87 ( m, 2H), 4.41 (q, J = 7.2 Hz, 2H), 4.28 (m, 4H), 3.80 (s, 3H), 1.56 (m, 1H), 1.38 (t, J = 7.2 Hz, 3H), 0.82 (m, 4H).

7) Preparation of intermediate 11-7.

Intermediates 11-6 (400 mg, 0.75 mmol), cuprous iodide (29 mg, 0.15 mmol), L-valine (17 mg, 0.15 mmol) and cesium carbonate (489 mg, 1.5 mmol) were dissolved in DMF (10 mL) Argon protection, reaction at 100 ° C for 2 hours. After cooling to room temperature, DMF was evaporated, dissolved in dichloromethane, filtered, and the filtrate was evaporated to dryness. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 7.91 (d, J = 6.0Hz, 1H), 7.90 (s, 1H), 7.75 (s, 1H), 7.22 (m, 2H), 6.88 (m, 2H) , 4.77 (m, 2H), 4.44 (q, J = 7.2 Hz, 2H), 4.27 (m, 2H), 3.81 (s, 3H), 1.57 (m, 1H), 1.38 (t, J = 7.2 Hz, 3H), 0.81 (m, 4H).

8) Preparation of intermediate 11-8.

Intermediate 11-7 (80 mg, 0.18 mmol) was dissolved in MeOH (2 mL), THF (2 mL) and water (1 mL). Spin dry, add water (5mL), adjust the pH to about 3 with 1N HCl, precipitate the solid, filter, solid dry to obtain the product. The filtrate was extracted with a mixed solution of dichloromethane and tert-butanol, dried over anhydrous sodium sulfate and dried to give a product. A total of 61 mg of product was obtained, yield: 81%.

9) Preparation of Compound 11.

Compound 11 was prepared as in Example 6, except that Intermediate 11-8 was used instead of Intermediate 3-3. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.39 (m, 1H), 8.37 (s, 1H), 8.23 (d, J = 6.4Hz, 1H), 7.99 (m, 2H), 7.82 (s, 1H) , 7.24 (m, 2H), 6.89 (m, 2H), 5.57 (m, 1H), 4.78 (m, 2H), 4.31 (m, 2H), 3.82 (s, 3H), 1.60 (d, J = 6.4 Hz, 6H), 0.83 (m, 4H).

Example 12

3-cyclopropyl-8-fluoro-N-[2-(4-isopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl]-6-oxo- Preparation of 5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide (12).

Compound 11 (28 mg, 0.046 mmol) was dissolved in trifluoroacetic acid (3 mL), and trifluoromethanesulfonic acid (0.2 mL) was added and reacted at 65 ° C for 1 hour. After cooling, spin dry, add water (10 mL), adjust the pH to about 7 with saturated sodium bicarbonate solution, extract with dichloromethane (20 mL x 2), dry over anhydrous sodium sulfate, spin dry, and purified by thick plate (2) Methyl chloride: methanol = 12:1) yielded 5 mg as an off-white solid, yield: 23%. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.39 (s, 1H), 8.09 (m, 1H), 7.96 (m, 1H), 7.84-7.8 (m, 2H), 5.51 (m, 1H), 4.27 (m) , 2H), 1.73 (m, 1H), 1.53 (d, J = 6.8 Hz, 6H), 0.85 (m, 4H).

Example 13

3-cyclopropyl-5-(methylsulfonyl)-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine-2- Preparation of 5-methyl-6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide (13).

Compound 10 (20 mg, 0.042 mmol) was dissolved in dichloromethane (3 mL), methanesulfonyl chloride (20 μL, 0.26 mmol) and triethylamine (48 μL, 0.34 mmol) were added and allowed to react at room temperature for half an hour. The mixture was dried with EtOAc (EtOAc:EtOAc) 1H NMR (400MHz, CDCl ₃ ) δ: 9.09 (d, J = 15.4 Hz, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.39 (s, 1H), 8.27 (d, J = 6.8 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.46 (d, J = 11.2 Hz, 1H), 5.49 (m, 1H), 4.48 (s, 2H), 4.32 (s, 2H), 2.94 (s, 3H), 1.87 (m, 1H), 1.61 (d, J = 6.8 Hz, 6H), 0.99 (m, 4H).

Example 14

2-cyclopropyl-8-fluoro-N-[2-(4-isopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl]-5,6-di Preparation of hydrogen-4H-benzo[f]imidazo[1,2-a]diazepine-9-carboxamide (14).

1) Preparation of intermediate 14-1.

6-Amino-1,2,3,4-tetrahydro-1-naphthalenone (9.8 g, 60.87 mmol) was dissolved in a mixed solvent of 40 mL of DMF and 80 mL of o-dichlorobenzene, cooled to 0 ° C, and added dropwise. Boron fluoride-diethyl ether (12.96 g, 91.3 mmol) was added and stirring was continued for 30 min. Tert-butyl nitrite (7.5 g, 72.81 mmol) was added dropwise, and after completion of the dropwise addition, stirring was continued for 1 hour. The reaction was heated to 130-135 ° C, and a condenser was connected during the temperature rise to recover the DME solvent. After reacting for 2 hours, it was distilled under reduced pressure to recover o-dichlorobenzene. Purification by column chromatography (PE: EA = 20:1 to PE:PE = 10:1) afforded 5.5 g of white solid. Yield: 55%. ^{1 H NMR (400MHz, CDCl3)} δ: 8.08-8.04 (m, 1H), 6.99-6.91 (m, 2H), 2.97-2.94 (m, 2H), 2.66-2.62 (m, 2H), 2.17-2.11 ( m, 2H)

2) Preparation of intermediate 14-2.

Intermediate 14-1 (5.2 g, 31.7 mmol) was dissolved in 50 mL of concentrated sulfuric acid, cooled to -5-0 ° C, KNO ₃ (2.89 g, 28.5 mmol) was added portionwise and stirred at -5-0 ° C overnight. The reaction solution was poured into 500 mL of ice water, extracted with ethyl acetate (50 mL×3), washed with saturated brine, dried over anhydrous sodium sulfate, dried, and purified by column chromatography (PE: EA=10:1 to PE:EA = 2:1) gave 2.8 g of a white solid. Yield: 42%. ^{1 H NMR (400MHz, CDCl3)} δ: 8.7 (d, 1H), 7.2 (d, 1H), 2.97-2.94 (m, 2H), 2.66-2.62 (m, 2H), 3.06-3.03 (m, 2H) , 2.73 - 2.69 (m, 2H), 2.23 - 2.17 (m, 2H)

3) Preparation of intermediate 14-3.

Intermediate 14-2 (2.8 g, 13.4 mmol) was dissolved in methanol (50 mL), iron powder (7.5 g, 134 mmol) and acetic acid (8.0 g, 134 mol) were added, and the reaction was heated at 60 ° C for 2 hours. The reaction solution was cooled to room temperature, and the solvent was evaporated. EtOAc was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjj %.

4) Preparation of intermediate 14-4.

The intermediate 14-3 (1.9g, 10.6mmol) was dissolved in acetonitrile (20mL), the room temperature (20-30 deg.] C) was added dropwise to _{CuBr 2 (4.7g, 21.2mmol),} t-BuONO (2.2g, 21.2 A mixture of mmol) and acetonitrile (40 mL) was stirred at room temperature overnight. The reaction was quenched by the addition of EtOAc (EtOAc)EtOAc. ^{1 H NMR (400MHz, CDCl3)} δ: 8.2 (d, 1H), 7.0 (d, 1H), 2.93-2.91 (m, 2H), 2.66-2.63 (m, 2H), 2.17-2.12 (m, 2H)

5) Preparation of intermediate 14-5.

The intermediate 14-4 (2.3g, 9.47mmol) was dissolved in chloroform (20mL), was added NaN ₃ (1.8g, 28.3mmol) at, 20-30 ℃, 9mL of concentrated sulfuric acid was added dropwise over 30 minutes. After the completion of the dropwise addition, the reaction was carried out for 30 minutes, and the mixture was adjusted to pH 10 with a saturated solution of K ₂ CO ₃ , extracted with ethyl acetate (100 mL×3), washed with saturated brine, dried over anhydrous sodium sulfate and dried . The yield is 100%. ¹ H NMR (400 MHz, CDCl 3 ) δ: 7.26 (s, 1H), 7.1 (d, 1H), 7.0 (d, 1H), 2.78-2.75 (m, 2H), 2.37-2.33 (m, 2H), 2.26- 2.19 (m, 2H).

6) Preparation of intermediate 14-6.

The compound intermediate 14-5 (1.6 g, 6.23 mmol) was dissolved in DMF (10 mL), and then 2-bromo-1-cyclopropyl ethyl ketone (3.0 g, 18.7 mmol) and potassium carbonate (5.2 g, 37.4 mmol) , 0.5 mL of water, reacted at room temperature for 2 hours. The reaction mixture was poured into water (150 mL), EtOAc (150 mL, EtOAc) Ethyl ester = 4:1 to 2:1) gave 1.3 g of a white solid. Yield: 61%.

7) Preparation of intermediate 14-7

Intermediate 14-6 (1.3 g, 3.8 mmol) was dissolved in acetic acid (10 mL). After the reaction solution was cooled, the acetic acid was spun dry, and the solution was adjusted to pH 8 with a saturated Na ₂ CO ₃ solution. The mixture was extracted with ethyl acetate (50 mL×3), washed with saturated brine (500 mL×3), dried over anhydrous sodium sulfate Dry, over a flash column (petroleum ether: ethyl acetate = 1:2). ^{1 H NMR (400MHz, CDCl3)} δ: 7.4 (d, 2H), 7.1 (d, 1H), 6.8 (s, 1H), 2.70-2.68 (m, 2H), 2.58-2.54 (m, 2H), 2.27 -2.20 (m, 2H), 1.89-1.82 (m, 1H), 0.89-0.84 (m, 2H), 0.79 - 0.76 (m, 2H).

8) Preparation of intermediate 14-8.

Intermediate 14-7 (1.0 g, 3.1 mmol) was dissolved in THF (5 mL), DMF (1. <RTI ID=0.0>#</RTI></RTI><RTIgt; 1M in THF), after the addition, the reaction was carried out for 20 minutes, and the reaction was quenched with EtOAc (EtOAc) (EtOAc) Column chromatography purification (petroleum ether: ethyl acetate = 10:1 to 4:1) gave an oily product (yield: 24%). ¹ H NMR (400 MHz, CDCl 3 ) δ: 10.3 (s, 1H), 7.4 (d, 2H), 7.1 (d, 1H), 6.8 (s, 1H), 2.73-2.64 (m, 4H), 2.31-2.25 ( m, 2H), 1.88-1.82 (m, 1H), 0.89-0.84 (m, 2H), 0.79-0.76 (m, 2H),

9) Preparation of intermediate 14-9.

Intermediate 14-8 (200 mg, 0.74 mmol) was dissolved in tert-butanol (4 mL), tetrahydrofuran (4 mL) and water (2 mL), cooled to 0 &lt;0&gt; 7.4 mmol), sodium dihydrogen phosphate (444 mg, 3.7 mmol) and sodium chlorite (335 mg, 3.7 mmol) were completely reacted after half an hour. The mixture was stirred, added with water, and the mixture was adjusted to pH 3 with 1N HCl, and extracted with (dichloromethane: tert-butanol = 5:1), dried over anhydrous sodium sulfate and dried to give 155 mg of crude product. reaction.

10) Preparation of Compound 14.

Compound 14 was prepared as in Example 6, except that Intermediate 14-9 was used instead of Intermediate 3-3. ¹ H NMR (400 MHz, CDCl 3 ) δ: 9.33 (d, J = 14.8 Hz, 1H), 8.37 (s, 1H), 8.10 (d, J = 6.8 Hz, 1H), 7.97 (s, 1H), 7.21. , J = 11.6 Hz, 1H), 6.92 (s, 1H), 5.56 (m, 1H), 2.74 (t, J = 7.2 Hz, 2H), 2.69 (t, J = 7.2 Hz, 2H), 2.31 (m) , 2H), 1.88 (m, 1H), 1.59 (d, J = 6.8 Hz, 6H), 0.88 (m, 2H), 0.79 (m, 2H).

Example 15

2-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-5,6-di Preparation of hydrogen-4H-benzo[f]imidazo[1,2-a]diazepine-9-carboxamide (15).

Compound 15 was prepared as in Example 3 except that Intermediate 14-9 was used instead of Intermediate 3-3. ^{1 HNMR (400MHz, CDCl3) δ} : 9.11 (m, 1H), 8.44 (m, 2H), 8.09 (m, 2H), 7.94 (m, 1H), 7.21 (d, J = 11.6Hz, 1H), 6.95 (s, 1H), 5.54 (m, 1H), 2.69 (m, 4H), 2.32 (m, 2H), 1.91 (m, 1H), 1.61 (d, J = 6.4 Hz, 6H), 0.85 (m, 4H).

Example 16

3-cyclopropyl-5-(2,4-dimethoxybenzyl)benzyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazole -3-yl)pyridin-2-yl]-4-oxo-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine- Preparation of 9-carboxamide (17).

1) Preparation of intermediate 17-1.

Intermediate 8-7 (400 mg, 1.18 mmol) was dissolved in dichloromethane (10 mL). The mixture was dried with EtOAc (EtOAc:EtOAc)

2) Preparation of intermediate 17-2.

4-Cyclopropyl-1H-imidazol-5-carboxylic acid (170 mg, 1.13 mmol) and HATU (460 mg, 1.22 mmol) were dissolved in dichloromethane (5 mL), and triethylamine (260 μL, 1.88 mmol) After stirring for 10 minutes, intermediate intermediate 17-1 (400 mg, 0.94 mmol) was. The reaction mixture was poured into water (20 mL), EtOAc (EtOAc)EtOAc. 1) A pale yellow syrup of 180 mg was obtained in a yield: 34%.

3) Preparation of intermediate 17-3.

Intermediate 17-2 (170 mg, 0.3 mmol) was dissolved in DMF (6 mL), EtOAc (29 mg, 0.15 mmol), L-valine (39 mg, 0.3 mmol) and potassium carbonate (39 mg, 0.3 mmol) The reaction was heated at 100 ° C for 2 hours under a nitrogen atmosphere. The reaction solution was cooled, filtered, dried, and purified by column chromatography to yield 23 mg, yield: 16%. MS (m/z): 480.3 [M + 1].

4) Preparation of intermediate 17-4.

The intermediate 17-3 (23 mg, 0.048 mmol) was dissolved in methanol (1 mL), THF (1 mL) and water (1 mL). Spin dry, add water (3 mL), adjust the pH to about 5 with 1N HCl, filter and dry to give the product 20mg, yield: 91%. Ms: m/z = 452.2 [M+H].

5) Preparation of Compound 17.

Referring to Example 1, Compound 17 was prepared by substituting Intermediate 17-4 for Intermediate 1-13. _{^{1 H NMR (500MHz, CDCl 3}} ) δ: 9.03 (d, J = 15.0Hz, 1H), 8.39 (m, 2H), 8.15 (m, 1H), 8.07 (m, 1H), 7.95 (m, 1H) , 7.79 (s, 1H), 7.23 (m, 1H), 6.56 (m, 1H), 6.48 (m, 1H), 6.40 (s, 1H), 5.48 (m, 1H), 5.07 (s, 1H), 4.45 (s, 2H), 4.10 (s, 1H), 3.82 (s, 3H), 3.68 (s, 3H), 2.68 (m, 1H), 1.60 (d, J = 5.5 Hz, 6H), 0.88 (m) , 4H).

Example 17

3-cyclopropyl-5-phenylcarbonyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]- Preparation of 5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide (18).

1) Preparation of intermediate 18-6.

The preparation of Intermediate 18-6 was carried out in the same manner as in Example 8, except that 2,4-dimethoxybenzylamine was used instead of benzylamine. Ms: m/z = 623.4 [M+H]. 2) Preparation of intermediate 18-7.

Intermediate 18-6 (1.2 g, 1.93 mmol) was dissolved in trifluoroacetic acid (20 mL). The reaction solution was cooled, vortexed, and added with water (20 mL). The mixture was adjusted to pH 8 with saturated sodium bicarbonate and extracted with dichloromethane (20 mL×3). Purification by column chromatography (dichloromethane:methanol = 25:1)ield Ms: m/z = 473.3 [M+H].

3) Preparation of compound 18.

The intermediate 18-7 (30 mg, 0.063 mmol) was dissolved in dichloromethane (1 mL), triethylamine (26 μL, 0.19 mmol) and benzoyl chloride (15 μL, 0.13 mmol), and allowed to react at room temperature for half an hour, then dried. Purification by thick preparative plate (dichloromethane:methanol = 30:1) gave 20 mg of white solid, yield: 55%. _{^{1 H NMR (500MHz, CDCl 3}} ) δ: 9.09 (d, J = 15.0Hz, 1H), 8.41 (m, 2H), 8.28 (m, 1H), 8.10 (m, 1H), 7.96 (m, 1H) , 7.82 (s, 1H), 7.57-7.45 (m, 6H), 5.49 (m, 1H), 4.76 (m, 2H), 4.47 (s, 2H), 1.95 (m, 1H), 1.60 (d, J) = 5.5 Hz, 6H), 0.87 (m, 4H).

Example 18

3-cyclopropyl-5-[4-(trifluoromethyl)benzyl]-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazole-3 -yl)pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide (19) Preparation.

The intermediate 18-7 (30 mg, 0.063 mmol) was dissolved in acetonitrile, 4-trifluoromethylbenzyl chloride (19 μL, 0.13 mmol) and triethylamine (26 μL, 0.19 mmol) were added, and the reaction was stopped at room temperature for 3 hours, then the reaction was stopped. , spin dry, purified by thick preparation of a white solid 25 mg, yield: 63%. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.12 (d, J = 15.6Hz, 1H), 8.44-8.42 (m, 2H), 8.23 (d, J = 7.2Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.65 (m, 2H), 7.57 (m, 2H), 7.27 (m, 1H), 5.50 (m, 1H), 3.79 (s, 2H), 3.62 (s, 3H), 3.59 (s, 2H), 1.79 (m, 1H), 1.61 (d, J = 6.8 Hz, 6H), 0.93 (m, 4H).

Example 19

3-cyclopropyl-5-(3-chloro-4-fluorobenzyl)-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazole-3- Pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide (20) preparation.

Referring to Example 19, compound 20 was obtained by substituting 3-chloro-4-fluorobenzyl chloride for 4-trifluoromethylbenzyl chloride. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.12 (d, J = 15.6Hz, 1H), 8.44-8.39 (m, 2H), 8.23 (d, J = 6.4Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.52 (m, 1H), 7.30-7.25 (m, 2H), 7.15 (m, 1H), 5.50 ( m,1H), 3.68 (s, 2H), 3.60 (s, 3H), 3.57 (s, 2H), 1.77 (m, 1H), 1.61 (d, J = 6.8 Hz, 6H), 0.95 (m, 4H) ).

Example 20

3-cyclopropyl-5-[2-fluoro-4-(trifluoromethyl)benzenecarbonyl]-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-tri Azol-3-yl)pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9- Preparation of amide (21).

Compound 21 was prepared by referring to Example 18, using 2-fluoro-4-(trifluoromethyl)benzoyl chloride instead of benzoyl chloride. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.09 (m, 1H), 8.43-8.38 (m, 2H), 8.30 (m, 1H), 8.11 (m, 1H), 7.96 (m, 1H), 7.80 ( m,1H), 7.67-7.57 (m, 2H), 7.50 (m, 1H), 7.47 (m, 0.5H), 7.06 (m, 0.5H), 5.48 (m, 1H), 4.81 (m, 2H) , 4.37 (m, 2H), 1.95 (m, 0.5H), 1.61 (m, 6H), 1.46 (m, 0.5H), 0.98 (m, 2H), 0.85 (m, 2H).

Example 21

3-cyclopropyl-5-[4-(trifluoromethyl)phenylcarbonyl]-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazole-3 -yl)pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide (22) Preparation.

Compound 22 was prepared by reference to Example 18, using 4-trifluoromethylbenzoyl chloride instead of benzoyl chloride. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.10 (m, 1H), 8.44-8.41 (m, 2H), 8.22 (m, 1H), 8.11 (m, 1H), 7.97 (m, 1H), 7.79 ( m, 2H), 7.72 (m, 1H), 7.65 (m, 2H), 7.53 (m, 0.5H), 6.96 (m, 0.5H), 5.48 (m, 1H), 4.78 (m, 2H), 4.43 (m, 2H), 1.96 (m, 0.5H), 1.61 (m, 6H), 1.44 (m, 0.5H), 1.01 (m, 2H), 0.87 (m, 2H).

Example 22

3-cyclopropyl-5-[2-methyl-4-(trifluoromethyl)thiazol-5-carbonyl]-8-fluoro-N-[6-(4-isopropyl-4H-1,2 ,4-triazol-3-yl)pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine Preparation of -9-carboxamide (23).

2-Methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid (14.7 mg, 0.07 mmol) was dissolved in dichloromethane (2 mL), then HATU (31 mg, 0.082 mmol) and triethylamine (18 μL) After stirring at room temperature for 10 minutes, intermediate 18-7 (30 mg, 0.063 mmol). The mixture was dried with EtOAc (EtOAc m. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.11 (m, 1H), 8.42-8.40 (m, 2H), 8.30 (m, 1H), 8.11 (m, 1H), 7.95 (t, J = 8.0Hz, 1H), 7.81 (m, 1H), 7.49 (m, 0.5H), 7.11 (m, 0.5H), 5.49 (m, 1H), 4.77 (m, 2H), 4.38 (m, 2H), 2.82 (m) , 3H), 1.92 (m, 0.5H), 1.61 (m, 6H), 1.55 (m, 0.5H), 0.97 (m, 2H), 0.91 (m, 2H).

Example 23

3-cyclopropyl-5-(2-naphthalenylcarbonyl)-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine-2 Preparation of -5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide (24).

Compound 24 was prepared by referring to Example 23, substituting 2-naphthoic acid for 2-methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.10 (m, 1H), 8.44-8.41 (m, 2H), 8.29 (m, 1H), 8.09-7.93 (m, 6H), 7.79 (m, 1H), 7.60 (m, 3.5H), 6.92 (m, 0.5H), 5.47 (m, 1H), 4.80 (m, 2H), 4.54 (m, 2H), 2.00 (m, 0.5H), 1.60 (m, 6.5) H), 1.01 (m, 2H), 0.80 (m, 2H).

Example 24

3-cyclopropyl-5-(3-pyridinecarbonyl)-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine-2 Preparation of -5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide (25).

Referring to Example 23, compound 25 was obtained by substituting nicotinic acid for 2-methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.10 (m, 1H), 8.79 (m, 2H), 8.50 (m, 1H), 8.42 (m, 1H), 8.27 (m, 1H), 8.04 (m, 1H), 7.96 (m, 1H), 7.89 (m, 1H), 7.80 (m, 1H), 7.48 (m, 1.5H), 7.00 (m, 0.5H), 5.45 (m, 1H), 4.77 (m) , 2H), 4.50 (m, 2H), 1.93 (m, 1H), 1.60 (m, 6H), 0.99-0.89 (m, 4H).

Example 25

3-cyclopropyl-5-(cyclohexylcarbonyl)-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine-2- Preparation of 5-yl-6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide (26).

Compound 26 was prepared by reference to Example 18, using cyclohexylcarbonyl chloride instead of benzoyl chloride. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.10 (m, 1H), 8.42-8.40 (m, 2H), 8.27 (m, 1H), 8.10 (m, 1H), 7.95 (m, 1H), 7.77 ( m,1H), 7.42 (m, 0.65H), 7.32 (m, 0.35H), 5.49 (m, 1H), 4.63 (m, 3H), 4.50 (m, 1H), 2.59 (m, 1H), 1.84 - 1.70 (m, 6H), 1.60 (m, 7H), 1.32 (m, 3H), 0.96 (m, 4H).

Example 26

3-cyclopropyl-5-[4-(trifluoromethyl)phenyl]-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazole-3 -yl)pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide (27) Preparation.

Intermediate 18-7 (30 mg, 0.062 mmol), Pd ₂ (dba) ₃ (5.7 mg, 0.0062 mmol), BINAP (8.1 mg, 0.013 mol) and sodium tert-butoxide (12.5 mg, 0.13 mmol) were dissolved in toluene (2 mL), 1-bromo-4-(trifluoromethyl)benzene (29 mg, 0.13 mmol) was added. The reaction solution was cooled, celite was filtered, dried, and then purified, m. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.05 (d, J = 15.6 Hz, 1H), 8.42 - 8.37 (m, 2H), 8.28 (d, J = 6.8 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.97 (t, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.56 (m, 2H), 7.28 (m, 1H), 6.99 (m, 2H), 5.48 (m, 1H), 4.51 (s, 2H), 4.42 (s, 3H), 1.85 (m, 1H), 1.58 (d, J = 6.4 Hz, 6H), 0.95 (m, 4H).

Example 27

3-cyclopropyl-5-[2-(trifluoromethyl)pyridin-4-yl]-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazo) Zyrid-3-yl)pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide Preparation of (28).

Intermediate 18-7 (40 mg, 0.085 mmol) was dissolved in n-butanol (2 mL), 4-bromo-2-(trifluoromethyl)pyridine (38 mg, 0.17 mmol) and triethylamine (24 μL, 0.17) Mmmol), the reaction was heated at 135 ° C for two days in a sealed tube. The reaction liquid was cooled, dried, and purified by a thick-purified plate (dichloromethane: isopropyl alcohol = 12:1) to give a white solid (yield: 29%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.06 (d, J = 15.6Hz, 1H), 8.46 (d, J = 5.6Hz, 1H), 8.42-8.38 (m, 2H), 8.32 (d, J = 6.8 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.83 (s, 1H), 7.34 (d, J = 10.8 Hz, 1H), 7.13 (m, 1H), 6.89 (m, 1H), 5.46 (m, 1H), 4.55 (s, 2H), 4.49 (s, 3H), 1.85 (m, 1H), 1.58 (d, J = 6.8 Hz, 6H), 0.97 (m, 4H).

Example 28

3-cyclopropyl-5-(2-cyanopyridin-4-yl)-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazole-3- Preparation of pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Compound 29 was prepared by reference to Example 28, substituting 4-bromo-2-cyanopyridine for 4-bromo-2-(trifluoromethyl)pyridine. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.06 (d, J = 15.2Hz, 1H), 8.41-8.35 (m, 3H), 8.33 (d, J = 6.4Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.35 (d, J = 10.8 Hz, 1H), 7.17 (m, 1H), 6.90 (m, 1H) , 5.46 (m, 1H), 4.53 (s, 2H), 4.47 (s, 3H), 1.83 (m, 1H), 1.59 (d, J = 6.8 Hz, 6H), 0.98 (m, 4H).

Example 29

3-cyclopropyl-5-[4-chloro-3-(trifluoromethyl)phenyl]-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-tri Azol-3-yl)pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9- Preparation of amides.

Referring to Example 27, the compound 30 was obtained by substituting 1-chloro-4-bromo-2-(trifluoromethyl)benzene for 1-bromo-4-(trifluoromethyl)benzene. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.07 (d, J = 15.2Hz, 1H), 8.42-8.40 (m, 2H), 8.29 (d, J = 6.8Hz, 1H), 8.10 (d, J = 6.8 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.83 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.28 (m, 1H), 7.22 (d, J = 2.8 Hz, 1H), 7.04 (dd, J = 2.8 Hz, 8.8 Hz, 1H), 5.48 (m, 1H), 4.44 (s, 2H), 4.37 (s, 3H), 1.83 (m, 1H), 1.59 (d, J = 6.4 Hz, 6H), 0.94 (m, 4H).

Example 30

6-Benzylcarbonyl-2-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]- Preparation of 5,6-dihydro-4H-benzo[b]imidazo[1,2-d][1,4]diazepine-9-carboxamide.

1) Preparation of intermediate 31-1.

Methyl 2,4-difluoro-4-nitrobenzoate (5.0 g, 23 mmol) was dissolved in tetrahydrofuran (50 mL). Methyl 3-aminopropanoate hydrochloride (4.8 g, 34.5 mmol) Under the protection, it was cooled to 0 ° C, and triethylamine (5.8 g, 57.5 mmol) was added dropwise. After the dropwise addition was completed, stirring was continued at 0 ° C for 5 hours. Water (100 mL) and ethyl acetate (50 mL) were evaporated andEtOAc evaporated. The organic phase was combined, dried over anhydrous sodium sulfate and evaporated to dryness

2) Preparation of intermediate 31-2.

Intermediate 31-1 (7 g, 23 mmol) was dissolved in EtOAc (EtOAc) (EtOAc) (EtOAc) And water (100 mL), the pH was adjusted to about 8 with a saturated sodium carbonate solution, and extracted with ethyl acetate (100 mL×3). : petroleum ether = 1:5 to ethyl acetate: petroleum ether = 1:1) yielded 4.0 g of pale yellow solid, yield 64%.

3) Preparation of intermediate 31-3.

The intermediate 31-2 (3.7 g, 13.7 mmol) was dissolved in toluene (40 mL), EtOAc (1 mL) was evaporated. : 92%. ^{1 H NMR (400MHz, DMSO)} δ: 9.54 (s, 1H), 7.46 (d, 2H), 7.06 (s, 1H), 6.46 (d, 1H), 3.74 (s, 1H), 3.48 (m, 2H ), 2.89-2.73 (m, 2H).

4) Preparation of intermediate 31-4.

Intermediate 31-3 (0.5 g, 21 mmol) was dissolved in DMF (2 mL), pyridine (2 mL) was added, and then cooled to 0 ° C, benzoyl chloride (0.32 g, 2.3 mmol) was added dropwise. After stirring for 1 hour, water (10 mL) was added, EtOAc (EtOAc) (EtOAc) 1:2 to ethyl acetate: petroleum ether = 1:1) gave 400 mg of an oily material. Yield: 56%.

5) Preparation of intermediate 31-5.

Intermediate 31-4 (400mg, 1.17mmol) was dissolved in DMF (3mL), was added _{K 2 CO 3 (968mg, 7.0mmol} ) and cyclopropylmethyl bromide-ketone (572mg, 3.5mmol). After stirring at room temperature for 1 hour, water (10 mL) was added, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated Ethyl ester = 2:1 to petroleum ether: ethyl acetate = 1:1) 400 mg of yield, yield: 81%. Ms: m/z = 425.2 [M+H].

6) Preparation of intermediate 31-6.

Intermediate 31-5 (400 mg, 0.94 mmol) was dissolved in acetic acid (8 mL), and then ethyl acetate (367 mg, 4.77 mmol) was added and the mixture was heated to 120 ° C for 5 hours. The reaction solution was cooled to room temperature, then dried, and ethyl acetate (20 mL) and water (15 mL) was added, and the pH was adjusted to about 8 with a saturated sodium hydrogen carbonate solution, and the aqueous layer was extracted with ethyl acetate (20 mL x 2) The organic layer was combined, dried over anhydrous sodium sulfate, evaporated, evaporated Ms: m/z = 406.2 [M+H].

7) Preparation of intermediate 31-7.

Intermediate 31-6 (320 mg, 0.79 mmol) was dissolved in MeOH (2 mL), EtOAc (EtOAc) The organic solvent was sparged, the pH was adjusted to 3-4 with 1N hydrochloric acid, filtered and dried to give 253 g of white solid.

8) Preparation of Compound 31.

Intermediate 31-7 (40 mg, 0.10 mmol), HATU (46.6 mg, 0.12 mmol), pyridine (16.2 mg, 0.20 mmol) and dichloroethane (2 mL) were added to the reaction mixture and stirred at room temperature for 10 min. Intermediate 1-4 (18.6 mg, 0.09 mmol) was added, and the mixture was stirred at room temperature for 0.5 hr, and then stirred at 70 ° C overnight. The solvent was concentrated and purified by chromatography (dichloromethane: isopropyl alcohol = 15:1). _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.26 (m, 1H), 8.37 (m, 2H), 8.20 (m, 2H), 8.06 (m, 1H), 8.05-7.90 (m, 1H), 7.33- 7.29 (m, 1H), 7.26-7.13 (m, 1H), 7.11-6.80 (m, 3H), 6.81-6.78 (m, 1H), 5.44-5.37 (m, 1H), 3.26 (m, 2H), 2.68 (m, 2H), 1.86 (m, 1H), 1.54 (d, J = 6.4 Hz, 6H), 0.94-0.85 (m, 4H).

Example 31

6-Benzylcarbonyl-2-cyclopropyl-N-[2-(4-isopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl]-8-fluoro- Preparation of 5,6-dihydro-4H-benzo[b]imidazo[1,2-d][1,4]diazepine-9-carboxamide.

Referring to Example 31, Substituting 2-4 to Intermediate 1-4 gave Compound 32. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.26 (m, 1H), 8.21-8.19 (m, 2H), 7.97 (s, 1H), 7.33-7.29 (m, 1H), 7.26-7.19 (m, 2H ), 7.13 - 7.11 (m, 3H), 6.78 (d, 1H), 5.41 (m, 1H), 3.18 (m, 2H), 2.58 (m, 2H), 1.83 (m, 1H), 1.52 (d, J = 6.4 Hz, 6H), 0.95 - 0.87 (m, 4H).

Example 32

5-(2-Cyanobenzyl)-3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Referring to Example 19, compound 33 was obtained by substituting 2-cyanobenzyl bromide for 4-trifluoromethylbenzyl chloride. ^{1 H-NMR (400MHz, CDCl} 3) δ: 9.15 (m, 1H), 8.44 (m, 2H), 8.24 (m, 1H), 8.10 (d, J = 8.0Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.80-7.75 (m, 1H), 7.74 (m, 1H), 7.68-7.61 (m, 2H), 7.44 (m, 1H), 7.36 (m, 1H), 5.51 (m, 1H), 3.92 (s, 2H), 3.66 (s, 2H), 3.65 (s, 2H), 1.83 (m, 1H), 1.61 (d, J = 6.4 Hz, 6H), 1.00-0.88 (m, 4H) ).

Example 33

5-(2-chloro-4-fluorobenzyl)-3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazole-3- Preparation of pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Compound 34 was prepared by the procedure of Example 19, using 2-chloro-4-fluorobenzyl chloride instead of 4-trifluoromethylbenzyl chloride. ^{1 H-NMR (400MHz, CDCl} 3) δ: 9.15 (m, 1H), 8.44 (m, 2H), 8.24 (m, 1H), 8.10 (d, J = 8.0Hz, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.76 (m, 1H), 7.58 (m, 1H), 7.33 (m, 1H), 7.19 (m, 1H), 7.05 (m, 1H), 5.50 (m, 1H), 3.81 (s, 2H), 3.66 (s, 2H), 3.60 (s, 2H), 1.82 (m, 1H), 1.61 (d, J = 6.4 Hz, 6H), 0.99-0.86 (m, 4H).

Example 34

3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-5-(naphthalene- Preparation of 2-ylmethyl)-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Referring to Example 19, compound 35 was obtained by substituting 2-(bromomethyl)naphthalene for 4-trifluoromethylbenzyl chloride. ^{1 H-NMR (400MHz, CDCl} 3) δ: 9.15 (m, 1H), 8.44 (m, 2H), 8.24 (m, 1H), 8.10 (d, J = 8.0Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.90-7.87 (m, 2H), 7.86-7.82 (m, 2H), 7.77 (s, 1H), 7.62 (m, 1H), 7.53-7.49 (m, 2H), 7.30 ( m,1H),5.51(m,1H),3.90(s,2H),3.67(s,2H),3.63(s,2H),1.82(m,1H),1.61(d,J=6.4Hz,6H ), 1.01-0.94 (m, 2H), 0.92-0.86 (m, 2H).

Example 35

3-cyclopropyl-8-fluoro-5-(3-fluorobenzyl)-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- Preparation of 2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Referring to Example 19, compound 36 was prepared by substituting 3-fluorobenzyl bromide for 4-trifluoromethylbenzyl chloride. ^{1 H-NMR (400MHz, CDCl} 3) δ: 9.15 (m, 1H), 8.41 (m, 2H), 8.23 (m, 1H), 8.09 (d, J = 8.0Hz, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.37-7.31 (m, 1H), 7.28 (m, 1H), 7.21-7.15 (m, 2H), 7.02 (m, 1H), 5.49 (m, 1H), 3.72 (s, 2H), 3.62 (s, 2H), 3.57 (s, 2H), 1.80 (m, 1H), 1.60 (d, J = 6.4 Hz, 6H), 0.99-0.93 (m, 2H) ), 0.92-0.87 (m, 2H).

Example 36

3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-5-{3- [4-(Trifluoromethyl)phenyl]ureido}-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9 - Preparation of formamide.

Intermediate 18 (30 mg, 0.063 mmol) was dissolved in tetrahydrofuran (3 mL), 4-trifluoromethylphenylisocyanate (24 mg, 0.13 mmol) was added and reacted at 50 ° C for 4 hours. The mixture was dried with EtOAc (EtOAc m. ^{1 H NMR (400MHz, DMSO)} δ: 11.05 (s, 1H), 9.06 (s, 1H), 8.86 (s, 1H), 8.24 (m, 1H), 8.07 (m, 2H), 8.02 (m, 1H ), 7.93 (m, 1H), 7.75 (m, 2H), 7.65 (m, 3H), 5.66 (m, 1H), 4.66 (s, 2H), 4.53 (s, 2H), 1.99 (m, 1H) , 1.60 (d, J = 6.4 Hz, 6H), 0.89 - 0.83 (m, 2H), 0.82 - 0.75 (m, 2H).

Example 37

3-cyclopropyl-5-(2,4-difluorobenzyl)-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl Preparation of pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Referring to Example 19, compound 38 was prepared by substituting 2,4-difluorobenzyl chloride for 4-trifluoromethylbenzyl chloride. ^{1 H-NMR (400MHz, CDCl} 3) δ: 9.14 (m, 1H), 8.44 (d, J = 8.0Hz, 1H), 8.40 (s, 1H), 8.23 (m, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.51 (m, 1H), 7.31 (m, 1H), 6.93 (m, 1H), 6.87 (m) , 1H), 5.50 (m, 1H), 3.74 (s, 2H), 3.65 (s, 2H), 3.59 (s, 2H), 1.83 (m, 1H), 1.61 (d, J = 6.4 Hz, 6H) , 0.99-0.94 (m, 2H), 0.93-0.89 (m, 2H).

Example 38

5-(cyclohexylmethyl)-3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine-2 Preparation of -5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Compound 29 was prepared by reference to Example 28, substituting (chloromethyl)cyclohexane for 4-bromo-2-(trifluoromethyl)pyridine. ^{1 H-NMR (400MHz, CDCl} 3) δ: 9.14 (m, 1H), 8.43 (d, J = 8.0Hz, 1H), 8.39 (s, 1H), 8.21 (m, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.29 (m, 1H), 5.50 (m, 1H), 3.58 (s, 2H), 3.56 (s) , 2H), 2.39 (m, 2H), 1.88-1.85 (m, 1H), 1.85-1.81 (m, 2H), 1.80-1.74 (m, 4H), 1.60 (d, J = 6.4 Hz, 6H), 1.33-1.26 (m, 2H), 1.00-0.87 (m, 7H).

Example 39

2-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-4,5-di Preparation of hydrogen-4H-benzo[b]imidazo[1,2-d][1,4]oxazepine-9-carboxamide.

1) Preparation of intermediate 40-1.

Methyl 2-fluoro-4-hydroxybenzoate (10g, 64.2mmol) was dissolved in methanol (80mL), concentrated sulfuric acid (2mL) was added, and the reaction was heated to reflux for 4 hours, cooled to room temperature, and the pH was adjusted by adding NaHCO ₃ solution. The mixture was extracted with ethyl acetate (100 mL×3), and the organic phase was combined, dried over anhydrous sodium sulfate and dried to give 11 g of product.

2) Preparation of intermediate 40-2.

Intermediate 40-1 (11 g, 64.7 mmol) was dissolved in concentrated sulfuric acid (110 mL), cooled to 0 ° C, potassium nitrate (6.4 g, 63.3 mmol) was added portionwise, stirred at 0 ° C for 4 hours, and the reaction mixture was added. The mixture was extracted with ethyl acetate (200 mL×2).

3) Preparation of intermediate 40-3.

Intermediate 40-2 (11 g, 40 mmol) was dissolved in MeOH (100 mL). EtOAc (EtOAc (EtOAc) After the addition was completed, the reaction was carried out for 5 hours at room temperature. Add ethyl acetate (200 mL), EtOAc (EtOAc)EtOAcEtOAcEtOAcEtOAcEtOAc The ester was extracted (200 mL×3), EtOAc (EtOAc m. Yield: 81%. ¹ H NMR (400 MHz, DMSO) δ: 7.10 (m, 1 H), 6.52 (m, 1H), 3.75 (s, 3H).

4) Preparation of intermediate 40-4.

Intermediate 40-3 (5.5 g, 29.7 mmol) was dissolved in a mixed solvent of acetonitrile (25 mL) and water (25 mL), and zinc chloride (8.1 g, 59.5 mmol) was added, and Boc ₂ O (13 g, 59.5) was added dropwise. Methyl), after completion of the dropwise addition, the reaction was carried out at 45 ° C for 3 hours. Some of the solvent was spun off. Add water (100 mL), EtOAc (EtOAc (EtOAc) (EtOAc) , yield: 65%. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.67 (s, 1H), 7.77 (m, 1H), 6.94 (s, 1H), 3.78 (s, 3H), 1.51 (s, 9H).

5) Preparation of intermediate 40-5

Intermediate 40-4 (5.5 g, 19.3 mmol) was dissolved in DMF <RTI ID=0.0>(5 </RTI><RTIID=0.0></RTI></RTI><RTIgt; Methyl), reacted at 60 ° C overnight. After the reaction mixture was cooled, water (100 mL) was added, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated Ester = 15:1) gave a pale yellow solid 5.5 g, yield 74%. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.59 (m, 1H), 6.93 (s, 1H), 6.63 (m, 1H), 4.59 (m, 1H), 4.14 (m, 2H), 3.88 (s, 3H), 3.38 (s, 6H), 2.16 (m, 2H), 1.54 (s, 9H)

6) Preparation of intermediate 40-6.

Intermediate 40-5 (5.5 g, 14.2 mmol) was dissolved in tetrahydrofuran (50 mL), water (50 mL). Filtration, extraction with ethyl acetate (100 mL×3), dried over anhydrous sodium sulfate, evaporated, evaporated, evaporated, evaporated

7) Preparation of intermediate 40-7.

The intermediate 40-6 (4.0 g, 11.2 mmol) was dissolved in dioxane (20 mL), and then 5N HCl / dioxane solution (8 mL). The residue was added to EtOAc (EtOAc) (EtOAc) The reaction was carried out for 2 days at room temperature. Water (50 mL) was added, and the organic layer was evaporated. EtOAcjjjjjjjjjjjj 1) Yielded 700 mg of pale yellow solid, yield: 26%. 1H NMR (400MHz, CDCl ₃ ) δ: 7.51 (m, 1H), 7.46 (s, 1H), 6.81 (s, 1H), 4.52 (m, 2H), 3.92 (s, 3H), 2.91 (m, 2H) )

8) Preparation of intermediate 40-8.

Intermediate 40-7 (700 mg, 2.9 mmol) was dissolved in DMF (10 mL) EtOAc (EtOAc) After stirring at room temperature for three hours, after the reaction of the starting material was completed, water (10 mL) was added, and ethyl acetate (10 mL×4) was taken, and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate Purification (petroleum ether: ethyl acetate = 5:1 to petroleum ether: ethyl acetate = 2:1) afforded 550 g of product, yield: 58%.

9) Preparation of intermediate 40-9.

The intermediate 40-8 (550 mg, 1.7 mmol) was dissolved in acetic acid (5 mL), and then ammonium acetate (1.3 g, 17 mmol) was added, and the reaction was carried out at 120 ° C for 3 hours, the solvent was evaporated, water (5 mL) was added and the pH was adjusted to 8. Extraction with ethyl acetate (10 mL x 4) and purification by column chromatography ( petroleum ether: ethyl acetate = 2:1) afforded 150 mg. Yield: 28%. Ms: m/z = 303.1 [M+H]. 10) Preparation of intermediate 40-9.

Intermediate 40-9 (150 mg, 0.49 mmol) was dissolved in MeOH (2 mL), EtOAc (EtOAc) Water (5 mL) was added to adjust the pH to about 4 with 1N hydrochloric acid to precipitate a solid, which was filtered and dried to give a white solid.

11) Preparation of Compound 40.

Compound 40 was prepared by reference to Example 8, substituting Intermediate 40-9 for Intermediate 8-15. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.07 (d, J = 16.4Hz, 1H), 8.41 (d, J = 8.0Hz, 1H), 8.38 (s, 1H), 8.20 (d, J = 8.0Hz , 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.04 (m, 2H), 5.50 (m, 1H), 4.67 (t, J = 5.6 Hz) , 2H), 3.18 (m, 2H), 1.88 (m, 1H), 1.60 (d, J = 6.8 Hz, 6H), 0.90 (m, 2H), 0.79 (m, 2H).

Example 40

6-Benzyl-2-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]- Preparation of 5,6-dihydro-4H-benzo[b]imidazo[1,2-d][1,4]diazepine-9-carboxamide.

1) Preparation of intermediate 41-1.

Intermediate 31-3 (0.35 g, 0.42 mmol) was dissolved in DMF (5 mL), sodium hydrogen carbonate (0.35 g, 4.2 mmol) and benzyl chloride (0.7 g, 4.2 mmol), and warmed to 80 ° C, reaction three After the addition of water (5 mL), EtOAc (EtOAc) (EtOAc (EtOAc) Slurry, yield: 74%. Ms: m/z = 329.3 [M+H].

2) Preparation of Compound 41.

Referring to Example 31, the compound 41 was obtained by substituting the intermediate 41-1 for the intermediate 31-4. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.02 (d, J = 16.4Hz, 1H), 8.41-8.38 (m, 2H), 8.05 (m, 2H), 7.91 (t, J = 8.0Hz, 1H) , 7.36-7.28 (m, 3H), 7.17 (m, 2H), 6.95 (s, 1H), 6.77 (d, J = 11.2 Hz, 1H), 5.48 (m, 1H), 4.48 (s, 2H), 3.73 (m, 2H), 3.06 (m, 2H), 1.89 (m, 1H), 1.57 (d, J = 6.8 Hz, 6H), 0.89 - 0.80 (m, 4H).

Example 41

6-Benzyl-2-cyclopropyl-8-fluoro-N-[2-(4-isopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl]- Preparation of 5,6-dihydro-4H-benzo[b]imidazo[1,2-d][1,4]diazepine-9-carboxamide.

Compound 42 was prepared by reference to Example 32, substituting Intermediate 41-1 for Intermediate 31-4. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.22 (d, J = 15.6Hz, 1H), 8.36 (s, 1H), 8.06 (m, 2H), 7.92 (s, 1H), 7.35-7.27 (m, 3H), 7.16 (m, 2H), 6.94 (s, 1H), 6.79 (d, J = 10.8 Hz, 1H), 5.54 (m, 1H), 4.47 (s, 2H), 3.72 (m, 2H), 3.05 (m, 2H), 1.89 (m, 1H), 1.57 (d, J = 6.8 Hz, 6H), 0.91 - 0.80 (m, 4H).

Example 42

5-acetyl-3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]- Preparation of 5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Referring to Example 18, compound 43 was obtained by substituting acetyl chloride for benzoyl chloride. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.10 (m, 1H), 8.42-8.38 (m, 2H), 8.28 (m, 1H), 8.10 (m, 1H), 7.95 (m, 1H), 7.76 ( s, 1H), 7.42 (m, 0.6H), 7.32 (m, 0.4H), 5.49 (m, 1H), 4.65 (s, 23H), 4.58 (s, 1.3H), 4.48 (s, 0.7H) , 2.31 (s, 1H), 2.24 (s, 2H), 1.82 (m, 61H), 1.60 (m, 6H), 0.97 (m, 4H).

Example 43

3-cyclopropyl-8-fluoro-9-{[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]aminocarbonyl}-4H Preparation of benzo[f]imidazo[1,5-a][1,4]diazepine-5(6H)-carboxylic acid isopropyl ester.

Compound 44 was obtained by reference to Example 18, using isopropyl chloroformate instead of benzoyl chloride. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.09 (d, J = 15.6 Hz, 1H), 8.43 - 8.38 (m, 2H), 8.25 (d, J = 6.4 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.41 (m, 0.63H), 7.31 (m, 0.37H), 5.49 (m, 1H), 5.02 ( m, 1H), 4.52 (m, 4H), 1.85 (m, 1H), 1.60 (d, J = 6.8 Hz, 6H), 1.32 (m, 6H), 0.95 (m, 4H).

Example 44

3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-5-pivaloyl Preparation of -5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Compound 45 was prepared by referring to Example 18 using pivaloyl chloride instead of benzoyl chloride. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.10 (d, J = 15.2Hz, 1H), 8.41 (d, J = 8.0Hz, 1H), 8.38 (s, 1H), 8.26 (d, J = 6.8Hz , 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.40 (d, J = 11.2 Hz, 1H), 5.49 (m) , 1H), 4.68 (s, 2H), 4.64 (s, 2H), 1.83 (m, 1H), 1.60 (d, J = 6.8 Hz, 6H), 1.42 (s, 9H), 0.95 (m, 4H) .

Example 45

3-cyclopropyl-8-fluoro-9-{[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]aminocarbonyl}-4H Preparation of benzo[f]imidazo[1,5-a][1,4]diazepine-5(6H)-carboxylic acid tert-butyl ester.

Compound 46 was prepared by reference to Example 18, using Boc anhydride instead of benzoyl chloride. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.10 (d, J = 15.6Hz, 1H), 8.43-8.41 (m, 2H), 8.25 (d, J = 6.0Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.40 (m, 0.6H), 7.22 (m, 0.4H), 5.49 (m, 1H), 4.47 ( m, 4H), 1.85 (m, 1H), 1.60 (d, J = 6.8 Hz, 6H), 1.53 (s, 9H), 0.95 (m, 4H).

Example 46

3-cyclopropyl-5-(3,4-difluorophenylcarbonyl)-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl Preparation of pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Referring to Example 23, the compound 47 was obtained by substituting 2,4-difluorobenzoic acid for 2-methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.10 (d, J = 15.2Hz, 1H), 8.45-8.41 (m, 2H), 8.28 (d, J = 6.84Hz, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.51 (m, 0.5H), 7.39 (m, 1H), 7.30 (m, 2H), 6.99 (m) , 0.5H), 5.47 (m, 1H), 4.71 (s, 2H), 4.49 (s, 2H), 1.89 (m, 1H), 1.60 (d, J = 6.4 Hz, 6H), 0.91 (m, 4H) ).

Example 47

5-(cyclopentylcarbonyl)-3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine-2 Preparation of -5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Compound 48 was prepared by reference to Example 18, using cyclopentylcarbonyl chloride instead of benzoyl chloride. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.11 (m, 1H), 8.42-8.39 (m, 2H), 8.27 (m, 1H), 8.10 (m, 1H), 7.95 (m, 1H), 7.78 ( s, 1H), 7.42 (m, 0.6H), 7.33 (m, 0.4H), 5.49 (m, 1H), 4.65-4.53 (m, 4H), 3.02 (m, 1H), 1.96-1.65 (m, 9H), 1.60 (d, J = 6.8 Hz, 6H), 0.97 (m, 4H).

Example 48

3-cyclopropyl-5-(3-fluorophenylcarbonyl)-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- Preparation of 2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Compound 49 was prepared by referring to Example 18 using 3-fluorobenzoyl chloride instead of benzoyl chloride. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.11 (m, 1H), 8.43-8.41 (m, 2H), 8.29 (m, 1H), 8.10 (m, 1H), 7.96 (m, 1H), 7.82 ( m,1H), 7.50 (m, 2H), 7.31-7.22 (m, 3H), 5.49 (m, 1H), 4.76 (m, 2H), 4.46 (m, 2H), 1.95 (m, 1H), 1.61 (d, J = 6.4 Hz, 6H), 0.98 (m, 2H), 0.87 (m, 2H).

Example 49

5-(cyclopropylcarbonyl)-3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine-2 Preparation of -5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Compound 50 was prepared by reference to Example 18, using cyclopropylcarbonyl chloride in place of benzoyl chloride. ^{1 H-NMR (400MHz, CDCl} 3) δ: 9.12 (m, 1H), 8.43 (m, 2H), 8.29 (m, 1H), 8.11 (d, J = 8.0Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.85-7.70 (m, 1H), 7.45-7.35 (m, 1H), 5.49 (m, 1H), 4.83 (s, 2H), 4.71 (m, 1H), 4.65 (m, 2H), 1.87-1.82 (m, 1H), 1.60 (d, J = 6.4 Hz, 6H), 1.13-1.06 (m, 2H), 0.99-0.85 (m, 6H).

Example 50

3-cyclopropyl-8-fluoro-5-isobutyryl-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl] Preparation of -5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Compound 51 was obtained by referring to Example 18, using isobutyryl chloride instead of benzoyl chloride. ^{1 H-NMR (400MHz, CDCl} 3) δ: 9.13 (m, 1H), 8.44 (s, 1H), 8.42 (d, J = 8.0Hz, 1H) ,, 8.27 (m, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.95 (t, J=8.0 Hz, 1H), 7.89-7.74 (m, 1H), 7.44 (m, 0.7H), 7.34 (m, 0.3H), 5.49 (m, 1H) ), 4.65 (s, 1.4H), 4.64 (s, 2H), 4.51 (s, 0.6H), 3.0-2.95 (m, 0.3H), 2.94 - 2.86 (m, 0.7H), 1.84-1.79 (m , 1H), 1.60 (d, J = 6.4 Hz, 6H), 1.22 (m, 3H), 1.20 (m, 3H), 0.99-0.89 (m, 4H).

Example 51

5-(2-Cyanophenylcarbonyl)-3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Compound 52 was obtained by referring to Example 23, substituting 2-cyanobenzoic acid for 2-methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid. ^{1 H-NMR (400MHz, CDCl} 3) δ: 9.14-9.04 (m, 1H), 8.50 (s, 1H), 8.43 (d, J = 8.0Hz, 1H), 8.27 (m, 1H), 8.08 (m , 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.86 (m, 1H), 7.82-7.73 (m, 2H), 7.67-7.54 (m, 3H), 5.50 (m, 1H), 4.87 ( s, 1H), 4.81 (s, 1H), 4.38 (s, 1H), 4.32 (s, 1H), 2.02-1.91 (m, 1H), 1.65-1.56 (m, 6H), 1.05-0.94 (m, 2H), 0.88-0.79 (m, 2H).

Example 52

3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-5-(1- Methyl-1H-pyrazole-3-carbonyl)-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide Preparation.

Referring to Example 23, compound 53 was obtained by substituting 1-methyl-1H-pyrazole-3-carboxylic acid for 2-methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid. ^{1 H-NMR (400MHz, CDCl} 3) δ: 9.11 (m, 1H), 8.46 (m, 1H), 8.44 (m, 1H), 8.26 (m, 1H), 8.06 (m, 1H), 7.95 (m , 1H), 7.79 (s, 1H), 7.49-7.41 (m, 2H), 6.85 (m, 1H), 5.48 (m, 1H), 5.23 (s, 1H), 5.17 (s, 0.8H), 4.79 (s, 1H), 4.77 (s, 0.8H), 4.05 (s, 1.6H), 3.96 (s, 1.3H), 1.91 (m, 1H), 1.63-1.56 (m, 6H), 1.00-0.90 ( m, 3H), 0.89-0.83 (m, 1H).

Example 53

3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-5-(thiophene- Preparation of 2-carbonyl)-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Compound 54 was prepared by reference to Example 18, using thiophene-2-carbonyl chloride instead of benzoyl chloride. ¹ H-NMR (400MHz, CDCl ₃ ) δ: 9.12 (m, 1H), 8.44-8.40 (m, 2H), 8.30 (m, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.96 (t , J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.83 (m, 0.5H), 7.58 (m, 1H), 7.46 (m, 1H), 7.15 (m, 1H), 7.12 (m, 0.5) H), 5.49 (m, 1H), 4.80 (s, 2H), 4.75 (s, 2H), 1.80-1.67 (m, 1H), 1.60 (d, J = 6.4 Hz, 6H), 0.98-0.92 (m) , 2H), 0.91-0.85 (m, 2H).

Example 54

3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-5-(propyl- Preparation of 2-alkyn-1-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Compound 55 was prepared by referring to Example 19, substituting 3-bromopropyne for 4-trifluoromethylbenzyl chloride. ^{1 H-NMR (400MHz, CDCl} 3) δ: 9.17 (m, 1H), 8.43 (d, J = 8.0Hz, 1H), 8.39 (s, 1H), 8.23 (m, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.37 (m, 1H), 5.50 (m, 1H), 3.79 (s, 2H), 3.72 (s) , 2H), 3.44 (m, 2H), 2.33 (m, 1H), 1.89 (m, 1H), 1.61 (d, J = 6.4 Hz, 6H), 0.98-0.94 (m, 2H), 0.93-0.89 ( m, 2H).

Example 55

3-cyclopropyl-8-fluoro-5-{[3-(2-fluorophenyl)isoxazol-5-yl]methyl}-N-[6-(4-isopropyl-4H-1 ,2,4-triazol-3-yl)pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine Preparation of misc-9-formamide.

Compound 55 (17 mg, 0.033 mmol) was dissolved in dichloromethane (1 mL), and 2-fluorobenzaldehyde hydrazide (18 mg, 0.10 mmol) and triethylamine (1 mL) were added, and the mixture was refluxed for 4 hours. It was cooled, dried, and purified by a thick-purified plate (dichloromethane:methanol = 30:1). ^{1 H-NMR (400MHz, CDCl} 3) δ: 9.13 (m, 1H), 8.43-8.41 (m, 2H), 8.24 (m, 1H), 8.10 (m, 1H), 8.01 (m, 1H), 7.95 (m, 1H), 7.77 (m, 1H), 7.47-7.43 (m, 1H), 7.37 (m, 1H), 7.27-7.24 (m, 1H), 7.20 (m, 1H), 6.79 (m, 1H) ), 5.50 (m, 1H), 3.94 (s, 2H), 3.77 (s, 2H), 3.69 (s, 2H), 1.88 (m, 1H), 1.61 (d, J = 6.4 Hz, 6H), 0.98 (m, 2H), 0.94 (m, 2H).

Example 56

3-cyclopropyl-8-fluoro-N ⁵ ,N ⁵ -diisopropyl-N ⁹ -[6-(4-isopropyl-4H-1,2,4-triazol-3-yl) Preparation of pyridin-2-yl]-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-5,9(6H)-dimethylamide.

Compound 57 was obtained by referring to Example 18 using diisopropylcarbamoyl chloride instead of benzoyl chloride. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.10 (d, J = 15.6 Hz, 1H), 8.42 - 8.38 (m, 2H), 8.20 (d, J = 6.4 Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.39 (d, J = 11.6 Hz, 1H), 5.50 (m, 1H), 4.20 (s, 2H) , 4.12 (s, 2H), 3.74 (m, 2H), 1.76 (m, 1H), 1.60 (d, J = 6.8 Hz, 6H), 1.35 (d, J = 6.8 Hz, 12H), 0.92 (m, 4H).

Example 57

N ⁵ -(tert-butyl)-3-cyclopropyl-8-fluoro-N ⁹ -[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- Preparation of 2-yl]-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-5,9(6H)-dimethylamide.

Compound 58 was prepared by reference to Example 37, substituting tert-butyl isocyanate for 4-trifluoromethylphenylisocyanate. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.11 (d, J = 15.6Hz, 1H), 8.42-8.38 (m, 2H), 8.24 (d, J = 6.8Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.43 (d, J = 11.2 Hz, 1H), 5.49 (m, 1H), 4.49 (s, 2H) , 4.39 (s, 2H), 4.33 (s, 1H), 1.84 (m, 1H), 1.60 (d, J = 6.4 Hz, 6H), 1.39 (s, 9H), 0.95 (m, 4H).

Example 58

3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-5-(morpholine Preparation of 4-carbonyl)-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Referring to Example 18, compound 59 was obtained by substituting 4-morpholinyl chloride for benzoyl chloride. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.09 (d, J = 15.6 Hz, 1H), 8.42 - 8.38 (m, 2H), 8.23 (d, J = 6.8 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.40 (d, J = 11.6 Hz, 1H), 5.49 (m, 1H), 4.35 (s, 2H) , 4.27 (s, 2H), 3.76 (m, 4H), 3.38 (m, 4H), 1.79 (m, 1H), 1.60 (d, J = 6.4 Hz, 6H), 0.93 (m, 4H).

Example 59

3-cyclopropyl-8-fluoro-9-{[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]aminocarbonyl}-4H Preparation of benzo[f]imidazo[1,5-a][1,4]diazepine-5(6H)-isobutylate.

Referring to Example 18, compound 60 was prepared by substituting isobutyl chloroformate for benzoyl chloride. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.09 (d, J = 15.2 Hz, 1H), 8.42 - 8.38 (m, 2H), 8.26 (d, J = 6.8 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.41 (m, 0.6H), 7.30 (m, 0.4H), 5.49 (m, 1H), 4.54 ( m, 4H), 3.96 (m, 2H), 2.01 (m, 1H), 1.84 (m, 1H), 1.60 (d, J = 6.4 Hz, 6H), 0.96 (m, 10H).

Example 60

3-cyclopropyl-8-fluoro-N ⁵ ,N ⁵ -dimethyl-N ⁹ -[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine Preparation of 2-yl]-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-5,9(6H)-dimethylamide.

Compound 61 was obtained by referring to Example 18, using dimethylcarbamoyl chloride instead of benzoyl chloride. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.09 (d, J = 15.2 Hz, 1H), 8.42 - 8.38 (m, 2H), 8.22 (d, J = 6.8 Hz, 1H), 8.10 (d, J = 7.2 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.41 (d, J = 11.6 Hz, 1H), 5.50 (m, 1H), 4.32 (s, 2H) , 4.25 (s, 2H), 2.94 (s, 6H), 1.80 (m, 1H), 1.60 (d, J = 6.8 Hz, 6H), 0.93 (m, 4H).

Example 61

3-cyclopropyl-8-fluoro-9-{[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]aminocarbonyl}-4H Preparation of benzo[f]imidazo[1,5-a][1,4]diazepine-5(6H)-carboxylic acid cyclopentyl ester.

Compound 62 was prepared by reference to Example 18, using cyclopentyl chloroformate instead of benzoyl chloride. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.09 (d, J = 15.6 Hz, 1H), 8.42 - 8.38 (m, 2H), 8.25 (d, J = 6.8 Hz, 1H), 8.10 (d, J = 7.2 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.41 (m, 1H), 5.49 (m, 1H), 5.20 (m, 1H), 4.50 (m, 4H), 1.92 (m, 2H), 1.77 (m, 3H), 1.60 (d, J = 6.8 Hz, 6H), 0.95 (m, 4H).

Example 62

3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-5-(pyrrolidine Preparation of 1-carbonylcarbonyl)-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Referring to Example 18, compound 63 was obtained by using pyrrolidine-1-carbonyl chloride in place of benzoyl chloride. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.09 (d, J = 15.2 Hz, 1H), 8.42 - 8.37 (m, 2H), 8.22 (d, J = 6.8 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.45 (d, J = 11.2 Hz, 1H), 5.50 (m, 1H), 4.38 (s, 2H) , 4.30 (s, 2H), 3.47 (m, 4H), 1.91 (m, 4H), 1.81 (m, 1H), 1.60 (d, J = 6.48 Hz, 6H), 0.94 (m, 4H).

Example 63

3-cyclopropyl-8-fluoro-9-{[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]aminocarbonyl}-4H Preparation of benzo[f]imidazo[1,5-a][1,4]diazepine-5(6H)-carboxylic acid cyclopropylmethyl ester.

Compound 64 was prepared by reference to Example 18, substituting benzoyl chloride chloroformate for benzoyl chloride. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.09 (d, J = 15.2Hz, 1H), 8.43-8.38 (m, 2H), 8.26 (d, J = 6.8Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.40 (m, 1H), 5.49 (m, 1H), 4.58 (s, 2H), 4.53 (s, 2H), 4.01 (m, 2H), 1.88 (m, 1H), 1.60 (d, J = 6.8 Hz, 6H), 1.20 (m, 1H), 0.95 (m, 4H), 0.60 (m, 2H), 0.33 (m, 2H).

Example 64

3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-5-(2- Preparation of methoxypyrimidin-4-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Compound 65 was prepared by referring to Example 28, substituting 4-chloro-2-methoxypyrimidine for 4-bromo-2-(trifluoromethyl)pyridine. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.09 (m, 1H), 8.43 (d, J = 8.4Hz, 1H), 8.39 (s, 1H), 8.31 (d, J = 6.8Hz, 1H), 8.18 (d, J = 6.0 Hz, 1H), 8.12 (d, J = 7.2 Hz, 1H), 7.96 (m, 1H), 7.81 (s, 1H), 7.46 (d, J = 11.2 Hz, 1H), 6.30 (d, J = 5.6 Hz, 1H), 5.50 (m, 1H), 4.89 (s, 2H), 4.60 (s, 2H), 4.05 (s, 3H), 1.88 (m, 1H), 1.61 (m, 6H), 0.98 (m, 4H).

Example 65

3-cyclopropyl-8-fluoro-5-(5-fluoropyrimidin-2-yl)-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl Preparation of pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Compound 66 was prepared by reference to Example 28, substituting 2-chloro-5-fluoropyrimidine for 4-bromo-2-(trifluoromethyl)pyridine. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.09 (m, 1H), 8.43 (d, J = 8.4Hz, 1H), 8.39 (s, 1H), 8.32 (s, 2H), 8.29 (d, J = 6.8 Hz, 1H), 8.11 (d, J = 7.2 Hz, 1H), 7.96 (m, 1H), 7.79 (s, 1H), 7.45 (d, J = 11.6 Hz, 1H), 5.50 (m, 1H) , 4.92 (s, 2H), 4.78 (s, 2H), 1.94 (m, 1H), 1.61 (m, 6H), 0.98 (m, 4H).

Example 66

3-cyclopropyl-5-(2,4-difluorophenyl)-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl Preparation of pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Compound 67 was prepared by referring to Example 27, substituting 2,4-difluorobromobenzene for 1-bromo-4-(trifluoromethyl)benzene. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.11 (d, J = 15.2Hz, 1H), 8.43 (d, J = 8.4Hz, 1H), 8.40 (s, 1H), 8.27 (d, J = 6.4Hz , 1H), 8.11 (d, J = 7.6 Hz, 1H), 8.07 (m, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.55 (d, J = 11.6 Hz) , 1H), 7.34 (m, 1H), 6.83 (m, 1H), 5.51 (m, 1H), 4.69 (s, 2H), 4.67 (s, 2H), 1.92 (m, 1H), 1.61 (d, J = 6.8 Hz, 6H), 0.95 (m, 4H).

Example 67

3-cyclopropyl-8-fluoro-5-(5-fluoropyridin-2-yl)-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl Preparation of pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Compound 68 was prepared by reference to Example 27, substituting 5-fluoro-2-bromopyridine for 1-bromo-4-(trifluoromethyl)benzene. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.42-8.37 (m, 2H), 8.25 (d, J = 6.8Hz, 1H), 8.14 (m, 1H), 8.05 (m, 1H), 7.95 (t, J=8.0 Hz, 1H), 7.79 (s, 1H), 7.46 (m, 1H), 7.35 (m, 1H), 6.64 (m, 1H), 5.47 (m, 1H), 4.82 (s, 2H), 4.48 (s, 2H), 1.88 (m, 1H), 1.59 (m, 6H), 0.95 (m, 4H).

Example 68

3-cyclopropyl-8-fluoro-5-(3-fluoropyridin-2-yl)-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl Preparation of pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Compound 69 was prepared by the procedure of Example 27, substituting 3-fluoro-2-bromopyridinylbenzene for 1-bromo-4-(trifluoromethyl)benzene. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.12 (m, 1H), 8.44 (d, J = 8.4Hz, 1H), 8.40 (s, 1H), 8.29 (d, J = 6.8Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.97 (t, J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.31 (m, 1H), 7.05 (m, 1H), 6.93 (m, 1H) , 6.84 (m, 1H), 5.50 (m, 1H), 4.25 (s, 2H), 4.19 (s, 2H), 2.03 (m, 1H), 1.61 (m, 6H), 0.90 (m, 4H).

Example 69

5-(4-Chloro-3-fluorophenylcarbonyl)-3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazole-3- Preparation of pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Referring to Example 23, compound 70 was obtained by substituting 3-fluoro-4-chlorobenzoic acid for 2-methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid. ^{1 H-NMR (400MHz, CDCl} 3) δ: 9.16-9.05 (m, 1H), 8.44 (d, J = 8.0Hz, 1H), 8.41 (s, 1H), 8.32 (m, 1H), 8.13 (d , J = 8.0 Hz, 1H), 7.98 (t, J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.61 - 7.55 (m, 1H), 7.54 - 7.46 (m, 0.5H), 7.37 (m) , 1H), 7.30 (m, 1H), 7.07-6.94 (m, 0.5H), 5.50 (m, 1H), 4.74 (m, 2H), 4.48 (m, 2H), 1.80-1.77 (m, 1H) , 1.62 (d, J = 6.8 Hz, 6H)), 1.00 - 0.85 (m, 4H).

Example 70

5-(4-bromo-3-fluorophenylcarbonyl)-3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazole-3- Preparation of pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Referring to Example 23, the compound 71 was obtained by substituting 3-fluoro-4-bromobenzoic acid for 2-methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid. ^{1 H-NMR (400MHz, CDCl} 3) δ: 9.16-9.05 (m, 1H), 8.45 (d, J = 8.0Hz, 1H), 8.43 (s, 1H), 8.32 (m, 1H), 8.14 (d , J=8.0 Hz, 1H), 7.98 (t, J=8.0 Hz, 1H), 7.84 (m, 1H), 7.78-7.70 (m, 1H), 7.58-7.51 (m, 0.5H), 7.34 (m) , 1H), 7.24 (m, 1H), 7.07-6.98 (m, 0.5H), 5.51 (m, 1H), 4.75 (m, 2H), 4.48 (m, 2H), 1.81-1.78 (m, 1H) , 1.63 (d, J = 6.8 Hz, 6H)), 1.01 - 0.85 (m, 4H).

Example 71

3-cyclopropyl-5-(2,6-dichlorophenylcarbonyl)-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl Preparation of pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Referring to Example 23, compound 72 was obtained by substituting 2,6-dichlorobenzoic acid for 2-methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid. ^{1 H-NMR (400MHz, CDCl} 3) δ: 9.17-9.07 (m, 1H), 8.45 (d, J = 8.0Hz, 1H), 8.41 (m, 1H), 8.32 (t, J = 7.2Hz, 1H ), 8.13 (t, J = 8.0 Hz, 1H), 7.98 (t, J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.59 (d, J = 7.2 Hz, 0.5H), 7.49 (m, 0.3H), 7.46 (s, 0.5H), 7.44-7.39 (m, 1.5H), 7.38-7.33 (m, 0.7H), 7.17 (d, J = 7.2 Hz, 0.5H), 5.52 (m, 1H) ), 4.91 (s, 1H), 4.89 (s, 1H), 4.32 (s, 1H), 4.24 (s, 1H), 1.99 (m, 1H), 1.64 (d, J = 6.8 Hz, 6H)), 1.02-0.99 (m, 1H), 0.95-0.87 (m, 3H).

Example 72

3-cyclopropyl-5-(3,3-difluoropyrrolidine-1-carbonyl)-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazole 3-yl)pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide preparation.

Triphosgene (18.7 mg, 0.063 mmol) was dissolved in dichloromethane (1 mL) and cooled to 0 °C. 3,3-Difluoropyrrolidine hydrochloride (27 mg, 0.19 mmol) was dissolved in dichloromethane (1 mL), triethylamine (53 μL, 0.38 mmol) was added, and the mixture was added dropwise to the above reaction mixture at 0 ° C. . After stirring at 0 ° C for 1 hour, intermediate 18-7 (30 mg, 0.063 mmol) and triethylamine (18 μL, 0.13 mmol) It was spin-dried and purified by a thick preparative plate (dichloromethane: isopropyl alcohol = 20:1) to afford 13 mg of white solid. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.11 (d, J = 15.6Hz, 1H), 8.44-8.41 (m, 2H), 8.27 (d, J = 6.8Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.97 (t, J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.45 (d, J = 11.6 Hz, 1H), 5.51 (m, 1H), 4.40 (s, 2H) , 4.33 (s, 2H), 3.83 (t, J = 12.4 Hz, 2H), 3.75 (t, J = 7.2 Hz, 1H), 2.41 (m, 2H), 1.82 (m, 1H), 1.62 (d, J = 6.8 Hz, 6H), 0.97 (m, 4H).

Example 73

3-cyclopropyl-8-fluoro-N ⁹ -[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-N ⁵ - ( Preparation of 2,2,2-trifluoromethyl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-5,9(6H)-dimethylamide .

Compound 74 was prepared by the procedure of Example 73, substituting trifluoroethylamine in 3,3-difluoropyrrolidine hydrochloride. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.11 (d, J = 15.6Hz, 1H), 8.44-8.40 (m, 2H), 8.29 (d, J = 6.8Hz, 1H), 8.11 (d, J = 7.2 Hz, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.45 (d, J = 11.2 Hz, 1H), 5.51 (m, 1H), 5.11 (m, 1H) , 4.59 (s, 2H), 4.55 (s, 2H), 4.00 (m, 1H), 1.85 (m, 1H), 1.62 (d, J = 6.8 Hz, 6H), 0.98 (m, 4H).

Example 74

5-(cyanomethyl)-3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine-2 Preparation of -5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Intermediate 18-7 (30 mg, 0.063 mmol) was dissolved in dichloromethane (2 mL), bromoacetonitrile (9 [mu]L, 0.13 <RTIgt; The mixture was applied to a solution. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.13 (d, J = 15.6 Hz, 1H), 8.45 - 8.41 (m, 2H), 8.26 (d, J = 6.8 Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.97 (t, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.41 (d, J = 11.2 Hz, 1H), 5.53 (m, 1H), 3.84 (s, 2H) , 3.80 (s, 2H), 3.70 (s, 2H), 1.88 (m, 1H), 1.63 (d, J = 6.8 Hz, 6H), 0.98 (m, 4H).

Example 75

N ⁵ ,3-dicyclopropyl-8-fluoro-N ⁹ -[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]- Preparation of 4H-benzo[f]imidazo[1,5-a][1,4]diazepine-5,9(6H)-dimethylamide.

Referring to Example 73, compound 76 was prepared by substituting cyclopropylamine for 3,3-difluoropyrrolidine hydrochloride. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.11 (d, J = 15.6Hz, 1H), 8.44-8.40 (m, 2H), 8.26 (d, J = 6.8Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.46 (d, J = 11.6 Hz, 1H), 5.52 (m, 1H), 4.83 (s, 1H) , 4.56 (s, 2H), 4.22 (s, 2H), 2.72 (m, 1H), 1.84 (m, 1H), 1.63 (d, J = 6.8 Hz, 6H), 0.97 (m, 4H), 0.80 ( m, 2H), 0.55 (m, 2H).

Example 76

3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-5-(3, 3,4,4-tetrafluoropyrrolidine-1-carbonyl)-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9 - Preparation of formamide.

Referring to Example 73, compound 77 was obtained by substituting 3,3,4,4-tetrafluoropyrrolidine hydrochloride for 3,3-difluoropyrrolidine hydrochloride. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.11 (d, J = 15.2Hz, 1H), 8.45-8.41 (m, 2H), 8.29 (d, J = 6.4Hz, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.98 (t, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.45 (d, J = 11.2 Hz, 1H), 5.51 (m, 1H), 4.40 (s, 2H) , 4.34 (s, 2H), 3.99 (m, 4H), 1.80 (m, 1H), 1.63 (d, J = 6.8 Hz, 6H), 0.98 (m, 4H).

Example 77

3-cyclopropyl-5-(3,3-difluoroazetidin-1-carbonyl)-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4- Triazol-3-yl)pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9- Preparation of formamide.

Triphosgene (18.7 mg, 0.063 mmol) was dissolved in dichloromethane (1 mL) and cooled to 0 °C. The intermediate 18-7 (30 mg, 0.063 mmol) was dissolved in dichloromethane (1 mL), triethylamine (53 μL, 0.38 mmol) was added, and the obtained mixture was added dropwise to the above-mentioned reaction mixture at 0 ° C. After stirring at 0 ° C for 1 hour, 3,3-difluoroazetidine hydrochloride (41 mg, 0.32 mmol) and triethylamine (53 μL, 0.38 mmol) were added, and the mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was poured into water and extracted with dichloromethane (10 mL×3). 12 mg white solid, yield: 32%. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.10 (d, J = 15.2Hz, 1H), 8.44-8.41 (m, 2H), 8.28 (d, J = 6.8Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.97 (t, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.45 (d, J = 11.2 Hz, 1H), 5.51 (m, 1H), 4.45 - 4.38 (m, 8H), 1.83 (m, 1H), 1.62 (d, J = 6.8 Hz, 6H), 0.98 (m, 4H).

Example 78

3-cyclopropyl-N ⁵ -(3,3,-difluorocyclobutyl)-8-fluoro-N ⁹ -[6-(4-isopropyl-4H-1,2,4-triazole Preparation of -3-yl)pyridin-2-yl]-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-5,9(6H)-dimethylamide .

Compound 79 was prepared by the procedure of Example 78, substituting 3,3-difluorocyclobutylamine hydrochloride for 3,3-difluoroazetidine hydrochloride. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.10 (d, J = 15.2Hz, 1H), 8.44-8.40 (m, 2H), 8.28 (d, J = 6.8Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.97 (t, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.44 (d, J = 11.2 Hz, 1H), 5.51 (m, 1H), 4.82 (d, J = 6.0 Hz, 1H), 4.56 (s, 2H), 4.49 (s, 2H), 4.24 (m, 1H), 3.05 (m, 2H), 2.54 (m, 2H), 1.85 (m, 1H), 1.62 ( d, J = 6.8 Hz, 6H), 0.98 (m, 4H).

Example 79

N ⁵ -(1-cyanocyclopropyl)-3-cyclopropyl-8-fluoro-N ⁹ -[6-(4-isopropyl-4H-1,2,4-triazole-3- Preparation of pyridin-2-yl]-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-5,9(6H)-dimethylamide.

Referring to Example 78, compound 80 was obtained by substituting 1-cyanocyclopropylamine hydrochloride for 3,3-difluoroazetidine hydrochloride. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.11 (d, J = 15.6Hz, 1H), 8.44-8.41 (m, 2H), 8.28 (d, J = 6.4Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.97 (t, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.46 (d, J = 11.2 Hz, 1H), 5.51 (m, 1H), 5.43 (s, 1H) , 4.58 (s, 2H), 4.45 (s, 2H), 1.82 (m, 1H), 1.63 (d, J = 6.8 Hz, 6H), 0.97 (m, 4H), 0.89 (m, 4H).

Example 80

3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-5-(2- Oxa-6-azaspiro[3.3]heptane-6-carbonyl)-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine Preparation of Zhuo-9-formamide.

Referring to Example 73, compound 81 was obtained by substituting 2-oxa-6-azaspiro[3.3]heptane hemioxalate for 3,3-difluoropyrrolidine hydrochloride. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.09 (d, J = 15.6Hz, 1H), 8.44-8.40 (m, 2H), 8.26 (d, J = 6.4Hz, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.97 (t, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.43 (d, J = 11.6 Hz, 1H), 5.51 (m, 1H), 4.84 (s, 4H) , 4.39 (m, 4H), 4.25 (s, 4H), 1.83 (m, 1H), 1.62 (d, J = 6.8 Hz, 6H), 0.98 (m, 4H).

Example 81

3-cyclopropyl-8-fluoro-N ⁹ -[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-N ⁵ - ( 1,1,1-trifluoro-2-methylpropan-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-5,9 ( Preparation of 6H)-dimethyl amide.

Referring to Example 73, the compound 82 was obtained by substituting 1,1,1-trifluoro-2-methylpropan-2-amine hydrochloride for 3,3-difluoropyrrolidine hydrochloride. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.12 (d, J = 16.0Hz, 1H), 8.45-8.40 (m, 2H), 8.29 (d, J = 6.8Hz, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.97 (t, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.43 (d, J = 11.6 Hz, 1H), 5.52 (m, 1H), 4.50 (m, 3H) , 4.47 (s, 2H), 1.85 (m, 1H), 1.66 (s, 6H), 1.63 (d, J = 6.8 Hz, 6H), 0.98 (m, 4H).

Example 82

3-cyclopropyl-9-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-4,5,6 Preparation of 7-tetrahydrobenzo[g]imidazo[1,5-a][1,5]diazepineoctane-10-carboxamide.

1) Preparation of intermediate 83-1.

Intermediate 8-10 (1.0 g, 7.35 mmol) was dissolved in nitromethane and ammonium acetate (1.13 g, 14.7 mmol) was added and the reaction was heated at 60 ° C for half an hour. After cooling to room temperature, the solvent was evaporated to drynesshhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh : ethyl acetate = 2:1) gave a yellow solid, 1.0 g, yield: 76%. Ms: m/z = 180.1 [M+H].

2) Preparation of intermediate 83-2.

The intermediate 83-1 (1.0 g, 5.59 mmol) was dissolved in tetrahydrofuran (50 mL), argon gas was applied, and lithium aluminum hydride (425 mg, 11.2 mmol) was added, and the reaction was transferred to 55 ° C for 5 hours. Under ice-cooling, the reaction was quenched with water (1.0 mL), then anhydrous sodium sulfate (10 g) was added, and the mixture was stirred for 30 minutes, filtered over celite, washed with THF, and the filtrate was evaporated to dryness. Carry out the next reaction. Ms: m/z = 152.2 [M+H].

3) Preparation of intermediate 83-3.

Intermediate 83-2 (900 mg, 5.59 mmol) was dissolved in ethanol (20 mL), 2,4-dimethoxybenzaldehyde (1.86 g, 11.2 mmol) and anhydrous magnesium sulfate (2.0 g) hour. The reaction solution was cooled, filtered through celite, and the filtrate was evaporated to dryness. Ms: m/z = 300.2 [M+H].

4) Preparation of intermediate 83-4.

The intermediate 83-3 (1.67 g, 5.59 mmol) was dissolved in methanol (50 mL), and sodium borohydride (425 mg, 11.2 mmol) was added portionwise in an ice bath. The reaction was quenched by the addition of water (2OmL), EtOAc (EtOAc)EtOAc. 1) A pale yellow oil of 800 mg was obtained in a three-step yield: 47%. Ms: m/z = 302.2 [M+H].

5) Preparation of intermediate 83-5.

Intermediate 83-4 and Intermediate 8-6 (800 mg, 2.35 mmol) were dissolved in dichloromethane (20 mL). After adding dichloromethane (30 mL), it was washed with water (20 mL), brine (20 mL) A pale yellow foam solid of 900 mg was obtained in a yield: 60%. Ms: m/z = 560.2 [M+H], 562.2 [M+H]. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.03 (d, J = 7.2Hz, 1H), 7.31 (m, 2H), 7.14 (d, J = 8.0Hz, 1H), 6.48 (d, J = 2.4Hz , 1H), 6.46 (dd, J = 8.0 Hz, J = 2.4 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 3.88 (s, 2H), 3.81 (s, 2H), 3.69 (s , 2H), 3.67 (s, 2H), 2.86 (t, J = 6.8 Hz, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.06 (m, 1H), 1.67 (m, 1H), 1.40 (t, J = 7.2 Hz, 3H), 1.28 (m, 2H), 0.76 (m, 2H).

6) Preparation of intermediate 83-6.

Intermediate 83-5 (850 mg, 1.52 mmol) was dissolved in DMF (30 mL), EtOAc (EtOAc, EtOAc, EtOAc, EtOAc 0.61 mmol), protected with argon, heated to 100 ° C for 2 hours. The reaction solution was cooled, and the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. Light yellow foam solid 200 mg, yield: 27%. Ms: m/z = 480.3 [M+H].

7) Preparation of intermediate 83-7.

Intermediate 83-6 (200 mg, 0.42 mmol) was dissolved in methanol (5 mL) and THF (5 mL), and water (2.5mL) and lithium hydroxide (90 mg, 2.1 mmol) were added and allowed to react at room temperature for 1 hour. Cyclohexane and tetrahydrofuran, add water (15mL) and stir evenly, then adjust the pH to 4-5 with 1N hydrochloric acid, then extract (15mL x 3) with (dichloromethane: methanol = 20:1) solution, and combine organic The layer was dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness. Ms: m/z = 452.2 [M+H].

8) Preparation of intermediate 83-8.

The intermediate 83-7 (100 mg, 0.22 mmol) was dissolved in methylene chloride, argon-protected, oxalyl chloride (0.275 mL, 0.55 mmol) was added, and the mixture was stirred at room temperature for 3 hours, and the solvent was evaporated under reduced pressure. After drying for half an hour, intermediate 1-4 (41 mg, 0.20 mmol), dichloromethane (3 mL) and pyridine (0.07 mL, Filtration, the filtrate was spun dry, and the thick-purified plate was purified (dichloromethane:methanol = 20:1) to give a brown foam (yield: 16%). Ms: m/z = 637.4 [M+H].

8) Preparation of Compound 83.

Intermediate 83-8 (16 mg, 2.54 mmol) was dissolved in trifluoroacetic acid (2.0 mL) After the reaction mixture was cooled, the trifluoroacetic acid was evaporated, and the mixture was dissolved in dichloromethane, and the mixture was adjusted to pH 8 with a saturated sodium hydrogen carbonate solution and extracted with dichloromethane (10 mL x 3). The thick preparation plate was purified (dichloromethane:methanol = 18:1) to give a white solid (yield: 10%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.08 (m, 1H), 8.44-8.40 (m, 2H), 8.12 (m, 2H), 7.96 (m, 1H), 7.51 (s, 1H), 7.32 ( m,1H), 5.42 (m,1H), 4.02-3.98 (m,1H), 3.41-3.36 (m,1H),3.33-3.29 (m,1H),3.24-3.19 (m,1H),2.93- 2.87 (m, 1H), 2.20-2.11 (m, 1H), 1.81-1.76 (m, 1H), 1.63 (d, J = 6.8 Hz, 6H), 1.29-1.27 (m, 2H), 0.92-0.89 ( m, 2H).

Example 83

5-benzyl 3-cyclopropyl-7-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-4 Preparation of oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxamide.

1) Preparation of intermediate 84-1.

2,5-Difluoro-4-nitrobenzoic acid (6 g, 29.56 mmol) was dissolved in dichloromethane (60 mL) and triethylamine (11 mL), DMAP (1 g, 8.87 mmol) and Boc anhydride (10 mL, 44.34 mmol). Stir slowly to room temperature and stir for 2 hours. The reaction was completed, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. Rate: 97%.

2) Preparation of intermediate 84-2.

Intermediate 84-1 (3 g, 11.58 mmol) was dissolved in DMF (35 mL) EtOAc (EtOAc) hour. After the reaction mixture was cooled to room temperature, water (70 mL) was added, and ethyl acetate (50 mL×3), and the organic layer was combined, washed with saturated brine (80 mL×3) Purification (petroleum ether: ethyl acetate = 5:1) gave product 2.25 g, yield: 46%. MS (m/z): 420.2 [M + 1].

3) Preparation of intermediate 84-3.

Intermediate 84-2 (2.25 g, 5.37 mmol) was dissolved in acetic acid (20 mL), and iron powder (1.5 g, 26.85 mmol) was added, and the mixture was stirred at 110 ° C for 2 hours. The reaction mixture was cooled, EtOAc EtOAc (EtOAc m. Dry over sodium sulfate and spin dry to give a product 1.32 g, yield: 71%. MS (m/z): 344.2 [M + 1].

4) Preparation of intermediate 84-4.

Intermediate 84-3 (0.2 g, 0.58 mmol) was dissolved in DMF (5 mL). EtOAc (EtOAc, EtOAc, After the reaction mixture was cooled, water (20 mL) was added, and ethyl acetate (50 mL×3) was evaporated. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. MS (m/z): 434.2 [M + 1].

5) Preparation of intermediate 84-5.

Intermediate 84-4 (0.2 g, 0.46 mmol) was dissolved in dichloromethane (4 mL). After stirring at room temperature for 4 hours, the reaction was completed, and the solvent was evaporated to dryness to give 156 mg of product (yield: 89%). MS (m/z): 378.15 [M + 1].

6) Preparation of Compound 84.

Referring to Example 8, compound 84 was prepared by substituting intermediate 84-5 for intermediate 8-15. MS (m/z): 563.2 [M + 1]. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.07 (d, J = 16Hz, 1H), 8.43 (d, J = 8.4Hz, 1H), 8.56 (d, J = 7.2Hz, 1H), 8.41 (d, J = 8.0 Hz, 1H), 8.38 (s, 2H), 8.10 (d, J = 7.6 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.42 - 7.32 (m, 5H), 7.02 ( d, J = 13.6 Hz, 1H), 5.46 (m, 3H), 2.98 (m, 1H), 1.58 (d, J = 6.8 Hz, 6H), 1.16 (m, 4H).

Example 84

5-benzyl 3-cyclopropyl-7-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-4 Preparation of 5-dihydroimidazo[1,5-a]quinoxaline-8-carboxamide.

1) Preparation of intermediate 85-1.

Intermediate 84-3 (0.66 g, 1.92 mmol) was dissolved in tetrahydrofuran (8 mL), and 1M borane in tetrahydrofuran (6 ml, 5.77 mmol) was added dropwise, and the mixture was warmed to 60 ° C for 2 hours. The reaction solution was cooled, and the reaction was quenched by adding methanol (1 mL). It was dried to a pale yellow solid (0.62 g, yield: 98%). MS (m/z): 330.25 [M + 1].

2) Preparation of Compound 85.

Compound 85 was prepared by reference to Example 84, substituting Intermediate 85-1 for Intermediate 84-3. MS (m/z): 549.25 [M + 1].

Example 85

2-{3-cyclopropyl-8-fluoro-9-[(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamate Preparation of acyl]-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-5(6H)-yl}acetic acid.

1) Preparation of intermediate 86-1.

Intermediate 18-7 (40 mg, 0.085 mmol) was dissolved in acetonitrile (3 mL). EtOAc EtOAc (EtOAc (EtOAc) The mixture was reacted at room temperature for 6 hours, filtered, dried, and purified by column chromatography (dichloromethane:methanol = 30:1) to yield 40 mg, yield: 80%. MS (m/z): 587.4 [M + 1].

2) Preparation of Compound 86.

Intermediate 86-1 (40 mg, 0.068 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added and the mixture was reacted at room temperature for 3 hrs, then dried, and water (3 mL) The mixture was extracted with a mixed solution of dichloromethane and isopropyl alcohol. The organic layer was combined, dried over anhydrous sodium sulfate and evaporated to dryness. ^{1 H NMR (400MHz, DMSO)} δ: 8.43 (m, 1H), 8.31 (m, 1H), 8.09 (m, 1H), 7.95 (m, 2H), 7.83 (m, 1H), 7.43 (m, 1H ), 5.52 (m, 1H), 3.73 (s, 2H), 3.41 (s, 2H), 3.33 (s, 2H), 1.84 (m, 1H), 1.57 (d, J = 6.4 Hz, 6H), 0.90 (m, 4H).

Example 86

3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-5-(3, Preparation of 3,3-trifluoroethyl)-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

The intermediate 18-7 was dissolved in tetrahydrofuran (3 mL), triethylamine (31 μL, 0.22 mmol) and trifluoroethyl trifluoromethanesulfonate (16 μL, 0.11 mmol). The reaction solution was cooled, vortexed, and purified on a thick-purified plate (dichloromethane: isopropyl alcohol = 20:1) to give a white solid (yield: 44%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.12 (d, J = 15.6Hz, 1H), 8.45-8.41 (m, 2H), 8.26 (d, J = 6.8Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.98 (t, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.35 (d, J = 11.2 Hz, 1H), 5.52 (m, 1H), 3.86 (s, 2H) , 3.78 (s, 2H), 3.22 (q, J = 9.2 Hz, 2H), 1.87 (m, 1H), 1.63 (d, J = 6.8 Hz, 6H), 0.97 (m, 4H).

Example 87

5-(tert-butyl)-3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine-2- Preparation of 5-yl-6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide.

Compound 88 was prepared by reference to Example 8, using tert-butylamine in place of benzylamine. ^{1 H-NMR (400MHz, CDCl} 3) δ: 9.16 (m, 1H), 8.45 (d, J = 8.0Hz, 1H), 8.40 (s, 1H), 8.21 (m, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.40 (m, 1H), 5.52 (m, 1H), 3.91 (s, 2H), 3.81 (s) , 2H), 1.85 (m, 1H), 1.63 (s, 3H), 1.61 (s, 3H), 1.30 (s, 9H), 0.99-0.92 (m, 4H).

Example 88

N ⁵ -(tert-butyl)-3-cyclopropyl-8-fluoro-N ⁹ -[6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridine- Preparation of 2-yl]-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-5,9(6H)-dimethylamide.

Compound 89 was prepared by reference to Example 58 using cyclopropylamine instead of isopropylamine. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.16 (m, 1H), 8.45 (d, J = 8.0Hz, 2H), 8.27 (d, J = 6.8Hz, 1H), 8.25 (s, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.44 (d, J = 11.6 Hz, 1H), 4.51 (s, 2H), 4.41 (s, 2H), 3.85 (m, 1H), 1.87 (m, 1H), 1.41 (s, 9H), 1.28 (m, 4H), 0.99 (m, 4H).

Example 89

N ⁵ -(tert-butyl)-3-cyclopropyl-8-fluoro-N ⁹ -[6-(4-methyl-4H-1,2,4-triazol-3-yl)pyridine-2 Preparation of -yl]-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-5,9(6H)-dimethylamide.

Compound 90 was prepared by reference to Example 58 using a methylamine ethanol solution instead of isopropylamine. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.13 (d, J = 15.2Hz, 1H), 8.44 (d, J = 8.0Hz, 2H), 8.26 (d, J = 6.8Hz, 1H), 8.22 (s , 1H), 8.17 (d, J = 7.6 Hz, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.46 (d, J = 11.6 Hz, 1H), 4.52 (s) , 2H), 4.41 (s, 2H), 4.14 (s, 3H), 1.87 (m, 1H), 1.42 (s, 9H), 0.98 (m, 4H).

Example 90

5-[2-(tert-butylamino)-2-oxoethyl]-3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4- Triazol-3-yl)pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9- Preparation of formamide.

1) Preparation of intermediate 91-1.

tert-Butylamine (3.6 g, 49.32 mmol) was dissolved in dichloromethane (40 mL) and triethylamine (13.7 mL, 98.64 mmol). Chloroacetyl chloride (3.98 ml, 49.81 mmol) was slowly added dropwise, and the mixture was allowed to react to room temperature for 2 hours after the addition. The solvent was evaporated, EtOAc (EtOAc)EtOAc. , yield: 40%.

2) Preparation of Compound 91.

Intermediate 91-1 (25 mg, 0.17 mmol) and intermediate 18-7 (40 mg, 0.085 mmol) were dissolved in acetonitrile (4 mL), and potassium carbonate (35 mg, 0.25 mmol) and potassium iodide (3 mg) Stir at °C for 4 hours. The reaction solution was cooled, filtered, dried, and then purified, m. MS (m/z): 586.2 [M + 1]. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.13 (d, J = 15.6Hz, 1H), 8.44-8.40 (m, 2H), 8.24 (d, J = 6.0Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.97 (t, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.32 (m, 1H), 6.91 (s, 1H), 5.51 (m, 1H), 3.65 (s, 4H), 3.17 (s, 2H), 1.86 (m, 1H), 1.62 (d, J = 6.0 Hz, 6H), 1.44 (s, 9H), 0.97 (m, 4H).

Example 91

3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-5-[2- Oxo-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)ethyl]-5,6-dihydro-4H-benzo[f]imidazo[1] Preparation of 5-a][1,4]diazepine-9-carboxamide.

Compound 92 was prepared by reference to Example 91, substituting 1,1,1-trifluoro-2-methylpropan-2-amine hydrochloride for t-butylamine. Ms (m/z): 640.28 [M + 1]. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.13 (d, J = 15.2Hz, 1H), 8.44 (d, J = 8.0Hz, 1H), 8.40 (s, 1H), 8.26 (d, J = 6.8Hz , 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.97 (t, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.33 - 7.29 (m, 2H), 5.52 (m, 1H) , 3.69 (s, 2H), 3.66 (s, 2H), 1.83 (m, 1H), 1.69 (s, 6H), 1.63 (d, J = 6.4 Hz, 6H), 0.97 (m, 4H).

Example 92

N ⁵ -(tert-butyl)-3-cyclopropyl-8-fluoro-N ⁹ -[6-(5,6,7,8-tetrahydro-[1,2,4]triazole [4, 3-a]pyridin-3-yl)pyridin-2-yl]-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-5,9(6H)- Preparation of dimethyl amide.

1) Preparation of Intermediate 93-1.

Piperidin-2-one (1 g, 10.1 mmol) was dissolved in toluene (20 mL) and Lawson reagent (5.1 g, 12.6 mmol) was added. After replacing the nitrogen three times, the mixture was heated to 110 ° C for 4 hours. The reaction solution was cooled, the solvent was evaporated, and purified by column chromatography to yield 1 g, yield: 86%. Ms (m/z): 116.1 [M + 1].

2) Preparation of intermediate 93-2.

Intermediate 93-1 (1 g, 8.69 mmol) was dissolved in EtOAc (EtOAc) (EtOAc) (EtOAcjjjjjjjjjj The solvent obtained 1 g of a crude product in a yield of 89%. Ms (m/z): 130.1 [M + 1].

3) Preparation of intermediate 93-3.

Intermediate 93-2 (1 g, 7.75 mmol) was dissolved in ethanol (10 mL). Intermediate 1-2 was added and then warmed to <RTIgt; The reaction solution was cooled to room temperature, spin-dried, and purified by column chromatography to obtain 1.5 g of product. Yield: 90%. Ms (m/z): 216.2 [M + 1].

4) Preparation of Compound 93.

Compound 93 was prepared by reference to Example 58 substituting Intermediate 93-3 for Intermediate 1-4. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.10 (d, J = 14.4Hz, 1H), 8.38 (d, J = 8.4Hz, 1H), 8.24 (d, J = 6.4Hz, 1H), 8.11 (d , J = 7.6 Hz, 1H), 7.92 (t, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.45 (d, J = 11.2 Hz, 1H), 4.51 (m, 4H), 3.11 (m) , 2H), 2.08-1.98 (m, 5H), 1.86 (m, 2H), 1.41 (s, 9H), 0.98 (m, 4H).

Example 93

(R)-N ⁵ -(tert-butyl)-3-cyclopropyl-8-fluoro-N ⁹ -[6-(4-(1-hydroxypropan-2-yl)-4H-1,2,4 -triazol-3-yl)pyridin-2-yl]-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-5,9(6H)-di Preparation of formamide.

Compound 94 was prepared by reference to Example 58 using D-aminopropanol instead of isopropylamine. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.17 (d, J = 15.6Hz, 1H), 8.37 (d, J = 8.4Hz, 1H), 8.25 (m, 2H), 7.96 (d, J = 7.2Hz , 1H), 7.85 (t, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.46 (d, J = 11.6 Hz, 1H), 4.76 (m, 1H), 4.51 (s, 2H), 4.42 -4.37 (m, 4H), 4.16 (m, 1H), 1.86 (m, 1H), 1.40 (m, 12H), 0.97 (m, 4H).

Example 94

1-{3-cyclopropyl-8-fluoro-9-[(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamate Acyl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-5-carbonyl}azetidin-3-carboxylic acid Preparation of the ester.

Referring to Example 73, compound 95 was obtained by substituting azetidine-3-carboxylic acid methyl ester hydrochloride for 3,3-difluoropyrrolidine hydrochloride. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.10 (d, J = 15.6Hz, 1H), 8.44-8.41 (m, 2H), 8.25 (d, J = 6.8Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.97 (t, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.44 (d, J = 11.2 Hz, 1H), 5.52 (m, 1H), 4.40 (m, 4H) , 4.27 (m, 4H), 3.80 (s, 3H), 3.49 (m, 1H), 1.84 (m, 1H), 1.63 (d, J = 6.8 Hz, 6H), 0.98 (m, 4H).

Example 95

1-{3-cyclopropyl-8-fluoro-9-[(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamate Acyl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-5-carbonyl}azetidin-3-carboxylic acid Preparation.

Compound 95 (35 mg, 0.057 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL). After the reaction was completed, it was spun dry, water (3 mL) was added, and the pH was adjusted to about 5 with 1N hydrochloric acid, filtered, and the filter cake was washed with a small amount of water, and dried to give a white solid (yield: 58%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.84 (m, 1H), 8.39 (d, J = 8.4Hz, 1H), 8.06 (m, 3H), 7.93 (m, 1H), 7.56 (m, 1H) , 5.74 (m, 1H), 4.46 (s, 2H), 4.41-4.18 (m, 6H), 3.51 (m, 1H), 1.94 (m, 1H), 1.56 (d, J = 6.8 Hz, 6H), 0.96 (m, 2H), 0.86 (m, 2H).

Example 96

3-cyclopropyl-8-fluoro-5-(3-fluoroazetidin-1-carbonyl)-N-[6-(4-isopropyl-4H-1,2,4-triazole 3-yl)pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide preparation.

Compound 97 was prepared by the procedure of Example 78, using 3-fluoroazetidine hydrochloride instead of 3,3-difluoroazetidine hydrochloride. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.10 (d, J = 15.2Hz, 1H), 8.44-8.41 (m, 2H), 8.26 (d, J = 6.4Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.97 (t, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.44 (d, J = 11.2 Hz, 1H), 5.52 (m, 1H), 5.42 (m, 0.5H) ), 5.30 (m, 0.5H), 4.41-4.32 (m, 6H), 4.27-4.17 (m, 2H), 1.83 (m, 1H), 1.62 (d, J = 6.8 Hz, 6H), 0.98 (m) , 4H).

Example 97

3-cyclopropyl-8-fluoro-5-(3-hydroxyazetidin-1-carbonyl)-N-[6-(4-isopropyl-4H-1,2,4-triazole 3-yl)pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide preparation.

Referring to Example 78, compound 97 was obtained by substituting 3-hydroxyazetidine hydrochloride for 3,3-difluoroazetidine hydrochloride. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.10 (d, J = 15.2Hz, 1H), 8.43-8.40 (m, 2H), 8.24 (d, J = 6.4Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.43 (d, J = 11.2 Hz, 1H), 5.51 (m, 1H), 4.73 (m, 1H) , 4.40 (m, 4H), 4.34 (m, 2H), 4.00 (m, 2H), 1.83 (m, 1H), 1.62 (d, J = 6.8 Hz, 6H), 0.97 (m, 4H).

Example 98

5-(3-cyanoazetidin-1-carbonyl)-3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazole Zyrid-3-yl)pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide Preparation.

Referring to Example 73, compound 99 was obtained by substituting 3-cyanoazetidine hydrochloride for 3,3-difluoropyrrolidine hydrochloride. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.10 (d, J = 15.2Hz, 1H), 8.44-8.41 (m, 2H), 8.27 (d, J = 6.4Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.97 (t, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.43 (d, J = 11.2 Hz, 1H), 5.51 (m, 1H), 4.40-4.320 (m, 8H), 3.54 (m, 1H), 1.82 (m, 1H), 1.62 (d, J = 6.8 Hz, 6H), 0.98 (m, 4H).

Example 99

3-cyclopropyl-5-(3,3-difluorocyclobutanecarbonyl)-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazole- Preparation of 3-yl)pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide .

Compound 100 was prepared by referring to Example 23, substituting 3,3-difluorocyclobutanecarboxylic acid for 2-methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid. ^{1 H-NMR (400MHz, CDCl} 3) δ: 9.12 (m, 1H), 8.48 (m, 1H), 8.44 (d, J = 8.0Hz, 1H), 8.29 (m, 1H), 8.08 (m, 1H ), 7.98 (t, J = 8.0 Hz, 1H), 7.81 (s, 1H), 7.44 (m, 0.7H), 7.31 (m, 0.3H), 5.49 (m, 1H), 4.68 (s, 2H) , 4.54 (s, 1.4H), 4.43 (s, 0.6H), 3.25 (m, 1H), 3.03 (m, 2H), 2.88 (m, 2H), 1.77 (m, 1H), 1.62 (d, J) = 6.8 Hz, 6H), 0.97 (m, 4H).

Example 100

3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-5-(3, 3,3-Trifluoro-2,2-dimethylpropanoyl)-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine Preparation of -9-formamide.

Compound 101 was prepared by referring to Example 23, substituting 3,3,3-trifluoro-2,2-dimethylpropanoic acid for 2-methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.12 (d, J = 15.2Hz, 1H), 8.44 (d, J = 8.4Hz, 1H), 8.41 (s, 1H), 8.30 (d, J = 6.8Hz , 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.98 (t, J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.42 (d, J = 11.2 Hz, 1H), 5.51 (m) , 1H), 4.70 (s, 2H), 4.68 (s, 2H), 1.85 (m, 1H), 1.63 (m, 12H), 0.98 (m, 4H).

Example 101

3-cyclopropyl-8-fluoro-N-[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-5-[1- (trifluoromethyl)cyclopropanecarbonyl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-9-carboxamide preparation.

Referring to Example 23, compound 102 was obtained by substituting 1-(trifluoromethyl)cyclopropanecarboxylic acid for 2-methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.12 (d, J = 15.2Hz, 1H), 8.50 (s, 1H), 8.45 (d, J = 8.4Hz, 1H), 8.29 (d, J = 6.4Hz , 1H), 8.09 (d, J = 7.2 Hz, 1H), 7.98 (t, J = 8.0 Hz, 1H), 7.83 (s, 1H), 7.43 (d, J = 10.8 Hz, 1H), 5.50 (m) , 1H), 4.70 (m, 4H), 1.78 (m, 2H), 1.63 (d, J = 6.8 Hz, 6H), 1.52 (m, 2H), 1.36 (m, 2H), 0.99 (m, 4H) .

Example 102

3-cyclopropyl-8-fluoro-N ⁹ -[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-N ⁵ -[ 1-(Trifluoromethyl)cyclopropyl]-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-5,9(6H)-dimethylamide preparation.

1-(Trifluoromethyl)cyclopropanecarboxylic acid (20 mg, 0.13 mmol) was dissolved in ultra dry dioxane (2 mL), and DPPA (34 μL, 0.15 mmol) and triethylamine (24 μL, 0.17 mmol). Protected with nitrogen and reacted at 100 ° C for 2 hours. After cooling to room temperature, intermediate 18-7 (40 mg, 0.085 mmol) was added and the mixture was reacted at 50 ° C for 3 hours. After spin-drying, purification by thick preparative plates (dichloromethane: isopropanol = 16:1) afforded 30 mg of white solid, yield: 60%. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.13 (d, J = 15.6Hz, 1H), 8.44-8.41 (m, 2H), 8.28 (d, J = 6.8Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.97 (t, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.45 (d, J = 11.2 Hz, 1H), 5.51 (m, 1H), 5.38 (s, 1H) , 4.55 (s, 1H), 4.49 (s, 2H), 1.85 (m, 1H), 1.63 (d, J = 6.8 Hz, 6H), 1.39 (m, 2H), 1.19 (m, 2H), 0.97 ( m, 4H).

Example 103

3-cyclopropyl-8-fluoro-5-(3-hydroxy-3-methylazetidin-1-carbonyl)-N-[6-(4-isopropyl-4H-1,2, 4-triazol-3-yl)pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine- Preparation of 9-carboxamide.

Referring to Example 78, compound 104 was obtained by substituting 3-hydroxy-3-methylazetidine hydrochloride for 3,3-difluoroazetidine hydrochloride. Ms (m/z): 586.2 [M + 1]. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.09 (d, J = 15.2Hz, 1H), 8.43-8.40 (m, 2H), 8.26 (d, J = 6.8Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.43 (d, J = 11.2 Hz, 1H), 5.50 (m, 1H), 4.40 - 4.32 (m, 8H), 1.82 (m, 1H), 1.60 (d, J = 6.8 Hz, 6H), 1.32 (s, 3H), 0.97 (m, 4H).

Example 104

3-cyclopropyl-8-fluoro-5-[3-hydroxy-3-(trifluoromethyl)azetidin-1-carbonyl]-N-[6-(4-isopropyl-4H- 1,2,4-triazol-3-yl)pyridin-2-yl]-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4] Preparation of azaoxa-9-carboxamide.

Referring to Example 78, compound 105 was obtained by substituting 3-hydroxy-3-trifluoromethylazetidine hydrochloride for 3,3-difluoroazetidine hydrochloride. Ms (m/z): 640.2 [M + 1]. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.11 (d, J = 15.6Hz, 1H), 8.43-8.40 (m, 2H), 8.27 (d, J = 6.4Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.44 (d, J = 11.2 Hz, 1H), 5.51 (m, 1H), 4.43-4.36 (m, 8H), 1.82 (m, 1H), 1.61 (d, J = 6.8 Hz, 6H), 0.98 (m, 4H).

Example 105

3-cyclopropyl-N ⁹ -[6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-N ⁵ -(1,1, 1-trifluoro-2-methylpropan-2-yl)-4H-imidazo[1,5-a]pyrido[3,4-f]diazepine-5,9(6H)-dimethyl Preparation of amides.

1) Preparation of intermediate 106-1.

Methyl 2,4-dichlorochloride (5 g, 24.3 mmol) was dissolved in ethanol (100 mL) and lithium bromide (3.17 g, 36.5 mmol) was added, and sodium borohydride (2.75 g, 72.8 mmol) was added portionwise. After the reaction was carried out for 2 hours at room temperature, the ethanol was evaporated, EtOAc (EtOAc)EtOAc. g, yield: 97%. Ms (m/z): 206.0 [M + 1].

2) Preparation of intermediate 106-2.

Intermediate 106-1 (4.2 g, 23.6 mmol) was dissolved in dichloromethane <RTI ID=0.0>(</RTI> </RTI> <RTI ID=0.0> The solution was reacted at room temperature for 1 hour after the addition. The reaction mixture was poured into ice water (80 mL), and the mixture was adjusted to pH 8 with sodium bicarbonate solid, and the layers were separated. The aqueous layer was extracted with dichloromethane (80 mL), dried over anhydrous sodium sulfate A pale yellow solid was obtained in 3.1 g, yield: 55%. Ms (m/z): 241.9 [M + 1].

3) Preparation of intermediate 106-3.

Intermediate 18-2 (1.2 g, 4.18 mmol) was dissolved in dichloromethane <RTI ID=0.0>(20</RTI> <RTI ID=0.0> 9.36 mmol), reacted at room temperature for 3 hours. The mixture was dried with EtOAc EtOAc EtOAc. Ms (m/z): 446.2 [M + 1].

4) Preparation of intermediate 106-4.

Intermediate 106-3 (1.50 g, 3.35 mmol) was dissolved in DMF (15 mL), EtOAc (EtOAc, EtOAc, EtOAc, EtOAc, EtOAc Methyl), the reaction was heated at 100 ° C for 2 hours under nitrogen. The reaction solution was cooled, filtered, dried, and purified by column chromatography to yield 650 mg of pale yellow solid. MS (m/z): 411.2 [M + 1].

5) Preparation of intermediate 106-5.

Intermediate 106-4 (650mg, 1.58mmol) was dissolved in DMF (10mL), was added zinc cyanide _{(371mg, 3.16mmol), Pd 2} (dba) 3 (119mg, 0.13mmol) and dppf (140mg, 0.25mmol) After nitrogen protection, the reaction was carried out at 120 ° C for 2 hours. The reaction mixture was cooled, celite was filtered, and the filtrate was filtered, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated (Dichloromethane: methanol = 50:1) 550 mg of pale yellow solid. MS (m/z): 402.2 [M + 1].

6) Preparation of intermediate 106-6.

Intermediate 106-5 (550 mg, 1.37 mmol) was dissolved in ethanol (20 mL) and water (10 mL). After the reaction liquid was cooled, it was spun dry, water was added, and the mixture was cooled. The pH was adjusted to about 5 with 1N HCl to precipitate a solid, which was filtered and dried to give a brown solid (400 mg, yield: 69%). MS (m/z): 421.2 [M + 1].

7) Preparation of Compound 106.

Compound 106 was prepared by reference to Example 82, substituting Intermediate 106-6 for Intermediate 18-5. MS (m/z): 609.3 [M + 1].

Example 106

{[3-Cyclopropyl-8-fluoro-9-((6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamoyl) Preparation of -4H-benzo[f]imidazo[1,5-a][1,4]diazepine-5(6H)-yl]methyl}phosphonic acid diethyl ester.

Intermediate 18-7 (48 mg, 0.10 mmol) was dissolved in toluene (1. 5 mL). EtOAc (EtOAc, EtOAc (EtOAc) 0.01 mmol), 4A molecular sieves (0.2 g) were further added, and the mixture was heated under reflux for 5 hours. The reaction solution was cooled, filtered, dried, and then purified, mjjjjjjj MS (m/z): 623.3 [M + 1]. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.11 (d, J = 15.2Hz, 1H), 8.44-8.40 (m, 2H), 8.25 (d, J = 6.8Hz, 1H), 8.11 (d, J = 7.4 Hz, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.34 (d, J = 10.8 Hz, 1H), 5.51 (m, 1H), 4.22 (m, 4H) , 3.73 (s, 2H), 3.65 (s, 2H), 3.05 (s, 2H), 1.85 (m, 1H), 1.63 (d, J = 6.8 Hz, 6H), 1.31 (m, 6H), 0.96 ( m, 4H).

Example 107

{[3-Cyclopropyl-8-fluoro-9-((6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamoyl) -4H-benzo[f]imidazo[1,5-a][1,4]diazepine-5(6H)-yl]methyl}phosphonic acid

Compound 107 (30 mg, 0.048 mol) was dissolved in dichloromethane (1 mL), trimethylbromosilane (29 mg, 0.19 mmol) was added, and the mixture was reacted at room temperature for 2 days, quenched by the addition of methanol, dried, and purified by HPLC (acetonitrile) : water = 20: 80 to 70: 30) obtained as a white solid 12 mg, yield: 44%. MS (m/z): 567.2 [M + 1]. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.10 (d, J = 15.2Hz, 1H), 8.44-8.40 (m, 2H), 8.24 (d, J = 6.8Hz, 1H), 8.12 (d, J = 7.4 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.33 (d, J = 10.8 Hz, 1H), 5.50 (m, 1H), 3.75 (s, 2H) , 3.68 (s, 2H), 3.12 (s, 2H), 1.82 (m, 1H), 1.62 (d, J = 6.8 Hz, 6H), 0.97 (m, 4H).

Example 108

Experimental method for determining enzyme activity of target compound

Principle: The enzymatic activity of an inhibitor of apoptosis signal-regulating kinase (ASK-1) was determined using HTRF (Homogeneous Time-Resolved Fluorescence) technology. Fluorescence resonance energy transfer between a donor and a receptor (second fluorescent label) based on Eu cryptate is utilized as a donor using chelating and labeling elements of Eu elements having a cryptate structure. When two fluorophores are brought close due to biomolecular interaction, part of the energy captured by the cryptate at the time of excitation is released, and the emission wavelength is 620 nm; the other part of the energy is transferred to the receptor at an emission wavelength of 665 nm. The emission light of 665 nm is only produced by the FRET caused by the donor. Therefore, when the biomolecules interact, there are two excitation lights of 620 nm and 665 nm; when there is no interaction, only one excitation light of 620 nm, and finally by a fluorometer Detection.

Reagents and instruments: HTRF kinEASE-STK kit (Cisbio, 62ST3PEC), MAP3K5 (ASK1) (Invitrogen, PV3809), DMSO (Sigma, D8418-1L), ATP (Sigma, A7699), DTT (Sigma, D0632), MgCl2 ( Sigma, M1028). Plate shaker (Thermo, 4625-1CECN/THZ Q), Centrifuge (Eppendorf, 5810R), Envision 2014 multilabel Reader (PerkinElmer, 2104-0010), Echo (Labcyte, 550).

Experimental procedure: The test compound was formulated into a 10 mM stock solution in DMSO, and the test compound was diluted 3 times from 10 mM for a total of 10 gradients. 1X Kinase Reaction Buffer (5 mM MgCl ₂ , 1 mM DTT) was prepared by adding 4 volumes of water to 1 volume of 5X kinase reaction solution. 10 nL of the diluted compound was added to the corresponding well of the reaction plate, and the reaction plate was sealed with a sealing plate, centrifuged at 1000 g for 1 minute, and 5X ASK1 (15 nM) was prepared by using 1X enzyme reaction buffer, and the reaction plate of the compound was added per well. Add 2 μL of 5X ASK1, 4 μL of 1X enzyme reaction buffer, centrifuge at 1000g for 30 seconds, and let stand for 10 minutes at room temperature. Prepare 5X STK-substrate-bi otin (5μM) and 5X ATP (500μM) in 1X enzyme reaction buffer. Add 2 μL of STK-substrate-biotin and 2 μL of ATP to each well of the plate, seal the plate with 1000 g of the sealing plate for 30 seconds, react at room temperature for 3 hours, and prepare 4X Sa-XL665 (250 nM) and 4X STK-antibody with the detection buffer solution. -Cryptate, 5 μL of Sa-XL665 and 5 μL of STK-antibody-Cryptate were added to each well, centrifuged at 1000 g for 30 seconds, reacted at room temperature for 2 hours, and fluorescent signals of 615 nm (Cryptate) and 665 nm (XL665) were read with Envision 2014. The inhibition rate of each compound of the test compound was calculated, and the IC ₅₀ value was calculated by data analysis using Graphpad 5.0 software.

The average IC50 values of the compounds were summarized into three grades: A: IC ₅₀ <10 nM; B: 10 nM < IC ₅₀ <50 nM; C: IC ₅₀ >50 nM.

The experimental results are shown in Table 1 below: The compounds of the present invention are effective in binding to ASK1 and acting as ASK1 inhibitors.

Table 1 Inhibitory activity of target compound against ASK1

Compound number	Activity level	Compound number	Activity level	Compound number	Activity level
1	B	2	C	3	A
4	A	5	A	6	C
7	C	8	A	9	A
10	A	11	A	12	B
13	B	14	C	15	A
17	A	18	A	19	A
20	A	twenty one	A	twenty two	A
twenty three	A	twenty four	A	25	A
26	A	27	A	28	A
29	A	30	A	31	B
32	C	33	A	34	A
35	A	36	A	37	A
38	A	39	A	40	A
41	A	42	C	43	A
44	A	45	A	46	A
47	A	48	A	49	A
50	A	51	A	52	A
53	A	54	A	55	A
56	A	57	A	58	A
59	A	60	A	61	A
62	A	63	A	64	A
65	A	66	A	67	A
68	A	69	A	70	A

71	A	72	A	73	A
74	A	75	A	76	A
77	A	78	A	79	A
80	A	81	A	82	A
83	A	84	A	85	B
86	A	87	A	88	A
89	A	90	A	91	A
92	A	93	B	94	A
95	A	96	A	97	A
98	A	99	A	100	A
101	A	102	A	103	A
104	A	105	A	106	A
107	A	108	A

Note: The compound numbers in Table 1 correspond to the compound numbers in Examples 1-107.

The technical features of the above-described embodiments may be arbitrarily combined. For the sake of brevity of description, all possible combinations of the technical features in the above embodiments are not described. However, as long as there is no contradiction between the combinations of these technical features, All should be considered as the scope of this manual.

The above-described embodiments are merely illustrative of several embodiments of the present invention, and the description thereof is more specific and detailed, but is not to be construed as limiting the scope of the invention. It should be noted that a number of variations and modifications may be made by those skilled in the art without departing from the spirit and scope of the invention. Therefore, the scope of the invention should be determined by the appended claims.

Claims (25)

1. A fused ring compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a solvate thereof or a prodrug molecule thereof:

   

   Wherein V ₁ and V ₆ are each independently selected from: N or C;

   V ₂ , V ₃ , V ₄ and V ₅ are each independently selected from: O, S, N, -N(R ₁ )-, -C(R ₂ )- or none;

   Each R _{1 is} independently selected from the group consisting of: H, D, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₂ -C ₄ alkenyl, substituted or unsubstituted C ₂ -C ₄ alkyne a substituted or unsubstituted C ₃ -C ₇ cycloalkyl group, or a substituted or unsubstituted heterocycloalkyl group of 3-7 atoms;

   Each R _{2 is} independently selected from the group consisting of: H, D, oxo, thio, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₂ -C ₄ alkenyl, substituted or unsubstituted a C ₂ -C ₄ alkynyl group, a substituted or unsubstituted C ₃ -C ₇ cycloalkyl group, or a substituted or unsubstituted heterocycloalkyl group of 3-7 atoms;

   X, Y and Z are each independently selected from: O, -N(R ₃ )-, -(CR ₄ R ₅ ) _a -, -C(=O)-, -S(=O)-, -S( =O) ₂ -, -P(=O)N(R ₇ )-, -P(=O)(OR ₈ )- or none, and X, Y and Z cannot be simultaneously;

   Each R _{3 is} independently selected from: H, D, -(CR ₄ R ₅ ) _a R ₉ , -C(=O)R ₉ , -C(=O)OR ₉ , -C(=O)-NR ₉ R ₁₀ , -(CH ₂ ) _a -C(=O)-NR ₉ R ₁₀ , -N(R ₉ )-C(=O)-NR ₉ R ₁₀ , -S(=O) _0-2 NR ₉ R ₁₀ , -S(=O) _0-2 R ₁₀ , 1 or more R ₁₆ substituted or unsubstituted C ₁ -C ₆ alkyl, 1 or more R ₁₆ substituted or unsubstituted C ₃ -C ₆ cycloalkyl, 1 or more R ₁₆ substituted or unsubstituted C ₂ -C ₆ alkenyl, 1 or more R ₁₆ substituted or unsubstituted C ₂ -C ₆ alkynyl, 1 or a plurality of R ₁₆ substituted or unsubstituted monocyclic aryl groups, 1 or more R ₁₆ substituted or unsubstituted monocyclic heteroaryl groups, 1 or more R ₁₆ substituted or unsubstituted fused cycloalkyl groups, 1 or more R ₁₆ substituted or unsubstituted bridged cycloalkyl groups, 1 or more R ₁₆ substituted or unsubstituted spirocycloalkyl groups, 1 or more R ₁₆ substituted or unsubstituted fused aryl groups, Or one or more R ₁₆ substituted or unsubstituted fused heteroaryl groups;

   Each of R ₄ and R _{5 is} independently selected from the group consisting of: H, D, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ a -C ₆ alkenyl group, a substituted or unsubstituted C ₂ -C ₆ alkynyl group, a substituted or unsubstituted C ₆ -C ₁₀ aryl group, or a substituted or unsubstituted heteroaryl group of 5-10 atoms, or R ₄ and R ₅ together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring of 3 to 6 atoms;

   a is 1, 2 or 3;

   Each of R ₇ and R _{8 is} independently selected from the group consisting of: H, D, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ a -C ₆ alkenyl group, a substituted or unsubstituted C ₂ -C ₆ alkynyl group, a substituted or unsubstituted C ₆ -C ₁₀ aryl group, or a substituted or unsubstituted heteroaryl group of 5-10 atoms;

   Each of R ₉ and R _{10 is} independently selected from the group consisting of: H, D, -P(=O)(OR ₈ )(OR ₈ ), cyano, carboxy, 1 or more R ₁₆ substituted C ₁ -C ₆ Alkyl, 1 or more R ₁₆ substituted or unsubstituted C ₃ -C ₆ cycloalkyl, 1 or more R ₁₆ substituted or unsubstituted C ₂ -C ₆ alkenyl, 1 or more R ₁₆ substituted or unsubstituted C ₂ -C ₆ alkynyl, 1 or more R ₁₆ substituted or unsubstituted C ₃ -C ₇ heterocycloalkyl, 1 or more R ₁₆ substituted or unsubstituted monocyclic An aryl group, one or more R ₁₆ substituted or unsubstituted monocyclic heteroaryl groups, one or more R ₁₆ substituted or unsubstituted fused aryl groups, or one or more R ₁₆ substituted or unsubstituted a heteroheteroaryl group; or, R ₉ , R ₁₀ together with the nitrogen to which they are attached form one or more R ₁₆ substituted or unsubstituted heterocycloalkyl groups of 3 to 6 atoms; or, R ₉ , R ₁₀ together with the nitrogen to which it is attached form one or more R ₁₆ substituted or unsubstituted spiroheterocycloalkyl groups of 6 to 12 atoms;

   W ₁ , W ₂ and W ₃ are each independently selected from: N or -C(R ₁₁ )-;

   Each R _{11 is} independently selected from the group consisting of: H, D, halogen, -CN, substituted or unsubstituted C ₁ -C ₃ alkyl, substituted or unsubstituted ester, amide, amino, ether, sulfonamide, Or a phosphoramide group;

   A ₁ and A ₂ are each independently selected from: -C(=O)-, -S(=O) _1-2 -, -N(R ₁₂ )-, or -P(=O)(OR ₁₂ )- Or A ₁ and A _{2 are} connected to form

   

   Each R _{12 is} independently selected from the group consisting of: H, D, substituted or unsubstituted C ₁ -C ₃ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkyne a group, or a C ₃ -C ₆ cycloalkyl group;

   b is 1, 2, 3 or 4;

   Ar ₁ and Ar ₂ are each independently selected from: unsubstituted or one or more R ₁₆ substituted aryl groups of 6-10 atoms, or unsubstituted or one or more R ₁₆ substituted 5- a heteroaryl group consisting of 6 atoms;

   Each R _{16 is} independently selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, one or more R ₁₇ substituted or unsubstituted C ₁ -C ₆ alkyl, one or more R ₁₇ substituted or unsubstituted C ₂ -C ₄ alkenyl, 1 or more R ₁₇ substituted or unsubstituted C ₂ -C ₄ alkynyl, 1 or more R ₁₇ substituted or unsubstituted C ₃ -C ₆ cycloalkyl, 1 One or more R ₁₇ substituted or unsubstituted C ₂ -C ₇ heterocycloalkyl groups, one or more R ₁₇ substituted or unsubstituted C ₁ -C ₆ alkoxy groups, substituted by one or more R ₁₇ Or an unsubstituted C ₆ -C ₁₀ aryl group, one or more R ₁₇ substituted or unsubstituted heteroaryl groups of 5-10 atoms, or -COOR ₁₈ ;

   Each R _{17 is} independently selected from the group consisting of: H, halogen, hydroxy, or cyano;

   R _{18 is} selected from the group consisting of: H, or a C ₁ -C ₄ alkyl group.
2. The fused ring compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a solvate thereof or a prodrug molecule thereof, according to claim 1, wherein V ₁ , V ₂ , V ₃ , V ₄ , V ₅ and V ₆ together constitute the following cyclic structure:

   

   Wherein R ₁ and R _{2 are} as defined in claim 1.
3. The fused ring compound according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a solvate thereof or a prodrug molecule thereof, wherein the fused ring compound has a structure represented by Formula II:

   

   Wherein V ₃ and V ₄ are each independently selected from -C(R ₂ )- or N;

   R ₂ , X, Y, Z, W ₁ , W ₂ , W ₃ , Ar ₁ and Ar _{2 are} as defined in claim 1.
4. The fused ring compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a solvate thereof or a prodrug molecule thereof according to claim 3, wherein the fused ring compound has a structure represented by Formula III:

   

   Wherein V ₃ is -C(R ₂ )- and V ₄ is N, or V ₃ is N and V ₄ is -C(R ₂ )-;

   W _{2 is} selected from: N or -C(R ₁₁ )-;

   B ₁ , B ₂ , B ₃ and B ₄ are each independently selected from: O, N, S, -C(R ₁₅ )- or none;

   E ₁ and E ₂ are each independently selected from: N or -C(R ₁₅ )-;

   R _{13 is} selected from the group consisting of: H, unsubstituted or one or more R ₁₇ -substituted C ₁ -C ₄ alkyl groups, or one or more R ₁₇ -substituted or unsubstituted C ₃ -C ₆ cycloalkyl groups;

   R _{14 is} selected from the group consisting of: H, D, 1 or more R ₁₇ substituted or unsubstituted C ₁ -C ₄ alkyl, 1 or more R ₁₇ substituted or unsubstituted C ₂ -C ₄ alkenyl, 1 One or more R ₁₇ substituted or unsubstituted C ₂ -C ₄ alkynyl groups, or one or more R ₁₇ substituted or unsubstituted C ₃ -C ₆ cycloalkyl groups; or, R ₁₃ , R ₁₄ and The linked N and C together form a heterocyclic group consisting of 5-8 atoms;

   Each R _{15 is} independently selected from: H, D, 1 or more R ₁₇ substituted or unsubstituted C ₁ -C ₄ alkyl, 1 or more R ₁₇ substituted or unsubstituted C ₂ -C ₄ Alkenyl, 1 or more R ₁₇ substituted or unsubstituted C ₂ -C ₄ alkynyl, or 1 or more R ₁₇ substituted or unsubstituted C ₃ -C ₆ cycloalkyl;

   R ₂ , X, Y, Z, R ₁₁ and R _{17 are} as defined in claim 1.
5. The fused ring compound according to claim 4 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a solvate thereof or a prodrug molecule thereof, wherein the fused ring compound has a structure represented by Formula IV:

   

   Wherein V ₃ , V ₄ , X, Y, Z, W ₂ and R _{13 are} as defined in claim 4.
6. The fused ring compound according to claim 4 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a solvate thereof or a prodrug molecule thereof, wherein the fused ring compound has a structure represented by Formula V:

   

   Wherein V ₃ , V ₄ , X, Y, Z, W ₂ and R _{13 are} as defined in claim 4.
7. The fused ring compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof or a prodrug molecule thereof, according to any one of claims 1 to 6, wherein X, Y and Z are bonded to each other. The following structure:

   
8. The fused ring compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a solvate thereof or a prodrug molecule thereof according to any one of claims 1 to 6, wherein each R _{2 is} independently selected From: C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, or C ₃ -C ₆ cycloalkyl.
9. The fused ring compound according to claim 8 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a solvate thereof or a prodrug molecule thereof, wherein each R _{2 is} independently selected from the group consisting of methyl group, Ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, or cyclopentyl.
10. The fused ring compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a solvate thereof or a prodrug molecule thereof according to any one of claims 1 to 6, wherein each R _{11 is} independently selected From: H, halogen, or C ₁ -C ₃ alkyl.
11. The fused ring compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof or a prodrug molecule thereof, according to claim 10, wherein R _{11 is} selected from the group consisting of F, Cl, Br, I , methyl, ethyl, propyl, or isopropyl.
12. The fused ring compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a solvate thereof or a prodrug molecule thereof, according to any one of claims 4 to 6, wherein R _{13 is} selected from the group consisting of: H, C ₁ -C ₄ alkyl, hydroxy-substituted C ₁ -C ₄ alkyl, or C ₃ -C ₆ cycloalkyl.
13. The fused ring compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof or a prodrug molecule thereof, according to claim 12, wherein R _{13 is} selected from the group consisting of methyl, ethyl, and propyl A isopropyl group, an isopropyl group, a cyclopropyl group, or a hydroxy group-substituted isopropyl group.
14. The fused ring compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a solvate thereof or a prodrug molecule thereof, according to any one of claims 1 to 6, wherein R ₄ and R ₅ are each independently Selected from: H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, or R ₄ and R ₅ together with the carbon atom to which they are bonded form a carbocyclic or heterocyclic ring of 3 to 6 atoms .
15. The fused ring compound according to claim 14 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a solvate thereof or a prodrug molecule thereof, wherein R ₄ and R ₅ are each independently selected from the group consisting of: H , methyl, ethyl, or propyl.
16. The fused ring compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a solvate thereof or a prodrug molecule thereof, according to any one of claims 1 to 6, wherein R _{3 is} selected from the group consisting of H, -(CH ₂ ) _a R ₉ , -S(=O) ₂ R ₁₀ , -C(=O)R ₉ , -C(=O)OR ₉ , -C(=O)-NR ₉ R ₁₀ ,- (CH ₂ ) _a -C(=O)-NR ₉ R ₁₀ , -N(R ₉ )-C(=O)-NR ₉ R ₁₀ , -S(=O) _0-2 NR ₉ R ₁₀ ,- S(=O) _0-2 R ₁₀ , 1 or more R ₁₆ substituted or unsubstituted C ₁ -C ₆ alkyl, 1 or more R ₁₆ substituted or unsubstituted C ₃ -C ₆ naphthenes a heteroaryl group consisting of 1 or more R ₁₆ substituted or unsubstituted C ₆ -C ₁₀ aryl groups, or 1 or more R ₁₆ substituted or unsubstituted 5-6 atoms; wherein a is 1 or 2.
17. The fused ring compound according to claim 16 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a solvate thereof or a prodrug molecule thereof, wherein R _{3 is} selected from the group consisting of: H, -(CH ₂ ) _a R ₉ , -C(=O)R ₉ , -C(=O)OR ₉ , -C(=O)-NR ₉ R ₁₀ , -(CH ₂ ) _a -C(=O)-NR ₉ R ₁₀ , -N(R ₉ )-C(=O)-NR ₉ R ₁₀ , -S(=O) _0-2 NR ₉ R ₁₀ , -S(=O) _0-2 R ₁₀ , 1 or more a R ₁₆ substituted or unsubstituted C ₆ -C ₁₀ aryl group, or one or more R ₁₆ substituted or unsubstituted heteroaryl groups of 5-6 atoms; wherein a is 1 or 2;

    R _{16 is} selected from the group consisting of hydrogen, halogen, hydroxy, cyano, halogen substituted C ₁ -C ₆ alkyl, hydroxy substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₃ -C ₆ ring Alkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, halogen substituted C ₆ -C ₁₀ aryl, or -C(=O)OR ₁₈ ; R _{18 is} selected from: H, or C _1- C ₄ alkyl.
18. The fused ring compound according to claim 16 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a solvate thereof or a prodrug molecule thereof, wherein R ₉ and R ₁₀ are each independently selected from the group consisting of: H , -P(=O)(OR ₈ )(OR ₈ ), cyano, carboxy, 1 or more R ₁₆ substituted or unsubstituted C ₁ -C ₆ alkyl, 1 or more R ₁₆ substituted or Unsubstituted C ₃ -C ₆ cycloalkyl, 1 or more R ₁₆ substituted or unsubstituted C ₂ -C ₆ alkynyl, 1 or more R ₁₆ substituted or unsubstituted C ₃ -C ₆ hetero a cycloalkyl group, one or more R ₁₆ substituted or unsubstituted C ₆ -C ₁₀ aryl groups, one or more R ₁₆ substituted or unsubstituted heteroaryl groups of 5-6 atoms, 1 or a plurality of R ₁₆ substituted or unsubstituted C ₈ -C ₁₂ fused aryl groups, or one or more R ₁₆ substituted or unsubstituted fused heteroaryl groups of 8-12 atoms; or, R ₉ , R ₁₀ And a nitrogen group attached thereto to form one or more R ₁₆ substituted or unsubstituted heterocyclic alkyl groups of 3 to 6 atoms; or, R ₉ and R ₁₀ together with the nitrogen to which they are bonded form one or a plurality of R ₁₆ substituted or unsubstituted spiroheterocycloalkyl groups of 6 to 12 atoms;

    R _{16 is} selected from the group consisting of: hydrogen, halogen, halogen-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, halogen-substituted C ₆ -C ₁₀ aryl, hydroxy, cyano, or -C(=O)OR ₁₈ ; R _{18 is} selected from: H, or C ₁ -C ₄ alkyl.
19. The fused ring compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a solvate thereof or a prodrug molecule thereof according to claim 1, wherein the fused ring compound has a structure represented by the formula VI:

    

    Wherein W _{2 is} selected from the group consisting of: N or -C(R ₁₁ )-;

    R _{2 is} selected from the group consisting of: C ₃ -C ₆ cycloalkyl;

    R _{3 is} selected from the group consisting of: H, -(CH ₂ ) _a R ₉ , one or more R ₁₆ substituted or unsubstituted heteroaryl groups of 5-6 atoms, -C(=O)R ₉ , -C (=O)-NR ₉ R ₁₀ , -(CH ₂ ) _a -C(=O)-NR ₉ R ₁₀ , -N(R ₉ )-C(=O)-NR ₉ R ₁₀ ,-S(= O) _0-2 R ₁₀ , or 1 or more R ₁₆ substituted or unsubstituted C ₆ -C ₁₀ aryl, wherein a is 1 or 2;

    Each R ₉ and R ₁₀ are independently selected from: H, 1 or more R ₁₆ substituted or unsubstituted C ₂ -C ₆ alkynyl groups, 1 or more R ₁₆ substituted or unsubstituted C ₁ -C _{a 6} alkyl group, one or more R ₁₆ substituted or unsubstituted C ₆ -C ₁₀ aryl groups, one or more R ₁₆ substituted or unsubstituted heteroaryl groups of 5-6 atoms, 1 or a plurality of R ₁₆ substituted or unsubstituted C _3-7 heterocyclic groups, or one or more R ₁₆ substituted or unsubstituted C ₃ -C ₆ cycloalkyl groups;

    R _{11 is} selected from the group consisting of halogen;

    R _{13 is} selected from the group consisting of: C ₁ -C ₄ alkyl;

    Each R _{16 is} independently selected from the group consisting of: hydrogen, -CN, -OH, carboxyl, -COOMe, halogen-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C _1-6 alkyl or halogen .
20. The fused ring compound according to Claims 1-6 or Claim 19, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a solvate thereof or a prodrug molecule thereof, wherein R _{3 is} selected from the group consisting of: H , -(CH ₂ )R ₉ , trifluoromethyl substituted pyridyl, -C(=O)R ₉ , -C(=O)-NR ₉ R ₁₀ , -(CH ₂ )-C(=O) -NR ₉ R ₁₀ , -N(R ₉ )-C(=O)-NR ₉ R ₁₀ , or -S(=O) _0-2 -C _1-4 alkyl;

    Each of R ₉ and R _{10 is} independently selected from the group consisting of: H, ethynyl, C ₁ -C ₆ alkyl, phenyl, C ₃ -C ₆ cycloalkyl, heteroaryl of 5-6 atoms, naphthyl Or a C _3-7 heterocyclic group; wherein the C ₁ -C ₆ alkyl group, phenyl group, C ₃ -C ₆ cycloalkyl group, heteroaryl group composed of 5-6 atoms, naphthyl group and C _{3- The 7} heterocyclic group may be optionally selected from one or more independently selected from the group consisting of F, Cl, Br, I, CH ₃ O-, CH ₃ CH ₂ O-, -CF ₃ , -CH ₂ CF ₃ , C _1-4 Substituted by alkyl, -CN, -OH, C _1-4 haloalkyl, carboxy, and -COOMe substituents.
21. The fused ring compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a solvate thereof or a prodrug molecule thereof according to claim 1, wherein the fused ring compound is selected from the group consisting of the following compounds:

    

    

    

    

    

    

    
22. Use of the fused ring compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug molecule thereof, according to any one of claims 1 to 21, for the preparation of an ASK1 inhibitor.
23. The fused ring compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof or a prodrug molecule thereof, for the preparation of a medicament for preventing and treating a disease mediated by ASK1 Application in .
24. The use according to claim 23, wherein the ASK1-mediated diseases include: renal fibrosis, liver fibrosis, pulmonary fibrosis, chronic kidney disease, diabetic nephropathy, pulmonary hypertension, tumor.
25. A pharmaceutical composition for preventing and treating a disease mediated by ASK1, characterized in that the active ingredient comprises the fused ring compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof or a stereo An isomer or a solvate thereof or a prodrug molecule thereof.