WO2011140936A1 - 5,5-disubstituted-2-imino-pyrrolidine derivatives, preparation methods and pharmaceutical uses thereof - Google Patents

Abstract

Disclosed are 5,5-disubstituted-2-imino-pyrrolidine derivatives of formula (I) and their pharmaceutically acceptable salts, preparation methods and uses thereof in medicine as thrombin receptor antagonists, wherein each substituents of formula (I) is defined as the description.

Description

 5,5-disubstituted-2-iminopyrrole derivative, preparation method thereof and application thereof in medicine

 The present invention relates to a novel 5,5-disubstituted-2-iminopyrrolidine derivative, a process for the preparation thereof, and a pharmaceutical composition containing the same, and as a therapeutic agent, particularly as a thrombin receptor antagonist the use of. Background technique

Thrombotic diseases are currently the leading cause of high rates of cardiovascular disease and high mortality worldwide. Arterial thrombosis can cause a variety of acute symptoms including acute coronary syndrome, ischemic stroke / transient cerebral ischemia and peripheral arterial disease. These symptoms are caused by vascular damage caused by atherosclerotic plaque damage or vascular endothelial cell damage, which in turn induces arterial thromboembolism, resulting in insufficient blood supply. Platelets play a very important role in the formation of arterial thrombosis. In this pathological process, rupture of atherosclerotic plaque or damage to vascular endothelial cells can cause vascular damage, resulting in platelet activation under the action of various platelet activating factors such as thrombin, thromboxane A ₂ and ADP. The loss of control of the mechanism leads to activation and aggregation of a large number of platelets, which then form a thrombus mediated by the platelet glycoprotein (GP) lib I Ilia receptor, which ultimately blocks blood flow. Among these platelet agonists, thrombin is the most potent platelet activator, and activates platelets and induces aggregation by interacting with members of the PAR family in the G protein-coupled receptor family, thereby realizing blood coagulation and other organisms. Learning role.

 Proteinase-activated receptors (PARs) belong to the G-protein coupled receptor family, which members are widely expressed on various cells in the cardiovascular system, such as platelets, vascular endothelial cells, and blood vessels. Smooth muscle cells. The PARs family is involved in the coagulation under normal physiological conditions, maintaining the stability of the intravascular environment, as well as various physiological processes such as inflammatory reactions under pathological conditions, thrombosis and atherosclerosis, and plays a key role in it. This family of receptors uses a unique mechanism to achieve the activation process: thrombin (thrombin) that binds to PARs hydrolyzes the original N-terminus of the extracellular domain of the PARs receptor and forms a new N-terminus, new The formed N-terminus binds to PARs in a "tethered ligand" manner to induce receptor activation, thereby enabling signal transduction.

It has been confirmed that the PARs family contains four receptor subtypes including PARI, PAR2, PAR3 and PAR4. PAR2 is removed as a receptor for trypsin and tryptase, and the other three subtypes are activated by binding to thrombin and are therefore considered to be the major thrombin receptors (thrombin re _Ce pt _0rS ). Wherein PARI is a high-affinity thrombin receptor that is activated at lower concentrations (less than nanomolar) of thrombin conditions. In contrast, PAR4 is a low-affinity thrombin receptor involved in the activation and delivery of thrombin signals only at higher concentrations of thrombin. Similar to PARI, although PAR3 is also a high-affinity receptor, it usually does not activate the signaling alone, but acts as a co-receptor to synergize with PAR4 to increase PAR4 activity and achieve corresponding biological functions (see Ho-Sam et al). ; Current Pharmaceutical Design, 2003, 9, 2349-2365). As the most important thrombin receptor, PARI is widely expressed in many cells and tissues in human body, including platelets, endothelial cells, vascular or tracheal smooth muscle, inflammatory cells (macrophages, lymphocytes), fibroblasts. , nerve cells, cardiovascular and skeletal muscle cells. In addition to cardiovascular disease, elevated levels of PARI expression can be observed in a variety of pathological conditions such as trauma, inflammatory conditions, and a variety of tumor cells. In addition, PARI can also activate receptor tyrosine kinase activity and affect the corresponding signal cascade through G protein signal cross-linking, thereby regulating cell proliferation and metastasis (see Derian CK, et al; Expert Opin. Investig Drugs , 2003, 12: 209-21). These further herald the potential of PARI as a therapeutic target for a variety of diseases.

Currently, a large number of non-peptide PARI inhibitors for the treatment of arterial thrombosis are in preclinical or clinical trials. In the early stages of development, oral antiplatelet agents are primarily targeted at thromboxane A ₂ (such as aspirin aspirin) or P2Y ₁₂ ADP receptor-mediated platelet activation (such as ticlopidine ticlopidine), which regulates platelet synthesis. point. However, both have no direct inhibitory effect on the thrombin-platelet activation pathway achieved via the PARI receptor CDavi G, et al; N Engl J Med., 2007, 357: 2482-2494). At the same time, since both can weaken or interfere with collagen-induced platelet aggregation, it may have an effect on the normal hemostasis process, resulting in an increased incidence of bleeding during treatment. In contrast, antagonists developed with PARI as a target directly target thrombin-platelet activation, which leads to a more comprehensive and direct inhibition of platelet activation, which directly reduces thrombosis and acute ischemic symptoms. risks of. Furthermore, since PARI is not necessary in a normal coagulation-hemostatic mechanism, inhibition of PARI can reduce the risk of bleeding during treatment (see Coughlin SR.; J Thromb Haemost., 2005, 3: 1800-1814). More importantly, PARI-targeted antagonists do not affect Thrombin's own normal clotting activity. In special emergency situations, thrombin can still induce platelet activation and aggregation through PAR4 signaling, which is normal. Coagulation. Therefore, antiplatelet drugs developed with the target of inhibiting PARI not only improve the therapeutic effect and specificity, but also reduce the possible side effects, and thus become an ideal drug for treating arterial thrombosis diseases.

 A series of patent applications for thrombin receptor antagonists have been published, including

A series of 2-iminopyrrolidin derivatives are disclosed in PCT patent applications, such as WO2002085855, WO2005084679, WO2004078721, and WO2006051623.

 The present invention has been designed to have a compound represented by the general formula (I), and it has been found that a compound having such a structure exhibits excellent thrombin receptor inhibitory activity. Summary of the invention

In order to overcome the deficiencies of the prior art, it is an object of the present invention to provide novel pyridazinone derivatives of the formula (I), and their tautomers, enantiomers, non-pairs Enantiomers, racemates and pharmaceutically acceptable salts, as well as metabolites and metabolic precursors or prodrugs,

(I)

 Its towel:

Ar is selected from aryl or heteroaryl, wherein said aryl or heteroaryl is optionally further substituted with one or more substituents of R ^a ;

Y is selected from -CR ¹² - or N atom;

L is selected from -CR ¹³ R ¹⁴ - or -(CH ₂ ) _m -;

I ¹ , R ² and R ³ are each independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a nitro group, an alkoxy group, an alkyl group, an alkenyl group, a blocked group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heterocyclic group. Aryl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0 R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S( 0) ONR ¹⁶ R ¹⁷ wherein the alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, and nitrate Alkyl, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ -0(CH ₂ ) _n C(0) OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC( 0) Substituted by a substituent of NR ¹⁶ R ¹⁷ or -C(0)NR ¹⁶ R ¹⁷ ;

R ¹ and R ² or R ² and R ³ together with the carbon atom to which they are attached form an aryl group, wherein said aryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy Alkyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0)pR ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ Substituted by a substituent of R ¹⁷ , —C(0)NR ¹⁶ R ¹⁷ or —S(0)ONR ¹⁶ R ¹⁷ ;

R ⁴ and R ⁵ are each independently selected from cyano, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, hetero The cyclo, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, aryl, heteroaryl, -C(0)OR ¹⁵ , -OC ( 0) R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S (0) Substituting a substituent of _p R ¹⁵ , —NR ¹⁶ R ¹⁷ , —OC(0)NR ¹⁶ R ¹⁷ , —C(0)NR ¹⁶ R ¹⁷ or —S(0)ONR ¹⁶ R ¹⁷ ;

Alternatively, R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cycloalkyl group, wherein said cycloalkyl group is optionally further further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, alkane Substituted by an oxy group, a cycloalkyl group, a heterocyclic group or a substituent of -NR ¹⁶ R ¹⁷ ;

R ^{6 is} selected from a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, an aryl group, a heteroaryl group, -C(0)OR ¹⁵ , -C(0)R ¹⁵ or -C(0)NR ¹⁶ R ¹⁷ wherein the alkyl, alkoxy, cycloalkyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, alkoxy Substituted by a substituent of a cycloalkyl or heterocyclic group; R ^a may be the same or different and each independently selected from a hydrogen atom, a hydroxyl group, a halogen, a cyano group, a nitro group, a silane group, an alkoxy group, an alkyl group, an alkenyl group, a blocked group, a cycloalkyl group, a heterocyclic group, an aryl group. , heteroaryl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C (0) R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or - S(0)ONR ¹⁶ R ¹⁷ , wherein the silane group, alkoxy group, alkyl group, alkenyl group, blocked group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further one or more Selected from halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyalkyl, -C(0)OR ¹⁵ , -OC ( 0) R ¹⁵ -0(CH ₂ ) _n C(0)OR ¹⁵ -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0 Substituting _p R ¹⁵ -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ ;

R ^{12 is} selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a nitro group, an alkoxy group, an alkyl group, an alkenyl group, a aryl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -C(0) OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0 R ¹⁵ , -S(0) _p R ¹⁵ -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ , where The alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C Substituting (0) a substituent of NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ ;

R ¹³ and R ¹⁴ are each independently selected from alkyl or halo, wherein said alkyl group is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano or nitro;

R ^{15 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further Substituted by one or more substituents selected from halogen, hydroxy, cyano, nitro, alkoxy or alkyl;

R ¹⁶ and R ¹⁷ are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group Or a heterocyclic group, an aryl group or a heteroaryl group, optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, hetero Aryl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0 R ¹⁵ , -NHC(0)R ¹⁵ , -S(0)pR ¹⁵ , -NR ¹⁸ R ¹⁹ , -OC(0)NR ¹⁸ R ¹⁹ , -C(0)NR ¹⁸ R ¹⁹ or -S(0 Substituted by a substituent of ONR ¹⁸ R ¹⁹ ;

Alternatively, R ¹⁶ and R ¹⁷ together with the nitrogen atom are attached form a heterocyclic group containing one or more N, 0 or S (0) _p hetero atoms in the heterocyclic group, and wherein any heterocyclyl group Further selected by one or more of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyalkyl, -C(0)OR ¹⁵ -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ^{15, -S (0) pR 15} , -NR 18 R 19, -OC (0) NR 18 R 19, -C (0) NR 18 R 19 or -S (0) ONR ¹⁸ R ¹⁹ group substituted with a substituent ;

R ¹⁸ and R ¹⁹ are each independently selected from a hydrogen atom, a halogen, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group; m is selected from 1, 2 or 3;

 n is selected from 1, 2 or 3;

 p is selected from 0, 1 or 2. A preferred embodiment of the invention, a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which comprises a compound of the formula (A)

(II)

 Its towel:

Y is selected from -CR ¹² - or N atom;

L is selected from -CR ¹³ R ¹⁴ - or -(CH ₂ ) _m -;

RR ² and R ³ are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a nitro group, an alkoxy group, an alkyl group, an alkenyl group, a blocked group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ wherein the alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkane Oxy group, alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC(0)NR Substituted by a substituent of ¹⁶ R ¹⁷ or -C(0)NR ¹⁶ R ¹⁷ ;

R ¹ and R ² or R ² and R ³ together with the attached carbon form an aryl group, wherein said aryl group is optionally further further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy , alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , (CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0)pR ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ^{17, -C (0) NR 16} R 17 , or -S (0) ONR ¹⁶ R ¹⁷ substituents a;

R ⁴ and R ⁵ are each independently selected from cyano, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, hetero The cyclo, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, aryl, heteroaryl, -C(0)OR ¹⁵ , -OC ( 0) R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S (0) Substituting a substituent of _p R ¹⁵ , —NR ¹⁶ R ¹⁷ , —OC(0)NR ¹⁶ R ¹⁷ , —C(0)NR ¹⁶ R ¹⁷ or —S(0)ONR ¹⁶ R ¹⁷ ;

Alternatively, R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cycloalkyl group, wherein said cycloalkyl group is optionally further further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, alkane Substituted by an oxy group, a cycloalkyl group, a heterocyclic group or a substituent of -NR ¹⁶ R ¹⁷ ; R ^{6 is} selected from a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, an aryl group, a heteroaryl group, -C(0)OR ¹⁵ , -C(0)R ¹⁵ or -C(0)NR ¹⁶ R ¹⁷ wherein the alkyl, alkoxy, cycloalkyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, alkoxy Substituted by a substituent of a cycloalkyl or heterocyclic group;

RR ⁸ , R ⁹ , R ^1Q and R ¹¹ are each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a halogen, a cyano group, a nitro group, a silyl group, an alkoxy group, an alkyl group, an alkenyl group, a blocked group, a cycloalkyl group, and a heterocyclic ring. Base, aryl, heteroaryl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ wherein said silane group, alkoxy group, alkyl group, alkenyl group, blocked group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further One or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyalkyl, -C(0)OR ¹⁵ -OC(0)R ¹⁵ -0(CH ₂ ) _n C(0)OR ¹⁵ -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ substituted with a substituent of R ¹⁷ ;

Alternatively, R ⁹ and R ^1Q together with the carbon atom to which they are attached form a heterocyclic group, an aryl group or a heteroaryl group, wherein the heterocyclic group, aryl group or heteroaryl group is optionally further selected from one or more selected from one or more Halogen, hydroxy, cyano, nitro, silyl, alkoxy, alkyl, alkenyl, aryl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)OR ¹⁵ , - OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ substituted;

R ^{12 is} selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a nitro group, an alkoxy group, an alkyl group, an alkenyl group, a aryl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -C(0) OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0 R ¹⁵ , -S(0) _p R ¹⁵ -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ , where The alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C Substituting (0) a substituent of NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ ;

R ¹³ and R ¹⁴ are each independently selected from alkyl or halo, wherein said alkyl group is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano or nitro;

R ^{15 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further Substituted by one or more substituents selected from halogen, hydroxy, cyano, nitro, alkoxy or alkyl;

R ¹⁶ and R ¹⁷ are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group Or a heterocyclic group, an aryl group or a heteroaryl group, optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, hetero Aryl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0)pR ¹⁵ , -NR ¹⁸ R ¹⁹ , -OC(0)NR ¹⁸ R ¹⁹ , -C(0)NR ¹⁸ R ¹⁹ or Substituted by a substituent of -S(0)ONR ¹⁸ R ¹⁹ ;

Alternatively, R ¹⁶ and R ¹⁷ form a heterocyclic group with a nitrogen atom to which the ring is bonded, wherein the heterocyclic group contains one or more N, 0 or S(0) _p heteroatoms, and the heterocyclic group is Further selected by one or more of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyalkyl, -C(0)OR ¹⁵ -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ^{15, -S (0) pR 15} , -NR 18 R 19, -OC (0) NR 18 R 19, -C (0) NR 18 R 19 or -S (0) ONR ¹⁸ R ¹⁹ group substituted with a substituent ;

R ¹⁸ and R ¹⁹ are each independently selected from a hydrogen atom, a halogen, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group.

 m is selected from 1, 2 or 3;

 n is selected from 1, 2 or 3;

 p is selected from 0, 1 or 2. A preferred embodiment of the invention, a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein

Ar is selected from a 5- or 6-membered heteroaryl group, preferably a pyrrolyl group or a pyridyl group.

A preferred embodiment of the invention - a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R ⁴ and R ^{5 are} selected from alkyl or aryl.

A preferred embodiment of the invention - a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclopropyl group.

A preferred embodiment of the invention - a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R ^{6 is} selected from a hydrogen atom.

A preferred embodiment of the invention - a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R ^{12 is} selected from a hydrogen atom or a halogen.

A preferred embodiment of the invention - a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein L is selected from -(CH ₂ ) _m -, m is 1. Typical compounds of the invention include, but are not limited to:

Salt πττ.

1-(3-tert-butylpyrrole-1-yl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-Isoporphyrin]-2'-yl)ethanone hydrobromide Typical compounds of the invention also include, but are not limited to:

3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro

73'-3-Imino-1,1-dimethyl-isoindoline-2-yl)acetyl]benzoic acid

1-[3-tert-butyl-5-(morpholine-4-carbonyl)benzene

74' yl]-2-(5,6-diethoxy-4-fluoro-3-imino

-1,1-dimethyl-isoindol-2-yl)ethanone

v , (.

 ( 〇〇 〇 v

 3-tert-butyl-N-cyclopropyl-5-[2-(5,6-di-B

75' oxy- 4-fluoro-3-imino-1,1-dimethyl-isoindolin-2-yl)acetyl]benzamide^human 1 o 3-tert-butyl-5-[ 2-(5',6'-diethoxy-4'-fluoro

76'-3'-Imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)acetyl]benzoic acid

2-[[3-tert-butyl-5-[2-(5,6-diethoxy-4-)

77' Fluoro-3-imino-1,1-dimethyl-isoporphyrin

 -2-yl)acetyl]phenyl]amino]acetonitrile

N-[3-tert-butyl-5-[2-(5',6'-diethoxy-4'-

78' Fluorine-3'-imino-spiro [cyclopropane-1,1'-isoindoline]-2'-yl)acetyl]phenyl]acetamide

N-[3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoporphyrin)

79'

 -2-yl)acetyl]phenyl]acetamide

3-tert-butyl-N-cyclopropyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-iso

80'

 Porphyrin-2-yl)acetyl]-2-methoxy-benzenecarboxamide

 3-tert-Butyl-N-cyclopropyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro [cyclopropane]

81 '

-1,1'-isoporphyrin] -2'-yl)acetyl]-2-methoxy-benzamide 3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro

 -3-imino-1,1-dimethyl-isoindoline -2-

82'

 Acetyl]-N-(2,3-dihydroxypropyl)benzenecarboxamide

 3-tert-Butyl-N-cyclopropyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro [cyclopropane]

83'

 -1,1'-isoporphyrin]-2'-yl)acetyl]benzamide

 1-[3-tert-butyl-5-(morpholine-4-carbonyl)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imine

84'

 Base-spiro [cyclopropane-1,1'-isoindoline]-2'-yl Ao ethyl ketone

 . Work

 3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindoline-2-

85'

 Acetyl]-N-(2-hydroxyethyl)benzoylamine

 2-[[3-tert-butyl-5-[2-(5',6'-diethoxy-4'--

86' Fluorine-3'-imino-spiro [cyclopropane-1,1'-isoindoline]-2'-yl)acetyl]phenyl]amino]acetonitrile

3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindoline-2-

87'

 Acetyl] -N,N-bis(2-hydroxyethyl)benzene. Formamide

 3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro [cyclopropane-1,1'-isoindole]

88'

 -2'-yl)acetyl]-N-(2,3-dihydroxypropyl)benzamide

 3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro [cyclopropane-1,1'-isoindole]

89'

 -2'-yl)acetyl]-N-(2-hydroxypropyl)benzenecarboxamide

 1-[3-tert-butyl-5-(2-hydroxyethoxy)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imine

90'

Yl - spiro [cyclopropane-1,1'-indoline] - ² '- yl) ethanone

L-[3-tert-Butyl-5-0methylpyrazol-4-yl)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imine

100'

Yl - spiro [cyclopropane-1,1'-indoline] - ² '- yl) ethanone

 1- 3-tert-butyl-5-isopropyl-phenyl)-2-(5,6-

101 'Diethoxy-4-fluoro-3-imino-1,1-dimethyl

 -isoporphyrin-2-yl)ethanone

[1-(3-tert-butyl-5-isopropyl-phenyl)-2-(5',6'-

102' Diethoxy- 4'-fluoro-3'-imino-spiro [cyclopropane-1,1'-isoindoline]-2'-yl)ethanone

1-[3-tert-butyl-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]-2-(5',6'-diethoxy-4'-fluoro

103' o -3'-imino-spiro [cyclopropane -1,1'-isoindoline] -2'-yl)ethanone

 1- 3-tert-butyl-5-cyclopropyl-phenyl)-2-(5',6'-

104' Diethoxy- 4'-fluoro-3'-imino-spiro [cyclopropyl

Alkane-1,1'-isoporphyrin]-2'-yl)ethanone

 1- 3-tert-butyl-5-cyclopropyl-phenyl)-2-(5,6-

105' Diethoxy-4-fluoro-3-imino-1,1-dimethyl

 -isoporphyrin-2-yl)ethanone

1-[3-tert-butyl-5-(trifluoromethyl)-benzene

106' yl]-2-(5,6-diethoxy-4-fluoro-3-imino

 -1,1-dimethyl-isoindoline-2-yl)ethanone

1-[3-tert-butyl-5-(trifluoromethyl)-benzene f NH 0 yl] -2-(5',6'-diethoxy-4'-fluoro-3'-imine

107'

Yl - spiro [cyclopropane-1,1'-indoline] - ² '- yl) ethanone

 2-[3-tert-butyl-5-[2-(5',6'-diethoxy-4'--

108' Fluoro-3'-imino-spiro [cyclopropane-1,1'-isoindoline]-2'-yl)acetyl]phenyl]-2-methyl-propanenitrile

2-[3-tert-butyl-5-[2-(5,6-diethoxy-4-

109' Fluoro-3-imino-1,1-dimethyl-isoporphyrin

-2-yl)acetyl]phenyl]-2-methyl-propanenitrile

L-(3-tert-Butylpyrrol-1-yl)-2-(5,6-diethyl

119' oxy- 4-fluoro-3-imino-1,1-dimethyl-isoporphyrin-2-yl)ethanone

1-(3-tert-butylpyrrole-1-yl)-2-(5',6'-diethyl

120'oxy-4'-fluoro-3'-imino-spiro[cyclopropane

-1,1'-isoporphyrin]-2'-yl)ethanone or a pharmaceutically acceptable salt thereof. The present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (I) is present in the form of a free or pharmaceutically acceptable acid addition salt, said pharmaceutically acceptable Acid addition salts include hydrochloride, hydrobromide, methanesulfonate, sulfate, phosphate, maleate, malate, citrate, acetate or trifluoroacetate, preferably It is a hydrobromide salt and a hydrochloride salt. The present invention relates to a method for synthesizing a compound of the formula (I), which comprises:

 a compound of the formula (IA) or a compound of (IB)

 (IA) or

 Reaction with a compound of the formula (IC) to give a compound of the formula (I);

 Its towel:

 X is selected from a halogen, preferably a chlorine atom or a bromine atom;

Wherein: L, Y, R^ R ¹¹ are as defined in the compound of the formula. The present invention relates to a compound of the formula (IA) or (IB) which is used as a intermediate for the preparation of a compound of the formula (I)

 (IA) (IB)

 Its towel:

Y is selected from -CR ¹² - or N atom;

RR ² and R ³ are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a nitro group, an alkoxy group, an alkyl group, an alkenyl group, a blocked group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ wherein the alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkane Oxy group, alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC(0)NR Substituted by a substituent of ¹⁶ R ¹⁷ or -C(0)NR ¹⁶ R ¹⁷ ;

R ¹ and R ² or R ² and R ³ together with the carbon atom to which they are attached form an aryl group, wherein said aryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy Alkyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ Substituted by a substituent of R ¹⁷ , —C(0)NR ¹⁶ R ¹⁷ or —S(0)ONR ¹⁶ R ¹⁷ ;

R ⁴ and R ⁵ are each independently selected from cyano, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, hetero The cyclo, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, aryl, heteroaryl, -C(0)OR ¹⁵ , -OC ( 0) R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S (0) Substituting a substituent of _p R ¹⁵ , —NR ¹⁶ R ¹⁷ , —OC(0)NR ¹⁶ R ¹⁷ , —C(0)NR ¹⁶ R ¹⁷ or —S(0)ONR ¹⁶ R ¹⁷ ;

Alternatively, R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cycloalkyl group, wherein said cycloalkyl group is optionally further further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, alkane Substituted by an oxy group, a cycloalkyl group, a heterocyclic group or a substituent of -NR ¹⁶ R ¹⁷ ;

R ^{6 is} selected from the group consisting of a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, an aryl group, a heteroaryl group, -C(0)OR ¹⁵ ,

-C(0)R ¹⁵ or -C(0)NR ¹⁶ R ¹⁷ , wherein the alkyl, alkoxy, cycloalkyl, aryl or heteroaryl group is further optionally further selected from one or more halogens Substituted with a substituent of a hydroxyl group, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group or a heterocyclic group;

R ^{12 is} selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a nitro group, an alkoxy group, an alkyl group, an alkenyl group, a aryl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -C(0) OR ¹⁵ , -OC(0)R ¹⁵ -0(CH ₂ ) _n C(0)OR ¹⁵ -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ , wherein the alkoxy group, alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further Or a plurality selected from halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(0)OR ¹⁵ , -OC(0) R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0 Substituting _p R ¹⁵ -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ ;

R ^{15 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further Substituted by one or more substituents selected from halogen, hydroxy, cyano, nitro, alkoxy or alkyl;

R ¹⁶ and R ¹⁷ are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group Or a heterocyclic group, an aryl group or a heteroaryl group, optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, hetero Aryl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0 R ¹⁵ , -NHC(0)R ¹⁵ , -S(0)pR ¹⁵ , -NR ¹⁸ R ¹⁹ , -OC(0)NR ¹⁸ R ¹⁹ , -C(0)NR ¹⁸ R ¹⁹ or -S(0 Substituted by a substituent of ONR ¹⁸ R ¹⁹ ;

Alternatively, R ¹⁶ and R ¹⁷ form a heterocyclic group with a nitrogen atom to which the ring is bonded, wherein the heterocyclic group contains one or more N, 0 or S(0) _p heteroatoms, and the heterocyclic group is Further selected by one or more of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)OR ¹⁵ , -OC ( 0) R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S (0) Substituting a substituent of _p R ¹⁵ , -NR ¹⁸ R ¹⁹ , -OC(0)NR ¹⁸ R ¹⁹ , -C(0)NR ¹⁸ R ¹⁹ or -S(0)ONR ¹⁸ R ¹⁹ ;

R ¹⁸ and R ¹⁹ are each independently selected from a hydrogen atom, a halogen, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group;

 n is selected from 1, 2 or 3;

p is selected from 0, 1 or 2. A preferred embodiment of the invention, a compound of the formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, wherein R ⁴ and R ^{5 are} selected from alkyl or aryl.

A preferred embodiment of the invention is a compound of the formula (IA) or (IB) or a pharmaceutically acceptable salt thereof, wherein R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclopropyl group.

 A preferred embodiment of the invention, a compound of the formula (IA) or (IB) or a pharmaceutically acceptable salt thereof, wherein

R ^{6 is} selected from a hydrogen atom.

A preferred embodiment of the invention is a compound of the formula (IA) or (IB) or a pharmaceutically acceptable salt thereof, wherein R ^{12 is} selected from a hydrogen atom or a halogen.

Equivalents considered will be understood by one of ordinary skill in the art that compound (IA) may also exist in the form of tautomers. The tautomeric form of the compound (IA) may include, but is not limited to, a structure represented by the following formula (IB):

 (IA) (IB)

 All such tautomeric forms are included within the scope of the invention and are inherently included in the definition of compound (IA). Typical compounds of the compounds of formula (IA) or (IB) include, but are not limited to:

Or a pharmaceutically acceptable salt thereof. The present invention relates to a process for the preparation of a compound of the formula (1) or (IB), which comprises:

The dimethyl sulfoxide solution of the compound of the formula (III) is heated in the presence of cuprous cyanide and cuprous iodide to obtain a compound of the formula (IA) or (IB);

 (IV)

Alternatively, the compound of the formula (IV) is mixed with a format reagent and a titanate under ice bath, and the reaction is stirred at room temperature to obtain a compound of the formula (IA) or (IB);

 (V)

Alternatively, a compound of the formula (V) is reacted with concentrated aqueous ammonia and t-butoxy hydrogen peroxide to give a compound of the formula (IA) or (IB);

 (VI)

 Alternatively, a tetrahydrofuran solution of the compound of the formula (VI) can be stirred in the presence of water and triphenylphosphine at room temperature to obtain a compound of the formula (IA) or (IB). Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Another aspect of the invention relates to a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof Use of a pharmaceutical composition for the preparation of a calcium ion transport inhibitor.

 Another aspect of the invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the preparation of a thrombin receptor antagonist, wherein said thrombin receptor antagonism Agent is

PARI receptor antagonist.

 The present invention relates to the use of a compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for the preparation of a platelet aggregation inhibitor.

 The present invention relates to the use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for inhibiting smooth muscle cell proliferation.

 The present invention relates to the use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for the preparation of a medicament for treating a thrombin receptor-related disease, wherein said thrombin Receptor-related diseases are selected from thrombosis, vascular restenosis, deep vein thrombosis, pulmonary embolism, cerebral infarction, heart disease, sowing intravascular coagulation syndrome, hypertension, inflammatory disease, rheumatism, asthma, kidney Small ball nephritis, osteoporosis, neurological disease and/or malignancy.

 The present invention relates to a method of inhibiting calcium ion transport comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

 The present invention relates to a method of inhibiting a thrombin receptor comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein said The thrombin receptor is a PARI receptor.

 The present invention relates to a method of inhibiting platelet aggregation comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

 The present invention relates to a method for inhibiting proliferation of smooth muscle cells, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

 The present invention relates to a method for treating a thrombin receptor-related disease, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same The thrombin receptor-related disease is selected from the group consisting of thrombosis, vascular restenosis, deep venous thrombosis, pulmonary embolism, cerebral infarction, heart disease, sowing intravascular coagulation syndrome, hypertension, inflammation Sexual diseases, rheumatism, asthma, glomerulonephritis, osteoporosis, neurological diseases and/or malignancies.

 The present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same as a medicament for inhibiting calcium ion transport.

 The present invention relates to a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, wherein the thrombin receptor is a PARI receptor.

 The present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same as a medicament for inhibiting platelet aggregation.

 The present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same as a medicament for inhibiting proliferation of smooth muscle cells.

The present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same as a treatment A medicament for treating a thrombin receptor-related disease, wherein the thrombin receptor-related disease is selected from the group consisting of thrombosis, vascular restenosis, deep venous thrombosis, pulmonary embolism, cerebral infarction, heart disease, sowing Intravascular coagulation syndrome, hypertension, inflammatory disease, rheumatism, asthma, glomerulonephritis, osteoporosis, neurological disease and/or malignancy. Detailed description of the invention

 Terms used in the specification and claims have the following meanings unless stated to the contrary.

"Alkyl" means a saturated aliphatic hydrocarbon group including straight chain and branched chain groups of 1 to 20 carbon atoms. Preference is given to alkyl groups having 1 to 12 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl 1,1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methyl Butyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4- Dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethyl Hexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2- Ethylhexyl, 3-ethylhexyl, 4-B Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Hexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl, Block group, alkoxy group, alkylthio group, alkylamino group, halogen, thiol, hydroxy group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, hetero Cycloalkoxy, cycloalkylthio, heterocycloalkylthio, carbonyl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -( CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ .

"Cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably the cycloalkyl ring comprises from 3 to 10 One carbon atom. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Alkenyl, cyclooctyl and the like. Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups. "Spirocycloalkyl" means a polycyclic group of 5 to 20 members which shares a carbon atom (referred to as a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings are fully conjugated. π electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the ring and the ring. . More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospirocycloalkyl. Non-limiting real

 "Fused cycloalkyl" refers to 5 to 20 members, each ring in the system sharing an adjacent carbon atom of an all-carbon polycyclic group with other rings in the system, wherein one or more rings may contain one or more Two double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The number of the constituent rings may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or a 5-membered/6-membered bicycloalkyl group. Non-limiting examples of fused cycloalkyl groups include

 "Bridge cycloalkyl" means 5 to 20 members, any two rings sharing two carbon-free all-carbon polycyclic groups, which may contain one or more double bonds, but none of the rings have a total The π-electron system of the yoke. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, more preferably a bicyclic ring or a tricyclic ring. Unrestricted

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydrogen Naphthyl, benzocycloheptyl and the like. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carbonyl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ .

"Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. For example, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio, alkane. Amino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C( 0) R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S (0) ONR ¹⁶ R ¹⁷ .

"Block group" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. For example, an ethyl group, a 1-propyl block group, a 2-propyl block group, a 1-, 2- or 3-butyl block group, and the like. The block group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio, alkane. Amino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C( 0) R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S (0) ONR ¹⁶ R ¹⁷ .

"Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(0) _n ( Wherein n is a hetero atom of the integer 0 to 2), but does not include a ring moiety of -0-0-, -0-S- or -SS-, and the remaining ring atoms are carbon. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms, more preferably the cycloalkyl ring contains from 3 to 10 ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like. Polycyclic cycloalkyl groups include spiro, fused, and bridged heterocyclic groups. "spiroheterocyclyl" means a polycyclic heterocyclic group of 5 to 20 members in which one atom (called a spiro atom) is shared between monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(0) _p The hetero atom (where p is an integer from 0 to 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of common spiro atoms between the rings, preferably a monospirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include

"Fused heterocyclic group" means 5 to 20 members, and each ring in the system shares a pair of adjacent atoms with other rings in the system. Polycyclic heterocyclic group, one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S ( 0) _p (where p is an integer 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. It may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl group according to the number of constituent rings, preferably a bicyclic or tricyclic ring, more preferably a 5-member/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. . Non-limiting examples of fused heterocyclic groups include

"Bridge heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 14 members in which two rings share two atoms which are not directly bonded, and these may contain one or more double bonds, but none of the rings have a complete conjugation A π-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(0) _p (where ρ is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. 7 to 10 yuan. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and a more tricyclic ring. Non-limiting examples of bridged cycloalkyl groups include:

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, and the examples include:

Wait. The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocyclomethoxy, cycloalkylthio ,heterocycloalkylthio,carbonyl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ Or -S(0)ONR ¹⁶ R ¹⁷ .

"Aryl" means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms), A polycyclic ring having a conjugated π-electron system (i.e., a ring having an adjacent pair of carbon atoms) is preferably 6 to 10 members, such as a phenyl group and a naphthyl group. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio, alkane. Amino, thiol, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cyclodecylthio, hetero Cycloalkylthio, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C ^{(0) R 15, -NHC (} 0) R 15, -S (0) p R 15 -NR 16 R 17, -OC (0) NR 16 R 17, -C (0) NR 16 R 17 , or -S (0) ONR ¹⁶ R ¹⁷ .

 "Heteroaryl" means a heteroaromatic system containing from 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. It is preferably 6 to 10 yuan. The heteroaryl group is preferably a 5- or 6-membered compound such as a furyl group, a thienyl group, a pyridyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, an imidazolyl group, a tetrazolyl group and the like. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the parent structure is attached:

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocyclomethoxy, cycloalkylthio , heterocycloalkylthio, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ -(CH ₂ ) _n C(0)OR ¹⁵ , C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or - S(0)ONR ¹⁶ R ¹⁷ .

"Alkoxy" means -O-(indenyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. The alkoxy group may be optionally substituted or unsubstituted, when substituted, substituted The group is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, blocked, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, -C(0)OR ¹⁵ , -OC(0 R ¹⁵ -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0 ) _p R ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ .

"Silyl" means an organosilane in which the hydrogen in the silane (SiH ₄ ) is replaced by one or more alkyl, alkenyl, blocked, aryl, heteroaryl, alkoxy, cycloalkyl or heterocyclic groups. a group wherein an alkyl group, an alkenyl group, a blocked group, an aryl group, a heteroaryl group, an alkoxy group, a cycloalkyl group, a heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably Is one or more of the following groups, independently selected from alkyl, alkoxy, halogen, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, carbonyl, -C ( 0) OR ¹⁵ , -OC(0)R ¹⁵ ,

-0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ . Non-limiting examples include trimethylsilyl, dimethylethylsilyl, tri-tert-butylsilyl, methyldiethoxysilyl, trimethoxysilyl, phenylsilyl, and the like.

 "Hydroxy" means an -OH group.

 "Halogen" means fluoro, chloro, bromo or iodo.

"Amino" means -NH ₂ .

 "Cyano" means -CN.

"Nitro" means -N0 ₂ .

 "Urotropine" means hexamethylenetetramine.

 "Hydroxyalkyl" means an alkyl group substituted by a hydroxy group.

.

 "Optional" or "optionally" means that the event or environment described subsequently may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, including the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .

 "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote administration to an organism, to facilitate absorption of the active ingredient and to exert biological activity.

m, n, p and R ^{15 to} R ¹⁷ are as defined in the compound of the formula (I). Methods of Synthesizing the Compounds of the Invention In order to accomplish the objectives of the present invention, the present invention employs the following technical solutions:

The preparation method of the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof comprises the following steps:

 (IA) (IB) (IC)

 A solution of the compound of the formula (I) or a compound of the formula (IB) in tetrahydrofuran is reacted with a compound of the formula (IC) at room temperature to obtain a compound of the formula (I) under triethylamine;

The compound of the formula (IA) or (IB) of the invention or:

 (II) (IA) (IB) The dimethyl sulfoxide solution of the compound of the formula (π) is heated in the presence of cuprous cyanide and cuprous iodide to obtain a compound of the formula (ΙΑ) or (IB);

( ^m ) (IA) (IB) Alternatively, the compound of the formula (ΠΙ) is mixed with a format reagent and titanate under an ice bath, and the reaction is stirred at room temperature to obtain a compound of the formula (IA) or (IB);

Alternatively, a compound of the formula (IV) is reacted with concentrated aqueous ammonia and t-butoxy hydrogen peroxide to give a compound of the formula (IA) or (IB).

 (V) (IA) (IB)

 Alternatively, a tetrahydrofuran solution of the compound of the formula (V) is stirred in the presence of water and triphenylphosphine at room temperature to obtain a compound of the formula (IA) or (IB).

Wherein X is selected from halogen, preferably a chlorine atom or a bromine atom; L, Y and ! The definition of ^~^ ¹ is as described in the general formula (I). detailed description

 The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.

 Example

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is given in units of parts per million (ppm). The NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus. The solvent was deuterated dimethyl sulfoxide (DMSO-), deuterated chloroform (CDC1 ₃ ), deuterated methanol (CH ₃ OD), and the internal standard was tetramethyl. silane (TMS), chemical shifts are 10- ⁶ (ppmM given in units of first glance.

 The MS was assayed using a FINMGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

 The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).

The IC ₅₀ value was determined using a NovoStar plate reader (BMG, Germany).

 The thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used for thin layer chromatography (TLC) has a specification of 0.15 mm~0.2 mm, and the thin layer chromatography separation and purification product adopts a specification of 0.4 mm. ~0.5 mm.

 Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as a carrier.

 The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Companies such as Dare Chemicals.

 Unless otherwise specified in the examples, they were all carried out under a nitrogen atmosphere or an argon atmosphere.

 An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.

 The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.

The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenation apparatus and a clear blue QL-500 hydrogen generator or HC2-SS type hydrogenation instrument.

 The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.

 The microwave reaction was carried out using a CEM Discover-S Model 908860 microwave reactor.

 There is no particular description in the examples, and the solution means an aqueous solution.

 There is no particular description in the examples, and the reaction temperature is room temperature.

 The optimum temperature for the reaction at room temperature is from 20 ° C to 30 ° C.

 The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The systems used for the reaction were: dichloromethane and methanol systems, n-hexane and ethyl acetate systems, petroleum ether and ethyl acetate systems, The volume ratio of acetone to solvent is adjusted depending on the polarity of the compound.

 The system for the eluent of the column chromatography and the system for the thin layer chromatography of the developer used for the purification of the compound include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: ethyl acetate and Methanol system, D: hexamethylene, E: ethyl acetate, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of an alkaline reagent such as triethylamine or an acidic reagent such as acetic acid. Example 1

 1- 3,5-di-tert-butyl-4-hydroxyphenyl)-2- 3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1,1'-isoindole -2'-ethyl ethyl ketone hydrobromide

4,5-dimethoxy phthalonitrile

Dissolve 1,2-dibromo-4,5-dimethoxybenzene (20.01 g, 68 mmol) in 100 mL of N,N-dimethylformamide and add cuprous cyanide (24.00 g, 272 Methyl), the reaction was stirred at 150 ° C for 1 hour, and the reaction was continued at 170 ° C for 5 hours. The reaction solution was poured into 100 mL of aqueous ammonia, 400 mL of ethyl acetate was added, filtered, and the filter cake was washed with ethyl acetate (100 mL×6). The filtrate was extracted with ethyl acetate (200 mL×2). EtOAcjjjjjjjjjj Product 4,5-Dimethoxyphthalonitrile lb (4.50 g, white solid), Yield: 35.0%. NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 7.20 (s, 2H), 4.01 (s, 6H)

 Second step

 5',6'-dimethoxyspiro[cyclopropane-1,3'-isoporphyrin]-indole-imine hydrobromide salt, 4,5-dimethoxyorthophenone The nitrile lb (0.94 g, 5 mmol) was dissolved in 50 mL of diethyl ether. <RTI ID=0.0>>>> 55 mL of methanol was added to the reaction mixture, and the residue obtained was purified by silica gel column chromatography eluting with eluent system A to give the title product 5',6'-dimethoxyspiro[cyclopropane-1,3'-isoindole. Porphyrin]-indole-imine hydrobromide lc (407 mg, brown solid), Yield: 37.3%.

MS m/z (ESI): 219 [M+l]

1H NMR (400 MHz, DMSO-, ppm): δ 10.37 (br. s, 1H), 9.39 (br. s, 1H), 9.15 (br. s, 1H), 7.88 (s, 1H), 7.06 (s , 1H), 4.96 (m, 3H), 3.83 (s, 3H), 1.78 (m, 2H), 1.64 (m, 2H)

 2-bromo-l-(3,5-di-tert-butyl-4-hydroxyphenyl)ethanone

 In a dry ice-acetone bath, aluminum chloride (16.00 g, 0.12 mol) was dissolved in 150 mL of dichloromethane, followed by the addition of bromoacetyl chloride le (10 mL, 0.12 mol) and 70 mL of 2,6-di-tert-butyl. A solution of phenol Id (24.50 g, 0.12 mol) in dichloromethane was stirred for 1 hour. 300 mL of ice water was added to the reaction solution, and the aqueous phase was washed with dichloromethane (200 mL×3). The organic phase was combined and washed sequentially with saturated sodium hydrogen carbonate solution (200 mL×3) and saturated sodium chloride solution (200 mL×3) The residue was dried over anhydrous sodium sulfate (MgSO4). 4-hydroxyphenyl)ethanone If (28 g, yellow solid), Yield: 72.0%.

MS m/z (ESI): 326 [M-l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.89 (s, 2H), 5.84 (br. s, 1H), 4.40 (s, 2H), 1.48 (s, 18H)

 the fourth step

 L-(3,5-di-tert-butyl-4-hydroxyphenyl)-2- 3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1, fluorene-isoindole Porphyrin]-2'-yl)ethanone hydrobromide

 Dissolve 5',6'-dimethoxyspiro[cyclopropane-1,3'-isoporphyrin]-indole-imine hydrobromide lc (223 mg, 1.02 mmol) in 3 mL of tetrahydrofuran. 2-Bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)ethanone If (398 mg, 1.22 mmol) and triethylamine (0.15 mL, 1.08 mmol) were added, and the mixture was stirred for 12 hr. Filtration, the filter cake was washed with hexane (5 mL EtOAc) (EtOAc) -2-C3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 1 ( 138 mg, yellow solid), 29.1%.

MS m/z (ESI): 465 [M+l]

1H NMR (400 MHz, DMSO-, ppm): δ 9.64 (br. s, 1H), 9.08 (br. s, 1H), 7.86 (br. s, lH), 7.85 (s, 1H), 7.82 (s , 2H), 7.02 (s, 1H), 5.17 (s, 2H), 3.92 (s, 3H), 3.83 (s, 3H), 1.66 (m, 4H), 1.44 (s, 18H) Example 2

 L-(3-tert-butyl-4-methoxy-5-morpholinylphenyl)-2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1, Γ- 异

 -2'-yl) ethyl ketone hydrobromide

first step

 1-(3-tert-butyl-4-hydroxyphenyl)ethanone

 Dry ice - acetone bath C71.0 g, 0.53 mol) was dissolved in 250 mL of dichloromethane, added

2-tert-Butyl-phenol 2a (81.6 mL, 0.53 mol) was stirred for 2 hours, and acetyl chloride 2b (37.9 mL, 0.53 mol) was added dropwise, and stirring was continued for 1 hour. After adding 300 mL of ice water to the reaction mixture, the mixture was filtered,jjjjjjjjjjjjjjjjjjj .

MS m/z (ESI): 191 [M-l]

 Second step

 1- 3-tert-butyl-4-hydroxy-5-iodo-phenyl)ethanone

 1-(3-tert-Butyl-4-hydroxyphenyl)ethanone 2c (16.2 g, 84.3 mmol) was dissolved in 200 mL of acetonitrile and N-iodosuccinimide C 20.9 g, 92.8 mmol ), the reaction was stirred for 4 hours. Concentrate under reduced pressure, add 50 mL of water and 50 mL of ethyl acetate. EtOAc (EtOAc) The sodium was dried, filtered, and the filtrate was evaporated, evaporated,jjjjjjjjjjjjjjjjj Ethylketone 2d (16.1 g, yellow solid), Yield: 60.0%

 MS m/z (ESI): 317 [M-l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.17 (s, 1H), 7.90 (d, / = 1.6 Hz, 1H), 5.98 (br. s,

1H), 2.55 (s, 3H), 1.48 (s, 9H) third step

 1- 3-tert-butyl-5-iodo-4-methoxyphenyl)ethanone

 1-(3-tert-Butyl-4-hydroxy-5-iodo-phenyl)ethanone 2d (16.1 g, 51 mmol) was dissolved in 200 mL of acetone at 25 ° C, and potassium carbonate (21.14 g, 153 mmol) and methyl iodide (18 g, 127 mmol) were stirred for 12 hours. Filtration and concentration of the filtrate under reduced pressure. EtOAc m. 2e (14.2 g, pale yellow oil), yield: 84.5%.

1H NMR (400 MHz, CDC1 ₃ , ppm): 5 8.25 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 3.93 (s, 3H), 2.54 (s, 3H) , 1.39 (s, 9H)

 the fourth step

 1-(tert-butyl-5-(l,l-dimethoxyethyl)-3-iodo-2-methoxybenzene 1-(3-tert-butyl-5-iodo-4-methoxy Phenyl)ethanone 2e (2.6 g, 7.83 mmol) and trimethyl orthoformate (2.49 g, 23.5 mol) were dissolved in 2.6 mL of methanol and D(+)-10-camphorsulfonic acid (91 mg, 0.39 mmol) ), the reaction was stirred for 12 hours. 217 mg of potassium carbonate was added to the reaction solution, stirred for 0.5 hour, 10 mL of water and 10 mL of n-hexane were added, and the aqueous phase was extracted with n-hexane (20 mL×3), and the organic phase was combined and washed with saturated sodium chloride solution (10 mL×3) The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. 2.3 g, pale yellow oil), Yield: 79.3%.

1H NMR (400 MHz, CDC1 ₃ , ppm): 5 7.82 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 3.89 (s, 3H), 3.18 (s, 6H) , 1.51 (s, 3H), 1.40 (s, 9H)

 the fifth step

 4-[3-tert-butyl-5-(l,l-dimethoxyethyl)-2-methoxyphenyl]-morpholine 1-tert-butyl-5-(1,1-di Methoxyethyl)-3-iodo-2-methoxybenzene 2f (3.3 g, 8.73 mmol) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl ( 172 mg, 0.44 mmol) dissolved in 33 mL of toluene, palladium/carbon (330 mg, 10%), sodium tert-butoxide (1.68 g, 17.46 mmol) and morpholine (1.52 g, 17.46 mmol), 60 ° C The reaction was stirred for 3 hours. To the reaction mixture, 100 mL of water was added, and the aqueous layer was extracted with ethyl acetate (50 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate The residue obtained was purified by silica gel column chromatography eluting elut elut - morpholine 2g (1.5 g, brown oil), Yield: 51.0%.

 MS m/z (ESI): 338 [M+l]

 Step 6

2-bromo-l-(3-tert-butyl-4-methoxy-5-morpholinylphenyl)ethanone 4-[3-tert-butyl-5-(1,1-dimethoxy B) 2,2-methoxyphenyl]-morpholine 2 g (1.5 g, 4.45 mmol) was dissolved in 18 mL of acetic acid, tribromopyridinium salt (1.57 g, 4.90 mmol) was added, and the reaction was stirred for 2 hours. Add 30 mL of water to the reaction solution, extract the aqueous phase with ethyl acetate (20 mL×3), combine the organic phase, and sat. It was washed with a sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate, filtered and evaporated. (3-tert-Butyl-4-methoxy-5-morpholinylphenyl)ethanone 2h (930 mg, pale yellow solid), yield: 56.4%.

MS m/z (ESI): 370 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): 5 7.70 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 4.41 (s, 2H), 4.0 l(s, 3H ), 3.90 (m, 4H), 3.09 (m, 4H), 1.40 (s, 9H)

 Seventh step

 L-(3-tert-butyl-4-methoxy-5-morpholinylphenyl)-2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1, Γ-isoporphyrin]-2'-yl)ethanone hydrobromide

 Dissolve 5',6'-dimethoxyspiro[cyclopropane-1,3'-isoporphyrin]-indole-imine hydrobromide lc (229 mg, 1.05 mmol) in 4 mL of tetrahydrofuran. Add 2-bromo-1-(3-tert-butyl-4-methoxy-5-morpholinylphenyl)ethanone 2h (440 mg, 1.19 mmol) and triethylamine (0.2 mL, 1.44 mmol), stir Reaction for 12 hours. Filtration, the filter cake was washed with hexane (5 mL EtOAc) (EtOAc) -morpholinylphenyl)-2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone Hydrobromide 2 (168 mg, pale yellow powder), Yield: 31.5% MS m/z (ESI): 508 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.71 (br. s, 1H), 9.13 (br. s, 1H), 7.91 (s, 1H), 7.62 (d, / = 1.6 Hz, 1H ), 7.55 (d, / = 1.6 Hz, 1H), 7.08 (s, 1H), 5.34 (s, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 3.91 (s, 3H), 3.88 (m, 4H), 3.03 (m, 4H), 1.66 (m, 4H), 1.39 (s, 9H) Example 3

 L-(3-tert-Butyl-4-methoxyphenyl)-2-(3'-imino-5',6'-dimethoxy-spiro [cyclopropane-1, Γ-isoindole]

 '-yl) ethyl ketone hydrobromide

 2c 3a 3b 3 HBr

 First step

 L-(3-tert-butyl-4-methoxyphenyl)ethanone

10O-tert-Butyl-4-hydroxyphenyl)ethanone 2c (6.3 g, 32.8 mmol) was dissolved in 50 mL of acetone and potassium carbonate (13.6 g, 98.4 mmol) and iodomethane (11.65 g, 82 mmol). The reaction was stirred at 50 ° C for 2 hours. Filtration, the filtrate was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc) Get the title The product, 1- 3-tert-butyl-4-methoxyphenyl)ethanone 3a (6.0 g, white solid), yield: 88.6%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.99 (d, J = 2.0 Hz, 1H), 7.87 (dd, = 8.4 Hz, J ₂

= 2.0 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 3.97 (s, 3H), 2.60 (s, 3H), 1.46 (s, 9H)

 Second step

 2-bromo-l-(3-tert-butyl-4-methoxyphenyl)ethanone

 Dissolve 1-(3-tert-butyl-4-methoxyphenyl)ethanone 3a (1.0 g, 4.8 mmol) in 8 mL of acetic acid, add tribromopyridinium salt (1.6 g, 5.04 mmol), stir Reaction for 3.5 hours. Concentrate under reduced pressure, add 20 mL of water and 20 mL of ethyl acetate. EtOAc (EtOAc) (EtOAc m. The sodium was dried, filtered, and the filtrate was evaporated,jjjjjjjjjjjjjj Ethylketone 3b (900 mg, pale yellow oil), Yield: 66.2%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.02 (d, J = 2.0 Hz, 1H), 7.91 (dd, /;= 8.8 Hz, J ₂ = 2.0 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 4.44 (s, 2H), 3.97 (s, 3H), 1.44 (s, 9H)

 third step

 L-(3-tert-Butyl-4-methoxyphenyl)-2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1, fluorene-isoindole] Porphyrin]-2'-yl)ethanone hydrobromide

 Dissolve 5',6'-dimethoxyspiro[cyclopropane-1,3'-isoporphyrin]-indole-imine hydrobromide lc (240 mg, 1.1 mmol) in 3 mL of tetrahydrofuran. 2-Bromo-1-(3-tert-butyl-4-methoxyphenyl)ethanone 3b (360 mg, 1.26 mmol) and triethylamine (0.3 mL, 2.16 mmol). Filtration, the filter cake was washed with hexane (5 mL EtOAc) (EtOAc) -2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 3 (287 mg, light yellow powder), Yield: 61.7%

MS m/z (ESI): 423 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.68 (br. s, 1H), 9.14 (br. s, 1H), 8.00 (dd, /; = 8.8 Hz, / ₂ = 1.6 Hz, 1H ), 7.88 (s, lH), 7.86 (d, / = 1.6 Hz, 1H), 7.21 (d, / = 8.8 Hz, 1H) 7.08 (s, 1H), 5.18 (s, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 3.87 (s, 3H), 1.73 (m, 4H), 1.39 (s _: 9H) Example 4

 L-(3-Bromo-5-tert-butyl-4-hydroxyphenyl)-2-(3'-imino-5',6'-dimethoxyspiro[cyclopropane-1, fluorene-isoindole] Porphyrin-2'-yl)ethanone hydrobromide

 First step

L-(3-bromo-5-tert-butyl- ⁴ -hydroxyphenyl)-ethanone

 Dissolve 1-(3-tert-butyl-4-hydroxyphenyl)ethanone 2c (6.3 g, 32.8 mmol) in 50 mL of acetonitrile and N,N-dimethylformamide (V/V = 10:1) N-bromosuccinimide (10.2 g, 57 mmol) was added to the mixed solvent, and the mixture was stirred for 0.5 hr. The residue was purified by silica gel column chromatography elut elut elut elut elut elut elut White solid), Yield: 85.8%.

MS m/z (ESI): 269 [M-l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.03 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 2.0 Hz, 1H), 6.33 (br. s, 1H), 2.58 (s, 3H), 1.46 (s, 9H)

 Second step

 2-bromo-l-(3-bromo-5-tert-butyl-4-hydroxyphenyl)ethanone

 Dissolve 1-(3-bromo-5-tert-butyl-4-hydroxyphenyl)ethanone 4a (5.0 g, 18.4 mmol) in 50 mL of acetic acid and add tribromopyridinium salt (6.2 g, 19.4 mmol) The reaction was stirred for 12 hours. Concentrated under reduced pressure, 100 mL of water and 100 mL of ethyl acetate were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (100 mL×3). The organic phase was combined and washed with saturated sodium chloride solution (50 mL×3), anhydrous sulfuric acid The sodium was dried, filtered, and the filtrate was evaporated, evaporated,jjjjjjjjjjj Phenyl)ethanone 4b (6.4 g, gray oil), Yield: 99.2%.

MS m/z (ESI): 349 [M-l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.07 (d, J = 2.0 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 6.41 (br. s, 1H), 4.40 (s, 2H), 1.48 (s, 9H)

 third step

 L-(3-Bromo-5-tert-butyl-4-hydroxyphenyl)-2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1, oxime-iso Porphyrin]-2'-yl)ethanone hydrobromide

 5',6'-Dimethoxyspiro[cyclopropane-1,3'-isoporphyrin]-indole-imine hydrobromide lc (228 mg, 1.05 mmol) was dissolved in 4 mL of tetrahydrofuran. Add 2-bromo-1-(3-bromo-5-tert-butyl-4-hydroxyphenyl)ethanone 4b (540 mg, 1.54 mmol) and triethylamine (0.3 mL, 2.16 mmol). . Filtration, the filter cake was washed with hexane (10 mL EtOAc) (EtOAc (EtOAc) Phenyl)-2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide Salt 4 (166 mg, pale yellow powder), Yield: 32.6% MS m/z (ESI): 487 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.63 (br. s, 1H), 9.12 (br. s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 7.55 (s, 1H), 7.05 (s, 1H), 4.95 (s, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 1.65 (m _: 4H), 1.33 (s, 9H) Example 5

 2-[8-tert-Butyl-6-[2-C3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1,indole-isoindoline]-2'-yl Acetyl

 First step

 1-(3-tert-butyl-4-hydroxy-5-nitro-phenyl)-ethanone

 Dissolve 68% concentrated nitric acid (105 mL, 1.6 mol) in a mixed solvent of 60 mL of dichloromethane and water (V/V = 2:1) at 10 ° C, and add 1-(3-tert-butyl- 4-Hydroxyphenyl)ethanone 2c (12.87 g, 66.9 mmol) was stirred for 0.5 hour, then 60 mL of diethyl ether, 0.6 mL of acetic anhydride and 105 mL of concentrated hydrochloric acid were added and stirring was continued for 1.5 hours. Add 200 mL of ice water to the reaction solution, extract with ethyl acetate (150 mIX3), combine the organic phase, adjust the pH to 5~6 with saturated sodium bicarbonate, wash with saturated sodium chloride solution (50 mL×3), anhydrous The residue was purified by EtOAcjjjjjjjjjjjjjjj Ethyl ketone 5a (6.27 g, yellow solid), Yield: 39.6%.

MS m/z (ESI): 236 [M-l]

1H NMR (400 MHz, DMSO-, ppm): δ 11.40 (br. s, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 2.59 (s, 3H), 1.42 (s, 9H)

 Second step

1-(3-tert-Butyl-4-hydroxy-5-nitro-benzene) 1-[4-(2-bromoethoxy)-3-tert-butyl-5-nitro-phenyl]ethanone Ethyl ketone 5a (6.26 g, 26.4 mmol) was dissolved in 80 mL of N,N-dimethylformamide, and potassium carbonate (18.25 g, 132 mmol) and 1,2-dibromoethane (24.8 g, 132 Methyl), the reaction was stirred at 100 ° C for 10 hours. The organic layer was extracted with EtOAc (EtOAc) (EtOAc). The obtained residue was purified to silica gel column chromatography elutd elut elut elut (5.74 g, yellow oil), Yield: 48.6%.

 1H NMR (400 MHz, DMS0-, ppm): δ 8.32 (d, J = 2.0 Hz, 1H), 8.11 (d, / = 2.0 Hz, 1H), 4.25 (m, 2H), 3.82 (m, 2H) , 2.62 (s, 3H), 1.44 (s, 9H)

 third step

 1-(4-(2-Bromoethoxy)-3--l-(8-tert-butyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)ethanone tert-Butyl-5-nitro-phenyl]ethanone 5b (3.65 g, 10.6 mmol) was dissolved in 35 mL of toluene, palladium/carbon (0.5 g, 10%) was added, and the mixture was replaced with hydrogen three times, and the reaction was stirred for 40 hours. 30 mL of ethyl acetate was added to the reaction mixture, and the filtrate was evaporated. -Dihydro-2H-1,4-benzoxazin-6-yl)ethanone 5c (400 mg, yellow solid), Yield: 14.8% o

MS m/z (ESI): 234 [M+l]

 the fourth step

 Ethyl 2-(6-acetyl-8-tert-butyl-2,3-dihydro-1,4-benzoxazin-4-yl)acetate 1-(8-tert-butyl-3,4 -Dihydro-2H-1,4-benzoxazin-6-yl)ethanone 5c (4.8 g, 20.5 mmol) was dissolved in 80 mL of N,N-dimethylformamide and potassium carbonate (8.5 g) , 61.7 mmol) and ethyl bromoacetate (11.5 mL, 102 mmol), and stirred at 100 ° C for 3 hours. The organic layer was combined with EtOAc (EtOAc) (EtOAc)EtOAc. The obtained residue was purified to silica gel column chromatography eluting elut elut elut Ethyl acetate 5d (4.7 g, yellow solid), yield: 71.5%.

MS m/z (ESI): 320 [M+l]

 1H NMR (400 MHz, DMSO-, ppm): δ 7.11 (d, / = 2.0 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 5.94 (br. s, 1H), 4.19 (m, 2H), 3.32 (m, 2H), 2.44 (s, 3H), 1.33 (s, 9H)

 the fifth step

 Ethyl 2-[6-(2-bromoacetyl)-8-tert-butyl-2,3-dihydro-1,4-benzoxazin-4-yl]acetate 2-(6-acetyl Ethyl 8-(t-butyl-2,3-dihydro-1,4-benzoxazin-4-yl)acetate 5d (6.68 g,

20.9 mmol) was dissolved in 80 mL of acetic acid, and tribromopyridinium salt (8.18 g, 25.6 mmol) was added, and the reaction was stirred for 5 hours. Concentrate under reduced pressure, add 100 mL of saturated sodium bicarbonate solution, and partition. The aqueous phase is extracted with ethyl acetate (100 mL×3). The organic phase is combined, washed with saturated sodium chloride solution (50 mL×3), dried over anhydrous sodium sulfate After filtration, the filtrate was concentrated under reduced pressure. EtOAcjjjjjjjjjjj -Dihydro-1,4-benzoxazin-4-yl]acetate 5e (3.3 g, brown-brown solid), Yield: 39.0%. MS m/z (ESI): 400 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.42 (d, / = 2.0 Hz, 1H), 7.13 (d, / = 2.0 Hz, 1H), 4.43 (s, 2H), 4.36 (m, 2H) , 4.21 (m, 2H), 4.10 (s, 2H), 3.58 (m, 2H), 1.42 (s, 9H), 1.35 (m, 3H)

 Step 6

 2-[8-tert-Butyl-6-[2-C3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1,indole-isoindoline]-2'-yl Acetyl]-2,3-dihydro-1,4-benzoxazin-4-yl]ethyl acetate hydrobromide 5',6'-dimethoxyspiro[cyclopropane-1, 3'-Isoporphyrin]-indole-imine hydrobromide lc (241 mg, 1.11 mmol) was dissolved in 4 mL of tetrahydrofuran, and 2-[6-(2-bromoacetyl)-8-tert-butyl was added. Ethyl 2,3-dihydro-1,4-benzoxazin-4-yl]acetate 5e (708 mg, 1.77 mmol) and triethylamine (0.4 mL, 2.88 mmol). Filtration, the filter cake was washed with hexane (10 mL×2), EtOAc (EtOAc (EtOAc) '-Imino-5',6'-dimethoxy-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)acetyl]-2,3-dihydro-1, 4-benzoxazin-4-yl]ethyl acetate hydrobromide 5 (142 mg, white powder), yield: 23.9%.

MS m/z (ESI): 536 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.70 (br. s, 1H), 9.18 (br. s, 1H), 7.93 (s, 1H), 7.31 (s, 1H), 7.11 (s , 1H), 7.08 (s, 1H), 5.14 (s, 2H), 4.32 (t, / = 4.4 Hz, 2H), 4.00 (s, 2H), 4.14 (q, / = 7.2 Hz, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.51 (t, / = 4.4 Hz, 2H), 1.63 (m, 4H), 1.39 (s, 9H), 1.22 (t, / = 7.2 Hz, 3H) Example 6

L-(8-tert-Butyl-4-ethyl-2,3-dihydro-1,4-benzoxazin-6-yl)-2-(3'-imino-5',6'- Dimethoxy-spiro

 -1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

 5c 6a 6b 6

 First step

1 -(8-tert-butyl-4-ethyl-2,3-dihydro-1,4-benzoxazin-6-yl)ethanone 1-(8-tert-butyl-3,4- Dihydro-2H-1,4-benzoxazin-6-yl)ethanone 5c (1.5 g, 6.4 mmol) was dissolved in 20 mL of N,N-dimethylformamide and potassium carbonate (2.66 g, 19.3 mmol) and iodoethane (2.6 mL, 32.1 mmol) were stirred at 80 ° C for 12 hours. Concentrated under reduced pressure, adding 100 mL of water with ethyl acetate The organic phase was extracted with a saturated sodium chloride solution (50 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B The title product 1-(8-tert-butyl-4-ethyl-2,3-dihydro-1,4-benzoxazin-6-yl)ethanone 6a (1.0 g, yellow solid) Yield: 59.5%.

MS m/z (ESI): 262 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.35 (d, J = 2.0 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 4.33 (t, J = 4.4 Hz, 2H), 3.45 (q, J= 6.6 Hz, 2H), 3.40 (t, J = 4.4 Hz, 2H), 2.58 (s, 3H), 1.42 (s, 9H), 1.22 (t, J = 6.6 Hz, 3H)

 Second step

 2-bromo-l-(8-tert-butyl-4-ethyl-2,3-dihydro-1,4-benzoxazin-6-yl)ethanone 1-(8-tert-butyl- 4-ethyl-2,3-dihydro-1,4-benzoxazin-6-yl)ethanone 6a (1.0 g, 3.8 mmol) was dissolved in 18 mL of acetic acid and tribromopyridine salt was added (1.28). g, 4.0 mmol), the reaction was stirred at 100 ° C for 10 hours. Concentrate under reduced pressure, add 100 mL of saturated sodium bicarbonate solution, and extract with ethyl acetate (100 mL×3). The organic phase is combined and washed with saturated sodium chloride solution (50 mL×3), dried over anhydrous sodium sulfate, filtered The residue was purified by silica gel column chromatography elut elut elut elut elut 4-benzoxazin-6-yl)ethanone 6b (194 mg, yellow solid), yield: 29.2%.

 MS m/z (ESI): 340 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 7.38 (d, J = 2.0 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 4.45 (s, 2H), 4.35 (t, / = 4.4 Hz, 2H), 3.45 (m, 2H), 3.41 (t, / = 4.4 Hz, 2H), 1.42 (s, 9H), 1.22 (m, 3H)

 third step

L-(8-tert-Butyl-4-ethyl-2,3-dihydro-1,4-benzoxazin-6-yl)-2-(3'-imino-5',6'- Dimethoxy-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide

 Dissolve 5',6'-dimethoxyspiro[cyclopropane-1,3'-isoporphyrin]-indole-imine hydrobromide lc (151 mg, 0.69 mmol) in 3 mL of tetrahydrofuran. Add 2-bromo small (8-tert-butyl-4-ethyl-2,3-dihydro-1,4-benzoxazin-6-yl)ethanone 6b (253 mg, 0.74 mmol) and triethyl Amine (0.2 mL, 1.44 mmol) was stirred for 12 h. Filtration, the filter cake was washed with n-hexane (10 mL×2) and water (10 mL×3) and dried in vacuo to give the title product 1-(8-tert-butyl-4-ethyl-2,3-dihydro-1,4 -benzoxazin-6-yl)-2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1,1'-isoindoline]-2'- Ethyl ketone hydrobromide 6 (139 mg, white powder), Yield: 35.9%

 MS m/z (ESI): 478 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.68 (br. s, 1H), 9.13 (br. s, 1H), 7.90 (s, 1H), 7.28 (s, 1H), 7.24 (s , 1H), 7.08 (s, 1H), 5.16 (s, 2H), 4.30 (t, / = 4.4 Hz, 2H), 3.92 (s, 3H), 3.86 (s, 3H), 3.44 (q, / = 7.2 Hz, 2H), 3.38 (t, / = 4.4 Hz, 2H), 1.68 (m, 4H), 1.37 (s, 9H), 1.23 (t, / = 7.2 Hz, 3H) Example 7

 1-(3-tert-Butyl-4-methoxy-5-morpholinylphenyl)-2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1, Γ-isoindole-2'-yl) ethyl ketone hydrobromide

 First step

 1,2-dibromo-4,5-diethoxybenzene

 1,2-diethoxybenzene 7a (16.6 g, 100 mmol) was dissolved in 200 mL of dichloromethane, and bromo (10 mL, 200 mmol) was added dropwise, and the mixture was stirred at room temperature for 4 hours. To the reaction mixture, 100 mL of water and 1 g of sodium sulfite were added, and the organic phase was washed with saturated sodium chloride (150 mL), dried over anhydrous sodium sulfate, filtered, -Dibromo-4,5-diethoxybenzene 7b (29.8 g, white solid), Yield: 92.0%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.10 (s, 2H), 4.07 (q, / = 7.2 Hz, 4H), 1.47 (t, / = 7.2 Hz, 6H)

 Second step

 4,5-diethoxy phthalonitrile

 1,2-Dibromo-4,5-diethoxybenzene 7b (13.62 g, 42 mmol) was dissolved in 150 mL of dimethyl sulfoxide, cuprous cyanide (14.97 g, 167.2 mmol) and iodinated. Cuprous (7.18 g, 37.7 mmol), and the reaction was stirred at 160 ° C for 4 hours. The reaction solution was poured into a mixed solvent of 250 mL of concentrated aqueous ammonia and ethyl acetate (V/V = 1 : 1.5), filtered, and the filter cake was washed with water (100 mL) and ethyl acetate (100 mL×2). The organic phase was combined with concentrated aqueous ammonia (50 mL), water (250 mL) and saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate and filtered. The obtained residue was purified to silica gel elution elution elution elution elution elution elution elution

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.16 (s, 2H), 4.20 (q, / = 4.1 Hz, 4H), 1.54 (t, / = 4.1 Hz, 6H)

 third step

5',6'-diethoxyspiro[cyclopropane-1,3'-isoindoline]-1'-imine hydrobromide 4,5-diethoxyphthalonitrile 7c (2.16 g, 10 mmol) was dissolved in 100 mL of diethyl ether under ice bath, tetraisopropyl titanate (3.3 mL, 11.2 mmol) and ethyl bromide were added. Magnesium (7.3 mL, 21.9 mmol) was stirred at room temperature for 2 hours. After adding 55 mL of methanol, the obtained residue was purified by silica gel column chromatography eluting to afford the title product 5',6'-diethoxyspiro[cyclopropane-1,3'-isoporphyrin] - Γ-imine hydrobromide 7d (1.26 g, orange powder), Yield: 51.2%.

MS m/z (ESI): 247 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 10.35 (br. s, 1H), 9.37 (br. s, 1H), 9.14 (br. s, 1H), 7.88 (s, 1H), 7.01 (s, 1H), 4.17 (m, 4H), 1.69 (m, 2H), 1.43 (m, 2H), 1.37 (m, 6H)

 1-(3-tert-Butyl-4-methoxy-5-morpholinylphenyl)-2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1, Γ-isoporphyrin]-2'-yl)ethanone hydrobromide

 Dissolve 5',6'-diethoxyspiro[cyclopropane-1,3'-isoporphyrin]-indole-imine hydrobromide 7d (195 mg, 0.79 mmol) in 3 mL of tetrahydrofuran. Add 2-bromo-1-(3-tert-butyl-4-methoxy-5-morpholinylphenyl)ethanone 2h (310 mg, 0.84 mmol) and triethylamine (0.15 mL, 1.08 mmol), stir Reaction for 12 hours. Filtration, the filter cake was washed with n-hexane (10 mL×2) and water (10 mL×3) and dried in vacuo to give the title product 1-(3-tert-butyl-4-methoxy-5-morpholinylphenyl) -2 -(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 7 (180 mg , white powder), Yield: 36.9%

MS m/z (ESI): 536 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.69 (br. s, 1H), 9.13 (br. s, 1H), 7.91 (s, 1H), 7.65 (d, / = 2.0 Hz, 1H ), 7.56 (d, / = 2.0 Hz, 1H), 7.06 (s, 1H), 5.23(s, 2H), 4.18 (q, / = 7.2 Hz, 2H), 4.12 (q, / = 7.2 Hz, 2H ), 3.97 (s, 3H), 3.83 (m, 4H), 3.03 (m, 4H), 1.64 - 1.61 (m, 4H), 1.41 (m, 15H) Example 8

 L-(3-tert-Butyl-4-methoxy-5-pyrrolidin-1-yl-phenyl)-2-(5',6'-diethoxy-3'-imino-spiro[ Cyclopropane

 -1,1'- -2'-yl)ethanone hydrobromide

 First step

 1-(3-tert-Butyl-4-methoxy-5-nitro-phenyl)ethanone 5-(3-tert-butyl-4-methoxy-5-nitro-phenyl)ethanone 5a (11.6 g, 48.9 mmol) was dissolved in 150 mL of acetone, and potassium carbonate (16.9 g, 122 mmol) and iodomethane (23.2 mL, 372 mmol) were added, and the reaction was stirred at 80 ° C for 12 hours. The organic layer was combined with EtOAc (EtOAc) (EtOAc). The obtained residue was purified to silica gel elut elut elut elut elut elut elut eluting Oil), Yield: 72.8%.

MS m/z (ESI): 252 [M+l]

 Second step

 1- 3-amino-5-tert-butyl-4-methoxyphenyl)ethanone

 Dissolve 1-(3-tert-butyl-4-methoxy-5-nitro-phenyl)ethanone 8a (4.8 g, 19 mmol) in 50 mL ethanol and water (V/V = 4:1) Ammonium chloride (4.1 g, 75 mmol) and iron powder (2.1 g, 38 mmol) were added to the mixed solvent, and the mixture was stirred at 80 ° C for 1 hour. Filtration, the filtrate was concentrated under reduced pressure, and then 100 mL of water and 100 mL of ethyl acetate were added. The aqueous phase was extracted with ethyl acetate (100 mL×3), and the organic phase was combined and washed with saturated sodium chloride solution (50 mL×3), anhydrous sulfuric acid The sodium was dried, filtered, and the filtrate was evaporated.jjjjjjjjjjjjjjj Ethylketone 8b (3.6 g, gray solid), Yield: 81.0%.

MS m/z (ESI): 222 [M+l]

 third step

1-(3-tert-butyl-4-methoxy-5-pyrrolidin-1-yl-phenyl)ethanone 1-(3-amino-5-tert-butyl-4-methoxyphenyl) Ethyl ketone 8b (2.0 g, 9.05 mmol) and 1,4-dibromobutane (2.54 g, 11.77 mmol) were dissolved in 20 mL of N,N-dimethylformamide and potassium carbonate (3.1 g, 22.63) Methyl) and potassium iodide (0.15 g, 0.91 mmol) were stirred at 80 ° C for 48 hours. Filtration, and the filtrate was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) The residue obtained was purified by silica gel column chromatography elutd elut elut elut (1.1 g, white solid), Yield: 44.2%. MS m/z (ESI): 276 [M+l]

 the fourth step

 1-bromo-l-(3-tert-butyl-4-methoxy-5-pyrrolidin-1-yl-phenyl)ethanone 1-(3-tert-butyl-4-methoxy-5 -Pyrrolidin-1-yl-phenyl)ethanone 8c (900 mg, 3.27 mmol) was dissolved in 10 mL of acetic acid, tribromopyridine salt (1.1 g, 3.43 mmol) was added, and the reaction was stirred for 12 hours. The organic layer was combined with ethyl acetate (30 mL EtOAc). Filtration, the filtrate was concentrated under reduced pressure and purified tolululululululululululululululululululu -1-yl-phenyl)ethanone 8d (560 mg, yellow solid), yield: 48.3%. MS m/z (ESI): 356 [M+l]

 the fifth step

 L-(3-tert-Butyl-4-methoxy-5-pyrrolidin-1-yl-phenyl)-2-(5',6'-diethoxy-3'-imino-spiro[ Cyclopropane

 -1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

 Dissolve 5',6'-diethoxyspiro[cyclopropane-1,3'-isoporphyrin]-indole-imine hydrobromide 7d (250 mg, 1.02 mmol) in 4 mL of tetrahydrofuran. Add 2-bromo-1-(3-tert-butyl-4-methoxy-5-pyrrolidin-1-yl-phenyl)ethanone 8d (360 mg, 1.02 mmol) and triethylamine (0.2 mL, 1.44 mmol), the reaction was stirred for 12 hours. Filtration, the filter cake was washed sequentially with hexane (10 mL×2) and water (10 mL×3) and dried in vacuo to give the title product 1-(3-tert-butyl-4-methoxy-5-pyrrolidin-1-yl- Phenyl)-2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide Salt 8 (232 mg, white powder), Yield: 38.0%.

MS m/z (ESI): 520 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.65 (br. s, 1H), 9.08 (br. s, 1H), 7.88 (s, 1H), 7.77 (b, / = 2.0 Hz, 1H ), 7.41 (b, / = 2.0 Hz, 1H), 7.05 (s, 1H), 5.19 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H), 4.11 (q, / = 7.2 Hz, 2H ), 3.66 (s, 3H), 3.10 (m, 4H), 1.93 (m, 4H), 1.74-1.60 (m, 4H), 1.39 (m, 15H) Example 9

 L-(3-tert-butyl-4-methoxy-5-morpholinylphenyl)-2-(7-imino-2,5-dimethyl-5-phenyl-pyrrolo[3,4 -b]

 First step

L-( ₆ -methyl-3-pyridine)-I-phenyl-ethanol

 5-bromo-2-methyl-B-pyridyl 9a (1.72 g, 10 mmol) was dissolved in 10 mL of diethyl ether under dry ice-acetone bath, and 2.5 M n-butyllithium (4.4 mL, 11 mmol) was added dropwise. The n-hexane solution was stirred for 1 hour, acetophenone (1.29 mL, 11 mmol) was added and stirring was continued for 1 hour. 10 mL of a saturated ammonium chloride solution was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (20 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate, filtered, filtrate The residue was purified by EtOAcjjjjjjjjjj ), Yield: 84.5%.

MS m/z (ESI): 214 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.55 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.35 (m, 5H), 7.11 (d, /= 8.4 Hz, 1H) , 2.56 (s, 3H), 1.98 (s, 3H)

 Second step

 5-(l-azido-1-phenyl-ethyl)-2-methyl-pyridine

 1-(6-Methyl-3-pyridyl)-1-phenyl-ethanol 9b (1.75 g, 8.2 mmol) and sodium azide (1.6 g, 24.6 mmol) were dissolved in 10 mL water under ice bath. 9 mL of concentrated hydrochloric acid was added dropwise, and the reaction was stirred for 12 hours. Add 200 mL of saturated sodium bicarbonate solution to the reaction solution to adjust the pH to 7~8, extract with ethyl acetate (50 mL×3), combine the organic phase, wash with saturated sodium chloride solution (20 mL×3), dry over anhydrous sodium sulfate Filtration, and the filtrate was concentrated under reduced pressure to give the title product 5-(1-azit-1-phenyl-ethyl)-2-methyl-B-pyridin 9c (1.8 g, pale yellow oil). : 92.3%.

MS m/z (ESI): 239 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.53 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.37 (m, 5H), 7.16 (d, J = 8.0 Hz, 1H) , 2.62 (s, 3H), 2.07 (s, 3H)

 third step

5-(l-azido-1-phenyl-ethyl)-2-methyl-pyridine 1-oxide 5-(1-azido-1-phenyl-ethyl)-2-methyl- B was dissolved in 30 mL of dichloromethane with pyridine 9c (1.8 g, 7.6 mmol), m-chloroperoxybenzoic acid (2.6 g, 15.1 mmol) was added, and the reaction was stirred for 12 hours. 20 mL of dichloromethane was added to the reaction solution, and the mixture was washed with saturated sodium hydrogen carbonate (30 mL×3), and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phase was combined and washed with saturated sodium chloride solution (20 mL×3) , dried anhydrous sodium sulfate, Filtration, and the filtrate was concentrated under reduced pressure. 1-oxide 9d (1.42 g, pale yellow oil), Yield: 74.0%

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.31 (s, 1H), 7.36 (m, 7H), 2.58 (s, 3H), 2.04 (s, 3H)

 the fourth step

 3-(1-azido-1-phenyl-ethyl-6-methyl-pyridine-2-carbonitrile to 5-(1-azido-1-phenyl-ethyl)-2-methyl-B ratio Pyridine 1-oxide 9d (1.3 g, 5.1 mmol) was dissolved in 15 mL of acetonitrile, cyanotrimethylsilane (1.16 mL, 8.7 mmol) and dimethylcarbamoyl chloride (0.70 mL, 7.7 mmol), 80° The reaction was stirred for 2 hours under C. The reaction mixture was evaporated to dryness. 6-Methyl-pyridine-2-carbonitrile 9e (1.6 g, pale yellow oil) crude.

MS m/z (ESI): 264 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.04 (d, J = 8.4 Hz, 1H), 7.47 (m, 6H), 2.63 (s, 3H), 2.28 (s, 3H)

 the fifth step

 2,5-Dimethyl-5-phenyl-6H-pyrrolo[3,4-b]pyridine-7-imine 3-(1-azido-1-phenyl-ethyl)-6- Methyl-pyridine-2-carbonitrile 9e (1.68 g, 6.39 mmol) was dissolved in 35 mL of tetrahydrofuran, and 1 mL of water and triphenylphosphine (3.35 g, 12.8 mmol) were added, and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjj Pyridine-7-imine 9f (0.44 g, pale yellow solid), yield: 29.1%.

 MS m/z (ESI): 238 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.91 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.17 (m, 5H), 6.61 (s, 2H) , 2.55 (s, 3H), 1.69 (s, 3H)

 Step 6

 L-(3-tert-butyl-4-methoxy-5-morpholinylphenyl)-2-(7-imino-2,5-dimethyl-5-phenyl-pyrrolo[3,4 -b] Pyridin-6-yl)ethanone hydrobromide

 2,5-Dimethyl-5-phenyl-6H-pyrrolo[3,4-b]pyridine-7-imine 9f (237 mg, 1 mmol) and 2-bromo-1-(3-tert) Butyl-4-methoxy-5-morpholinylphenyl)ethanone 2h (444 mg, 1.2 mmol) was dissolved in 3 mL of N,N-dimethylformamide and stirred for 12 hours. To the reaction mixture, 5 mL of water was added, and the mixture was combined with ethyl acetate (20 mL×3), and the organic phase was combined, washed with a saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate, filtered, The residue obtained was purified by silica gel column chromatography elut elut elut elut elut elut elut elut 5-Dimethyl-5-phenyl-pyrrolo[3,4-b]pyridin-6-yl)ethanone hydrobromide 9 (120 mg, pale yellow solid), yield: 19.8%.

MS m/z (ESI): 527 [M+l] NMR NMR (400 MHz, DMSO-J ₆ , ppm): δ 7.97 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.47 (s, 1H), 7.38 (m, 5H), 5.50 (d, / = 18.8 Hz, 1H), 5.16 (d, / = 18.8 Hz, 1H), 4.03 (s, 3H), 3.80 (m, 4H), 2.98 ( m, 4H), 2.74 (s, 3H), 1.99 (s, 3H), 1.33 (s, 9H) Example 10

 1- 3,5-di-tert-butyl-4-hydroxyphenyl)-2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1, fluorene-isoindole]

 -2'-yl) ethyl ketone hydrobromide

 First step

 1- 3,5-di-tert-butyl-4-hydroxyphenyl)-2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1,1'-isoindole Porphyrin]-2'-yl)ethanone hydrobromide

 Dissolve 5',6'-diethoxyspiro[cyclopropane-1,3'-isoporphyrin]-indole-imine hydrobromide 7d (247 mg, 1 mmol) in 4 mL of tetrahydrofuran. 2-Bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)ethanone If (393 mg, 1.27 mmol) and triethylamine (0.15 mL, 1.08 mmol) were added and the mixture was stirred for 12 hr. Filtration, the filter cake was washed with n-hexane (10 mL×2) and water (10 mL×3) and dried in vacuo to give the title product 1-(3,5-di-tert-butyl-4-hydroxyphenyl) -2- (5' ,6'-diethoxy-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 10 (233 mg, white powder) , Yield: 41.8%.

MS m/z (ESI): 493 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.65 (br. s, 1H), 9.10 (br. s, 1H), 8.06 (br. s, 1H), 7.91 (s, 1H), 7.85 (s, 2H), 7.06 (s, 1H), 5.30 (s, 2H), 4.18 (q, / = 7.2 Hz, 2H), 4.11 (q, / = 7.2 Hz, 2H), 1.76 -1.66 (m, 2H), 1.35 (m, 24H) Example 11

 L-(3-tert-Butyl-5-diethylamino-4-methoxyphenyl)-2-(5',6'-diethoxy-3'-imino-spiro [cyclopropane]

-1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

 First step

 1-(3-Amino-5-tert-butyl-4-methoxyphenyl)ethanone 1-(3-aminobutyl-5-diethylamino-4-methoxyphenyl)ethanone 8b (9.8 g, 44 mmol) dissolved in 50 mL

To the N,N-dimethylformamide, potassium carbonate (18.35 g, 133 mmol) and ethyl iodide (20.7 g, 133 mmol) were added, and the reaction was stirred for 12 hours. After adding 100 mL of water to the reaction mixture, the mixture was extracted with ethyl ether (50 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution (20 mL×3), dried over anhydrous sodium sulfate, filtered, Chromatography of the residue obtained from EtOAc EtOAc (EtOAc) ), Yield: 19.5%. MS m/z (ESI): 278 [M+l]

 Second step

 2-bromo-l-(3-tert-butyl-5-diethylamino-4-methoxyphenyl)ethanone 1-(3-tert-butyl-5-diethylamino-4-methyl Ethyl phenyl) ethyl ketone 11a (2.4 g, 8.66 mmol) was dissolved in 10 mL of acetic acid, tribromopyridine salt (3.6 g, 11.25 mmol) was added, and the reaction was stirred for 12 hours. The organic layer was combined with EtOAc (EtOAc) (EtOAc) The obtained residue was purified to silica gel column chromatography elut elut elut elut (850 mg, yellow solid), Yield: 27.5%

MS m/z (ESI): 358 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.67 (m, 1H), 7.56 (m, 1H), 4.46 (s, 2H), 3.96 (s, 3H), 3.21 (m, 4H), 1.45 ( s, 9H), 1.11 (m, 6H)

 third step

 L-(3-tert-Butyl-5-diethylamino-4-methoxyphenyl)-2-(5',6'-diethoxy-3'-imino-spiro [cyclopropane]

 -1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

Dissolve 5',6'-diethoxyspiro[cyclopropane-1,3'-isoporphyrin]-indole-imine hydrobromide 7d (246 mg, 1 mmol) in 5 mL of tetrahydrofuran. Add 2-bromo-1-(3-tert-butyl-5-diethylamino-4-methoxyphenyl)ethanone lib (368 mg, 1.03 mmol) and triethylamine (0.15 mL, 1.08 mmol) The reaction was stirred for 12 hours. Filtration, the filter cake was washed with EtOAc (1 mL) EtOAc (EtOAc (EtOAc) Methoxyphenyl)-2-(5',6'-diethoxy-3'- Imino-spiro[cyclopropane-1, hydrazine-isoporphyrin]-2'-yl)ethanone hydrobromide 11 (314 mg, white powder), yield: 52.2%.

 MS m/z (ESI): 523 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.69 (br. s, 1H), 9.15 (br. s, 1H), 7.93 (s, 1H), 7.59 (d, / = 1.6 Hz, 1H ), 7.54 (d, / = 1.6 Hz, 1H), 7.06 (s, 1H), 5.20 (s, 2H), 4.18 (q, J = 7.2 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H ), 3.88 (s, 3H), 3.17 (q, J = 7.2 Hz, 4H), 1.76 -1.61 (m, 4H), 1.40 (m, 15H), 1.20 (t, / = 7.2 Hz, 6H) 12

1-[3-tert-Butyl-4-methoxy-5-(l-piperidine)phenyl]-2-(5',6'-diethoxy-3'-imino-spiro[ring Propane-1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

 First step

 Tert-butyl-4-methoxy-5-(1-piperidinyl)phenyl]ethanone

 1-(3-Amino-5-tert-butyl-4-methoxyphenyl)ethanone 8b (2.21 g, 10 mmol) and 1,5-dibromopentenyl (4.6 g, 20 1^^1) Dissolved in 20 1111^, dimethylformamide, potassium carbonate (4.14 g, 30 mmol) and potassium iodide (0.17 g, 1.0 mmol), and the reaction was stirred at 50 ° C for 12 hours. After adding 20 mL of water to the reaction mixture, the mixture was combined with EtOAc (EtOAc (EtOAc) The obtained residue was purified to silica gel elution elution elution g, gray solid), Yield: 62.3%.

MS m/z (ESI): 290 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.66 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 4.03 (s, 3H), 3.03 (m, 4H) , 2.60 (s, 3H), 1.79 (m, 4H), 1.62 (m, 2H), 1.45 (s, 9H)

 Second step

1-Bromo-[3-tert-butyl-4-methoxy-5-(l-piperidine)phenyl]ethanone 1-[3-tert-butyl-4-methoxy-5-(1) - Piperidine) Phenyl]ethanone 12a (1.8 g, 6.2 mmol) was dissolved in 20 mL of acetic acid, tribromopyridinium salt (2.29 g, 7.15 mmol) was added, and the reaction was stirred for 12 hours. Concentrated under reduced pressure, After adding 20 mL of water, and extracting with ethyl acetate (50 mL×3), the organic phase is combined, washed with saturated sodium chloride solution (20 mL×3), dried over anhydrous sodium sulfate, filtered, The resulting residue was purified with EtOAc EtOAc (EtOAc). , yellow solid), Yield: 37.3%.

MS m/z (ESI): 370 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.68 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 4.54 (s, 2H), 4.04 (s, 3H) , 3.03 (m, 4H), 1.80 (m, 4H), 1.66 (m, 2H), 1.47 (s, 9H)

 third step

1-[3-tert-Butyl-4-methoxy-5-(l-piperidine)phenyl]-2-(5',6'-diethoxy-3'-imino-spiro[ring Propane-1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

 Dissolve 5',6'-diethoxyspiro[cyclopropane-1,3'-isoporphyrin]-indole-imine hydrobromide 7d (247 mg, 1 mmol) in 5 mL of tetrahydrofuran. Add 2-bromo-1-[3-tert-butyl-4-methoxy-5-(1-piperidinyl)phenyl]ethanone 12b (424 mg, 1.15 mmol) and triethylamine (0.2 mL, 1.44) Methyl), the reaction was stirred for 12 hours. Filtration, the filter cake was washed with n-hexane (5 mL×2) and water (5 mL×2) and dried in vacuo to give the title product 1-[3-tert-butyl-4-methoxy-5-(1-piperidine)benzene -2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 12 (246 mg, white powder), Yield: 39.9%.

MS m/z (ESI): 523 [M+l]

 1H NMR (400 MHz, DMSO-, ppm): δ 9.70 (br. s, 1H), 9.13 (br. s, 1H), 7.93 (s, 1H), 7.62 (d, / = 1.8 Hz, 1H), 7.56 (d, / = 1.8 Hz, 1H), 7.06 (s, 1H), 5.22 (s, 2H), 4.18 (q, J = 7.2 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.97 (s, 3H), 2.98 (m, 4H), 1.74 (m, 6H), 1.57 (m, 4H), 1.39 (m, 15H) Example 13

 N-[3-tert-butyl-5-[2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline]-2'- Acetyl

 -2-methoxyphenyl]acetamide hydrobromide

 First step

Ν-(5-Acetyl-3-tert-butyl-2-methoxyphenyl)acetamide, 1-0 amino-5-tert-butyl-4-methoxyphenyl)ethanone under ice bath 8b (12.0 g, 54 mmol) dissolved Triethylamine (15 mL, 109 mmol) was added to 100 mL of THF. The mixture was stirred for 0.5 hr, and then acetyl chloride 2b (6.14 mL, 81 mmol) was added dropwise. Concentrated under reduced pressure, EtOAc (EtOAc) (EtOAc (EtOAc) The residue obtained was purified by silica gel column chromatography elut elut elut elut eluting Solid), Yield: 94.4%.

MS m/z (ESI): 264 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.54 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.38 (br. s, 1H), 3.74 (s, 3H), 2.50 (s, 3H), 2.20 (s, 3H), 1.33 (s, 9H)

 Second step

 N-[5-(2-bromoacetyl)-3-tert-butyl-2-methoxyphenyl]acetamide N-(5-acetyl-3-tert-butyl-2-methoxybenzene Acetylamine 13a (3.7 g, 14.1 mmol) was dissolved in 20 mL of acetic acid, tribromopyridinium salt (4.5 g, 14.1 mmol) was added, and the reaction was stirred for 12 hours. The organic layer was concentrated under reduced pressure. EtOAc (EtOAc m. The obtained residue was purified to silica gel elut elut elut elut elut elut elut elut 3.2 g, white solid), Yield: 66.0%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.68 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.30 (br. s, 1H), 4.48 (s, 2H), 3.86 (s, 3H), 2.31 (s, 3H), 1.43 (s, 9H)

 third step

 N-[3-tert-butyl-5-[2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline]-2'- Acetyl]-2-methoxyphenyl]acetamide hydrobromide

 Dissolve 5',6'-diethoxyspiro[cyclopropane-1,3'-isoporphyrin]-indole-imine hydrobromide 7d (243 mg, 0.99 mmol) in 5 mL of tetrahydrofuran. Add N-[5-(2-bromoacetyl)-3-tert-butyl-2-methoxyphenyl]acetamide 13b (395 mg, 1.15 mmol) and triethylamine (0.15 mL, 1.08 mmol). The reaction was stirred for 12 hours. Filtration, the filter cake was washed with n-hexane (5 mL×2) and water (10 mL×3) and dried in vacuo to give the title product N-[3-ter-butyl-5-[2-(5',6'-diethoxy -3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)acetyl]-2-methoxyphenyl]acetamide hydrobromide 13 (193 Mg, white powder), Yield: 33.2%.

MS m/z (ESI): 508 [M+l]

1H NMR (400 MHz, DMSO-, ppm): δ 9.76 (br. s, 1H), 9.68 (br. s, 1H), 9.18 (br. s, 1H), 8.23 (s, 1H), 7.91 (s , 1H), 7.73 (s, 1H), 7.06 (s, 1H), 5.18 (s, 2H), 4.18 (q, J = 7.2 Hz, 2H), 4.16 (q, / = 7.2 Hz, 2H), 3.80 (s, 3H), 2.15 (s, 3H), 1.74 -1.60 (m, 4H), 1.39 (m, 15H) Example 14

2-[[3-tert-butyl-5-[2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline]-2' -yl)acetyl

 First step

 1-[(5-Acetyl-3-tert-butyl-2-methoxyphenyl)amino]acetonitrile 1-(3-amino-5-tert-butyl-4-methoxyphenyl)ethanone 8b (14.4 g, 65.2 mmol) was dissolved in 100 mL of N,N-dimethylformamide, and potassium carbonate (9.9 g, 72 mmol) and bromoacetonitrile (26.4 g, 220 mmol) were added and stirred at 70 ° C 12 hours. Filtration, and the filtrate was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) The residue obtained was purified by silica gel column chromatography elut elut elut elut eluting , yellow solid), Yield: 88.0%.

MS m/z (ESI): 261 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.56 (d, J = 2.0 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 4.49 (br. s, 1H), 4.24 (d, / = 6.8 Hz, 2H), 3.82 (s, 3H), 2.62 (s, 3H), 1.45 (s, 9H)

 Second step

 2-[(5-(2-bromoacetyl)-3-tert-butyl-2-methoxyphenyl]amino]acetonitrile 2-[(5-acetyl-3-tert-butyl-2-methyl) Oxyphenyl)amino]acetonitrile 14a (14.24 g, 54.7 mmol) was dissolved in 80 mL of acetic acid, tribromopyridine salt (18.37 g, 57.4 mmol) was added, and the reaction was stirred for 24 hours. 300 mL of water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (200 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution (50 mL×3), dried over anhydrous sodium sulfate The residue obtained was purified by silica gel column chromatography elutd elut elut elut Acetonitrile 14b (1.26 g, yellow oil), Yield: 7.0%.

MS m/z (ESI): 339 [M+l]

 third step

 2-[[3-tert-butyl-5-[2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline]-2' -yl)acetyl]-2-methoxyphenyl]amino]acetonitrile hydrobromide

Dissolve 5',6'-diethoxyspiro[cyclopropane-1,3'-isoporphyrin]-indole-imine hydrobromide 7d (249 mg, 1.03 mmol) in 5 mL of tetrahydrofuran. 2-[[5-(2-Bromoacetyl)-3-tert-butyl-2-methoxyphenyl]amino]acetonitrile 14b (408 mg, 1.19 mmol) and triethylamine (0.15 mL, 1.08 mmol) ), stirring reaction 12 small Time. Filtration, the filter cake was washed sequentially with n-hexane (5 mL×2) and water (10 mL×3) and dried in vacuo to give the title product 2-[[3-(4-butyl-5-[2-(5',6'- Oxy-3'-imino-spiro[cyclopropane-1,1'-isoporphyrin]-2'-yl)acetyl]-2-methoxyphenyl]amino]acetonitrile hydrobromide 14 (262 mg, white powder), Yield: 43.6%. MS m/z (ESI): 504 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.66 (br. s, 1H), 9.17 (br. s, 1H), 7.87 (s, 1H), 7.43 (d, / = 1.6 Hz, 1H ), 7.36 (d, / = 1.6 Hz, 1H), 7.07 (s, 1H), 6.16 (t, / = 6.8 Hz, 1H), 5.20 (s, 2H), 4.40 (d, / = 6.8 Hz, 2H ), 4.18 (q, / = 7.2 Hz, 2H), 4.11 (q, / = 7.2 Hz, 2H) _: 3.74 (s, 3H), 1.73 -1.62 (m, 4H), 1.40 (m, 15H) 15

L-(8-tert-Butyl-4-ethyl-2,3-dihydro-1,4-benzoxazin-6-yl)-2-(5',6'-diethoxy-3 '-Imino-spiro[cyclopropane-1,1'--2'-yl)ethanone hydrobromide

 First step

 1-(8-tert-butyl-4-ethyl-2,3-dihydro-1,4-benzoxazin-6-yl)-2-(5',6'-diethoxy-3 '-Imino-spiro[cyclopropane-1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

 Dissolve 5',6'-diethoxyspiro[cyclopropane-1,3'-isoporphyrin]-indole-imine hydrobromide 7d (250 mg, 1.02 mmol) in 5 mL of tetrahydrofuran. Add 2-bromo small (8-tert-butyl-4-ethyl-2,3-dihydro-1,4-benzoxazin-6-yl)-ethanone 6b (408 mg, 1.19 mmol) and three Ethylamine (0.15 mL, 1.08 mmol) was stirred for 12 h. Filtration, the filter cake was washed with n-hexane (5 mL×2) and water (10 mL×2) and dried in vacuo to give the title product 1-(8-tert-butyl-4-ethyl-2,3-dihydro-1,4 -benzoxazin-6-yl)-2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'- Ethyl ketone hydrobromide 15 (224 mg, white powder), yield: 37.6%.

MS m/z (ESI): 506 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.70 (br. s, 1H), 9.14 (br. s, 1H), 7.89 (s, 1H), 7.27 (m, 2H), 7.04 (s , 1H), 5.16 (s, 2H), 4.29 (t, / = 4.4 Hz, 2H), 4.17 (q, / = 7.2 Hz, 2H), 4.11 (q, / = 7.2 Hz, 2H), 3.10 (m , 4H), 1.75 (m, 4H), 1.36 (m, 15H), 1.19 (t, / = 7.2 Hz, 3H) Example 16

 2-[8-tert-butyl-6-[2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1, fluorenyl-isoindoline]-2'- Acetyl

 - 2,3-Dihydro-1,4-benzoxazine-4-yl]acetonitrile hydrobromide

 First step

 2-(6-acetyl-8-tert-butyl-2,3-dihydro-1,4-benzoxazin-4-yl)-acetonitrile 1-(8-tert-butyl-3,4- Dihydro-2H-1,4-benzoxazin-6-yl)ethanone 5c (12 g, 51.4 mmol) was dissolved in 60 mL of N,N-dimethylformamide and potassium carbonate (7.82 g, 56.6 mmol) and bromoacetonitrile (12.33 g, 103 mmol) were stirred at 70 ° C for 4 hours. To the reaction mixture, 200 mL of water was added, and the mixture was combined with ethyl ether (200 mL×3), and the organic phase was combined, washed with saturated sodium chloride (50 mL×3), dried over anhydrous sodium sulfate, filtered, Chromatography The residue obtained was purified using eluent B to give the title product 2-(6-acetyl-8-tert-butyl-2,3-dihydro-1,4-benzoxazin-4-yl) Acetonitrile 16a (9.4 g, white solid yield: 67.3%.

MS m/z (ESI): 273 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.52 (d, J = 2.0 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 4.44 (m, 2H), 4.29 (s, 2H) , 3.45 (m, 2H), 2.60 (s, 3H), 1.43 (s, 9H)

 Second step

 2-[6-(2-bromoacetyl)-8-tert-butyl-2,3-dihydro-1,4-benzoxazin-4-yl]acetonitrile 2-(6-acetyl-8 -tert-Butyl-2,3-dihydro-1,4-benzoxazin-4-yl)acetonitrile 16a (9.38 g, 34.4 mmol) was dissolved in 80 mL of acetic acid and tribromopyridine salt (11 g) , 34.4 mmol), stir the reaction for 24 hours. After adding 200 mL of water to the reaction mixture, the mixture was extracted with diethyl ether (100 mIX3), and the organic phase was combined, washed with a saturated sodium chloride solution (50 mL×3), dried over anhydrous sodium sulfate, filtered and evaporated. Chromatography of the residue obtained in eluent B to give the title product 2-[6-(2-bromoacetyl)-8-tert-butyl-2,3-dihydro-1,4-benzoxazine. 4-yl]acetonitrile 16b (3.0 g, black solid), Yield: 24.6%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.57 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 4.47 (m, 2H), 4.43 (s, 2H) , 4.29 (s, 2H), 3.47 (m, 2H), 1.43 (s, 9H)

 third step

2-[8-tert-butyl-6-[2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1, fluorenyl-isoindoline]-2'- Acetyl]- 2,3-dihydro-1,4-benzoxazin-4-yl]acetonitrile hydrobromide Dissolve 5',6'-diethoxyspiro[cyclopropane-1,3'-isoporphyrin]-indole-imine hydrobromide 7d (257 mg, 1.04 mmol) in 5 mL of tetrahydrofuran. 2-[6-(2-Bromoacetyl)-8-tert-butyl-2,3-dihydro-1,4-benzoxazin-4-yl]acetonitrile 16b (458 mg, 1.30 mmol) and Triethylamine (0.15 mL, 1.08 mmol) was stirred for 12 h. Filtration, the filter cake was washed with n-hexane (5 mL×2) and water (10 mL×2) and dried in vacuo to give the title product 2-[8-tert-butyl-6-[2-(5',6'-diethoxy -3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)acetyl]- 2,3-dihydro-1,4-benzoxazine-4 -yl]acetonitrile hydrobromide 16 (317 mg, yellow powder), yield: 50.8%.

MS m/z (ESI): 517 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.67 (br. s, 1H), 9.17 (br. s, 1H), 7.89 (s, 1H), 7.48 (s, 1H), 7.45 (s , 1H), 7.07 (s, 1H), 5.19 (s, 2H), 4.72 (s, 2H), 4.42 (m, 2H), 4.18 (q _: / = 7.2 Hz, 2H), 4.11 (q, / = 7.2 Hz, 2H), 3.40 (m, 2H), 1.75 - 1.62 (m, 4H), 1.38 (m, 15H) Example 17

 L-[3-(l-adamantyl)-4-methoxy-5-morpholinyl]-2-(5',6'-diethoxy-3'-imino-spiro[ring Propane

 -1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

1-[3-(1-adamantyl)-4-hydroxyphenyl]ethanone

1-(4-Hydroxyphenyl)ethanone 17a (408 mg, 3 mmol) and adamantyl-1-ol 17b (456 mg, 3 mmol) were dissolved in 2 mL dichloromethane and concentrated sulfuric acid (0.16 mL) , 3 mmol), stir at room temperature for 12 hours. Pour the reaction solution into 10 mL of water, add 10 mL of saturated sodium bicarbonate solution, and extract with methylene chloride (15 mL×3). The organic phase is combined, dried over anhydrous sodium sulfate and filtered. Law The obtained residue was purified with EtOAc EtOAc (EtOAc).

MS m/z (ESI): 271 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.94 (d, J = 2.0 Hz, 1H), 7.75 (dd, /; = 8.4 Hz, J ₂ = 2.0 Hz, 1H), 6.76 (d, / = 8.4 Hz, 1H), 6.00 (s, 1H), 2.60 (s, 3H), 2.24 (s, 9H), 1.83 (s, 6H)

 Second step

 1-[3-(1-Adamantyl)-4-hydroxy-5-iodo-phenyl]ethanone 1-[3-(1-adamantyl)-4-hydroxyphenyl]ethanone 17c ( 435 mg, 1.61 mmol) dissolved in 11 mL of a mixture of acetonitrile and N,N-dimethylformamide (V/V = 9:2). N-iodosuccinimide (398.4 mg, 1.77 mmol) ), the reaction was stirred for 0.5 hours. The residue was purified by silica gel column chromatography eluting elut elut elut elut eluting (300 mg, white solid), Yield: 47.0%

MS m/z (ESI): 395 [M-l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.20 (d, J = 2.0 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 6.02 (s, 1H), 2.58 (s, 3H) , 2.15 (s, 9H), 1.82 (s, 6H)

 third step

 1-[3-(1-Adamantyl)-4-hydroxy-5-iodo-benzene 1-[3-(l-adamantyl)-5-iodo-4-methoxyphenyl]ethanone Ethyl ketone 17d (303 mg, 0.77 mmol) was dissolved in 15 mL of acetone, and then potassium carbonate (316.8 mg, 2.3 mmol) and io Filtration, the filter cake was washed with ethyl acetate (10 mL×2), the filtrate was concentrated under reduced pressure, and 20 mL of ethyl acetate was added. The organic phase was combined and washed with water (20 mL×3) and saturated sodium chloride solution (20 mL), The aqueous sodium sulfate was dried, filtered, and the filtrate was evaporated.

MS m/z (ESI): 411 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.30 (d, J = 2.4 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 3.98 (s, 3H), 2.60 (s, 3H) , 2.09 (s, 9H), 1.82 (s, 6H)

 the fourth step

 1-[5-(l,l-Dimethoxyethyl)-3-iodo-2-methoxyphenyl]adamantane 1-[3-(1-adamantyl)-5-iodo- 4-Methoxyphenyl]ethanone 17e (123 mg, 0.3 mmol) was dissolved in 2 mL of methanol and trimethyl orthoformate (95.5 mg, 0.9 mmol) and camphorsulfonic acid (3.48 mg, 0.015 mmol). The reaction was stirred at 60 ° C for 3 hours. Add 200 mg of potassium carbonate and 20 mL of water, extract with ethyl acetate (10 mL×3), combine the organic phases, wash with saturated potassium carbonate solution (10 mL×3) and saturated sodium chloride solution (10 mL×2), anhydrous sodium sulfate Drying and filtration gave the title product 1-[5-(1,1-dimethoxyethyl)-3-iodo-2-methoxyphenyl]adamantane 17f (135 mg, yellow oil) Rate: 98.7%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.85 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 3.93 (s, 3H), 3.21 (s, 6H), 2.11 (s, 9H), 1.81 (s, 6H), 1.54 (s, 3H)

 the fifth step

 1-[5-(1,1-Dimethoxyethyl)-3-iodo-1-[1-(l-adamantyl)-4-methoxy-5-morpholinylphenyl]ethanone 2-methoxyphenyl]adamantane 17f (123 mg, 0.3 mmol) was dissolved in 20 mL of toluene, followed by morpholine (1.74 g, 20 mmol), 2-dicyclohexylphosphino-2'-( N,N-dimethylamine)-biphenyl (196.8 mg, 0.5 mmol), tris(dibenzylideneacetone)dipalladium (228.9 mg, 0.25 mmol) and sodium tert-butoxide (1.92 g, 20 mmol), 90 The reaction was stirred at ° C for 3 hours. Filtration, the filter cake was washed with ethyl acetate (10 mL×3), the filtrate was concentrated under reduced pressure, and 5 mL of acetic acid was added, and the mixture was stirred for 1 hour, concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with eluent system B. The title product 1-[3-(1-adamantyl)-4-methoxy-5-morpholinylphenyl]ethanone 17 g (560 mg, yellow solid) was obtained.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.61 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 3.99 (s, 3H), 3.89 (m, 4H) , 3.08 (m, 4H), 2.57 (s, 3H), 2.09 (s, 9H), 1.79 (s, 6H)

 Step 6

 1-[3-(1-Adamantyl)-4-methoxy-5-morpholinylphenyl]-2-bromo-ethanone 1-[3-(1-adamantyl)-4-methyl 17 g (527 mg, 1.42 mmol) of oxy-5-morpholinyl phenyl]ethanone was dissolved in 8 mL of acetic acid, tribromopyridinium salt (455 mg, 1.42 mmol) was added, and the reaction was stirred for 3.5 hours. The organic layer was combined with EtOAc (EtOAc) (EtOAc)EtOAc. The residue obtained was purified by eluent B to give the title product 1-[3-(1-adamantyl)-4-methoxy-5-morpholinylphenyl]-2-bromo-ethanone 17h ( 230 mg, yellow solid), Yield: 36.0%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.65 (d, / = 2.4 Hz, 1H), 7.53 (d, / = 2.4 Hz, 1H), 4.42 (s, 2H), 4.01 (s, 3H) , 3.90 (m, 4H), 3.09 (m, 4H), 2.09 (s, 9H), 1.79 (s, 6H)

 Seventh step

 L-[3-(l-adamantyl)-4-methoxy-5-morpholinyl]-2-(5',6'-diethoxy-3'-imino-spiro[ring Propane

 -1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

 Dissolve 5',6'-diethoxyspiro[cyclopropane-1,3'-isoporphyrin]-indole-imine hydrobromide 7d (246 mg, 1 mmol) in 6 mL of tetrahydrofuran. Add 1-[3-(1-adamantyl)-4-methoxy-5-morpholinylphenyl]-2-bromo-ethanone 17h (516 mg, 1.15 mmol) and triethylamine (0.15 mL, 1.08 mmol), the reaction was stirred for 12 hours. Filtration, the filter cake was washed with n-hexane (5 mL×2) and water (10 mL×2) and dried in vacuo to give the title product 1-[3-(1-adamantyl)-4-methoxy-5-morpholinylphenyl -2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 17 ( 317 mg, white powder), Yield: 22.9%.

MS m/z (ESI): 614 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.64 (br. s, 1H), 9.08 (br. s, 1H), 7.87 (s, 1H), 7.59 (d, / = 1.6 Hz, 1H ), 7.52 (d, / = 1.6 Hz, 1H), 7.05 (s, 1H), 5.20 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H), 4.11 (q, / = 7.2 Hz, 2H ), 3.96 (s, 3H), 3.82 (m, 4H), 3.01 (m, 4H), 2.07 (m, 9H), 1.76 (m, 6H), 1.75 - 1.60 (m, 4H), 1.40 (m, 6H) Example 18

 2-[8-tert-butyl-6-[2-(5',6'-diethoxy-3'-imino-spiro[cyclopropene-1, hydrazine-isoindoline]-2' -yl)acetyl-2,3-dihydro-1,4-benzoxazin-4-yl]ethyl acetate hydrobromide

 First step

 2-[8-tert-butyl-6-[2-(5',6'-diethoxy-3'-imino-spiro[cyclopropene-oxime, fluorene-isoindole]-2'- Acetyl]-2,3-dihydro-1,4-benzoxazin-4-yl]ethyl acetate hydrobromide 5',6'-diethoxyspiro[cyclopropane-1 , 3'-Isoporphyrin]-indole-imine hydrobromide 7d (252 mg, 1.02 mmol) was dissolved in 5 mL of tetrahydrofuran and 2-[6-(2-bromo-acetyl)-8- tert-Butyl-2,3-dihydro-1,4-benzoxazin-4-yl]-ethyl acetate 5e (440 mg, 1.10 mmol) and triethylamine (0.15 mL, 1.08 mmol), stirring 12 hours. Filtration, filter cake washed with n-hexane (10 mL×2) and water (10 mL×2) and dried in vacuo to give the title product 2-[8-t-butyl-6-[2-(5',6'-diethoxy) -3'-imino-spiro[cyclopropane-1, fluorene-isoindole]-2'-yl)acetyl]-2,3-dihydro-1,4-benzoxazin-4-yl] Ethyl acetate hydrobromide 22 (317 mg, yellow powder), Yield: 50.8%.

MS m/z (ESI): 565 [M+l ]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.67 (br. s, 1H), 9.16 (br. s, 1H), 7.92 (s, 1H), 7.30 (d, / = 1.2 Hz, 1H ), 7.08 (d, / = 1.2 Hz, 1H), 7.05 (s, 1H), 5.12 (s, 2H), 4.31 (m, 4H), 4.12 (m, 4H), 3.51 (m, 2H), 1.68 -1.60 (m, 4H), 1.38 (m, 15H), 1.20 (t, / = 7.2 Hz _; 3H) Example 19

l -(8-tert-Butyl 4-methyl-2,3-dihydro-1,4-benzoxazin-6-yl)-2-(5',6'-diethoxy-3' -imino-spiro[cyclopropane-1,1'-isoindoline-2'-yl)ethanone hydrobromide

first step

 1-(8-tert-butyl-3,4-l-(8-tert-butyl-4-methyl-2,3-dihydro-1,4-benzoxazin-6-yl)ethanone Dihydro-2H-1,4-benzoxazin-6-yl)ethanone 5c (1.5 g, 6.4 mmol) was dissolved in 20 mL of acetone and potassium carbonate (1.78 g, 12.8 mmol) and methyl iodide (4.56) g, 32.1 mmol), the reaction was stirred for 40 hours. The organic layer was combined with EtOAc (EtOAc) (EtOAc) The title product 1-C8-tert-butyl-4-methyl-2,3-dihydro-1,4-benzoxazin-6-yl)ethanone 19a (375 mg, brown oil) : 23.6%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.40 (d, J = 2.0 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 4.37-4.40 (m, 2H), 3.34-3.36 ( m, 2H), 2.99 (s, 3H), 2.58 (s, 3H), 1.42 (s, 9H)

 Second step

 2-bromo-l-(8-tert-butyl-4-methyl-2,3-dihydro-1,4-benzoxazin-6-yl)ethanone 1-(8-tert-butyl- 4-Methyl-2,3-dihydro-1,4-benzoxazin-6-yl)ethanone 19a (511 mg, 2.1 mmol) was dissolved in 6 mL of acetic acid and tribromopyridinium salt was added. Mg, 2.48 mmol), stirred for 3 hours. Concentrate under reduced pressure, add 50 mL of saturated sodium bicarbonate solution, and extract with ethyl acetate (50 mL×3). The organic phase is combined, washed with saturated sodium chloride solution (20 mL×3), dried over anhydrous sodium sulfate, filtered The residue was purified by silica gel column chromatography eluting elut elut 4-benzoxazin-6-yl)ethanone 19b (200 mg, yellow oil), yield: 29.6%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.42 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 4.45 (s, 2H), 4.39-4.42 (m, 2H), 3.35-3.38 (m, 2H), 2.99 (s, 3H), 1.44 (s, 9H)

 third step

L-(8-tert-Butyl 4-methyl-2,3-dihydro-1,4-benzoxazin-6-yl)-2-(5',6'-diethoxy-3' -imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide

 5',6'-Diethoxyspiro[cyclopropane-1,3'-isoporphyrin]-indole-imine hydrobromide 7d (249 mg, 1.01 mmol) and B 2-bromo-1 -(8-tert-Butyl-4-methyl-2,3-dihydro-1,4-benzoxazin-6-yl)ethanone 19b (390 mg, 1.2 mmol) was dissolved in 6 mL of THF. Triethylamine (0.15 mL, 1.08 mmol) was added and the reaction was stirred for 24 hours. Filtration, the filter cake was washed with n-hexane (10 mL) and water (10 mIX3) and dried in vacuo to give the title product 1-(8-tert-butyl 4-methyl-2,3-dihydro-1,4-benzene And oxazin-6-yl)-2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl) Ethyl ketone hydrobromide 19 (316 mg, pale yellow powder), Yield: 54.6%.

MS m/z (ESI): 492 [M+l] NMR NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.69 (br. s, 1H), 9.14 (br. s, 1H), 7.94 (s, 1H) _: 7.30 (d, / = 1.6 Hz, 1H ), 7.22 (d, / = 1.6 Hz, 1H), 7.05 (s, 1H), 5.18 (s, 2H), 4.35 (m _: 2H), 4.13 (m, 4H), 3.07 (m, 2H), 2.94 (s, 3H), 1.70 - 1.60 (m, 4H), 1.38 (m, 15H) Example 20

 L-[3-(4-Acetylpiperazin-1-yl)-5-tert-butyl-4-methoxyphenyl]-2-(5',6'-diethoxy-3'- Imino-snail

 '-Isoporphyrin]-2'-yl)ethanone hydrobromide

 First step

1-[4-[3-tert-butyl-5-(1,1-dimethoxyethyl)-2-methoxyphenyl]piperazine small group] ethyl ketone 1-tert-butyl-5 -(1,1-Dimethoxyethyl)-3-iodo-2-methoxybenzene 2f (11.5 g, 30.42 mmol) was dissolved in 60 mL of dioxane, followed by 1-piperazine-1 - keto-ketone (5.7 g, 39.55 mmol), tris(dibenzylideneacetone)dipalladium (1.15 g, 10%), 4,5-bis(diphenylphosphino)-9,9-dimethyl Xanthoxane (880 mg, 1.52 mmol) and sodium tert-butoxide C 5.85 g, 60.84 mmol) were stirred at 60 ° C for 7 hours. The reaction mixture was poured into 30 mL of ice water and 150 mL of ethyl acetate, and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (50 mL×2). The organic phase was combined and washed with saturated sodium chloride solution (50 mL×2) Concentration, the title product 1-[4-[3-tert-butyl- _{5- (U} -dimethoxyethyl)-2-methoxyphenyl]piperazine small group] ethyl ketone _{20a was obtained} directly. reaction.

 Second step

Ip-acetylpiperazin-1-yl)-5-tert-butyl-4-methoxyphenyl]ethanone 1-[4-[3-tert-butyl-5-(1,1-dimethyl) Ethyloxy)-2-methoxyphenyl]piperazin-1-yl]ethanone 20a (6.7 g, 17.7 mmol) was dissolved in 50 mL dichloromethane. The reaction was stirred for 12 hours. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut elut elut Methoxyphenyl]ethanone 20b (2.0 g, yellow solid (body), Yield: 20.0%.

MS m/z (ESI): 333 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.68 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 3.99 (s, 3H), 3.81 (m, 2H) , 3.66 (m, 2H), 3.07 (m, 4H), 2.56 (s, 3H), 2.15 (s, 3H), 1.41 (s, 9H)

 third step

1-[3-(4-Acetylpiperazin-1-yl)-5-tert-butyl-4-methoxyphenyl]-2 bromo-ethanone 1-[3-(4-acetylpiperidine) Pyrazin-1-yl)-5-tert-butyl-4-methoxyphenyl]ethanone 20b (1.8 g, 5.1 mmol) was dissolved in 15 mL of dichloromethane, and then acetic acid (1.2 g, 20.4 mmol) and Tribromopyridine salt (2.1 g _: 5.36 mmol), and the reaction was stirred for 12 hours. The residue was purified by silica gel column chromatography elut eluting Methoxyphenyl]-2 bromo-ethanone 20c (950 mg, yellow solid), Yield: 43.0%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.72 (d, J = 2.0 Hz, 1H), 7.51 (d, / = 2.0 Hz, 1H), 4.40 (s, 2H), 4.01 (s, 3H) , 3.81 (m, 2H), 3.66 (m, 2H), 3.07 (m, 4H), 2.16 (s, 3H), 1.41 (s, 9H)

 the fourth step

 L-[3-(4-Acetylpiperazin-1-yl)-5-tert-butyl-4-methoxyphenyl]-2-(5',6'-diethoxy-3'- Imino-snail

 [Cyclopropane-1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide salt 5',6'-diethoxyspiro[cyclopropane-1,3'-isoindole啉]-Γ-imine hydrobromide 7d (125 mg, 0.5 mmol) was dissolved in 3 mL of tetrahydrofuran, and 1-[3-(4-acetylpiperazin-1-yl)-5-tert-butyl was added. 4-methoxyphenyl]-2bromo-ethanone 20c (206 mg, 0.5 mmol) and triethylamine (76 mg, 0.75 mmol). Filtration, the filter cake was washed with EtOAc (EtOAc) (EtOAc) (EtOAcjjjjjjjj -tert-Butyl-4-methoxyphenyl]-2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1,1'-isoindoline] - 2'-yl)ethanone hydrobromide 20 (62 mg, white solid), yield: 21.5%.

MS m/z (ESI): 577 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.64 (br. s, 1H), 9.08 (br. s, 1H), 7.86 (s, 1H), 7.65 (d, J = 2.0 Hz, 1H ), 7.55 (d, J = 2.0 Hz, 1H), 7.05 (s, 1H), 5.18 (s, 2H), 4.41 (m, 4H), 3.98 (s, 3H), 3.67 (m, 4H), 3.02 (m, 2H), 2.96 (m, 2H), 2.06 (s, 3H), 1.73 -1.60 (m, 4H), 1.42-1.36 (m, 15H) Example 21

1- 3,5-di-tert-butyl-4-methoxyphenyl)-2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1, oxime-iso Porphyrin]-2'-yl)ethanone hydrobromide

first step

 1- 3,5-di-tert-butyl-4-hydroxyphenyl)ethanone

 Aluminum chloride (1.31 g, 9.79 mmol) was dissolved in 20 mL of dichloromethane under dry ice-acetone bath, 2,6-di-tert-butyl-phenol Id (2.0 g, 9.63 mmol) was added, and the reaction was stirred for 1 hour. Acetyl chloride le (0.401 mL, 9.79 mmol) was added dropwise, and the reaction was further stirred for 4 hours. To the reaction mixture, 20 mL of ice water was added, and the mixture was combined with methylene chloride (40 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate The title product was 1-3,5-di-tert-butyl-4-hydroxyphenyl)ethanone 21a (1.98 g,yield of yellow solid).

MS m/z (ESI): 249 [M+l]

 Second step

 1- 3,5-di-tert-butyl-4-methoxyphenyl)ethanone

 1-(3,5-Di-tert-butyl-4-hydroxyphenyl)ethanone 21a (1.29 g, 5.2 mmol) was dissolved in 50 mL of acetone and potassium carbonate (1.43 g, 10.34 mmol) and toluene-4 were added. Methyl sulfonate (1.93 g, 10.36 mmol) was stirred at 50 ° C for 12 hours. After filtration, the filtrate was concentrated under reduced pressure. (1.03 g, reddish brown oil), Yield: 75.4%.

MS m/z (ESI): 263 [M+l]

 third step

 2-bromo-l-(3,5-di-tert-butyl-4-methoxyphenyl)ethanone

 Dissolve 1-(3,5-di-tert-butyl-4-methoxyphenyl)ethanone 21b (711 mg, 2.71 mmol) in 20 mL of chloroform at 40 ° C and add copper bromide (964 mg) , 5.42 mmol), stir the reaction for 12 hours. Filtration, and the filtrate was concentrated under reduced pressure. Ethylketone 21c (295 mg, brown-red solid), yield: 31.9%. MS m/z (ESI): 343 [M+l]

 the fourth step

 1- 3,5-di-tert-butyl-4-methoxyphenyl)-2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1, oxime-iso Porphyrin]-2'-yl)ethanone hydrobromide

5',6'-Diethoxyspiro[cyclopropane-1,3'-isoporphyrin]-indole-imine hydrobromide 7d (198 mg, 0.8 Ment) dissolved in 3 mL of tetrahydrofuran, added 2-bromo-l-(3,5-di-tert-butyl-4-methoxyphenyl)ethanone 21c (303 mg, 0.89 mmol) and triethylamine (0.15) mL, 1.08 mmol), stirred for 48 hours. Filtration, the filter cake was washed with EtOAc (EtOAc) (EtOAc (EtOAcjjjjjjj -2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 21 ( 128 mg, white powder), Yield: 27.1%.

 MS m/z (ESI): 507 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.70 (br. s, 1H), 9.15 (br. s, 1H), 7.93 (s, 1H), 7.91 (s, 2H), 7.06 (s , 1H), 5.23 (s, 2H), 4.18 (q, J = 7.2 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.71 (s, 3H), 1.76- 1.60 (m, 2H) , 1.45 (s, 18H), 1.39 (m, 6H) Example 22

 L-(3,5-Di-tert-butylphenyl)-2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1, hydrazine-isoporphyrin] - 2'-base)

 First step

 1-(3,5-di-tert-butyl-phenyl)ethanone

 1-Bromo-3,5-di-tert-butyl-benzene 22a (3.58 g, 13.31 mmol) was dissolved in 26 mL of tetrahydrofuran under dry ice-acetone bath, and tetramethylethylenediamine (2.2 mL, 14.6 mmol) was added. The mixture was stirred for 1 hour with n-butyllithium (5.85 mL, 14.6 mmol), dimethylacetamide (2.46 mL, 26.6 mmol). To the reaction mixture, 20 mL of a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate (20 mL×3), and the organic phase was combined, washed with water (10 mL×2) and saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure and purified tolululululululululululululululululululululululululu Color oil), Yield: 58.2%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.82 (s, 2H), 7.66 (s, 1H), 2.62 (s, 3H), 1.37 (s, 18H)

 Second step

 2-bromo-l-(3,5-di-tert-butyl-phenyl)ethanone

Dissolve 1-(3,5-di-tert-butyl-phenyl)ethanone 22b (3.8 g, 16.4 mmol) in 100 mL of chloroform, add copper bromide (7.32 g, 32.7 mmol), stir at 36 °C Reaction for 24 hours. Filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified to silica crystal elut elut elut elut elut elut Yield: 66.8%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.85 (s, 2H), 7.70 (s, 1H), 4.48 (s, 2H), 1.37 (s, 18H)

 third step

 L-(3,5-Di-tert-butylphenyl)-2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1, hydrazine-isoporphyrin] - 2'-yl) ethyl ketone hydrobromide

 Dissolve 5',6'-diethoxyspiro[cyclopropane-1,3'-isoporphyrin]-indole-imine hydrobromide 7d (131 mg, 0.53 mmol) in 5 mL of tetrahydrofuran. 2-Bromo-1-(3,5-di-tert-butyl-phenyl)-ethanone 22c (193 mg, 0.62 mmol) and triethylamine (0.1 mL, 0.72 mmol). Filtration, filter cake washed with tetrahydrofuran (1 mL×2) and water (10 mL×3) and dried in vacuo to give the title product 1 3,5-di-tert-butylphenyl)-2-(5',6'-diethoxy -3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 22

(67 mg, white powder), Yield: 27.1%.

 MS m/z (ESI): 477 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.66 (br. s, 1H), 9.16 (br. s, 1H), 7.89 (s, 1H),

7.84 (s, 2H), 7.78 (s, 1H), 7.06 (s, 1H), 5.24 (s, 2H), 4.18 (q, / = 7.2 Hz, 2H), 4.11 (q, J

= 7.2 Hz, 2H), 1.76 -1.61 (m, 4H), 1.40 (m, 6H), 1.36 (s, 18H) Example 23

 L-(3,5-Di-tert-butyl-4-hydroxyphenyl)-2-(5',6'-diethoxy-7'-fluoro-3'-imino-spiro[cyclopropane-1 , Γ-isoporphyrin-2'-yl) ethyl ketone hydrobromide

4-bromo-2-fluorophenol

2-Fluorophenol 23a (210 g, 1.8 8 mol) was dissolved in 500 mL of chloroform under ice-cooling, and liquid bromine (94 mL, 1.88 mol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. Add 100 mL of saturated sodium sulfite solution, use two The methyl chloride was extracted (100 mL×3), and the organic phase was combined, washed with 10 mL of saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give the title product 4-bromo-2-fluorophenol 23b (321 g, pale yellow oil), Yield: 90.2%.

MS m/z (ESI): 191 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.21 (d, J = 2.4 Hz, 1H), 7.71 (m, 1H), 6.98 (m, m), 6A9 (br. s, 1H)

 Second step

 5-bromo-3-fluoro-2-hydroxy-benzaldehyde

 4-Bromo-2-fluorophenol 23b (170 g, 0.89 mol) was dissolved in 600 mL of trifluoroacetic acid, and urotropine (225 g, 1.6 mol) was added, and the reaction was refluxed for 5 hours. After cooling to room temperature, the reaction solution was poured into 1 L of water, 300 mL of 50% sulfuric acid solution was added, filtered, and the filter cake was washed with 20 mL of ethanol and dried in vacuo to give the title product 5-bromo-3-fluoro-2-hydroxy-benzene. Formaldehyde 23c (90 g, yellow solid), Yield: 46.2%.

MS m/z (ESI): 219 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 10.87 (br. s, 1H), 9.88 (s, 1H), 7.50 (m, 1H), 7.28 (s, 1H)

 third step

 5-bromo-3-fluoro-1,2-diphenol

 5-Bromo-3-fluoro-2-hydroxy-benzaldehyde 23c (80 g, 0.37 mol) was dissolved in 402 mL of 1M sodium hydroxide solution, and 402 mL of hydrogen peroxide was added thereto, and the reaction was stirred for 3 hours. To the reaction mixture was added 100 mL of EtOAc EtOAc (EtOAc m. -Bromo-3-fluoro-1,2-diphenol 23d (60 g, colorless solid), Yield: 79.4%.

MS m/z (ESI): 205 [M-l]

 the fourth step

 5-bromo-1,2-diethoxy-3-fluoro-benzene

 Dissolve 5-bromo-3-fluoro-1,2-diphenol 23d (20.7 g, 0.1 mol) in 150 mL of dimethyl sulfoxide, add ethyl iodide (24.2 mL, 0.3 mol) and potassium carbonate (34.5 g). , 0.25 mol), and the reaction was stirred at 50 ° C for 3.5 hours. To the reaction mixture, 600 mL of water was added, and the mixture was extracted with ethyl acetate (150 mIX3). The organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was obtained to give the title compound: 5-bromo-1,2-diethoxy-3-fluoro-benzene 23e (15.38 g, pale yellow oil).

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 6.89 (d, J = 2.0 Hz, 1H), 6.82 (t, J = 2.0 Hz, 1H), 4.09 (m, 4H), 1.45 (t, / = 7.2 Hz, 3H), 1.36 (t, / = 7.2 Hz, 3H)

 the fifth step

 1 ,2-dibromo -4,5-diethoxy-3-fluoro-benzene

Dissolve 5-bromo-1,2-diethoxy-3-fluoro-benzene 23e (15 g, 0.057 mol) in 100 mL of acetic acid, plus Sodium acetate (6.22 g, 0.076 mol) and liquid bromine (12.12 g, 0.076 mol) were added, and the reaction was stirred at 50 ° C for 5 hours. After adding 100 mL of water and extracting with n-hexane (100 mL×3), the organic phase was combined, washed with saturated sodium chloride (50 mL), dried over anhydrous magnesium sulfate, filtered, Dibromo-4,5-diethoxy-3-fluoro-benzene 23f (llg, colorless oil), yield: 56.0%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.05 (s, 1H), 4.29 (q, / = 6.4 Hz, 2H), 4.19 (q, / = 8.0 Hz, 2H), 1.52 (t, / = 6.4 Hz, 3H), 1.41 (t, / = 8.0 Hz, 3H)

 Step 6

 4,5-diethoxy-3-fluoro-dicarbonitrile

Dissolve 1,2-dibromo-4,5-diethoxy-3-fluoro-benzene 23f (11.1 g, 0.032 mol) in 60 mL of N,N-dimethylformamide, followed by cyanide Copper (11.6 g, 0.13 mol) and cuprous iodide (6.17 g, 0.032 mol) were stirred and refluxed for 8 hours. Concentrate under reduced pressure, add 50 mL of aqueous ammonia and 50 mL of ethyl acetate. The mixture is extracted with ethyl acetate (50 mL×3). The organic phase is combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate The filtrate was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Yield: 34.7%. 1H NMR (400 MHz, CDC1 ₃ , ppm): δ 6.83 (s, 1H), 4.55 (m, 2H), 4.13 (m, 2H), 1.48 (t, / = 6.0 Hz, 3H), 1.39 (t, / = 6.8 Hz, 3H)

 Seventh step

 5',6'-diethoxy-7-fluoro-spiro[cyclopropane-1,3'-isoindoline]-1'-imine 5',6'-diethoxy-4'- Fluorine-spiro[cyclopropane-1,3'-isoindoline]-1'-imine, 4 g of 4,5-diethoxy-3-fluoro-dicarbonitrile (2.26 g, 9.66 mmol) Dissolved in 100 mL of diethyl ether, and added tetraisopropyl titanate (3.18 mL, 10.75 mmol) and ethylmagnesium bromide (7.1 mL, 21.3 mmol), and the mixture was stirred for 2 hours. To the reaction liquid, 55 mL of methanol was added, and the obtained residue was purified by silica gel column chromatography to eluent system A to give the title product 5',6'-diethoxy-7'-fluoro-spiro[cyclopropene- 1,3'-isoporphyrin] -1'-imine 23h and 5',6'-diethoxy-4'-fluoro-spiro[cyclopropane-1,3'-isoindoline] - Γ-imine 23i (955 mg, dark red powder), Yield: 37.4%.

MS m/z (ESI): 265 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 7.01 (s, 1H), 4.14 (m, 4H), 1.82 (m, 2H), 1.67 (m, 2H), 1.34 (m, 6H)

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 7.94 (s, 1H), 4.17 (m, 4H), 1.81 (m, 2H), 1.69 (m, 2H), 1.34 (m, 6H)

 Eighth step

 1- 3,5-di-tert-butyl-4-hydroxyphenyl)-2-(5',6'-diethoxy-7'-fluoro-3'-imino-spiro[cyclopropane-1, Γ-isoporphyrin]-2'-yl)ethanone hydrobromide

5',6'-diethoxy-7-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 23h and 5',6'-diethoxy-4 '-Fluoro-spiro[cyclopropane-1,3'-isoporphyrin]-indole-imine 23i (277 mg, 1.05 mmol) was dissolved in 3 mL of tetrahydrofuran and added 2-bromo-1-(3,5 -di-tert-butyl-4-hydroxyphenyl)ethanone If (352 mg, 1.08 mmol) and three Ethylamine (0.2 mL, 1.44 mmol) was stirred for 12 h. Filtration, the filter cake was washed with n-hexane (10 mL×2) and water (10 mL×2) and dried in vacuo to give the title product 1-C3,5-di-tert-butyl-4-hydroxyphenyl) -2-(5',6 '-Diethoxy-7-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 23 (17 mg, brown Powder), Yield: 2.7%.

MS m/z (ESI): 511 [M+l]

 1H NMR (400 MHz, DMSO-, ppm): δ 7.95 (s, 1H), 7.79 (s, 2H), 5.19 (s, 2H), 4.22 (q, / = 7.2 Hz, 4H), 1.78 (m, 4H), 1.46 (s, 18H), 1.31 (t, / = 7.2 Hz, 6H) Example 24

 1- 3,5-di-tert-butyl-4-hydroxyphenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindole Porphyrin

 -2-yl)ethanone hydrobromide

 First step

 2-(3,4-diethoxy-5-fluoro-phenyl)propan-2-ol

 5-Bromo-1,2-diethoxy-3-fluoro-benzene 23e (26.3 g, 0.1 mol) was dissolved in 100 mL of diethyl ether at -78 ° C, and n-butyllithium (44 mL, 0.11 mol), the reaction was stirred for 30 minutes, acetone (8.1 mL, 0.11 mol) was added, and the reaction was continued for 2 hours. To the reaction mixture was added 200 mL of water, EtOAc (EtOAc (EtOAc) Diethoxy-5-fluoro-phenyl)propan-2-ol 24a (23.7 g, yellow oily yield: 97.9%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 6.87 (m, 1H), 6.81 (m, 1H), 4.14 (m, 4H), 1.57 (s, 6H), 1.47 (t, / = 7.2 Hz, 3H), 1.31 (t, / = 7.2 Hz, 3H)

 Second step

 5-(3,4-diethoxy-5-, 5-(l-azido-1-methyl-ethyl)-1,2-diethoxy-3-fluoro-benzene ice bath Fluoro-phenyl)propan-2-ol 24a (21.97 g, 0.091 mol) was dissolved in

In 200 mL of chloroform, sodium azide (17.7 g, 0.27 mol) and trifluoroacetic acid (33.7 mL, 0.46 mol) were added, and the reaction was stirred for 12 hours. Concentrated under reduced pressure, extracted with dichloromethane (200 mL×2), combined organic The mixture was washed with sodium hydrogen carbonate solution (100 mL×2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give the title product 5-(1-azido-1-methyl-ethyl)-1,2-di Oxy-3-fluoro-benzene 24b (24.1 g, yellow oily yield: 99.2%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 6.75 (m, 2H), 4.12 (m, 4H), 1.60 (s, 6H), 1.45 (t, J = 1.2 Hz, 3H), 1.36 (t, J = 7.2 Hz, 3H)

 third step

 1-(1-azido-1-methyl-ethyl)-2-bromo-4,5-diethoxy-3-fluoro-benzene 5-(1-azido-1-methyl-B -1,2-diethoxy-3-fluoro-benzene 24b (21.4 g, 0.08 mol) dissolved in 200 mL of acetic acid, sodium acetate (13.1 g, 0.16 mol) and liquid bromine (8 mL, 0.16) Mol), the reaction was stirred for 48 hours. Add 30 mL of saturated sodium sulfite solution, extract with n-hexane (150 mL×3), and combine the organic phase, then wash with saturated sodium bicarbonate solution (150 mL×2) and saturated sodium chloride solution (150 mL), dry over anhydrous magnesium sulfate The filtrate was concentrated under reduced pressure to give the title product 1-(1-azit-1-methyl-ethyl)-2-bromo-4,5-diethoxy-3-fluoro-benzene 24c (20.4 g, Yellow oil), Yield: 73.5%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.01 (d, J = 2.0 Hz, 1H), 4.16 (m, 4H), 1.83 (s, 6H), 1.49 (t, / = 7.2 Hz, 3H) , 1.41 (t, / = 7.2 Hz, 3H)

 the fourth step

 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 1-(1-azido small methyl-ethyl)-2-bromo-4,5- Diethoxy-3-fluoro-benzene 24c (10 g, 28.8 mmol) was dissolved in 100 mL of dimethyl sulfoxide, and copper cyanide (5.16 g, 57.6 mmol) and cuprous iodide (10.9 g, 57.6) were added. Methyl), the reaction was stirred at 150 ° C for 1 hour. 300 mL of water and 300 mL of ethyl acetate were added, the organic phase was washed with 300 mL of hydrochloric acid, and the aqueous phases were combined, and the pH was adjusted to 12 to 13 with 300 mL of 1 M sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate (150 mL×3). EtOAcjjjjjjjjjjjjjj The title product, 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (0.9 g, m. MS m/z (ESI): 267 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.01 (s, 1H), 4.18 (m, 2H), 4.10 (m, 2H), 1.48 (t, J = 1.2 Hz, 3H), 1.44 (s, 6H), 1.37 (t, / = 7.2 Hz, 3H)

 the fifth step

 1- 3,5-di-tert-butyl-4-hydroxyphenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindole Porphyrin

 -2-yl)ethanone hydrobromide

Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (266 mg, 1 mmol) in 7 mL of N,N-dimethylformamide. 2-Bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)ethanone lf (360 mg, 1.1 mmol) was added, and the mixture was stirred for 12 hr. To the reaction mixture was added with EtOAc (EtOAc) (EtOAc (EtOAc) The obtained residue was purified to silica gel column chromatography elut elut elut elut elut elut 4-fluoro-3-imino-U-dimethyl-isoporphyrin -2-yl)ethanone hydrobromide 24 (110 mg, yellow solid), yield: 21.6%.

 MS m/z (ESI): 513 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.37 (br. s, 1H), 8.98 (br. s, 1H), 8.05 (br. s 1H), 7.83 (s, 2H), 7.48 ( s, 1H), 5.47 (s, 2H), 4.26 (m, 2H), 4.11 (m, 2H), 1.51 (s, 6H) 1.44 (s, 18H), 1.41 (t, / = 7.2 Hz, 3H) , 1.31 (t, / = 7.2 Hz, 3H) Example 25

 1- 3-tert-butyl-4-methoxy-5-pyrrolidin-1-yl-phenyl)-2-(7-imino-2,5-dimethyl-5-phenyl-pyrrole

 [3,4-b]pyridine-6-ethylethanone hydrobromide

 9f 25

 First step

 1- 3-tert-butyl-4-methoxy-5-pyrrolidin-1-yl-phenyl)-2-(7-imino-2,5-dimethyl-5-phenyl-pyrrole

 [3,4-b]pyridine-6-yl)ethanone hydrobromide

 2,5-Dimethyl-5-phenyl-6H-pyrrolo[3,4-b]pyridine-7-imine 9f (237 mg, 1 mmol) and 2-bromo-1-(3-tert) Butyl-4-methoxy-5-pyrrolidin-1-yl-phenyl)ethanone 8d (424.8 mg, 1.2 mmol) was dissolved in 3 mL of N,N-dimethylformamide and stirred for 12 hours. . To the reaction mixture, 5 mL of water was added, and the mixture was combined with ethyl acetate (20 mL×3), and the organic phase was combined, washed with a saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate, filtered, The residue obtained was purified by silica gel column chromatography elut elut elut elut elut elut eluting Imino-2,5-dimethyl-5-phenyl-B-pyrolo[3,4-b]pyridin-6-yl)ethanone hydrobromide 25 (130 mg, yellow solid), yield : 22.0%.

 MS m/z (ESI): 512 [M+l]

1H NMR (400 MHz, DMSO-, ppm): δ 7.93 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.37 (m, 7H), 5.04 (d, / = 16.8 Hz, 1H), 3.82 (s, 3H), 3.14 (m, 4H), 2.74 (s, 3H), 1.99 (s, 3H), 1.90 (m, 4H), 1.36 (s, 9H) Example 26 L-(3-tert-Butyl-4-methoxy-5-pyrrolidin-1-yl-phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-1 , 1-dimethyl acid salt

 First step

 1-(3-tert-butyl-4-methoxy-5-pyrrolidin-1-yl-phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-1 ,1-dimethyl-isoindolin-2-yl)ethanone hydrobromide

 Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (266 mg, 1 mmol) in 7 mL of N,N-dimethylformamide. 2-Bromo-1-(3-tert-butyl-4-methoxy-5-pyrrolidin-1-yl-phenyl)ethanone 8d (390 mg, 1.1 mmol) was added, and the mixture was stirred for 12 hr. Add 50 mL of water to the reaction solution, and extract with ethyl acetate (25 mL×4). The organic phase is combined, washed with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate, filtered The residue was purified by silica gel column chromatography eluting elut elut -2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindolin-2-yl)ethanone hydrobromide 26 (61 mg, Yellow solid), Yield: 11.3%.

 MS m/z (ESI): 540 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 7.50 (d, / = 2.0 Hz, 1H), 7.45 (s, 2H), 5.41 (s, 2H), 4.27 (q, / = 7.2 Hz, 2H), 4.13 (q, / = 7.2 Hz, 2H), 3.67 (s, 3H), 3.19 (m, 4H), 1.94 (m, 4H), 1.51 (s, 6H), 1.41 (m, 12H), 1.32 (t, / = 7.2 Hz, 3H) Example 27

 1-(3-tert-Butyl-4-methoxy-5-morpholinylphenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-U-dimethyl- different

 First step

 1-(3-tert-Butyl-4-methoxy-5-morpholinylphenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-U-dimethyl- Isoindol-2-yl)ethanone hydrobromide

 Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (400 mg, 1.5 mmol) in

Add 2-bromo-1-(3-tert-butyl-4-methoxy-5-morpholinylphenyl)ethanone 2h (610 mg, 1.65 mmol) to 10 mL of N,N-dimethylformamide The reaction was stirred for 12 hours. Add 100 mL of water to the reaction solution, and extract with ethyl acetate (50 mL×5). The organic phase is combined, washed with water (50×3 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate, filtered Concentration by pressure gave the title product 1-(3-tert-butyl-4-methoxy-5-morpholinylphenyl)-2-(5,6-diethoxy-4-fluoro-3-imino -1 , 1-Dimethyl-isoindol-2-yl)ethanone hydrobromide 27 (84 mg, yellow solid), yield: 8.4%.

MS m/z (ESI): 556 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.35 (br. s, 1H), 8.99 (br. s, 1H), 7.67 (d, / = 2.0 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.46 (s, 1H), 5.47 (s, 2H), 4.27 (q, J = 7.2 Hz, 2H), 4.13 (q, J = 7.2 Hz, 2H), 4.01 (s, 3H) ), 3.84 (m, 4H), 3.04 (m, 4H), 1.58 (s, 6H), 1.41 (m, 12H), 1.32 (t, / = 7.2 Hz, 3H) Example 28

1-[3-tert-Butyl-4-methoxy-5-(l-piperidine)phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1, 1-two

 -2-yl)ethanone hydrobromide

 First step

 1-[3-tert-butyl-4-methoxy-5-(1-piperidinyl)phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1, 1-dimethyl-isoindolin-2-yl)ethanone hydrobromide

Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (266 mg, 1.0 mmol) in 7 mL of N,N-dimethylformamide. Add 2-bromo-1-[3-tert-butyl-4-methoxy-5-(1-piperidinyl)phenyl]ethanone 12b (400 mg, 1.1 mmol), stirred for 12 hours. 70 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL×2). The organic phase was combined, washed with water (50 mL) and saturated sodium chloride solution (50 mL). Concentrated to 15 mL under reduced pressure and filtered to give the title product 1-[3-tert-butyl-4-methoxy-5-(1-piperidine)phenyl]-2-(5,6-diethyl Oxy-4-fluoro-3-imino-1, 1-dimethyl-isoindolin-2-yl)ethanone hydrobromide 28 (116 mg, white solid), yield: 20.9%.

MS m/z (ESI): 554 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.27 (br. s, 1H), 8.95 (br. s, 1H), 7.64 (d, / = 2.0 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.45 (s, 1H), 5.41 (s, 2H), 4.27 (q, J = 7.2 Hz, 2H), 4.13 (q, / = 7.2 Hz, 2H), 3.98 (s, 3H ), 2.99 (m, 4H), 1.73 (m, 4H), 1.57 (m, 2H), 1.51 (s, 6H), 1.39 (m, 12H), 1.34 (t, / = 7.2 Hz, 3H) 29

 N-[3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl) Acetyl-2-methoxyphenyl]acetamide hydrobromide

first step

 N-[3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl) Acetyl]-2-methoxyphenyl]acetamide hydrobromide

 Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (266 mg, 1.0 mmol) in 6 mL of N,N-dimethylformamide. N-[5-(2-Bromoacetyl)-3-tert-butyl-2-methoxyphenyl]acetamide 13b (380 mg, 1.1 mmol) was added, and the mixture was stirred for 12 hr. Add 100 mL of water to the reaction solution, and extract with ethyl acetate (50 mL×3). The organic phase is combined, washed with water (50×2 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate, filtered Concentration by pressure gave the title product N-[3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-U-dimethyl-isoporphyrin) 2-yl)acetyl]-2-methoxyphenyl]acetamide hydrobromide 29 (90 mg, pale yellow solid), yield: 17.0%.

MS m/z (ESI): 528 [M+l]

1H NMR (400 MHz, DMSO-, ppm): δ 9.82 (s, 1H), 9.44 (br. s, 1H), 9.01 (br. s, 1H), 8.21 (s, 1H), 7.76 (s, 1H), 7.47 (s, 1H), 5.44 (s, 2H), 4.27 (q, 7 = 7.2 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H ), 3.80 (s, 3H), 2.14 (s, 3H), 1.50 (s, 6H), 1.41 (s, 9H), 1.33 (m, 6H) Example 30

 L-(8-tert-Butyl-4-methyl-2,3-dihydro-1,4-benzoxazin-6-yl)-2-(5,6-diethoxy-4-fluoro -3-imino

 First step

 1-(8-tert-butyl-4-methyl-2,3-dihydro-1,4-benzoxazin-6-yl)-2-(5,6-diethoxy-4-fluoro -3-imino

 -U-dimethyl-isoporphyrin-2-yl)ethanone hydrobromide

 Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (300 mg, 1.1 mmol) in 7 mL of N,N-dimethylformamide. Add 2-bromo small (8-tert-butyl-4-methyl-2,3-dihydro-1,4-benzoxazin-6-yl)ethanone 19b (440 mg, 1.35 mmol), stir the reaction 12 hours. After adding 75 mL of water to the reaction mixture, ethyl acetate (50 mL×2), EtOAc (EtOAc) Product 1-(8-tert-Butyl-4-methyl-2,3-dihydro-1,4-benzoxazin-6-yl)-2-(5,6-diethoxy-4- Fluoro-3-imino-U-dimethyl-isoindolin-2-yl)ethanone hydrobromide 30 (80 mg, pale yellow solid), yield: 10.8%.

MS m/z (ESI): 513 [M+l]

1H NMR (400 MHz, DMSO-, ppm): δ 7.40 (s, 1H), 7.34 (s, 1H), 7.26 (s, 1H), 5.28 (s _; 2H), 4.36 (m, 2H), 4.26 ( q, J = 7.2 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.33 (m, 2H), 2.95 (s, 3H), 1.48 (s, 6H), 1.37 (m, 12H), 1.31 (t, /= 7.2 Hz, 3H) Example 31

2-[8-tert-Butyl-6-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl) Acetyl] -

2,3-dihydro-1,4 ester hydrobromide

 First step

 2-[8-tert-Butyl-6-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl) Acetyl]-2,3-dihydro-1,4-benzoxazin-4-yl]ethyl acetate hydrobromide 5,6-diethoxy-7-fluoro-3,3-di Methyl-isoindoline 24d (200 mg, 0.75 mmol) dissolved in

Add 2-[6-(2-bromoacetyl)-8-tert-butyl-2,3-dihydro-1,4-benzoxazine-4 to 5 mL of N,N-dimethylformamide Ethyl acetate 5e (330 mg, 0.83 mmol) was stirred for 12 hours. Add 20 mL of water to the reaction solution, and extract with ethyl acetate (50 mL×2). The organic phase is combined, washed with water (10 mL×3) and saturated sodium chloride solution (10 mL×3), dried over anhydrous magnesium sulfate, filtered Concentration by pressure gave the title product 2-[8-tert-butyl-6-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindole) Porphyrin-2-yl)acetyl]- 2,3-dihydro-1,4-benzoxazin-4-yl]ethyl acetate hydrobromide 31 (88 mg, pale yellow solid), yield : 17.7%. MS m/z (ESI): 584 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.44 (br. s, 1H), 8.96 (br. s, 1H), 7.48 (s, 1H), 7.32 (s, 1H), 7.14 (s , 1H), 5.38 (s, 2H), 4.31 (m, 4H), 4.25 (m, 2H), 4.11 (m, 4H), 3.50 (m, 2H), 1.48 (s, 6H), 1.40 (t, / = 7.2 Hz, 3H), 1.37 (s, 9H), 1.30 (t, / = 7.2 Hz, 3H), 1.19 (t, / = 7.2 Hz, 3H) Example 32

1-[3-(l-Adamantyl)-4-methoxy-5-morpholinylphenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1, Γ-dimethyl--2-yl)ethanone hydrobromide

 First step

1-[3-(1-adamantyl)-4-methoxy-5-morpholinylphenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1, 1'-Dimethyl-isoindolin-2-yl)ethanone hydrobromide Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (266 mg, 1 mmol) in 5 mL of N,N-dimethylformamide. 1-[3-(1-Adamantyl)-4-methoxy-5-morpholinylphenyl]-2-bromo-ethanone 17h (493 mg, 1.1 mmol) was added, and the mixture was stirred for 12 hr. 20 mL of water and 15 mL of ethyl acetate were added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (5 mL×3), and the organic phase was combined, washed with water (10 mL×3) and saturated sodium chloride solution (10 mL×3), anhydrous Drying over magnesium sulfate, filtration, and EtOAc EtOAcjjjjjjjjjj Ethoxy-4-fluoro-3-imino-1,1 '-dimethyl-isoindolin-2-yl)ethanone hydrobromide 32 (40 mg, pale yellow solid), yield: 5.6%.

MS m/z (ESI): 634 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.35 (br. s, 1H), 8.99 (br. s, 1H), 7.61 (m, 1H), 7.56 (m, 1H), 7.46 (s , 1H), 5.46 (s, 2H), 4.26 (m, 2H), 4.11 (m, 2H), 3.96 (s, 3H), 3.82 (m, 4H), 3.02 (m, 4H), 2.07 (s, 9H), 1.75 (s, 6H), 1.50 (s, 6H), 1.41 (t, / = 7.2 Hz, 3H), 1.31 (t, / = 7.2 Hz, 3H) Example 33

 L-(8-tert-Butyl-4-ethyl-2,3-dihydro-1,4-benzoxazin-6-yl)-2-(5,6-diethoxy-4-fluoro -3-imino

 -1 , 1-dimethyl hydrobromide

first step

 1-(8-tert-butyl-4-ethyl-2,3-dihydro-1,4-benzoxazin-6-yl)-2-(5,6-diethoxy-4-fluoro -3-imino

 -1 , 1-dimethyl-isoindolin-2-yl)ethanone hydrobromide salt 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole Amine 24d (200 mg, 0.75 mmol) was dissolved in 4 mL of N,N-dimethylformamide and 2-bromo-1-(8-tert-butyl-4-ethyl-2,3-dihydro- 1, 4-benzoxazin-6-yl)ethanone 6b (282 mg, 0.83 mmol), and the reaction was stirred for 12 hours. 5 mL of water and 5 mL of ethyl acetate were added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (5 mIX3), and the organic phase was combined, washed with water (10 mL> <3) and saturated sodium chloride solution (10 mL×3) The title product was 1-(8-tert-butyl-4-ethyl-2,3-, the titled product was obtained. Dihydro-1,4-benzoxazin-6-yl)-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoporphyrin 2-yl) ethyl ketone hydrobromide 33 (55 mg, pale yellow solid), yield: 12.1%.

MS m/z (ESI): 526 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.23 (br. s, 1H), 8.92 (br. s, 1H), 7.45 (s, 1H), 7.56 (m, 1H), 7.27 (m, 1H), 5.35 (s, 2H), 4.27 (m, 4H), 4.12 (m, 2H), 3.43 (m, 2H), 3.37 (t, / = 4.0 Hz , 2H), 1.50 (s, 6H), 1.42 (t, / = 7.2 Hz, 3H), 1.37 (s, 9H), 1.31 (t, / = 7.2 Hz, 3H), 1.12 (t, / = 6.0 Hz , 3H) Example 34

L-(3,5-Di-tert-butyl-4-methoxyphenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-U-dimethyl-isoindole哚

 -2-yl)ethanone hydrobromide

 First step

 1-(3,5-di-tert-butyl-4-methoxyphenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-U-dimethyl-isoindole Porphyrin-2-yl)ethanone hydrobromide

 Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (200 mg, 0.75 mmol) in 4 mL of N,N-dimethylformamide. 2-Bromo-1-(3,5-di-tert-butyl-4-methoxyphenyl)ethanone 21c (0.28 g, 0.83 mmol) was added, and the mixture was stirred for 12 hr. 5 mL of water and 5 mL of ethyl acetate were added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (5 mL×3), and the organic phase was combined, washed with water (10 mL×3) and saturated sodium chloride solution (10 mL×3), anhydrous The title compound was 1-(3,5-di-tert-butyl-4-methoxyphenyl) -2-, ield. (5,6-Diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)ethanone hydrobromide 34 (60 mg, pale yellow solid ), yield: 13.2%.

 MS m/z (ESI): 527 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.31 (br. s, 1H), 8.96 (br. s, 1H), 7.93 (s, 2H), 7.45 (s, 1H), 5.43 (s , 2H), 4.27 (m, 2H), 4.12 (m, 2H), 3.71 (s, 3H), 1.51 (s, 6H), 1.45 (s, 18H), 1.41 (m, 3H), 1.31 (t, / = 7.2 Hz, 3H) Example 35

L-(3,5-Di-tert-butylphenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindole-2- -ethyl ketone hydrobromide

 First step

 L-(3,5-Di-tert-butylphenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindoline-2 -yl) ethyl ketone hydrobromide

 Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (266 mg, 1 mmol) in 4 mL of N,N-dimethylformamide. 2-Bromo-1-(3,5-di-tert-butyl-phenyl)ethanone 22c (0.34 g, 1.1 mmol) was added, and the mixture was stirred for 12 hr. 5 mL of water and 5 mL of ethyl acetate were added, and the aqueous phase was extracted with ethyl acetate (5 mL×3), and the organic phase was combined, washed with water (100 mL) Filtration, the filtrate was concentrated under reduced pressure, ethyl acetate (2 mL), filtered, and filtered, and evaporated to give the title product 1-C3,5-di-tert-butylphenyl)-2-(5,6-diethoxy) 4-fluoro-3-imino-U-dimethyl-isoindolin-2-yl)ethanone hydrobromide 35 (70 mg, white solid), yield: 12.1%.

MS m/z (ESI): 497 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.37 (br. s, 1H), 8.98 (br. s, 1H), 7.87 (m, 2H), 7.78 (m, 1H), 7.47 (s , 1H), 5.48 (s, 2H), 4.26 (m, 2H), 4.12 (m, 2H), 1.52 (s, 6H), 1.42 (t, / = 7.2 Hz, 3H), 1.36 (s, 18H) , 1.31 (t, / = 7.2 Hz, 3H) Example 36

1-[3-tert-Butyl-4-methoxy-5-(l-piperidine)phenyl]-2-(5,6-diethoxy-1,1-diethyl-4-fluoro -3-imino-salt

 First step

 3-(3,4-diethoxy-5-fluoro-phenyl)pentan-3-ol

 5-Bromo-1,2-diethoxy-3-fluoro-benzene 23e (26.3 g, 0.1 mol) was dissolved in 100 mL of diethyl ether at -78 ° C, and n-butyllithium (44 mL, 0.11) was added. Mol), the reaction was stirred for 30 minutes, 3-pentanone (11.6 mL, 0.11 mol) was added, and the reaction was continued for 2 hours. To the reaction mixture, 200 mL of water was added, and ethyl acetate (100 mL×2) was evaporated, and the organic phase was combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, The residue obtained was purified by column chromatography eluting with EtOAc EtOAc (EtOAc). Rate: 74.7%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 6.77 (d, J = 2.0 Hz, 1H), 6.72 (dd, /; = 12.0 Hz, J 2 = 2.0 Hz, 1H), 4.14 (m, 4H) , 1.85 (m, 4H), 1.47 (t, / = 7.2 Hz, 3H), 1.40 (t, / = 7.2 Hz, 3H), 0.80 (t, / = 7.6 Hz, 6H)

 Second step

 5-(3,4-diethoxy-5-, 5-(l-azido-1-ethyl-propyl)-1,2-diethoxy-3-fluoro-benzene ice bath Fluorine-phenyl)pentan-3-ol 36a (20 g, 0.074 mol) was dissolved in 250 mL of chloroform, and sodium azide (14.4 g, 0.22 mol) and trifluoroacetic acid (27.4 mL, 0.37 mol) were added and stirred. Reaction for 12 hours. To the reaction mixture, 200 ml of water was added, and the mixture was combined with methylene chloride (150 mL×2), and the organic phase was combined and washed with saturated sodium hydrogen carbonate solution (200 mL×5), dried over anhydrous sodium sulfate, filtered, The title product was 5-(1-azido-1-ethyl-propyl)-1,2-diethoxy-3-fluoro-benzene 36b (21.2 g,yield of pale yellow oil).

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 6.72 (d, J = 2.4 Hz, 1H), 6.69 (dd, /;= 11.6 Hz, J 2 = 2.4 Hz, 1H), 4.17 (m, 4H) , 1.96 (m, 4H), 1.48 (t, / = 7.2 Hz, 3H), 1.40 (t, / = 7.2 Hz, 3H), 0.82 (t, J = 7.6 Hz, 6H)

 third step

1-(1-azido-1-ethyl-propyl)-2-bromo-4,5-diethoxy-3-fluoro-benzene 5-(1-azido-1-ethyl-propyl -1,2-diethoxy-3-fluoro-benzene 36b (21 g, 71.2 mmol) was dissolved in 250 mL of acetic acid, and liquid bromine (7.1 mL, 142.3 mmol) and sodium acetate (11.67 g, 142.3) Methyl), the reaction was stirred for 144 hours. Add 250 mL of saturated sodium sulfite solution to the reaction solution, and extract with a mixed solvent of n-hexane and ethyl acetate ( _V /V = 5:1) (100 mL×3), and combine the organic phases with saturated sodium hydrogen carbonate solution (100 mL×5) and Wash with saturated sodium chloride solution (100 mL), dry over anhydrous magnesium sulfate, The title product 1-(1-azido-1-ethyl-propyl)-2-bromo-4,5-diethoxy-3-fluoro-benzene 36c (24.1 g, yellow oil) : 90.2%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.12 (d, J = 2.0 Hz, 1H), 4.16 (m, 4H), 2.69 (m, 2H), 1.97 (m, 2H), 1.48 (t, / = 7.2 Hz, 3H), 1.41 (t, / = 7.2 Hz, 3H), 0.79 (t, / = 7.6 Hz, 6H)

 the fourth step

 5,6-diethoxy-3,3-diethyl-7-fluoro-isoindolamine 1-(1-azido-1-ethyl-propyl)-2-bromo-4, 5-Diethoxy-3-fluoro-benzene 36c (11 g, 29.3 mmol) was dissolved in 100 mL of dimethyl sulfoxide, and cuprous cyanide (5.25 g, 58.7 mmol) and cuprous iodide (5.57 g) were added. , 29.3 mmol), the reaction was stirred at 150 ° C for 2 hours. 300 mL of water was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (400 mL). The organic phase was combined, washed with aqueous ammonia (100 mL), washed with water to blue, dilute hydrochloric acid (100 mL×5), pH The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. -7-fluoro-isoindolamine 36d (2.24 g, gray solid), Yield: 26.0% o

MS m/z (ESI): 295 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 6.93 (s, 1H), 6.37 (br. s, 2H), 4.12 (d, / = 6.8 Hz, 2H), 4.02 (d, / = 6.8 Hz, 2H), 1.74 (m, 4H), 1.36 (t, / = 6.8 Hz, 3H), 1.26 (t, / = 6.8 Hz, 3H), 0.46 (br. s, 6H)

 the fifth step

1-[3-tert-Butyl-4-methoxy-5-(l-piperidine)phenyl]-2-(5,6-diethoxy-1,1-diethyl-4-fluoro -3-imino-isoindolin-2-yl)ethanone hydrobromide

 5,6-diethoxy-3,3-diethyl-7-fluoro-isoindolamine 36d (0.3 g, 1 mmol) and 2-bromo small [3-tert-butyl-4-methyl Oxy-5-(1-piperidinyl)phenyl]-ethanone 12b (0.4 g, 1.1 mmol) was dissolved in 6 mL of N,N-dimethylformamide and reacted for 60 min at 60 ° C under microwave. Add 50 mL of water and 2 mL of saturated sodium chloride solution to the reaction solution, and filter. The filter cake is washed with water (100 mL) and a mixed solvent of n-hexane and ethyl acetate (V/V = 5:1) (100 mL) The residue obtained was purified by silica gel column chromatography elut elut elut elut elut elut 5,6-Diethoxy-1,1-diethyl-4-fluoro-3-imino-isoindolin-2-yl)ethanone hydrobromide 36 (0.02 g, yellow solid), Yield: 3.0%.

MS m/z (ESI): 582 [M+l]

1H NMR (400 MHz, DMSO-, ppm): δ 7.63 (s, 1H), 7.60 (s, 1H), 7.29 (s, 1H), 5.28 (s _: 2H), 4.25 (m, 2H), 4.15 ( m, 2H), 3.97 (s, 3H), 2.99 (m, 4H), 2.02 (m, 4H), 1.57 (m, 4H), 1.43 (m, 2H), 1.34 (m, 15H), 0.45 (t , / = 7.2 Hz, 6H) Example 37

L-(3-tert-Butyl-4-methoxy-5-pyrrolidin-1-yl-phenyl)-2-(5,6-diethoxy-1,1-diethyl-4- Fluoro-3-imino-isoindolin-2-yl)ethanone hydrobromide

 First step

 L-(3-tert-Butyl-4-methoxy-5-pyrrolidin-1-yl-phenyl)-2-(5,6-diethoxy-1,1-diethyl-4- Fluoro-3-imino-isoindolin-2-yl)ethanone hydrobromide

 5,6-Diethoxy-3,3-diethyl-7-fluoro-isoindolamine 36d (0.3 g, 1 mmol) and 2-bromo small (3-tert-butyl-4-methyl) Oxy-5-pyrrolidin-1-yl-phenyl)ethanone 8d (0.39 g, 1.1 mmol) was dissolved in 6 mL of N,N-dimethylformamide, and subjected to microwave reaction at 60 ° C for 60 minutes. 100 mL of water was added to the reaction mixture, and extracted with a mixed solvent of n-hexane and ethyl acetate (V/V = 5:1) (100 mL), and concentrated under reduced pressure. The obtained residue was purified to give the title product 1-(3-tert-butyl-4-methoxy-5-pyrrolidin-1-yl-phenyl)-2-(5,6-diethoxy-1, 1-Diethyl-4-fluoro-3-imino-isoindolin-2-yl)ethanone hydrobromide & 37 (0.05 g, yellow solid), Yield: 8.8%.

MS m/z (ESI): 568 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.43 (br. s, 1H), 9.06 (br. s, 1H), 7.49 (s, 1H), 7.46 (s, 1H), 7.30 (s , 1H), 5.30 (s, 2H), 4.27 (q, J = 7.2 Hz, 2H), 4.15 (q, J = 7.2 Hz, 2H), 3.67 (s, 3H), 3.20 (m, 4H), 2.05 (m, 4H), 1.94 (m, 4H), 1.40 (s, 9H), 1.33 (m, 6H) _: 0.45 (t, / = 7.2 Hz, 6H) Example 38

 L-(3-tert-butyl-4-methoxy-5-morpholinylphenyl)-2-(5,6-diethoxy-1,1-diethyl- 4-fluoro-3-ya Amino-iso

first step

 L-(3-tert-butyl-4-methoxy-5-morpholinylphenyl)-2-(5,6-diethoxy-1,1-diethyl-4-fluoro-3-ya Amino-isoindoline-2-yl)ethanone hydrobromide

 5,6-Diethoxy-3,3-diethyl-7-fluoro-isoindolamine 36d (0.3 g, 1 mmol) and 2-bromo small (3-tert-butyl-4-methyl) Oxy-5-morpholine phenyl)ethanone 2h (0.41 g, 1.1 mmol) was dissolved in 6 mL of N,N-dimethylformamide and reacted in vacuo at 60 ° C for 60 min. 100 mL of water was added to the reaction mixture, and extracted with a mixed solvent of n-hexane and ethyl acetate (V/V = 5:1) (100 mL), and concentrated under reduced pressure. The obtained residue was purified to give the title product 1-(3-tert-butyl-4-methoxy-5-morpholinylphenyl)-2-(5,6-diethoxy-1, 1-diethyl 4-fluoro-3-imino-isoindolin-2-yl)ethanone hydrobromide 38 (0.02 g, yellow solid), yield: 2%.

MS m/z (ESI): 568 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.48 (br. s, 1H), 9.10 (br. s, 1H), 7.66 (s, 1H), 7.61 (s, 1H), 7.32 (s , (H, 4H) (m, 4H), 2.00 (m, 4H), 1.39 (s, 9H), 1.33 (m, 6H) _: 0.52 (t, / = 7.2 Hz, 6H) Example 39

 L-[3-tert-Butyl-4-methoxy-5-[(lR,5^-8-oxa-3-azabicyclo[3.2.1]oct-3-yl]phenyl]-2 -(5,6-diethoxy-4-fluoro-3-imino-di-isoindoline-2-yl)ethanone hydrobromide

[( ² R, ⁵ - ⁵ - (hydroxymethyl) tetrahydrofuran- ^2, yl]methanol

 Dissolve 1,5-hexadiene 39a (4.6 g, 56 mmol) in a mixed solvent of 620 mL of tetrahydrofuran and dichloromethane (V/V = 9:1), and add sodium periodate (26.2 g, 123 mmol). ), antimony trichloride (23 mg, 0.11 mmol), 80 g of silica gel and 40 mL of water, and the reaction was stirred for 8 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m.) Hydroxymethyl)tetrahydrofuran-2yl]methanol 39M 4.34 g, colorless liquid), yield: 58.6 %.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 4.08 (m, 2H), 3.76 (m, 2H), 3.73 (m, 4H), 1.92 (m, 2H), 1.79 (m, 2H)

 Second step

[( ² R, ⁵ - ⁵ - (p-toluenesulfonyloxymethyl)-tetrahydrofuran- ² -yl]-methyl- ⁴ -methylbenzenesulfonate [(2R,5 -5-(hydroxymethyl) Tetrahydrofuran-2-yl]methanol 39b (3.0 g, 22.7 mmol) was dissolved in 20 mL of dichloromethane, then 4-toluenesulfonyl chloride (8.6 g, 45.4 mmol) and pyridine (4.4 mL, 54.5 mmol). Add 30 mL of water to the reaction solution, extract the aqueous phase with dichloromethane (20 mL×3), and combine the organic phases with saturated sodium carbonate solution (20 mL×2) and saturated sodium chloride solution (20 mL×2), The residue was dried over EtOAcqqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Base 4-methylbenzenesulfonate 39c (6.0 g, white solid), Yield: 60.0%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.79 (d, J = 8.0 Hz, 4H), 7.36 (d, / = 8.0 Hz, 4H), 4.11 (m, 2H), 3.94 (m, 4H) , 2.46 (s, 6H), 1.95 (m, 2H), 1.72 (m, 2H)

 third step

 (lR,5 -3-benzyl-8-oxa-3-azabicyclo[3.2.1]octane

 [(2R,5 -5-(p-Toluenesulfonyloxymethyl)-tetrahydrofuran-2-yl]-methyl-4-methylbenzenesulfonate 39c (4.1 g, 9.32 mmol) and benzylamine (3.56 The residue was dissolved in 40 mL of toluene, and the reaction was stirred for 12 hours at 120 ° C. The filtrate was concentrated under reduced pressure. -Benzyl-8-oxa-3-azabicyclo[3.2.1]octane 39d (1.58 g, colorless liquid), Yield: 83.6 %.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.32 (m, 5H), 4.28 (m, 2H), 3.47 (s, 2H), 2.56 (d, J = 12.0 Hz, 2H), 2.36 (d, / = 12.0 Hz, 2H), 2.01 (m, 2H), 1.99 (m, 2H)

 the fourth step

 (lWR)-8-oxa-3-azabicyclo[3.2.1]octane

 (1 5 Benzyl-8-oxa-3-azabicyclo[3.2.1]octane 39d (1.5 g, 7.39 mmol) was dissolved in 200 mL of ethyl acetate and palladium/carbon (75) Mg, 5%), three times of hydrogen, and the reaction was stirred at 80 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure. Heterobicyclo[3.2.1]octane 39e (; 347 mg, colorless liquid), Yield: 83.3%.

MS m/z (ESI): 114 [M+l] the fifth step

 1-[3-tert-Butyl-4-methoxy-5-[GR,5S)-8-oxa-3-azabicyclo[3.2.1]oct-3-yl]phenyl]ethanone 1-tert-butyl-5-(1,1-dimethoxyethyl)-3-iodo-2-methoxybenzene 2f (761 mg, 2.01 mmol) and

2-Dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (79 mg, 0.20 mmol) dissolved in 10 mL of toluene, palladium/carbon (76 mg, 10%), Potassium butoxide (786 mg, 7.00 mmol) and (1 5R)-8-oxa-3-azabicyclo[3.2.1]octane 396 (228 13⁄4, 2.01 11^101), stirred at 80 ° C 5 hours. 20 mL of water was added to the reaction mixture, and the aqueous layer was combined with ethyl acetate (5 mL EtOAc). 5 mL of acetic acid and 1 mL of water were added, and the reaction was stirred for 1 hour. After adding 20 mL of water, the aqueous phase was extracted with ethyl acetate (5 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, Chromatography the residue obtained was purified using eluent B to give the title product 1-[3-tert-butyl-4-methoxy.

-5-[(1 5 -8-oxa-3-azabicyclo[3.2.1]oct-3-yl]phenyl]ethanone 39f (286 mg, yellow solid), yield: 45.0%.

MS m/z (ESI): 318 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.67 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H),

4.44 (m, 2H), 3.94 (s, 3H), 3.17 (d, / = 12.0 Hz, 2H), 3.01 (d, / = 12.0 Hz, 2H), 2.57 (s _: 3H), 2.12 (m, 2H) ), 2.05 (m, 2H), 1.41 (s, 9H)

 Step 6

 2-bromo-[3-tert-butyl-4-methoxy-5-[(lR,5 -8-oxa-3-azabicyclo[3.2.1]oct-3-yl]phenyl] Ethyl ketone

1-[3-tert-Butyl-4-methoxy-5-[(lR,5 -8-oxa-3-azabicyclo[3.2.1]oct-3-yl] at 40 ° C -Phenyl]-ethanone 39f (258 mg, 0.81 mmol) was dissolved in 8 mL of chloroform, and then copper bromide (363.6 g, 1.63 mmol) was added, and the reaction was stirred for 12 hours. Chromatography of the residue obtained from eluent B to give the title product 2-bromo-1-[3-tert-butyl-4-methoxy-5-[(l,5,8- Azabicyclo[3.2.1]oct-3-yl]phenyl]ethanone 39g (220 mg, yellow solid yield: 68.3%. 1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.70 (d, J = 2.4 Hz, 1H), 7.55 (d, / = 2.4 Hz, 1H),

4.45 (m, 2H), 4.40 (s, 2H), 3.96 (s, 3H), 3.17 (d, / = 12.0 Hz, 2H), 2.99 (d, / = 12.0 Hz, 2H), 2.12 (m, 2H) ), 2.05 (m, 2H), 1.41 (s, 9H)

 Seventh step

1-[3-tert-Butyl-4-methoxy-5-[(lR,5 -8-oxa-3-azabicyclo[3.2.1]oct-3-yl]phenyl]-2- (5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)ethanone hydrobromide 5,6-diethoxy 7-fluoro-3,3-dimethyl-isoindol-1-amine 24d (189 mg, 0.71 mmol) and 2-bromo-1-[3-tert-butyl-4-methoxy- 5-[(lR,5 -8-oxa-3-azabicyclo[3.2.1]oct-3-yl]-phenyl]ethanone 39g (310 mg, 0.78 mmol) was dissolved in 5 mL of N, In N-dimethylformamide, the reaction was stirred for 12 hours. 5 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mIX3), and the organic phase was combined and washed with saturated sodium chloride solution (10 mL) Dry with sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained residue was purified to give the title product 1-[3-tert-butyl-4-methoxy-5-[(1R,5 -8-oxa-3-azabicyclo[3.2.1] s- 3-yl]phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)ethanone hydrobromide Acid 39 (72 mg, yellow powder), Yield: 15.3%.

MS m/z (ESI): 582 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.35 (br. s, 1H), 8.97 (br. s, 1H), 7.62 (m, 2H), 7.46 (s, 1H), 5.45 (s , 2H), 4.41 (m, 2H), 4.24 (q, J = 7.2 Hz, 2H), 4.13 (q, J = 7.2 Hz, 2H), 3.92 (s, 3H), 3.12 (m, 2H), 2.89 (m, 2H), 2.07 (m, 2H), 1.92 (m, 2H), 1.50 (s, 6H) _: 1.41 (t, / = 7.2 Hz, 3H), 1.39 (s, 9H), 1.31 (t, / = 7.2 Hz, 3H) Example 40

L-[3-tert-Butyl-4-methoxy-5-(2-oxa-6-azaspiro[3.3]hex-6-yl)phenyl]-2-(5,6-diethyl Oxy-4-fluoro

2-(p-toluenesulfonyl)-6-oxa-2-azaspiro[3.3]heptane 3-bromo-2,2-di(bromomethyl)propane small alcohol 40a (65.0 g, 0.20 mol) And 4-methylbenzenesulfonamide 40b (41.0 g, 0.24 mol) was dissolved in 600 mL of ethanol, potassium hydroxide (35.84 g, 0.64 mol) was added, and the reaction was stirred at 80 ° C for 12 hours. Filtration, the filter cake was washed with EtOAc (EtOAc (EtOAc) 59.2%.

 MS m/z (ESI): 254 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.71 (d, / = 8.0 Hz, 2H), 7.14 (d, / = 8.0 Hz, 2H), 4.59 (s, 4H), 3.91 (s, 4H) , 2.44 (s, 3H) Second step

 6-oxa-2-azaspiro[3.3]heptane oxalate

 Dissolve 2-(; p-toluenesulfonyl)-6-oxa-2-azaspiro[3,3]heptane 40c (5.5 g, 22.0 mmol) in 120 mL of methanol and add magnesium powder C4.2 g , 174 mmol), ultrasonic reaction for 1 hour. Concentrated under reduced pressure, 180 mL of diethyl ether and 30 g of sodium sulfate decahydrate were added, stirred for 1 hour, filtered, and 5 mL of 1 M oxalic acid in ethanol was added to the filtrate, stirred for 0.5 hour, filtered, and the filter cake was washed with ethanol (10 mL×3). The title product 6-oxa-2-azaspiro[3.3]heptane oxalate 40d (2.6 g, white solid).

MS m/z (ESI): 100 [M+l]

 third step

 1-[3-tert-Butyl 1-4-methoxy-5-(6-oxa-2-azaspiro[3.3]heptan-2-yl)phenyl]ethanone 1-tert-butyl -5-(1,1-Dimethoxyethyl)-3-iodo-2-methoxybenzene 2f (8.5 g, 23 mmol) and 2-dicyclohexylphosphino-2'-(N,N -Dimethylamine)-Biphenyl (443 mg, 1.13 mmol) was dissolved in 120 mL of toluene, palladium on carbon (850 mg, 10%), potassium t-butoxide (7.6 g, 68 mmol) and 6-oxo 2-Azaspiro[3.3]heptane oxalate 40d (9.0 g, 25 mmol) was stirred at 60 ° C for 1 hour. To the reaction mixture, 200 mL of water was added, and the aqueous layer was evaporated with EtOAc (EtOAc) Add 100 mL of acetic acid and 2 mL of water, and stir the reaction for 1 hour. After adding 200 mL of water, the aqueous phase was extracted with ethyl acetate (50 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate and filtered. Chromatography The residue obtained was purified using eluent B to give the title product 1-[3-tert-butyl 1-4-methoxy-5-(6-oxa-2-azaspiro[3.3]heptane 2-yl)phenyl]ethanone 40e (6.0 g, gray solid), yield: 88.2%.

MS m/z (ESI): 304 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.46 (d, / = 2.0 Hz, 1H), 7.05 (d, / = 2.0 Hz, 1H), 4.85 (s, 4H), 4.02 (s, 4H) , 3.70 (s, 3H), 2.56 (s, 3H), 1.41 (s, 9H)

 the fourth step

 2-bromo-l-[3-tert-butyl-4-methoxy-5-(6-oxa-2-azaspiro[3.3]heptan-2-yl)phenyl]ethanone

Lithium bis(;trimethylsilyl)amine (12.7 mL, 12.7 mmol) and 1-[3-tert-butyl1-4-methoxy-5-(6-oxa-- at -78 °C 2-Azaspiro[3.3]heptan-2-yl)phenyl]ethanone 40e (3.5 g, 11.6 mmol) was dissolved in 50 mL of THF, stirred for 1 hour, then bromo (1.85 g, 11.6 mmol). The reaction was stirred for 2 hours. 30 mL of water was added to the reaction mixture, the aqueous layer was extracted with EtOAc (EtOAc (EtOAc) The residue obtained was purified by silica gel column chromatography elutd elut elut elut Heterospiro[3.3]heptan-2-yl)phenyl]ethanone 40f (820 mg, yellow solid), yield: 18.6%.

 MS m/z (ESI): 383 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.49 (d, J = 2.4 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 4.85 (s, 4H), 4.41 (s, 2H) , 4.02 (s, 4H), 3.71 (s, 3H), 1.40 (s, 9H) the fifth step

 L-[3-tert-Butyl-4-methoxy-5-(2-oxa-6-azaspiro[3.3]hex-6-yl)phenyl]-2-(5,6-diethyl Oxyl

4-fluoro-3-imino-1, 1-dimethyl-isoindol-2-yl)ethanone hydrobromide 5,6-diethoxy-7-fluoro-3,3 - dimethyl-isoindol-1-amine 24d (132 mg, 0.50 mmol) and 2-bromo-1-[3-tert-butyl-4-methoxy-5-(6-oxa-2 -Azaspiro[3.3]heptan-2-yl)phenyl]ethanone 40f (190 mg, 0.50 mmol) was dissolved in 2 mL of THF, triethylamine (1 mL, 0.72 mmol). . Filtration, the filter cake was washed with n-hexane (10 mL) and water (10 mL×3) and dried in vacuo to give the title product 1-[3-tert-butyl-4-methoxy-5-(2-oxo-6- Azaspiro[3.3]hex-6-yl)phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindoline- 2-yl) ethyl ketone hydrobromide 40 (15 mg, yellow solid), yield: 4.6%.

 MS m/z (ESI): 567 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 8.99 (br. s, 1H), 7.45 (s, 2H), 7.13 (s, 1H), 5.42 (s, 2H), 4.71 (m, 4H) ), 4.25 (q, / = 7.2 Hz, 2H), 4.13 (q, / = 7.2 Hz, 2H), 4.09 (m, 4H), 3.67 (s, 3H), 1.50 (s, 6H), 1.41 (t , / = 7.2 Hz, 3H), 1.38 (s, 9H), 1.31 (t, / = 7.2 Hz, 3H) Example 41

 1-(3-tert-Butyl-4-methoxy-5-morpholinylphenyl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[ Cyclopropane

 -1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

first step 6-bromo-3,4-diethoxy-2-fluoro-benzaldehyde

 Dissolve 5-bromo-1,2-diethoxy-3-fluoro-benzene 23e (15.38 g, 58.5 mmol) in 250 mL of trifluoroacetic acid and add hexamethylenetetramine (16.4 g, 117 mmol) The reaction was stirred for 30 minutes and the reaction was continued at 90 ° C for 5 hours. Add 500 mL of water to the reaction solution, extract with ethyl acetate (250 mL×2), and combine the organic phases and wash with saturated sodium bicarbonate solution (250 mL×5), water (200 mL) and saturated sodium chloride solution (200 mL) The residue was purified by silica gel column chromatography eluting with eluent system B to give the title product 6-bromo-3,4-diethoxy-2-. Fluoro-benzaldehyde 41a (7.87 g, yellow solid), Yield: 46.3%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 10.25 (s, 1H), 7.00 (d, / = 1.6 Hz, 1H), 4.20 (m, 4H), 1.54 (t, J = 7.2 Hz, 3H) , 1.43 (t, J = 7.2 Hz, 3H)

 Second step

 6-bromo-3,4-diethoxy-2-fluoro-benzoic acid

 6-Bromo-3,4-diethoxy-2-fluoro-benzaldehyde 41a (5.5 g, 18.8 mmol) was dissolved in 50 mL of tetrahydrofuran under ice bath, 50 mL of water, sodium hydroxide (1.2 g) , 30.1 mmol) and potassium permanganate (3.28 g, 20.7 mmol) were reacted at room temperature for 12 hours. Filtration, the filtrate was concentrated under reduced EtOAc (EtOAc)EtOAc. Product 6-Bromo-3,4-diethoxy-2-fluoro-benzoic acid 41b (3.8 g, yellow solid), yield: 65.8%.

 MS m/z (ESI): 307 [M-l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 13.74 (br. s, 1H), 7.18 (s, 1H), 4.13 (q, / = 7.2 Hz. 2H), 4.05 (q, J = 7.2 Hz, 2H), 1.34 (t, / = 7.2 Hz, 3H), 1.25 (t, / = 7.2 Hz, 3H)

 third step

 6-bromo-3,4-diethoxy-2-fluoro-benzoic acid methyl ester

 6-Bromo-3,4-diethoxy-2-fluoro-benzoic acid 41b (3.8 g, 12.4 mmol) was dissolved in 30 mL of chlorosulfone and refluxed for 5 hr. After concentration under reduced pressure, a mixed solution of 45 mL of methanol and dichloromethane (V/V = 2:1) was added to the mixture, and the mixture was stirred at room temperature for 12 hours. Concentration under reduced pressure gave the title compound 6-bromo -3,4-diethoxy-2-fluoro-benzoic acid methyl ester 41c (3.46 g, yellow oil), yield: 86.9%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 6.90 (d, J = 2.0 Hz, 1H), 4.10 (m, 4H), 3.94 (s, 3H), 1.46 (t, / = 7.2 Hz, 3H) , 1.36 (t, / = 7.2 Hz, 3H)

 the fourth step

 6-Cyano-3,4-diethoxy-2-fluoro-benzoic acid methyl ester

Dissolve 6-bromo-3,4-diethoxy-2-fluoro-benzoic acid methyl ester 41c (3.46 g, 10.8 mmol) in 50 mL of N,N-dimethylformamide, and then add cyanide Copper (2.9 g, 32.3 mmol) and 1 mL of pyridine were stirred at 150 ° C for 3 hours. Add 300 mL of water to the reaction mixture, and filter with ethyl acetate (100 mL×3). The organic phase is combined, washed with water (200 mL) and saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography using eluent system B. The title product, 6-cyano-3,4-diethoxy-2-fluoro-benzoic acid methyl ester 41d (1.5 g, white solid).

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.08 (d, / = 1.2 Hz, 1H), 4.27 (q, / = 7.2 Hz, 2H), 4.19 (q, / = 7.2 Hz, 2H), 4.03 (s, 3H), 1.54 (t, / = 7.2 Hz, 3H), 1.43 (t, / = 7.2 Hz, 3H) Step 5

 5',6'-diethoxy-7-fluoro-spiro[cyclopropane-1,3'-isoindoline]-1'-one, 6-cyano-3,4-di Ethyloxy-2-fluoro-benzoic acid methyl ester 41d (2.66 g, 9.96 mmol) was dissolved in 30 mL of diethyl ether and tetraisopropyl titanate (3.3 mL, 11.1 mmol) and ethyl magnesium bromide (7.3 mL) , 21.9 mmol), stirred for 2.5 hours. 65 mL of methanol was added to the reaction mixture, and the obtained residue was purified by silica gel column chromatography to eluent to afford the title product 5',6'-diethoxy-7-fluoro-spiro[cyclopropane-1, 3'-Isoporphyrin]-indole-ketone 41e (1.48 g, yellow solid), Yield: 56.0%.

MS m/z (ESI): 266 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.02 (s, 1H), 6.25 (s, 1H), 4.12 (m, 4H), 1.63 (m, ,2H), 1.48 (t, J = 12 Hz , 3H), 1.38 (t, / = 7.2 Hz, 3H), 1.35 (m, 2H)

 Step 6

 5',6'-diethoxy-7-fluoro-spiro[cyclopropane-1,3'-isoindoline]-1'-thione 5',6'-diethoxy-7' -Fluoro-spiro[cyclopropane-1,3'-isoindoline]-fluorenone-ketone 41e (906 mg, 3.42 mmol) dissolved in 40 mL of tetrahydrofuran, adding Lawson's reagent C734 mg, 1.81 mmol), 50 ° The reaction was stirred at C for 12 hours. 50 mL of saturated potassium carbonate solution and 40 mL of ethyl acetate were added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (20 mL×3), and the organic phase was combined and washed with saturated sodium chloride solution (50 mL), anhydrous sodium sulfate The organic layer was dried, filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjjj , 3'-isoporphyrin]-indole-thione 41f (338 mg, gray powder), Yield: 22.8%.

MS m/z (ESI): 282 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 9.68 (s, 1H), 6.24 (s, 1H), 4.14 (m, 4H), 1.89 (m, 2H), 1.52 (m, 2H), 1.49 ( t, / = 7.2 Hz, 3H), 1.39 (t, / = 7.2 Hz, 3H)

 Seventh step

 5',6'-diethoxy-7-fluoro-spiro[cyclopropane-1,3'-isoindoline]-1'-imine 5',6'-diethoxy-7' -Fluoro-spiro[cyclopropane-1,3'-isoporphyrin]-indole-thione 41f (300 mg, 1.07 mmol) was dissolved in 30 mL of methanol, and 12 mL of 28% concentrated aqueous ammonia and tert-butyl were added. Hydrogen peroxide (0.6 mL, 6 mmol) was stirred for 12 hours. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc &EtOAc) (30 mL×3), EtOAc (3 mL, EtOAc) -Fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41 g (147 mg, gray solid), Yield: 52.1%.

MS m/z (ESI): 265 [M+l] O NMR (400 MHz, CDC1 ₃ , ppm): δ 6.71 (s, 1H), 6.10 (br. s, 2H), 4.09 (q, / = 7.2 Hz, 2H), 4.01 (q, J = 7.2 Hz, 2H), 1.49 (m, 2H), 1.42 (m, 2H), 1.35 (t, J = 7.2 Hz, 3H) _: 1.26 (t, / = 7.2 Hz, 3H)

 Eighth step

 1-(3-tert-Butyl-4-methoxy-5-morpholinylphenyl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[ Cyclopropane

 -1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

 5',6'-diethoxy-7-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (184 mg, 0.7 mmol) and 2-bromo-1 -(3-tert-Butyl-4-methoxy-5-morpholinylphenyl)ethanone 2h (370 mg, 0.7 mmol) was dissolved in 6 mL of THF, triethylamine (0.15 mL, 1.08 mmol). The reaction was stirred for 12 hours. Filtration, the filter cake was washed with n-hexane (10 mL) and water (EtOAc (EtOAc) (5',6'-Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 41 (52 mg, white powder), Yield: 11.8%.

MS m/z (ESI): 554 [M+l]

 1H NMR (400 MHz, DMSO-, ppm): δ 9.35 (br. s, 1H), 9.06 (br. s, 1H), 7.62 (d, / = 2.0 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.03 (s, 1H), 5.22 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 4.13 (q, / = 7.2 Hz, 2H), 3.96 (s, 3H), 3.82 (m, 4H), 3.02 (m, 4H), 1.80 (m, 2H), 1.66 (m, 2H), 1.40 (t, / = 7.2 Hz, 3H), 1.38 (s, 9H), 1.31 (t , / = 7.2 Hz, 3H) Example 42

 L-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1 , Γ-isoporphyrin-2'-yl) ethyl ketone hydrobromide

 First step

 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1 ,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

5',6'-diethoxy-7'-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (201 mg, 0.76 mmol) and B 2-bromo 1-(3,5-di-tert-butyl-4-hydroxyphenyl)ethanone If (327 mg, 0.87 mmol) was dissolved in 6 mL of tetrahydrofuran, then added triethylamine (0.15 mL, 1.08 mmol). The reaction was continued for 48 hours at 30 ° C for 12 hours. Filtration, filter cake washed with n-hexane (10 mL) and water (10 mIX3), dried in vacuo, To the title product 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclo] Propane-1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide 42 (66 mg, white powder), yield: 14.7%. MS m/z (ESI): 511 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.06 (br. s, 2H), 7.77 (s, 2H), 7.03 (s, 1H), 5.27 (s, 2H), 4.23 (q, J = 7.2 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 1.78 (m, 2H), 1.64 (m, 2H), 1.43 (s, 18H), 1.40 (t, / = 7.2 Hz, 3H ), 1.31 (t, / = 7.2 Hz, 3H) Example 43

 2-[8-tert-butyl-6-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoporphyrin) ] -2'-base) ethyl salt

 2-[8-tert-butyl-6-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindole] -2'-yl)acetyl]-2,3-dihydro-1,4-benzoxazin-4-yl]ethyl acetate hydrobromide 5',6'-diethoxy -7'-Fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (121 mg, 0.46 mmol) and 2-[6-(2-bromoacetyl)-8- Ethyl bromide 5e (201 mg, 0.50 mmol) of tert-butyl-2,3-dihydro-1,4-benzoxazin-4-yl] was dissolved in 4 mL of THF and triethylamine (0.1 mL, 0.72 mmol), the reaction was stirred at 25 ° C for 12 hours. Filtration, the filter cake was washed with n-hexane (10 mL) and water (10 mIX3) and dried in vacuo to give the title product 2-[8-t-butyl-6-[2-(5',6'-diethoxy) -4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)acetyl]-2,3-dihydro-1,4-benzo Oxazin-4-yl]ethyl acetate hydrobromide 43 (147 mg, yellow powder), yield: 48.4%.

MS m/z (ESI): 583 [M+l]

1H NMR (400 MHz, DMSO-, ppm): δ 9.72 (br. s, 1H), 9.18 (br. s, 1H), 7.30 (s, 1H), 7.13 (s, 1H), 7.06 (s, 1H) ), 5.33 (s, 2H), 4.31 (s, 2H), 4.29 (m, 2H), 4.23 (q, / = 7.2 Hz, 2H), 4.11 (m, 4H), 3.49 (m, 2H), 1.74 (m, 2H), 1.65 (m, 2H), 1.39 (t, / = 7.2 Hz, 3H), 1.36 (s, 9H), 1.30 (t, J = 12 Hz, 3H), 1.19 (t, / = 7.2 Hz, 3H) Example 44 1- 3,5-di-tert-butylphenyl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, fluorene-isoindole] Porphyrin-2'-yl)ethanone hydrobromide

 First step

 1-(3,5-di-tert-butylphenyl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'- Isoporphyrin]-2'-yl)ethanone hydrobromide

 5',6'-diethoxy-7-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (132 mg, 0.5 mmol) and 2-bromo- 1-(3,5-Di-tert-butyl-phenyl)ethanone 22c (178 mg, 0.57 mmol) was dissolved in 4 mL of tetrahydrofuran, triethylamine (0.1 mL, 0.72 mmol), and stirred at 25 ° C 12 hours. Filtration, the filter cake was washed with n-hexane (10 mL) and water (10 mL×3) and dried in vacuo to give the title product 1-(3,5-di-tert-butylphenyl)-2-(5',6'- Ethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 44 (54 mg, white powder) , Yield: 18.8%.

MS m/z (ESI): 495 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.38 (br. s, 1H), 9.05 (br. s, 1H), 7.82 (d, J = 1.6 Hz, 2H), 7.78 (d, / = 1.6 Hz, 1H), 7.03 (s, 1H), 5.25 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 4.13 (q, J = 7.2 Hz, 2H), 1.83 (m, 2H ), 1.67 (m, 2H), 1.41 (t, J = 7.2 Hz, 3H), 1.36 (s, 18H), 1.31 (t, / = 7.2 Hz, 3H) Example 45

 L-(3,5-Di-tert-butyl-4-methoxyphenyl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane] -1,Γ

 '-yl) ethyl ketone hydrobromide

 First step

1-(3,5-di-tert-butyl-4-methoxyphenyl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane] -1,1' Isoporphyrin]-2'-yl)ethanone hydrobromide

 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (147 mg, 0.56 mmol) and 2-bromo 1-(3,5-Di-tert-butyl-4-methoxyphenyl)ethanone 21c (198 mg, 0.58 mmol) was dissolved in 4 mL of THF. The reaction was stirred at 25 ° C for 12 hours. Filtration, the filter cake was washed with n-hexane (10 mL) and water (10 mL×3) and dried in vacuo to give the title product 1-(3,5-di-tert-butyl-4-methoxyphenyl) -2- (5) ',6'-Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 45 ( 47 mg, white powder), Yield: 13.9%.

MS m/z (ESI): 525 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.67 (br. s, 1H), 9.12 (br. s, 1H), 7.90 (s, 2H), 7.04 (s, 1H), 5.38 (s , 2H), 4.23 (q, J = 12 Hz, 2H), 4.11 (q, J = 7.2 Hz, 2H), 3.70 (s, 3H), 1.79 (m, 2H), 1.64 (m, 2H), 1.43 (s, 18H), 1.40 (m, 6H) Example 46

L-(3-tert-Butyl-4-methoxy-5-pyrrolidin-1-yl-phenyl)-2-(5',6'-diethoxy-4'-fluoro-3'- Imino-spiro

 -1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

 1-(3-tert-butyl-4-methoxy-5-pyrrolidin-1-yl-phenyl)-2-(5',6'-diethoxy-4'-fluoro-3'- Imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide

 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (160 mg, 0.56 mmol) and small 2-bromo (3-tert-Butyl-4-methoxy-5-pyrrolidinyl-phenyl)ethanone 8d (301 mg, 0.58 mmol) was dissolved in 4 mL of THF, triethylamine (0.1 mL, 0.72 mmol The reaction was stirred at 25 ° C for 12 hours. Filtration, the filter cake was washed with n-hexane (10 mL) and water (10 mL×3) and dried in vacuo to give the title product 1-(3-tert-butyl-4-methoxy-5-pyrrolidin-1-yl-benzene Benzyl-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl) Ketohydrobromide 46 (118 mg, white powder), Yield: 31.5%.

 MS m/z (ESI): 538 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.36 (br. s, 1H), 9.06 (br. s, 1H), 7.46 (s, 1H), 7.41 (s, 1H), 7.05 (s , 1H), 5.24 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.18 (m, 4H), 1.93 (m, 4H), 1.80 (m, 2H), 1.66 (m, 2H), 1.40 (t, / = 7.2 Hz, 3H) 1.36 (s, 9H), 1.31 (t, / = 7.2 Hz, 3H) Example 47

L-[3-(l-adamantane)-4-methoxy-5-morpholinyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino - snail [cyclopropane

 -1 1'-Isoporphyrin]-2'-yl)ethanone hydrobromide

 First step

1-[3-(1-adamantane)-4-methoxy-5-morpholinyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino - snail [cyclopropane

 -1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (156 mg, 0.59 mmol) and 1-[3 -(1-adamantyl)-4-methoxy-5-morpholinylphenyl]-2-bromo-ethanone 17h (298 mg, 0.67 mmol) was dissolved in 5 mL of tetrahydrofuran, then triethylamine (0.1) mL, 0.72 mmol), and the reaction was stirred at 25 ° C for 12 hours. Filtration, the filter cake was washed with n-hexane (10 mL) and water (10 mL×3) and dried in vacuo to give the title product 1-[3-(1-adamantane)-4-methoxy-5-morpholinyl] -2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrogen Bromate 47 (126 mg, white powder), yield: 29.9%. MS m/z (ESI): 632 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.74 (br. s, 1H), 9.16 (br. s, 1H), 7.57 (m, 2H), 7.07 (s, 1H), 5.44 (s , (2, H) (m, 9H), 1.76 (m, 6H), 1.72 (m, 2H), 1.66 (m, 2H), 1.40 (t, / = 7.2 Hz, 3H), 1.31 (t, / = 7.2 Hz, 3H) Example 48

1-[3-[(1 5 -3-azabicyclo[3丄0]hex-3-yl]-5-tert-butyl-4-methoxyphenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide

first step

 Cyclopropane -1,2-dicarboxylic acid diethyl ester

 Under ice bath, 60% sodium hydride (22.0 g, 0.51 mol) was dissolved in 150 mL of toluene, and ethyl 2-ethyl acrylate 48a (50.0 g, 0.5 mol) and ethyl 2-chloroacetate 48b (61.3 g) were added dropwise. , 0.5 mol) of the mixed solution, and the reaction was stirred for 12 hours. The reaction mixture was quenched with a small amount of water, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phase was combined and washed with water (50 mL) and saturated sodium chloride solution (50 mL) Drying over sodium sulfate, filtration, and concentrating the filtrate under reduced pressure. The residue was purified by distillation in vacuo to give a fraction of 65-92 ° C to give the title product: hexanes. Liquid), Yield: 42.8%.

MS m/z (ESI): 187 [M+l]

 Second step

 [(1 2R)-2-(hydroxymethyl)cyclopropyl]methanol

 Lithium aluminum hydride (8.98 g, 0.24 mol) was dissolved in 180 mL of tetrahydrofuran under ice bath, three times with hydrogen, and 20 mL of cyclopropane-1,2-dicarboxylate 48c (22.0 g, 0.12 mol) was added dropwise. The tetrahydrofuran solution was stirred at 70 ° C for 3 hours, and the reaction was further stirred at room temperature for 12 hours. Under ice-cooling, 22 mL of a saturated ammonium chloride solution was added dropwise to the reaction mixture, and the mixture was concentrated under reduced pressure. ethyl acetate (200 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue gave the title product [(1 2 -2-(hydroxymethyl)cyclopropyl]methanol 48 d (1.14 g, yellow liquid), yield: 9.4% and [(lS,2R)-2- (hydroxyl) Base) cyclopropyl]methanol 48e (5.3 g, yellow liquid), yield: 43.9%

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 3.81 (m, 2H), 3.53 (br. s, 2H), 3.10 (m, 2H), 1.03 (m, 2H), 0.45 (m, 2H)

1H NMR (400MHz, CDC1 ₃ , ppm): δ 4.11 (m, 2H), 3.24 (m, 4H), 1.32 (m, 2H), 0.81 (m _: 1H), 0.22 (m, 1H) third step

(1R, ² ^-1, ² -di(bromomethyl)cyclopropane

Under ice bath, triphenylphosphine (28.19 g, 0.107 mol) was dissolved in 130 mL of acetonitrile, liquid bromine (5.4 mL, 0.107 mol) was added dropwise, and 30 mL [(lS, 2R)-2- was added dropwise at room temperature. A solution of (hydroxymethyl)cyclopropyl]methanol 48e (5.22 g, 0.051 mol) in acetonitrile was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj - bis(bromomethyl)cyclopropane 48f (9.68 g, yellow liquid), yield: 83.9%. 1H NMR (400MHz, CDC1 ₃ , ppm): δ 3.50 (m, 4H), 1.66 (m, 2H), 1.18 (m, 1H), 0.43 (m, 1H)

 the fourth step

 1-[3-[(1 5 -3-azabicyclo[3丄0]hex-3-yl]-5-tert-butyl-4-methoxyphenyl]ethanone 1-(3-amino) -5-tert-butyl-4-methoxyphenyl)-ethanone 8b (1.0 g, 4.5 mmol) and (1R,2 -1,2-di(bromomethyl)cyclopropane 48f (2.06 g, 9.0 Methyl) dissolved in 20 mL of water, added potassium carbonate (680 mg, 4.95 mmol), and stirred for 20 min at 120 ° C under stirring. 20 mL of ethyl acetate was added and the aqueous phase was extracted with ethyl acetate (30 mL×3). The phase was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, filtered, and evaporated. The title product 1-[3-[(1 5 -3-azabicyclo[3.1.0]hex-3-yl]-5-tert-butyl-4-methoxyphenyl]ethanone 48 g (596 mg) , yellow liquid), Yield: 45.9%.

MS m/z (ESI): 288 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.52 (d, J = 2.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 3.64 (s, 3H), 3.61 (m, 2H) , 3.00 (m, 2H), 2.56 (s, 3H), 1.56 (m, 2H), 1.42 (s, 9H), 0.6 (m, 2H)

 the fifth step

 L-[3-[(lR,5 -3-Azabicyclo[3丄0]hex-3-yl]-5-tert-butyl-4-methoxyphenyl]-2-bromo-ethanone 40 1-[3-[(lR,5 -3-Azabicyclo[3丄0]hex-3-yl]-5-tert-butyl-4-methoxyphenyl]ethanone 48g at °C (2.0 g, 6.97 mmol) was dissolved in 20 mL of chloroform, copper bromide (3.11 g, 13.94 mmol) was added, and the reaction was stirred for 12 hours. The filtrate was concentrated under reduced pressure. The obtained residue was purified to give the title product l-[3-[GR,5-3-azabicyclo[3.1.0]hex-3-yl]-5-tert-butyl-4-methoxyphenyl]- 2-Bromo-ethanone 48h (558 mg, yellow solid), Yield: 21.9%.

MS m/z (ESI): 368 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.55 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 4.42 (s, 2H), 3.64 (s, 3H) , 3.60 (m, 2H), 3.01 (m, 2H), 1.56 (m, 2H), 1.41 (s, 9H), 0.6 (m, 2H)

 Step 6

1-[3-[(1 5 -3-azabicyclo[3丄0]hex-3-yl]-5-tert-butyl-4-methoxyphenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (161 mg, 0.61 mmol) and l-[3 -[(lR,5 -3-azabicyclo[3丄0]hex-3-yl]-5-tert-butyl-4-methoxyphenyl]-2-bromo-ethanone 48h (246 mg, 0.67 mmol) was dissolved in 5 mL of tetrahydrofuran, triethylamine (0.1 mL, 0.72 mmol) was added, and the reaction was stirred for 12 hours at 25 ° C. The filter cake was washed with n-hexane (10 mL) and water (10 mL×3). Drying in vacuo gave the title product 1-[3-[(1 5 -3-azabicyclo[3丄0]hex-3-yl]-5-tert-butyl-4-methoxyphenyl]-2- (5',6'-Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 48 (118 mg, white powder), Yield: 30.7%.

MS m/z (ESI): 550 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.34 (br. s, 1H), 9.05 (br. s, 1H), 7.49 (d, / = 1.6 Hz, 1H), 7.39 (d, / = 1.6 Hz, 1H), 7.04 (s, 1H), 5.22 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 4.12 (q, / = 7.2 Hz, 2H), 3.61 (s, 3H ), 3.54 (d, / = 8.8 Hz, 2H), 2.99 (d, / = 8.8 Hz _: 2H), 1.80 (br. s, 2H), 1.66 (m, 4H), 1.40 (t, / = 7.2 Hz) , 3H), 1.38 (s, 9H), 1.31 (t, / = 7.2 Hz, 3H), 0.61 (m, 1H), 0.55 (m, 1H) Example 49

 2-[8-tert-butyl-6-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoporphyrin) ] -2'-yl)acetyl]-2,3- -1 ,4-benzoxazin-4-yl]acetonitrile hydrobromide

 First step

 2-[8-tert-butyl-6-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindole]啉]] 2 '-yl) acetyl]-2,3-dihydro-1,4-benzoxazin-4-yl]acetonitrile hydrobromide 5',6'-diethoxy-7 '-Fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (160 mg, 0.61 mmol) and 2-[6-(2-bromo-acetyl)-8-tert Butyl-2,3-dihydro-1,4-benzoxazin-4-yl]acetonitrile 16b (320 mg, 0.91 mmol) was dissolved in 5 mL of THF and triethylamine (0.1 mL, 0.72 mmol) The reaction was stirred at 25 ° C for 12 hours. Filtration, the filter cake was washed with n-hexane (10 mL) and water (10 mIX3) and dried in vacuo to give the title product 2-[8-t-butyl-6-[2-(5',6'-diethoxy) -4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)acetyl]-2,3-dihydro-1,4-benzo Oxazin-4-yl]acetonitrile hydrobromide 49 (150 mg, yellow powder), Yield: 40.2%.

MS m/z (ESI): 535 [M+l] NMR NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.40 (br. s, 2H), 7.67 (s, 1H), 7.41 (s, 1H), 7.05 (s, 1H), 5.41 (s, 2H) ), 4.85 (s, 2H), 4.39 (m, 2H), 4.24 (q, J = 12 Hz, 2H), 4.11 (q, J = 7.2 Hz, 2H), 3.36 (m, 2H), 1.85 (m , 2H), 1.65 (m, 2H), 1.39 (t, J = 7.2 Hz, 3H), 1.35 (s, 9H), 1.30 (t, J = 12 Hz, 3H) Example 50

L-(8-tert-Butyl-4-methyl-2,3-dihydro-1,4-benzoxazin-6-yl)-2-(5',6'-diethoxy-4 '-Fluoro-3'-imino-

 First step

 1-(8-tert-butyl-4-methyl-2,3-dihydro-1,4-benzoxazin-6-yl)-2-(5',6'-diethoxy-4 '-Fluoro-3'-imino-spiro[cyclopropane-1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide 5',6'-diethoxy-7 -Fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (157 mg, 0.59 mmol) and B 2-bromo-1-(8-tert-butyl-4-methyl -2,3-Dihydro-1,4-benzoxazin-6-yl)ethanone 19b (230 mg, 0.71 mmol) was dissolved in 5 mL of THF, triethylamine (0.1 mL, 0.72 mmol). The reaction was stirred at 25 ° C for 12 hours. Filtration, the filter cake was washed with n-hexane (10 mL) and water (10 mIX3) and dried in vacuo to give the title product 1-(8-tert-butyl-4-methyl-2,3-dihydro-1,4- Benzoxazine-6-yl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoporphyrin] -2'-yl)ethanone hydrobromide 50 (164 mg, pale yellow powder), Yield: 46.7%

 MS m/z (ESI): 510 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.34 {br. s, 1H), 9.07 {br. s, 1H), 7.30 (s, 1H), 7.22 (s, 1H), 7.04 (s , 1H), 5.21 (s, 2H), 4.35 (m, 2H), 4.24 (q, / = 7.2 Hz, 2H), 4.13 (q, J = 1.2 Hz, 2H), 3.34 (m, 2H), 2.94 (s, 3H), 1.78 (m, 2H), 1.67 (m, 2H), 1.41 (t, / = 7.2 Hz, 3H), 1.36 (s, 9H), 1.31 (t, / = 7.2 Hz, 3H) Example 51

L-(8-tert-Butyl-4-ethyl-2,3-dihydro-1,4-benzoxazin-6-yl)-2-(5',6'-diethoxy-4 '-Fluoro-3'-imino-spiro[cyclopropane-1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

 First step

 L-(8-tert-Butyl-4-ethyl-2,3-dihydro-1,4-benzoxazin-6-yl)-2-(5',6'-diethoxy-4 '-Fluoro-3'-imino-spiro[cyclopropane-1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (165 mg, 0.62 mmol) and B 2-bromo 1-(8-tert-butyl-4-ethyl-2,3-dihydro-1,4-benzoxazin-6-yl)-ethanone 6b (255 mg, 0.75 mmol) dissolved in 4 mL Triethylamine (0.1 mL, 0.72 mmol) was added to tetrahydrofuran, and the reaction was stirred at 25 ° C for 12 hours. Filtration, the filter cake was washed with n-hexane (10 mL) and water (10 mIX3) and dried in vacuo to give the title product 1-(8-tert-butyl-4-ethyl-2,3-dihydro-1,4- Benzoxazine-6-yl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoporphyrin] -2'-yl)ethanone hydrobromide 51 (133 mg, white powder), yield: 35.2%.

 MS m/z (ESI): 524 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.35 (br. s, 1H), 9.04 (br. s, 1H), 7.24 (s, 1H), 7.22 (s, 1H), 7.04 (s , 1H), 5.19 (s, 2H), 4.29 (t, J = 4.4 Hz, 2H), 4.24 (q, J = 7.2 Hz, 2H), 4.12 (q, / = 7.2 Hz, 2H), 3.43 (q , / = 7.2 Hz, 2H), 3.37 (t, / = 4.4 Hz, 2H), 1.78 (m, 2H), 1.66 (m, 2H), 1.40 (t, / = 7.2 Hz, 3H), 1.36 (s , 9H), 1.31 (t, / = 7.2 Hz, 3H), 1.12 (t, / = 7.2 Hz, 3H)

1-[3-tert-Butyl-4-methoxy-5-G-piperidine)phenyl]-2-(7-imino-2,5-dimethyl-5-phenyl-pyrrole

 [3,4-b]pyridine-6-yl)ethanone hydrobromide

 2,5-Dimethyl-5-phenyl-6H-pyrrolo[3,4-b]pyridine-7-imine 9f (237 mg, 1 mmol) and 2-bromo small [3-tert-butyl 4-Methoxy-5-(1-piperidinyl)phenyl]-ethanone 12b (441.6 mg, 1.2 mmol) was dissolved in 3 mL of N,N-dimethylformamide, and the reaction was stirred for 12 hours. To the reaction mixture, 5 mL of water was added, and the mixture was combined with ethyl acetate (20 mL×3), and the organic phase was combined, washed with a saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate The residue obtained was purified by silica gel column chromatography elut elut elut elut elut elut elut elut elut Amino-2,5-dimethyl-5-phenyl-pyrrolo[3,4-b]pyridin-6-yl)ethanone hydrobromide 52 (150 mg, pale yellow solid), yield: 24.8 %. MS m/z (ESI): 525 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 7.92 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.46 (m, 7H), 5.43 (d, / = 18.8 Hz, 1H), 5.03 (d, / = 18.8 Hz, 1H), 3.94 (s, 3H), 2.92 (m, 4H), 2.67 (s, 3H), 1.99 (s, 3H), 1.71 ( m, 4H), 1.54 (m, 2H), 1.33 (s, 9H) Example 53

 2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, oxime-isoindoline]-2'-yl) small (4-A Oxy-3--3-5-trimethylsilyl-phenyl)ethanone hydrobromide

first step

 1-(4-hydroxy-3-iodo-phenyl)ethanone

1-(4-Hydroxyphenyl)ethanone 53a (4.0 g, 29.38 mmol) was dissolved in 250 mL of concentrated aqueous ammonia, and aqueous solution of 300 mL of iodine (7.46 g, 29.38 mmol) and potassium iodide (23.75 g, 143.08 mmol) was added. , stir at 50 ° C The reaction was mixed for 48 hours. Filtration, the filtrate was adjusted to pH = 1 with concentrated hydrochloric acid (100 mL), filtered, and the filter cake was washed with water (100 mL×3) and dried in vacuo to give the title product 1-(4-hydroxy-3-iodo-phenyl)ethanone 53M3.75 g , yellow solid), Yield: 48.8%.

MS m/z (ESI): 261 [M-l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 11.13 (s, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.70 (dd, /;= 8.4 Hz, J ₂ = 2.0 Hz, 1H), 6.81 (d, J = 8.4 Hz, 2H), 2.34 (s, 3H)

 Second step

 ^3-iodo-4-methoxyphenyl)ethanone

 Dissolve 1-(4-hydroxy-3-iodo-phenyl)ethanone 53b (3.52 g, 13 mmol) in 50 mL of EtOAc EtOAc (EtOAc) The reaction was stirred for 6 hours at 50 ° C with potassium carbonate (2.78 g, 20 mmol). Filtration, and the filtrate was concentrated under reduced pressure. Solid), Yield: 81.6%. MS m/z (ESI): 277 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.39 (d, / = 2.4 Hz, 1H), 7.95 (dd, = 8.4 Hz, J ₂ = 2.4 Hz, 1H), 6.85 (d, / = 8.4 Hz , 1H), 3.96 (s, 3H), 2.55 (s, 3H)

 third step

 L-(4-methoxy-3-morpholinylphenyl)ethanone

 1-(3-Iodo-4-methoxyphenyl)ethanone 53c (3.03 g, 10.96 mmol) and 2-dicyclohexylphosphino-2'-(^, dimethylamine)-biphenyl (216 Mg, 0.55 mmol) dissolved in 120 mL of toluene, palladium on carbon (302 mg, 10%), sodium tert-butoxide (2.10 g, 21.91 mmol) and morpholine (1.9 mL, 21.91 mmol) at 80 ° C The reaction was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjjjj Yellow oil), Yield: 68.8%.

 MS m/z (ESI): 236 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.66 (dd, /; = 8.4 Hz, J ₂ = 2.4 Hz, 1H), 7.58 (d, J = 2.4 Hz, 1H), 6.89 (d, / = 8.4 Hz, 1H), 3.94 (s, 3H), 3.90 (m, 4H), 3.10 (m, 4H), 2.56 (s, 3H)

 the fourth step

 4-[5-(l,l-dimethoxyethyl)-2-methoxyphenyl]morpholine 1-(4-methoxy-3-morpholinylphenyl)ethanone 53d (971 Methyl, 4.13 mmol) and trimethyl orthoformate (1.4 mL, 12.38 mol) were dissolved in 40 mL of methanol. D(+)- 10-camphorsulfonic acid (1.054 g, 4.54 mmol) was added and the reaction was stirred for 12 hours. To the reaction mixture, 626 mg of potassium carbonate was added, and the mixture was stirred for 0.5 hour, and then added with 50 mL of water, and extracted with ethyl acetate (50 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate Filtration and concentration of the filtrate under reduced pressure afforded the title product 4-[5-(1,1-dimethoxyethyl)-2-methoxyphenyl]morpholine 53e (1.09 g, m. , Yield: 94.0%.

MS m/z (ESI): 282 [M+l] NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 7.13 (dd, /;= 8.8 Hz, J ₂ = 2.0 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.84 (d, / = 8.8 Hz, 1H), 3.90 (m, 4H), 3.87 (s, 3H), 3.18 (s, 6H), 3.09 (m, 4H), 1.53 (s, 3H)

 the fifth step

 [5-(l,l-Dimethoxyethyl)-2-methoxy-3-morpholinylphenyl]-trimethylsilane dry ice-acetone bath, 4-[5-(1,1 -Dimethoxyethyl)-2-methoxyphenyl]morpholine 53e (1.09 g, 3.88 mmol) was dissolved in 40 mL of n-hexane and tetramethylethylenediamine (116 μM, 0.78 mmol) And n-butyllithium C 3.1 mL, 7.76 mmol), the reaction was stirred at room temperature for 4 hours, trimethylchlorosilane (975 μΐ, 7.76 mmol) was added under ice bath, and the reaction was stirred at room temperature for 12 hours. Add 50 mL of saturated ammonium chloride solution to the reaction solution, extract with ethyl acetate (30 mL×3), combine the organic phase, wash with water (20 mL><2) and saturated sodium chloride solution (20 mL×2), anhydrous sulfuric acid The sodium was dried, filtered, and the filtrate was evaporated. 1.31 g, brownish yellow oil), Yield: 95.7%.

 MS m/z (ESI): 354 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.14 (d, / = 2.0 Hz, 1H), 7.09 (d, / = 2.0 Hz, 1H), 3.90 (s, 3H), 3.87 (m, 4H) , 3.19 (s, 6H), 3.10 (m, 4H), 1.53 (s, 3H), 0.28 (s, 9H)

 Step 6

 2-bromo- 1.(4-methoxy-3-morpholine-5-trimethylsilyl-phenyl)ethanone [5-(1,1-dimethoxyethyl)-2- Methoxy-3-morpholinylphenyl]-trimethylsilane 53f (1.31 g, 3.71 mmol) was dissolved in 20 mL of acetic acid, tribromopyridinium salt (1.19 g, 3.71 mmol) was added, and the reaction was stirred for 2 hours. 30 mL of saturated sodium chloride solution was added to the reaction mixture, and extracted with ethyl acetate (30 mIX3). The organic phase was combined and washed with saturated sodium hydrogen carbonate solution (20 mL×2) and saturated sodium chloride solution (20 mL×2), The aqueous solution was dried over sodium sulfate, filtered, and evaporated. 5-Trimethylsilyl-phenyl)ethanone 53 g (560 mg, yellow solid), Yield: 39.0%.

MS m/z (ESI): 386 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 7.70 (d, / = 2.4 Hz, 1H), 7.63 (d, / = 2.4 Hz, 1H), 4.42 (s, 2H), 3.97 (s, 3H) , 3.90 (m, 4H), 3.11 (m, 4H), 0.32 (s, 9H)

 Seventh step

 2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, oxime-isoindoline]-2'-yl) small (4-A Oxy-3-morpholine-5-trimethylsilyl-phenyl)ethanone hydrobromide

5',6'-Diethoxy-7'-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (156 mg, 0.59 mmol) and 2-bromo- 1-(4-Methoxy-3-morpholine-5-trimethylsilyl-phenyl)ethanone 53 g (298 mg, 0.67 mmol) was dissolved in 5 mL of THF, triethylamine (0.1 mL, 0.72 mmol), the reaction was stirred at 25 ° C for 12 hours. Filtration, the filter cake was washed with n-hexane (10 mL) and water (10 mL×3) and dried in vacuo to give the title product 2-(5',6'-diethoxy-4'-fluoro-3'-imino- Spirulina [cyclopropane-1,1'-isoindoline] -2'-yl) small (4-A Oxy-3-morpholine-5-trimethylsilyl-phenyl)ethanone hydrobromide 53 (126 mg, yellow powder), Yield: 29.9%.

 MS m/z (ESI): 632 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.46 (br. s, 2H), 7.67 (d, J = 2.4 Hz, 2H), 7.07 (s, 1H), 5.49 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 4.11 (q, / = 7.2 Hz, 2H), 3.91 (s, 3H), 3.79 (m, 4H), 3.05 (m, 4H), 1.79 (m, 2H) ), 1.66 (m, 2H), 1.39 (t, / = 7.2 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H), 0.29 (s, 9H) Example 54

1-[3-tert-Butyl-4-methoxy-5-(l-piperidinyl)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'- Amino-spiro[cyclopropane

 -1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

 First step

1-[3-tert-butyl-4-methoxy-5-(1-piperidinyl)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'- Amino-spiro[cyclopropane

 -1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (198 mg, 0.75 mmol) and B 2-bromo 1-[3-tert-Butyl-4-methoxy-5-(1-piperidinyl)phenyl]ethanone 12b (324 mg, 0.88 mmol) was dissolved in 5 mL of tetrahydrofuran and added triethylamine (0.15 mL, 1.08 mmol), stir the reaction at 25 °C for 12 hours. Filtration, the filter cake was washed with n-hexane (10 mL) and water (10 mL×3) and dried in vacuo to give the title product 1-[3-tert-butyl-4-methoxy-5-(1-piperidine)phenyl -2-(5',6'-Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone Hydrobromide 54 (257 mg, white powder), Yield: 54.2%. MS m/z (ESI): 552 [M+l]

 1H NMR (400 MHz, DMSO-, ppm): δ 9.36 {br. s, 1H), 9.08 {br. s, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.05 (s, 1H) ), 5.24 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.96 (s, 3H), 2.97 (m, 4H), 1.82 (m , 2H), 1.73 (m, 4H), 1.66 (m, 2H), 1.55 (m, 2H), 1.40 (t, / = 7.2 Hz, 3H), 1.38 (s, 9H), 1.31 (t, / = 7.2 Hz, 3H) Example 55

L-[3-[(lR,5 -3-Azabicyclo[3.1.0]hex-3-yl]-5-tert-butyl-4-methoxyphenyl]-2-(5,6- Diethoxy -4-fluorate

 First step

 L-[3-[(lR,5 -3-Azabicyclo[3.1.0]hex-3-yl]-5-tert-butyl-4-methoxyphenyl]-2-(5,6- Diethoxy

 4-fluoro-3-imino-1, 1-dimethyl-isoindol-2-yl)ethanone hydrobromide 5,6-diethoxy-7-fluoro-3,3 -Dimethyl-isoindolamine 24d (258 mg, 0.97 mmol) was dissolved in 4 mL of N,N-dimethylformamide and added 1-[3-[(1 5 -3-azabicyclo[ 3丄0]hex-3-yl]-5-tert-butyl-4-methoxyphenyl]-2-bromo-ethanone 48h (558 mg, 1.07 mmol), stirred for 12 hours. After adding 10 mL of water and 10 mL of ethyl acetate, the organic phase was combined, washed with water (5 mL×3) and saturated sodium chloride solution (5 mL×3), dried over anhydrous magnesium sulfate, filtered, The residue obtained was purified by eluent system A to give the title product l-[3-[GR,5-3-azabicyclo[3.1.0]hex-3-yl]-5-tert-butyl-4- Methoxyphenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-U-dimethyl-isoindolin-2-yl)ethanone hydrobromide 55 (36 mg, yellow solid), Yield: 5.9%.

MS m/z (ESI): 552 [M+l]

1H NMR (400 MHz, DMSO-, ppm): δ 9.34 (br. s, 1H), 8.97 (br. s, 1H), 7.53 (s, 1H), 7.48 (s, 1H), 7.44 (s, 1H) ), 5.44 (s, 2H), 4.26 (m, 2H), 4.11 (m, 2H), 3.61 (s, 3H), 3.55 (m, 2H), 2.99 (m, 2H), 1.63 (m, 2H) , 1.50 (s, 6H), 1.41 (t, / = 7.2 Hz, 3H), 1.39 (s, 9H) _: 1.31 (t, / = 7.2 Hz, 3H), 0.60 (m, 2H) Example 56

L-[3-[(lR,5 -3-Azabicyclo[3.1.0]hex-3-yl]-5-tert-butyl-4-methoxyphenyl]-2-(5',6 '-diethoxy

 -3'-imino-spiro [cyclo-1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

 First step

L-[3-[(lR,5 -3-Azabicyclo[3.1.0]hex-3-yl]-5-tert-butyl-4-methoxyphenyl]-2-(5',6 '-diethoxy

 -3'-imino-spiro[cyclopropane-1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide 5',6'-diethoxyspiro[cyclopropane- 1,3'-Isoporphyrin]-indole-imine hydrobromide 7d (172 mg, 0.70 mmol) was dissolved in 4 mL of tetrahydrofuran, and l-[3-[(lR,5 -3- aza) was added. Bicyclo[3.1.0]hex-3-yl]-5-tert-butyl-4-methoxyphenyl]-2-bromo-ethanone 48h (360 mg, 0.98 mmol) and triethylamine (0.1 mL, 0.72 mmol), the reaction was stirred for 12 hrs. filtered and filtered, washed with hexane (10 mL EtOAc) [3.1.0]hex-3-yl]-5-tert-butyl-4-methoxyphenyl]-2-(5',6'-diethoxy-3'-imino-spiro[ring Propane-1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide 56 (27 mg, white powder), Yield: 6.3%

MS m/z (ESI): 532 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.64 (br. s, 1H), 9.08 (br. s, 1H), 7.87 (s, 1H), 7.500, 1H), 7.40 (s, 1H) ), 7.05 (s, 1H), 5.18 (s, 2H), 4.17 (q, / = 7.2 Hz, 2H), 4.11 (q, / = 7.2 Hz, 2H), 3.61 (s, 3H), 3.55 (d , / = 8.8 Hz, 2H), 2.99 (d, / = 8.8 Hz, 2H), 1.72 (m, 2H), 1.63 (m, 4H), 1.38 (m, 15H), 0.62 (d, / = 4.4 Hz , 1H), 0.55 (d, / = 4.4 Hz, 1H) Example 57

 2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl) small (4-methoxy-3-? 5-trimethylsilyl-phenyl)ethanone hydrobromide

 First step

 2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)small (4-methoxy-3-morpholine) -5-trimethylsilyl-phenyl)ethanone hydrobromide

5,6-Diethoxy-7-fluoro-3,3-dimethyl-isoindol-1-amine 24d (266 mg, 1.0 mmol) and 2-bromo small (4-methoxy-3) -morpholine-5-trimethylsilyl-phenyl)ethanone 53g (425 mg, 1.1 mmol) dissolved in 5 In mLN, N-dimethylformamide, the reaction was stirred for 12 hours. 5 mL of water was added to the reaction mixture, and the aqueous layer was combined with ethyl acetate (5 mL?). , filtered, the filter cake was washed with n-hexane (10 mL) and water (10 mL) and dried in vacuo to give the title product 2-(5,6-diethoxy-4-fluoro-3-imino-U-II Methyl-isoindol-2-yl)-1-(4-methoxy-3-morpholine-5-trimethylsilyl-phenyl)ethanone hydrobromide 57 (84 mg, yellow powder ), Yield: 12.0%.

 MS m/z (ESI): 572 [M+l]

 1H NMR (400 MHz, DMS0-d6, ppm): δ 9.35 (br. s, 1H), 8.99 (br. s, 1H), 7.67 (m, 2H), 7.46 (s, 1H), 5.47 (s, 2H), 4.26 (q, / = 7.2 Hz, 2H), 4.10 (q, / = 7.2 Hz, 2H), 3.93 (s, 3H), 3.89 (m, 4H), 3.05 (m, 4H), 1.51 ( s, 6H), 1.41 (t, / = 7.2 Hz, 3H), 1.31 (t, / = 7.2 Hz, 3H), 0.31 (s, 9H) Example 58

 L-(3-tert-Butyl-4-methoxy-5-pyrrolidin-1-yl-phenyl)-2-(7-imino-2-methoxy-5-methyl-5-benzene Base--b]pyridin-6-yl)ethanone hydrobromide

 First step

 1-(6-methoxy-3-pyridine)-1-phenylethanol

 5-Bromo-2-methoxy-B-pyridyl 58a (21.0 g, 111 mmol) was dissolved in 120 mL of diethyl ether under dry ice-acetone bath, and 2.5 M n-butyllithium (49.1 mL, 123 mmol) was added dropwise. The n-hexane solution was stirred for 1 hour, and acetophenone G4.4 mL (123 mmol) was added and the mixture was stirred for 1 hour. 50 mL of a saturated ammonium chloride solution was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (50 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution (20 mL×3), dried over anhydrous sodium sulfate, filtered, filtrate The residue was purified by EtOAcjjjjjjjjjj , Yield: 75.4%.

MS m/z (ESI): 230 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.26 (s, 1H), 7.63 (m, 6H), 6.72 (m, 1H), 3.96 (s, 3H), 1.99 (s, 3H)

 Second step

 5-(l-azido-1-phenyl-ethyl)-2-methoxypyridine

 Dissolve 1-(6-methoxy-3-pyridine)-1-phenyl-ethanol 58b (14.4 g, 63 mmol) and sodium azide C12.3 g, 189 1^^1) under ice bath In 72 11 ^ water, 56 mL of concentrated hydrochloric acid was added dropwise, and the reaction was stirred for 12 hours. Add 800 mL of saturated sodium bicarbonate solution to the reaction solution to adjust the pH to 7~8, extract with ethyl acetate (200 mL×3), combine the organic phase, wash with saturated sodium chloride solution (50 mL×3), dry over anhydrous sodium sulfate After filtration, the filtrate was evaporated to drynessjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

1H NMR (400 MHz, DMS0-, ppm): δ 8.23 (s, 1H), 7.51 (d, / = 9.2 Hz, 1H), 7.38 (m, 5H), 6.73 (d, J = 9.2 Hz, 1H) , 3.98 (s, 3H), 2.05 (s, 3H)

 third step

 5-(1-azido-1-phenyl-ethyl)-2-methoxy-pyridine 1-oxide 5-(1-azido-1-phenyl-ethyl)-2-methoxy -B was dissolved in 200 mL of dichloromethane with pyridine 58c (16.0 g, 63 mmol), m-chloroperoxybenzoic acid (21.7 g, 126 mmol) was added, and the reaction was stirred for 13 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) 50 mL x 3), dried over anhydrous sodium sulfate, filtered, EtOAcjjjjjjjjjjjj Ethyl)-2-methoxy-pyridine 1-oxide 58d (12.0 g, pale yellow oil), yield: 70.6%.

MS m/z (ESI): 271 [M+l]

 the fourth step

 3-(1-azido-1-phenyl-ethyl 6-methoxy-pyridine-2-carbonitrile 5-(1-azido-1-phenyl-ethyl)-2-methoxy- B was dissolved in 120 mL of acetonitrile with pyridine 1-oxide 58d (8.9 g, 33 mmol), cyanotrimethylsilane (17.6 mL, 132 mmol) and dimethylcarbamoyl chloride (3.63 mL, 39.5 mmol). The reaction was stirred for 24 hours. To the reaction mixture was added 100 mL of methylene chloride. The organic layer was combined and washed with saturated sodium hydrogen carbonate (20 mL×3) and saturated sodium chloride (20 mL×3) Filtration, and the filtrate was concentrated under reduced pressure. Pyridine-2-carbonitrile 58e (4.5 g, pale yellow oil), yield: 48.9%.

MS m/z (ESI): 280 [M+l]

 the fifth step

2-methoxy-5-methyl-5-phenyl-6H-pyrrole[3,4-b]pyridine-7-imine 3-(1-azido-1-phenyl-ethyl)- 6-Methoxy-pyridine-2-carbonitrile 58e (4.4 g, 15.7 mmol) was dissolved in 120 mL of tetrahydrofuran, and 6 mL of water and triphenylphosphine (8.26 mg, 31.5 mmol) were added, and the reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified from silica gel column chromatography The title product 2-methoxy-5-methyl-5-phenyl-6H-pyrrolo[3,4-b]pyridine-7-imine 58f (3.0 g, white solid).

MS m/z (ESI): 254 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 7.95 (d, J = 8.4 Hz, 1H), 7.48 (m, 2H), 7.28 (m, 2H), 7.20 (m, 1H), 6.84 ( d, / = 8.4 Hz, 1H), 3.95 (s, 3H), 1.71 (s, 3H)

 Step 6

 L-(3-tert-Butyl-4-methoxy-5-pyrrolidin-1-yl-phenyl)-2-(7-imino-2-methoxy-5-methyl-5-benzene Base-pyrrolo[3,4-b]pyridin-6-yl)ethanone hydrobromide

 2-Methoxy-5-methyl-5-phenyl-6H-pyrrolo[3,4-b]pyridine-7-imine 58f (253 mg, 1 mmol) and 2-bromo-1-( 3-tert-Butyl-4-methoxy-5-pyrrolidin-1-yl-phenyl)ethanone 8d (424.8 mg, 1.2 mmol) was dissolved in 5 mL of methanol and added triethylamine (0.166 mL, 1.2 Methyl), the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced vacuolululululululululululululu Phenyl)-2-(7-imino-2-methoxy-5-methyl-5-phenyl-pyrrolo[3,4-b]pyridin-6-yl)ethanone hydrobromide 58 (65 mg, pale yellow solid), Yield: 10.7%.

MS m/z (ESI): 527 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 7.92 (d, J = 8.8 Hz, 1H), 7.36 (m, 7H), 7.22 (d, J = 8.4 Hz, 1H), 5.46 (d, / = 18.4 Hz, 1H), 5.04 (d, / = 18.4 Hz, 1H), 4.03 (s, 3H), 3.82 (s, 3H), 3.14 (m, 4H), 1.98 (s, 3H), 1.91 ( m, 4H), 1.36 (s, 9H) Example 59

 1-(3-tert-Butyl-4-methoxy-5-morpholinylphenyl)-2-(7-imino-2-methoxy-5-methyl-5-phenyl-pyrrole

 3,4-b]pyridine-6-yl)ethanone hydrobromide

 First step

 1-(3-tert-butyl-4-methoxy-5-morpholinylphenyl)-2-(7-imino-2-methoxy-5-methyl-5-phenyl-pyrrole

 [3,4-b]pyridine-6-yl)ethanone hydrobromide

2-Methoxy-5-methyl-5-phenyl-6H-pyrrolo[3,4-b]pyridine-7-imine 58f (253 mg, 1 mmol) And 2-bromo-l-(3-tert-butyl-4-methoxy-5-morpholinylphenyl)ethanone 2h (444 mg, 1.2 mmol) was dissolved in 4 mL of tetrahydrofuran, and triethylamine (0.166) mL, 1.2 mmol), stirred for 12 hours. The reaction mixture was filtered, and the filtrate was evaporated, evaporated,jjjjjjjjjjj -2-(7-imino-2-methoxy-5-methyl-5-phenyl-pyrrolo[3,4-b]pyridin-6-yl)ethanone hydrobromide 59 (120 mg , pale yellow solid), Yield: 19.3%.

MS m/z (ESI): 543 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 7.96 (d, / = 8.8 Hz, 1H), 7.38 (m, 7H), 7.25 (d, J = 8.4 Hz, 1H), 5.53 (d, / = 18.8 Hz, 1H), 5.10 (d, / = 18.8 Hz, 1H), 4.06 (s, 3H), 3.88 (s, 3H), 3.80 (m, 4H), 3.03 (m, 4H), 2.13 ( s, 3H), 1.36 (s, 9H) Example 60

 L-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(7-imino-2-methoxy-5-methyl-5-phenyl-pyrrolo[3,4- b]

 First step

 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(7-imino-2-methoxy-5-methyl-5-phenyl-pyrrole [3,4-b Oral pyridin-6-yl)ethanone hydrobromide

 2-Methoxy-5-methyl-5-phenyl-6H-pyrrolo[3,4-b]pyridine-7-imine 58f (64 mg, 0.25 mmol) and B 2-bromo-1- (3,5-Di-tert-butyl-4-hydroxyphenyl)ethanone If (248 mg, 0.76 mmol) was dissolved in 2 mL of methanol, triethylamine (0.105 mL, 0.76 mmol). The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj Amino-2-methoxy-5-methyl-5-phenyl-pyrrolo[3,4-b]pyridin-6-yl)ethanone hydrobromide 60 (30 mg, yellow solid), yield : 23.8%.

MS m/z (ESI): 500 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 7.95 (d, / = 8.4 Hz, 1H), 7.69 (s, 2H), 7.39 (m, 5H), 7.25 (d, J = 8.8 Hz, 1H), 5.43 (d, / = 18.4 Hz, 1H), 5.06 (d, / = 18.4 Hz, 1H), 4.04 (s, 3H), 1.98 (s, 3H), 1.40 (s, 18H) Example 61

 1-[3-tert-Butyl-4-methoxy-5-(l-piperidinyl)phenyl]-2-(7-imino-2-methoxy-5-methyl-5-phenyl -pyrrole

 4-b]pyridine-6-yl)ethanone hydrobromide

 First step

 1-[3-tert-butyl-4-methoxy-5-(1-piperidinyl)phenyl]-2-(7-imino-2-methoxy-5-methyl-5-phenyl -pyrrolo[3,4-b]pyridin-6-yl)ethanone hydrobromide

 2-methoxy-5-methyl-5-phenyl-6H-pyrrolo[3,4-b]pyridine-7-imine 58f (253 mg, 1 mmol) and 2-bromo small [3- tert-Butyl-4-methoxy-5-(1-piperidinyl)phenyl]ethanone 12b (441.6 mg, 1.2 mmol) was dissolved in 3 mL of N,N-dimethylformamide and stirred for 12 hours. . To the reaction mixture, 5 mL of water was added, and the mixture was combined with ethyl acetate (20 mL×3), and the organic phase was combined, washed with a saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate, filtered, The residue obtained was purified by silica gel column chromatography elut elut elut elut elut eluting Imino-2-methoxy-5-methyl-5-phenyl-B-pyrolo[3,4-b]pyridin-6-yl)ethanone hydrobromide 61 (180 mg, pale yellow solid ), Yield: 30.0%

MS m/z (ESI): 541 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.96 (s, 2H), 7.94 (d, / = 8.8 Hz, 1H), 7.49 (s, 1H), 7.45 (s, 1H), 7.37 ( m, 5H), 7.22 (d, J = 8.4 Hz, 1H), 5.45 (d, J = 18.4 Hz, 1H), 5.07 (d, / = 18.4 Hz, 1H), 4.04 (s, 3H), 3.94 ( s, 3H), 2.90 (m, 4H), 1.91 (s, 3H), 1.70 (m, 4H), 1.54 (m, 2H), 1.34 (s, 9H) Example 62

2-[[3-tert-butyl-5-[2-(7-imino-2-methoxy-5-methyl-5-phenyl-pyrrolo[3,4-b]pyridine-6- Acetyl]-2-methoxyphenyl]amino]acetonitrile hydrobromide

 First step

2-[[3-tert-butyl-5-[2-(7-[3,4-b]pyridin-6-yl)acetyl

 2-methoxy-5-methyl-5-phenyl-6H-pyrrolo[3,4-b]pyridine-7-imine 58f (253 mg, 1 mmol) and 2-[[5-( 2-Bromoacetyl)-3-tert-butyl-2-methoxyphenyl]amino]acetonitrile 14b (406.8 mg, 1.2 mmol) dissolved in 3 mL of N,N-dimethylformamide, stirred for 12 hour. To the reaction mixture, 5 mL of water was added, and the mixture was combined with ethyl acetate (20 mL×3), and the organic phase was combined, washed with a saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate, filtered, The residue obtained was purified by silica gel column chromatography elutd elut elut elut elut elut eluting 5-phenyl-pyrrolo[3,4-b]pyridin-6-yl)acetyl]-2-methoxyphenyl]amino]acetonitrile hydrobromide 62 (150 mg, pale yellow solid) Rate: 25.3%.

MS m/z (ESI): 512 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.90 (s, 2H), 8.05 (d, J = 8.4 Hz, 1H), 7.37 (m, 7H), 7.10 (d, / = 6.8 Hz, 1H), 6.09 (t, / = 6.8 Hz, 1H), 5.50 (d, / = 18.8 Hz, 1H), 5.05 (d, / = 18.8 Hz, 1H), 4.38 (d, / = 7.2 Hz, 2H) , 4.03 (s, 3H), 3.72 (s, 3H), 1.99 (s, 3H), 1.36 (s, 9H) Example 63

 L-(3-tert-butyl-4-methoxy-5-morpholinylphenyl)-2-(3-imino-1-methyl-1-phenyl-pyrrolo[3,4-b] quinoline

 -2- ethyl ketone hydrobromide

first step

 1-phenyl-l-(3-quinoline)ethanol

 3-bromo-quinoline 63a (20.0 g, 96.6 mmol) was dissolved in 120 mL of diethyl ether under dry ice-acetone bath. 2.5 M n-butyllithium (42.5 mL, 106 mmol) in n-hexane was added dropwise and stirred. After 1 hour, acetophenone (12.4 mL, 106 mmol) was added and stirring was continued for 12 hours. 50 mL of saturated ammonium chloride solution was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (20 mL×3), dried over anhydrous sodium sulfate, filtered, filtrate The residue was purified by silica gel column chromatography elut elut elut elut elut elut elut elut elut Rate: 38.8%.

MS m/z (ESI): 250 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.90 (s, 1H), 8.24 (s, 1H), 8.11 (m, 1H), 7.73 (m, 1H), 7.60 (m, 1H), 7.57 ( m, 1H), 7.50 (m, 2H), 7.40 (m, 2H), 7.37 (m, 1H), 2.12 (s, 3H)

 Second step

 3-G-azido-1-phenyl-ethyl)quinoline

 1-phenyl-1-(3-quinoline)ethanol 63b (7.0 g, 28 mmol) and sodium azide (5.5 g, 84 mmol) were dissolved in 35 mL water under ice-cooling, and 35 mL concentrated Hydrochloric acid was stirred for 12 hours. Add 450 mL of saturated sodium bicarbonate solution to the reaction solution to adjust the pH to 7~8, extract the aqueous phase with ethyl acetate (150 mL×3), combine the organic phase, wash with saturated sodium chloride solution (50 mL×3), anhydrous sulfuric acid The sodium was dried, filtered, and the filtrate was evaporated, evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 6.8 g, pale yellow oil), Yield: 88.3%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.82 (s, 1Η), 8.24 (s, 1H), 8.13 (d, / = 8.8 Hz, 1H), 7.88 (d, / = 8.0 Hz, 1H) , 7.77 (t, / = 8.8 Hz, 1H), 7.63 (t, / = 8.0 Hz, 1H), 7.43 (m _: 5H), 2.19 (s, 3H)

 third step

 3-(l-azido-1-phenyl-ethyl)quinoline 1-oxide

Dissolve 3-(1-azido-1-phenyl-ethyl)quinoline 63c (6.2 g, 22.6 mmol) in 60 mL of dichloromethane and add m-chloroperoxybenzoic acid (4.8 g, 27 mmol) The reaction was stirred for 3 hours. Add 50 mL of saturated sodium bicarbonate solution to the reaction solution, extract the aqueous phase with dichloromethane (50 mL×3), and combine the organic phase with saturated sodium chloride The solution was washed (20 mL×3), dried over anhydrous sodium sulfate, filtered, evaporated, evaporated. Phenyl-ethyl)quinoline 1-oxide 63d (6.0 g, yellow oil), Yield: 91.0%.

MS m/z (ESI): 291 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.70 (d, J = 8.0 Hz, 1H), 8.49 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H) , 7.78 (t, J = 8.0 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.45 (m, 5H), 2.15 (s, 3H)

 the fourth step

 3-G-azido-1-phenyl-ethyl)-quinoline-2-carbonitrile

 3-G-Azido-1-phenyl-ethyl)quinoline 1-oxide 63d (5.95 g, 20 mmol) was dissolved in 120 mL of acetonitrile and cyanotrimethylsilane (4.65 mL, 35 mmol) And dimethylcarbamoyl chloride (2.82 mL, 30 mmol), and the reaction was stirred at 80 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. The residue was dried over anhydrous sodium sulfate (MgSO4). Quinoline-2-carbonitrile 63e (3.3 g, pale yellow oil), Yield: 54.1%.

MS m/z (ESI): 300 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.65 (s, 1H), 7.87 (m, 4H), 7.45 (m, 5H), 2.34 (s, 3H)

 the fifth step

Imethyl-I-phenyl-2H-pyrrolo[3,4-b]quinoline-3-iminoamine 3-(1-azido-1-phenyl-ethyl)-quinoline-2- The nitrile 63e (2.1 g, 7 mmol) was dissolved in 100 mL of THF, and 0.5 mL of water and triphenylphosphine (3.68 mL, 14 mmol) was added and the mixture was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj 3-imine 63f (1.6 g, pale yellow solid), Yield: 83.5%. 1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.53 (s, 1 Η), 8.13 (m, 1H), 8.07 (m, 1H), 7.69 (m, 1H), 7.60 (m, 1H), 7.59 ( m, 2H), 7.30 (m, 2H), 7.19 (m, 1H), 6.82 (s, 2H), 1.82 (s, 3H)

 L-(3-tert-butyl-4-methoxy-5-morpholinylphenyl)-2-(3-imino-1-methyl-1-phenyl-pyrrolo[3,4-b] quinoline

 -2-yl)ethanone hydrobromide

1-Methyl-1-phenyl-2H-pyrrolo[3,4-b]quinoline-3-imine 63f (273 mg, 1 mmol) and 2-bromo-1-(3-tert-butyl) -4-Methoxy-5-morpholinylphenyl)ethanone 2h (444 mg, 1.2 mmol) was dissolved in 5 mL of a mixture of methanol and tetrahydrofuran (V/V = 3:2) and added triethylamine (0.166) mL, 1.2 mmol), stir the reaction for 24 hours. The reaction mixture was concentrated under reduced pressure. mjjjjjjjj -(3-imino-1-methyl-1-phenyl-pyrrolo[3,4-b]quinolin-2-yl)ethanone hydrobromide 63 (120 mg, pale yellow solid) Rate: 18.7%. MS m/z (ESI): 563 [M+l]

 1H NMR (400 MHz, DMSO-, ppm): δ 8.29 (m, 12H), 5.60 (d, / = 18.0 Hz, 1H), 5.19 (d, J = 18.0 Hz, 1H), 3.95 (s, 3H) , 3.80 (m, 4H), 2.99 (m, 4H), 2.12 (s, 3H), 1.36 (s, 9H) Example 64

1-[3-tert-Butyl-4-methoxy-5-(l-piperidine)phenyl]-2-(3-imino-1-methyl-1-phenyl-pyrrolo[3, 4-b] quin

 -2-yl)ethanone hydrobromide

 First step

 1-[3-tert-butyl-4-methoxy-5-(1-piperidinyl)phenyl]-2-(3-imino-1-methyl-1-phenyl-pyrrolo[3, 4-b]quinolin-2-yl)ethanone hydrobromide

 1-Methyl-1-phenyl-2H-pyrrolo[3,4-b]quinoline-3-imine 63f (273 mg, 1 mmol) and 2-bromo-1-[3-tert-butyl 4-Methoxy-5-(1-piperidinyl)phenyl]-ethanone 12b (441.6 mg, 1.2 mmol) was dissolved in 3 mL of N,N-dimethylformamide and stirred for 12 hours. To the reaction mixture, 5 mL of water was added, and the mixture was combined with ethyl acetate (20 mL×3), and the organic phase was combined, washed with a saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate, filtered, The residue obtained was purified by silica gel column chromatography elut elut elut elut eluting -1-methyl-1-phenyl-cyclopyrolo[3,4-b]quinolin-2-yl)ethanone hydrobromide 64 (160 mg, pale yellow solid), yield: 25.0% . MS m/z (ESI): 561 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 8.64 (s, 1H), 8.28 (m, 1H), 8.15 (m, 1H), 7.97 (m, 1H), 7.80 (m, 1H), 7.39 (m, 7H), 5.56 (d, / = 18.4 Hz, 1H), 5.06 (d, / = 18.4 Hz, 1H), 3.94 (s, 3H), 2.93 (m, 4H), 2.11 (s, 3H) ), 1.70 (m, 4H), 1.53 (m, 2H), 1.34 (s, 9H) Example 65

N-[3-tert-butyl-5-[2-(7-imino-2,5-dimethyl-5-phenyl-pyrrolo[3,4-b]pyridin-6-yl)acetyl ]-2-methoxyphenyl]acetamide hydrobromide

first step

 N-[3-tert-butyl-5-[2-(7-imino-2,5-dimethyl-5-phenyl-pyrrolo[3,4-b]pyridin-6-yl)acetyl ]-2-methoxyphenyl]acetamide hydrobromide

 2,5-Dimethyl-5-phenyl-6H-pyrrolo[3,4-b]pyridine-7-imine 9f (237 mg, 1 mmol) and N-[5-(2-bromo- Acetyl)-3-tert-butyl-2-methoxyphenyl]acetamide 13b (410.4 mg, 1.2 mmol) was dissolved in 3 mL of N,N-dimethylformamide, and the reaction was stirred for 12 hours. To the reaction mixture, 5 mL of water was added, and the mixture was combined with ethyl acetate (20 mL×3), and the organic phase was combined, washed with a saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate, filtered, The residue obtained was purified by silica gel column chromatography elut elut elut elut elut elut eluting - Pyrrolo[3,4-b]pyridin-6-yl)acetyl]-2-methoxyphenyl]acetamide hydrobromide 65 (120 mg, pale yellow solid), Yield: 20.7%.

 MS m/z (ESI): 499 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 10.20 (br. s, 1H), 9.74 (br. s, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.96 (d, / = 8.4 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.62 (d, / = 2.0 Hz, 1H) _: 7.37 (m, 5H), 5.45 (d, / = 18.8 Hz, 1H), 5.08 (d, / = 18.8 Hz, lH), 4.12 (s, 3H), 2.64 (s _: 3H), 2.11 (s, 3H), 2.00 (s, 3H), 1.37 (s, 9H) Example 66

 L-[3-tert-Butyl-4-methoxy-5-(2-oxa-6-azaspiro[3.3]hex-6-yl)phenyl]-2-(5',6'- Diethoxy-4'-fluoro-3'-imino-spiro'-isoporphyrin]-2'-yl)ethanone hydrobromide

 First step

 L-[3-tert-Butyl-4-methoxy-5-(2-oxa-6-azaspiro[3.3]hex-6-yl)phenyl]-2-(5',6'- Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 5',6'- Diethoxy-7-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (134 mg, 0.51 mmol) and 2-bromo-1-[3-tert-butyl 4-methoxy-5-(6-oxa-2-azaspiro[3.3]heptan-2-yl)phenyl]ethanone 40f (202 mg, 0.53 mmol) was dissolved in 2 mL of THF. Triethylamine (0.1 mL, 0.72 mmol) was added and the reaction was stirred for 12 hr. Filtration, the filter cake was washed with n-hexane (10 mL) and water (10 m.sup.3) and dried in vacuo to give the title product 1-[3-tert-butyl-4-methoxy oxa-6-azaspiro[3.3] Hex-6-yl)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoporphyrin] -2'-yl)ethanone hydrobromide 66 (108 mg, yellow solid), yield: 32.9%.

MS m/z (ESI): 566 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.31 (br. s, 1H), 9.03 (br. s, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.07 (d, / = 2.0 Hz, 1H), 7.02 (s, 1H), 5.17 (s, 2H), 4.74 (m, 4H), 4.23 (q, J = 1.2 Hz, 2H), 4.12 (q, / = 7.2 Hz, 2H ), 3.99 (m, 4H), 3.67 (s, 3H), 1.77 (m, 2H), 1.65 (m, 2H), 1.40 (t, / = 7.2 Hz, 3H), 1.37 (s, 9H), 1.31 (t, / = 7.2 Hz, 3H) Example 67

 1-[3-tert-Butyl-4-methoxy-5-[(lR,5 -8-oxa-3-azabicyclo[3.2.1]oct-3-yl]phenyl]-2- (5',6'-Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide

first step 1-[3-tert-Butyl-4-methoxy-5-[(lR,5 -8-oxa-3-azabicyclo[3.2.1]oct-3-yl]phenyl]-2- (5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (156 mg, 0.56 mmol) and 2-bromo-1 -[3-tert-butyl-4-methoxy-5-[(lR,5 -8-oxa-3-azabicyclo[3.2.1]oct-3-yl]-phenyl]ethanone 39g (250 mg, 0.63 mmol) was dissolved in 5 mL of tetrahydrofuran, triethylamine (0.10 mL, 0.72 mmol) was added, and the reaction was stirred for 12 hr. The mixture was concentrated under reduced pressure. To give the title product 1-[3-tert-butyl-4-methoxy-5-[(lR,5 -8-oxa-3-azabicyclo[3.2.1]oct-3-yl]phenyl -2-(5',6'-Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone Hydrobromide 67 (102 mg, pale yellow solid), Yield: 26.1%.

MS m/z (ESI): 580 [M+l]

 1H NMR (400 MHz, DMSO-, ppm): 7.63 (d, / = 1.6 Hz, 1H), 7.57 (d, / = 1.6 Hz, 1H), 6.98 (s, 1H), 5.22 (s, 2H), 4.41 (m, 2H), 4.22 (q, / = 7.2 Hz, 2H), 4.11 (q, / = 7.2 Hz, 2H), 3.91 (s, 3H), 3.12 (d, J = 10.5 Hz, 2H), 2.88 (d, / = 10.5 Hz, 2H), 2.07 (m, 2H), 1.92 (m, 2H), 1.73 (m, 2H), 1.58 (m, 2H), 1.40 (t, J = 7.2 Hz, 3H ), 1.38 (s, 9H), 1.30 (t, / = 7.2 Hz, 3H) Example 68

1-[3-tert-Butyl-4-methoxy-5-(morpholin-4-carbonyl)phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino- U-dimethyl-isoindolin-2-yl)ethanone hydrobromide

1-tert-butyl-2-methoxy-benzene 2-tert-Butyl-phenol 2a (15 g, 100 mmol) was dissolved in 200 mL of acetone, potassium carbonate (20.70 g, 150 mmol) and methylene chloride (21 g, 150 mmol) were added, and the reaction was stirred for 12 hours. Filtration, and the filtrate was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) The residue was purified by silica gel chromatography eluting elut elut elut elut elut elut elut elut elut elut %.

 Second step

 3-tert-butyl-2-methoxy-benzaldehyde

 1-tert-Butyl-2-methoxy-benzene 68a (12.50 g, 76 mmol) and hydrazine, hydrazine, Ν', Ν'-tetramethylethylenediamine (12.40 g, 107 mmol). Dissolve in 200 mL of methyl tert-butyl ether, add 2.5 M n-butyllithium (33.40 mL, 84 mmol), stir the reaction at room temperature for 2 hours, and add N,N-dimethylformamide at 0 °C. (16.60 g, 228 mmol), the reaction was stirred for 2 hours. The reaction mixture was poured into 100 mL of ice water and extracted with ethyl acetate (100 mL×2). The organic phase was combined, washed with saturated sodium chloride solution (100 mL×2), dried over anhydrous sodium sulfate and filtered. The residue obtained was purified by silica gel column chromatography elut elut elut elut elut elut elut elut elut elut %.

MS m/z (ESI): 193.1 [M+l]

 third step

 3-tert-butyl-2-methoxy-benzoic acid

 3-tert-butyl-2-methoxy-benzaldehyde 68b (8.30 g, 43.20 mmol) was dissolved in 100 mL of acetonitrile under ice-cooling, and 50 mL of sodium hydroxide (3.80 g, 95 mmol) Butyl ammonium bromide (695 mg, 2.20 mmol) was added portionwise to potassium permanganate (8.90 g, 56.20 mmol), and the mixture was stirred at room temperature for 2 hours. Under ice bath, a 5% sodium thiosulfate solution was added to the reaction solution until the reaction solution was dark reddish. Add 200 mL of 1 M hydrochloric acid, extract with ethyl acetate (250 mL×2), and the organic phase was washed with saturated sodium chloride solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered, EtOAcjjjjjjjjjj Benzoic acid 68c (5.85 g, white solid), Yield: 65.0%.

 the fourth step

 (3-tert-Butyl-2-methoxy-phenyl)-morpholinyl-benzophenone 3-tert-butyl-2-methoxy-benzoic acid 68c (632 mg, 3.04 mmol) was dissolved in 10 In 1-mL dichloromethane, 1-hydroxybenzotriazole (432 mg, 3.20 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (613 mg, 3.20) were added. Methyl), stirred for 10 minutes, morpholine (265 mg, 3.04 mmol) was added and the reaction was stirred for 12 hours. 5 mL of water was added to the reaction mixture, and the mixture was extracted with methylene chloride (5 mL×2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B The title product (3-tert-butyl-2-methoxy-phenyl)-morpholinyl-benzophenone 68d (650 mg, m.

the fifth step 2-Bromo-[3-tert-butyl-4-hydroxy-5-(morpholinyl-4-carbonyl)phenyl]ethanone Dissolves aluminum trichloride (133 mg, 1 mmol) in 2 mL of dichloromethane Add 2-bromoacetyl bromide (110 mg, 0.55 mmol), then add 2 mL (3-tert-butyl-2-methoxy-phenyl)-morpholinyl-benzophenone 68d (139 mg, 0.50) A solution of mmol) in dichloromethane was stirred for 12 hours. 5 mL of ice water was added to the reaction mixture, and the mixture was combined with ethyl acetate (5 mL×2), and the organic phase was combined, washed with saturated sodium chloride solution (2 mL×2), dried over anhydrous sodium sulfate, filtered, The resulting residue was purified by EtOAc EtOAc (EtOAc) Ethanol 68e (71 mg, red oil), Yield: 39.0%

MS m/z (ESI): 384.1 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 11.57 (s, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7,87 (d, J = 2.0 Hz, 1H), 4.37 (s, 2H), 3.82 (m, 8H), 1.48 (s, 9H)

 Step 6

 2-bromo-[3-tert-butyl-4-methoxy-5-(morpholinyl-4-carbonyl)phenyl]ethanone 2-bromo-1-[3-tert-butyl-4-hydroxyl 5-(-morpholinyl-4-carbonyl)phenyl]ethanone 68e (30 mg, 0.08 mmol) was dissolved in 2 mL of THF. 2 mL of ice water was added to the reaction mixture, and the organic layer was washed with saturated sodium chloride solution (2 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified to give the title product 2-bromo-1-[3-tert-butyl-4-methoxy-5-(morpholinyl-4-carbonyl)phenyl]ethanone 68f (32 mg , colorless and viscous), Yield: 99.9%.

 Seventh step

 1-[3-tert-butyl-4-methoxy-5-(morpholin-4-carbonyl)phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino- U-dimethyl-isoindolin-2-yl)ethanone hydrobromide

 Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (19.70 mg, 0.08 mmol) in 0.5 mL of N,N-dimethylformamide. 2-Bromo-1-[3-tert-butyl-4-methoxy-5-(morpholinyl-4-carbonyl)phenyl]ethanone 68f (30 mg, 0.08 mmol) was added, and the mixture was stirred for 12 hr. 2 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL×2). The organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained gave the title product 1-[3-tert-butyl-4-methoxy-5-(morpholin-4-carbonyl)phenyl]-2-(5,6-diethoxy-4- Fluoro-3-imino-U-dimethyl-isoindolin-2-yl)ethanone hydrobromide 68 (13 mg, white solid), yield: 26.0%.

MS m/z (ESI): 584.3 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.35 (br, 1H), 8.99 (br, 1H), 7.93 (d, / = 2.2 Hz, 1H), 7.90 (d, / = 2.0 Hz, 1H), 7.44 (s, 1H), 5.44 (s, 2H), 4.25 (m, 2H), 4.11 (m, 2H), 3.85 (s, 3H), 3.70 (m, 4H), 3.58 (m, 2H) ), 3.20 (m, 2H), 1.51 (s, 6H), 1.42 (m, 3H) _: 1.38 (s, 9H), 1.29 (m, 3H) Example 69 L-[3-tert-Butyl-5-(l-hydroxy-1-methyl-ethyl)phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1 ,1-dimethyl-isoindol-2-yl ethyl ketone hydrobromide

first step

 3-tert-butyl-5-methoxycarbonyl-benzoic acid

 Dissolve 5-tert-butylbenzene-1,3-dibenzoic acid 69a (12 g, 54 mmol) and concentrated sulfuric acid (2 mL, cat.) in 360 mL of tetrahydrofuran and methanol (V/V = 10:1) The reaction was stirred at 80 ° C for 4 hours in a mixed solvent. The reaction mixture was concentrated to drynesshjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ), Yield: 24.3%. MS m/z (ESI): 237.2 [M+l]

 Second step

 Methyl 3-tert-butyl-5-(methoxy(methyl)carbamoyl)benzoate 3-tert-butyl-5-methoxycarbonyl-benzoic acid 69b (2.85 g, 12 mmol) The reaction was stirred at 85 ° C for 2 hours in 16.4 mL of thionyl chloride. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m.) The reaction took 0.5 hours. The reaction mixture was concentrated under reduced vacuo. EtOAc (EtOAc m. Methyl (meth)carbamoyl)benzoate 69c C3.27 g, yellow viscous liquid), Yield: 97.6%.

MS m/z (ESI): 280.1 [M+l]

 third step

1-[3-tert-butyl-5-(l-hydroxysuccinyl-ethyl)phenyl]ethanone, crude 3-tert-butyl-5-(methoxy(methyl)amino) Methyl formyl benzoate 69c (2.86 g, 10.25 mmol) was dissolved in 42 mL of tetrahydrofuran, and 5.20 mL of 3 M methylmagnesium bromide in diethyl ether was added dropwise. The mixture was stirred for 10 minutes, and the reaction was stirred at room temperature for 3.5 hours. In an ice bath, 1 M hydrochloric acid was added to the reaction mixture to adjust the pH to 3-5, which was extracted with ethyl acetate (100 mL×2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, The residue obtained was purified by eluent B to give the title product 1-[3-tert-butyl-5-(1-hydroxy-1-methyl-ethyl)phenyl]ethanone 69d (0.38 g, orange Liquid), Yield: 15.8%.

 MS m/z (ESI): 235.2 [M+l]

 the fourth step

 2-bromo[3-tert-butyl-5-(l-hydroxysodiummethyl-ethyl)phenyl]ethanone 1-[3-tert-butyl-5-(1-hydroxy-1-methyl) -ethyl)phenyl]ethanone 69d (420 mg, 1.79 mmol) and phenyltrimethylammonium tribromide (672 mg, 1.79 mmol) dissolved in 42 mL of tetrahydrofuran, stirred for 3 hours, allowed to stand 12 hour. 50 ml of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL×2). The organic phase was combined, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The title product 2-bromo-1-[3-tert-butyl-5-(1-hydroxy-1-methyl-ethyl)phenyl]ethanone 69e (287 mg, yellow oil). 51.3%.

MS m/z (ESI): 315.0 [M+l]

 the fifth step

 1-[3-tert-butyl-5-(1-hydroxy-1-methyl-ethyl)phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1 ,1-dimethyl-isoindolin-2-yl)ethanone hydrobromide

 Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (85 mg, 0.32 mmol) in 3 mL of N,N-dimethylformamide. 2-Bromo-1-[3-tert-butyl-5-(1-hydroxy-1-methyl-ethyl)phenyl]ethanone 69e (100 mg, 0.32 mmol) was added, and the mixture was stirred for 2 hr. 10 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL×2). The residue obtained gave the title product 1-[3-tert-butyl-5-(1-hydroxy-1-methyl-ethyl)phenyl]-2-(5,6-diethoxy-4-fluoro -3-imino-1,1-dimethyl-isoindolin-2-yl)ethanone hydrobromide 69 (61 mg, yellow solid), yield: 38.4%.

MS m/z (ESI) 499.3 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.37 (br, 1H), 8.98 (br, 1H), 7.97 (s, 1H), 7.89 (d, / = 1.5 Hz, 2H), 7.47 ( s, 1H), 5.47 (s, 2H), 5.25 (s, 1H), 4.30-4.24 (m, 2H),

4.16-4.11 (m, 2H), 1.50 (s, 9H), 1.45-1.41 (m, 3H), 1.31 (s, 6H), 1.34-1.30 (m, 3H) Example 70

1-[3-tert-Butyl-5-(l-hydroxysuccinyl-ethyl)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino - Spiro [cyclopropane-1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

first step

 1- 3,5-di-tert-butyl-4-hydroxyphenyl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, Γ-isoporphyrin]-2'-yl)ethanone hydrobromide

 5',6'-Diethoxy-7-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (91 mg, 0.35 mmol) and 2-bromo-1 -[3-tert-Butyl-5-(1-hydroxy-1-methyl-ethyl)phenyl]ethanone 69e (108 mg, 0.35 mmol) was dissolved in 2 mL of THF and triethylamine (51 mg , 0.52 mmol), the reaction was stirred for 12 hours. Filtration and concentration of the filtrate under reduced pressure. Phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'- Ethyl ketone hydrobromide 70 (22 mg, yellow solid), yield: 11.0%.

 MS m/z (ESI): 497.3 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.43 (br, 1H), 9.06 (br, 1H), 7.90 (s, 1H), 7.88 (s, 1H), 7.83 (s, 1H), 7.03 (s, 1H), 5.23 (s, 2H), 4.26-4.21 (m, 2H), 4.15-4.10 (m, 2H), 2.03-2.00 (m, 2H), 1.66-1.48 (m, 2H), 1.42 (s, 6H), 1.41-1.39 (m, 3H), 1.35 (s, 9H) Example 71

1-[3-(4-Acetylpiperazine)-5-tert-butyl-4-methoxy-phenyl]-2-(5',6'-diethoxy-4'-fluoro -3'-imino-spiro[cyclohydrobromide

 First step

1-[3-(4-Acetylpiperazine)-5-tert-butyl-4-methoxy-phenyl]-2-(5',6'-diethoxy-4'-fluoro -3'-imino-spiro[cyclopropane-1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide 5',6'-diethoxy-7-fluoro- Spirulina [cyclopropane-1,3'-isoindoline]-indole-imine 41g (112 mg, 0.27 mmol) was dissolved in 1 mL of N,N-dimethylformamide and 1-[3-( 4-Acetylpiperazin-1-yl)-5-tert-butyl-4-methoxyphenyl]-2 bromo-ethanone 20c (60 mg, 0.23 mmol). 4 mL of a saturated sodium chloride solution and 4 mL of ethyl acetate were added to the reaction mixture, and the mixture was separated. EtOAc (EtOAc m. The residue was purified by EtOAc (EtOAc) elut elut Oxy-phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2' -yl)ethanone hydrobromide 71 (14.50 mg, white solid), yield: 7.9%.

MS m/z (ESI): 595.4 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 7.64 (s, 1H), 7.54 (s, lH), 7.00 (s, 1H), 5.19 (s, 2H), 4.23 (m, 2H), 4.12 (m, 2H), 3.98 (s, 3H), 3.67 (m, 4H), 3.02 (m, 2H), 2.96 (m, 2H), 2.06 (s, 3H), 1.76 (m, 2H), 1.63 (m, 2H), 1.41 (m, 3H), 1.39 (s, 9H), 1.31 (m, 3H) Example 72

 L-[3-(4-Acetylpiperazin-1-yl)-5-tert-butyl-4-methoxy-phenyl]-2-(5,6-diethoxy-4-fluoro- 3-imine

L-[3-(4-Acetylpiperazin-1-yl)-5-tert-butyl-4-methoxy-phenyl]-2-(5,6-diethoxy-4-fluoro- 3-imino-iJ-dimethyl-isoindolin-2-yl)ethanone hydrobromide 5,6-diethoxy-7-fluoro-3,3-dimethyl-iso The small amine 24d (100 mg, 0.24 mmol) was dissolved in 1 mL of tetrahydrofuran, and 1-[3-(4-acetylpiperazine)-5-tert-butyl-4-methoxyphenyl] was added. -2 Bromo-ethanone 20c (61 mg, 0.24 mmol), stirred for 12 hr. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj 4-methoxy-phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-U-dimethyl-isoindol-2-yl) ethyl ketone hydrogen Bromate 72 (80 mg, pale yellow solid), Yield: 48.5%.

MS m/z (ESI): 597.4 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.27 (s, 1H), 8.96 (s, 1H), 7.68 (s, 1H), 7.60 (s _: 1H), 7.45 (s, 1H), 5.41 (s, 2H), 4.27 (m, 2H), 4.13 (m, 2H), 3.99 (s, 3H), 3.68 (m, 4H), 3.04 (m, 2H), 2.98 (m, 2H), 2.06 (s, 3H), 1.51 (s, 6H), 1.42 (m, 3H), 1.40 (s, 9H), 1.32 (m, 3H) Example 73

 3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)acetyl] Benzene

7 ^{30 73}

 First step

 3-acetyl-5-tert-butyl-benzoic acid methyl ester

The crude 3-tert-butyl-5-(methoxy(methyl)carbamoyl)benzoic acid methyl ester 69c (2.86 g, 10.25 mmol) was dissolved in 42 mL of THF. M methyl magnesium bromide in diethyl ether solution, The mixture was stirred for 10 minutes, and the reaction was stirred at room temperature for 3.5 hours. In an ice bath, 1 M hydrochloric acid was added to the reaction mixture to adjust the pH to 3-5, which was extracted with ethyl acetate (100 mL×2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, The residue obtained was purified by eluent B to give the title product 1-[3-tert-butyl-5-(1-hydroxy-s-methyl-ethyl)phenyl]ethanone 3-acetyl-5- Methyl butyl-benzoate 73a (1.37 g, white solid), Yield: 57.1%.

MS m/z (ESI): 235.2 [M+l]

 Second step

 3-(2-bromoacetyl)-5-tert-butyl-benzoate

 1-[3-tert-Butyl-5-(1-hydroxysuccine-ethyl)phenyl]ethanone 3-acetyl-5-tert-butyl-benzoic acid methyl ester 73a (598 mg, 2.60 mmol And phenyltrimethylammonium tribromide (978 mg, 2.60 mmol) was dissolved in 60 mL of tetrahydrofuran, and the reaction was stirred for 12 hours. 50 ml of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL×2). The organic phase was combined, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The title product 3-(2-bromoacetyl)-5-tert-butyl-benzoic acid methyl ester 73b (693 mg, yellow liquid) was obtained, yield: 85.1%.

MS m/z (ESI): 313.0 [M+l]

 third step

 3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)acetyl] Methyl benzoate hydrobromide

 Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (380 mg, 1.44 mmol) in 12 mL of N,N-dimethylformamide. 3-(2-Bromoacetyl)-5-tert-butyl-benzoic acid methyl ester 73b (450 mg, 1.44 mmol) was added, and the mixture was stirred for 4 hr. Add 30 mL of water to the reaction mixture, and extract with ethyl acetate (40 mL×2). The organic phase is combined, washed with water (20 mL×2) and saturated sodium chloride solution (20 mL×2), dried over anhydrous magnesium sulfate, filtered, filtrate Concentration under reduced pressure gave a white solid. m. Methyl 1,1-dimethyl-isoindol-2-yl) acetyl]benzoate hydrobromide 73c (229 mg, white solid), yield: 27.5%.

 the fourth step

 3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)acetyl] Benzoate

 The crude 3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-U-dimethyl-isoindol-2-yl)acetyl group] Methyl benzoate hydrobromide 73c (193 mg, 0.33 mmol) was dissolved in 8 mL of methanol, and 4 mL aqueous solution of lithium hydroxide (70 mg, 1.67 mmol) was added dropwise, and the reaction was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc (EtOAc) -(5,6-diethoxy-4-fluoro-3-imino-U-dimethyl-isoindolin-2-yl)acetyl]benzoic acid hydrobromide 73 (148 mg, yellow Solid), Yield: 85.5%. MS m/z (ESI): 483.2 [M-l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 13.37 (s, 1H), 9.43 (s, 1H), 9.02 (s, 1H), 8.43 (s, 1H), 8.27 (s, 1H), 8.25 (s, 1H), 7.46 (s, 1H), 5.56 (s, 2H), 4.26 (m, 2H), 4.12 (m _: 2H), 1.52 ( s, 6H), 1.44 (m, 3H), 1.39 (s, 9H), 1.33 (m, 3H) Example 74

L-[3-tert-Butyl-5-(morpholin-4-carbonyl)phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-U-dimethyl- Iso-B-pyridin-2-yl)ethanone hydrochloride

 First step

1-[3-tert-butyl-5-(morpholin-4-carbonyl)phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-U-dimethyl- Isoindol-2-yl)ethanone hydrochloride

 3-tert-Butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)acetyl ] Hydrobenzoate hydrobromide 73 (52 mg, 0.10 mmol) was dissolved in 2 mL of dichloromethane, and 1-hydroxybenzotriazole (14 mg, 0.10 mmol). -Dimethylaminopropyl)carbodiimide hydrochloride (38 mg, 0.20 mmol), stirred for 45 min, then morpholine (18 mg, 0.20 mmol). The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjj 2-(5,6-Diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)ethanone hydrochloride 74 (19 mg, white solid ), Yield: 32.2%.

MS m/z (ESI): 554.3 [M+l]

1H NMR (400 MHz, DMSO-, ppm): δ 9.42 (s, 1H), 9.02 (s, 1H), 8.06 (s, 1H), 7.94 (s 1H), 7.77 (s, 1H), 7.46 (s , 1H), 5.50 (s, 2H), 4.26 (m, 2H), 4.12 (m, 2H), 3.64 (m, 6H), 3.40 (m, 2H), 1.51 (s, 6H), 1.42 (m, 3H), 1.38 (s, 9H), 1.32 (m, 3H) Example 75

3-tert-butyl-N-cyclopropyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindoline-2 -yl)acetyl]benzamide hydrochloride

First step

 3-tert-butyl-N-cyclopropyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindoline-2 -yl)acetyl]benzamide hydrochloride

 3-tert-Butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)acetyl Benzyl hydrobromide 73 (52 mg, 0.10 mmol) was dissolved in 2 mL of N,N-dimethylformamide, and cyclopropylamine (11 mg, 0.20 mmol) and 2-(7-azo) were added. Benzotriazole)-Ν,Ν,Ν',Ν'-tetramethylurea hexafluorophosphate C46 mg, 0.12 mmol), stirred for 2 hours, then added N-isobutylpropyl-2-amine (24 mg, 0.24 mmol), and the reaction was stirred for 4 hours. 10 mL of a saturated sodium chloride solution was added to the reaction solution, and the mixture was combined with ethyl acetate (10 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution (10 mL×3), dried over anhydrous magnesium sulfate The resulting residue was purified by EtOAc (EtOAc) elut elut -Fluoro-3-imino-U-dimethyl-isoindolin-2-yl)acetyl]benzamide hydrochloride 75 (13 mg, white solid), yield: 23.2%.

MS m/z (ESI): 524.3 [M+l]

 1H NMR (400 MHz, DMSO-, ppm): δ 9.34 (br, 1H), 8.98 (br, 1H), 8.78 (br, 1H), 8.40 (s, 1H), 8.19 (s, 1H), 8.11 ( s, 1H), 7.45 (s, 1H), 5.51 (s, 2H), 4.26 (m, 2H), 4.12 (m, 2H), 2.89 (m, 1H), 1.52 (s, 6H), 1.38 (m , 12H), 1.31 (m, 3H), 0.74 (m, 2H), 0.64 (m, 2H) Example 76

3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline] -2 '-yl)acetyl]benzoic acid hydrochloride

first step

 3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline] -2 '-yl)acetyl]methyl benzoate hydrobromide

 Dissolve 5',6'-diethoxy-7-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (395 mg, 1.50 mmol) in 12 mL of N, To N-dimethylformamide, methyl 3-(2-bromoacetyl)-5-tert-butyl-benzoate 73b (540 mg, 1.50 mmol) was added, and the mixture was stirred at 30 ° C for 1.5 hours. Add 100 mL of saturated sodium chloride solution to the reaction solution, and extract with ethyl acetate (100 mL×3). The organic phase is combined, washed with saturated sodium chloride solution (100 mL×3), dried over anhydrous magnesium sulfate, filtered, The title compound (3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3') was obtained. -imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)acetyl]benzoic acid methyl ester hydrobromide 76a (231 mg, white solid), yield: 26.7% .

MS m/z (ESI): 497.3 [M+l]

 Second step

 3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline] -2 '-yl)acetyl]benzoic acid hydrochloride

 3-tert-Butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoporphyrin] -2'-yl)acetyl]methyl benzoate hydrobromide 76a (226 mg, 0.39 mmol) was dissolved in 20 mL of methanol, and 4 mL of aqueous solution of lithium hydroxide (164 mg, 3.92 mmol) was added dropwise. 6 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. 2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)acetyl]benzene Formate 76 (136 mg, white solid), Yield: 67.0%

MS m/z (ESI): 483.2 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.09 (br, 1H), 8.39 (s, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 7.03 (s, 1H), 5.38 (s, 2H), 4.23 (m, 2H), 4.12 (m, 2H), 1.85 (m, 2H), 1.64 (m, 2H), 1.41 (m, 3H), 1.34 (m, 12H) Example 77

 2-[[3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl) Acetyl] acetonitrile hydrobromide

 77f 77g

 First step

2, ₆ - dibromo-4-tert-butyl - aniline

 4-tert-Butylaniline 77a (50 g, 335.60 mmol) was dissolved in 300 mL of dichloromethane under ice-cooling, and liquid bromine (118 g, 738.30 mmol) was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. Under ice bath, add 1 M sodium hydroxide solution to the reaction solution to adjust the pH value to 9-10, extract the liquid, extract the aqueous phase with dichloromethane (30 mL×3), combine the organic phases, and sequentially use 1 M sodium hydroxide. The solution (30 mL×3), water (30 mL×3) and saturated sodium chloride solution (30 mL×3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title product 2,6-dibromo-4- tert-Butyl-aniline 77b (107 g, reddish brown liquid). The product was taken to the next step without purification.

 MS m/z (ESI): 307.9 [M+l]

 Second step

 i,3-dibromo-5-tert-butyl-benzene

2-Methyl-2-nitro-propane (53.90 g, 522.80 mmol) was dissolved in 200 mL of N,N-dimethylformamide, and 2,6-dibromo-4-tert-butyl-aniline was added dropwise. 77b (107 g, 348.50 mmol), stir the reaction at 65 °C for 12 hours. Add 400 mL of water to the reaction solution, extract with ethyl acetate (300 mL×4), and combine the organic phase, wash with water (100 mL×3) and saturated sodium chloride solution (100 mL×3), dry over anhydrous magnesium sulfate, filter, filtrate Concentration by pressure, the residue obtained was purified by silica gel column chromatography elut elut 1,3-Dibromo-5-tert-butyl-benzene 77c (80.60 g, colorless liquid), Yield: 79.2%.

 third step

 1-(3-bromo-5-tert-butyl-phenyl)ethanone

 In a dry ice bath, 1,3-dibromo-5-tert-butyl-benzene 77c (10 g, 34.25 mmol) was dissolved in 80 mL of tetrahydrofuran, and 13.40 mL of 2.5 M n-butyllithium solution was added dropwise. hour. Further, N,N-dimethylacetamide (4.47 g, 51.37 mmol) was added, and the reaction was stirred for 0.5 hour. Add 30 mL of water and 30 mL of saturated ammonium chloride solution to the reaction solution, extract with ethyl acetate (30 mL×5), and combine the organic phases, then wash with water (30 mL×3) and saturated sodium chloride solution (30 mL×3), anhydrous The title compound 1-(3-bromo-5-tert-butyl-phenyl)ethanone 77d was obtained by chromatography. (3.60 g, yellow liquid), Yield: 41.2%.

MS m/z (ESI): 255.0 [M+l]

 the fourth step

 L-(3-Amino-5-tert-butyl-phenyl)ethanone

 1-(3-Bromo-5-tert-butyl-phenyl)ethanone 77d (1.02 g, 4 mmol), cuprous oxide (60 mg, 0.40 mmol) and cuprous iodide (76 mg, 0.40 mmol) The solution was dissolved in 2.60 mL of N-methylpyrrolidone, and 2.60 mL of aqueous ammonia was added thereto, and the reaction was stirred under microwave at 110 ° C for 2 hours. Add 20 mL of water to the reaction solution, and extract with ethyl acetate (20 mL×3). The organic phase is combined, washed with water (20 mL×3) and saturated sodium chloride solution (20 mL×3), dried over anhydrous magnesium sulfate, filtered, filtrate The residue was purified by silica gel column chromatography eluting elut elut elut elut elut Yield: 90.3%.

MS m/z (ESI): 192.1 [M+l]

 the fifth step

 2-[(3-acetyl-5-tert-butyl-phenyl)amino]acetonitrile

 1-(3-Amino-5-tert-butyl-phenyl)ethanone 77e (760 mg, 3.98 mmol) was dissolved in 10 mL of N,N-dimethylformamide and potassium carbonate (825 mg, 5.97 mmol) And 2-bromoacetonitrile (955 mg, 7.96 mmol), and the reaction was stirred at 70 ° C for 3 hours. Add 30 mL of water to the reaction solution, extract with ethyl acetate (30 mL×3), and combine the organic phases, then water (15 mL×3) and washed saturated sodium chloride solution (15 mL×3), dried over anhydrous magnesium sulfate, filtered, filtrate The residue was purified by silica gel column chromatography elut elut elut elut elut elut elut elut Liquid), Yield: 99.9%.

 MS m/z (ESI): 248.2 [M+l 8]

 Step 6

2-[(3-(2-bromoacetyl)-5-tert-butyl-phenyl]amino]acetonitrile 2-[(3-acetyl-5-tert-butyl-phenyl)amino]acetonitrile 77f ( 200 mg, 0.87 mmol) was dissolved in 25 mL of tetrahydrofuran, and phenyltrimethylammonium bromide (327 mg, 0.87 mmol) was added portionwise, and the reaction was stirred for 20 hours. Filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by a thin layer chromatography chromatography to The title product, 2-[[3-(2-bromoacetyl)-5-tert-butyl-phenyl]amino]acetonitrile, 77 g (95 mg, m.

 MS m/z (ESI): 310.1 [M+l]

 Seventh step

2-[[3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl) Acetyl] phenyl]amino]acetonitrile hydrobromide

 Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (77 mg, 0.29 mmol) in 3 mL of N,N-dimethylformamide. 77 g (90 mg, 0.29 mmol) of 2-[[3-(2-bromoacetyl)-5-tert-butyl-phenyl]amino]acetonitrile was added, and the mixture was stirred for 1 hour. Add 10 mL of water to the reaction solution, extract with ethyl acetate (10 mL×3), and combine the organic phase, then wash with water (10 mL×3) and saturated sodium chloride solution (10 mL×3), dry over anhydrous magnesium sulfate, filter, filtrate Concentration by pressure, the residue obtained was purified by EtOAc EtOAc (EtOAc) -fluoro-3-imino-U-dimethyl-isoindolin-2-yl)acetyl]phenyl]amino]acetonitrile hydrobromide 77 (35 mg, yellow solid), yield: 21.1% .

MS m/z (ESI): 495.3 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.38 (br, 1H), 8.96 (br, 1H), 7.45 (s, 2H), 7.21 (s, 1H), 7.12 (s, 1H), 6.52 (t, J = 6.8 Hz, 1H), 5.39 (s, 2H), 4.40 (d, J = 6.8 Hz, 2H), 4.25 (m, 2H), 4.12 (m, 2H), 1.51 (s, 6H) ), 1.42 (m, 3H), 1.40 (m, 12H) Example 78

 N-[3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoporphyrin) ] -2'-yl) acetyl]phenyl]acetamide hydrobromide

 HBr

 78

 First step

 N-C3-acetyl-5-tert-butyl-phenyl)acetamide

Dissolve 10% amino-5-tert-butyl-phenyl)ethanone 77e (600 mg, 3.14 mmol) in 15 mL of dichloromethane, add triethylamine (635 mg, 6.28 mmol) and add acetyl chloride (495) Mg, 6.28 mmol), stirring The reaction took 0.5 hours. Add 30 mL of water to the reaction solution, dilute with dichloromethane (20 mIX3), and combine the organic phase, wash with water (15 mL×3) and saturated sodium chloride solution (15 mL×3), dry over anhydrous magnesium sulfate, filter, filtrate The residue was purified by silica gel column chromatography elut elut elut elut elut elut elut elut , Yield: 95.6%.

MS m/z (ESI): 234.2 [M+l]

 Second step

 N-[3-(2-Bromoacetyl)-5-tert-butyl-phenyl]acetamide N-0-acetyl-5-tert-butyl-phenyl)acetamide 78a (200 mg, 0.86 mmol) The solution was dissolved in 25 mL of tetrahydrofuran, and phenyltrimethylammonium bromide (323 mg, 0.86 mmol) was added portionwise, and the mixture was stirred for 1 hour. Filtration, and the filtrate was concentrated under reduced pressure. Acetamide 78b (110 mg, yellow liquid), Yield: 41.0%.

MS m/z (ESI): 311.1 [M-l]

 third step

 N-[3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoporphyrin) ] -2'-yl) acetyl]phenyl]acetamide hydrobromide

 Dissolve 5',6'-diethoxy-7-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (50 mg, 0.19 mmol) in 1.50 mL of tetrahydrofuran N-[3-(2-Bromoacetyl)-5-tert-butyl-phenyl]acetamide 78b (60 mg, 0.19 mmol) was added, and the mixture was stirred for 3 hr. Filtration gave a white solid which was washed with EtOAc (EtOAc (EtOAc) -imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)acetyl]phenyl]acetamide hydrobromide 78 (50 mg, white solid), Yield: 45.9 %.

MS m/z (ESI): 496.3 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 10.16 (s, 1H), 9.44 (br, 1H), 9.06 (br, 1H), 8.15 (s, 1H), 7.88 (s, 1H), 7.71 (s, 1H), 7.03 (s, 1H), 5.20 (s, 2H), 4.23 (m, 2H), 4.12 (m, 2H), 2.07 (s, 3H), 1.79 (m, 2H), 1.66 (m, 2H), 1.41 (m, 3H), 1.34 (m, 12H) Example 79

 N-[3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl) Acetyl:

79

First step

 N-[3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl) Acetyl:

 Phenyl]acetamide hydrobromide

 Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (47 mg, 0.18 mmol) in 1 mL of tetrahydrofuran and add N-[3-(2 -Bromoacetyl)-5-tert-butyl-phenyl]acetamide 78b (55 mg, 0.18 mmol). Filtration gave a white solid, which was purified eluted eluted elut elut elut Imino-U-dimethyl-isoindolin-2-yl)acetyl]phenyl]acetamide hydrobromide 79 (55 mg, white solid), yield: 53.9%. MS m/z (ESI): 498.3 [M+l]

 1H NMR (400 MHz, DMSO-, ppm): δ 10.16 (s, 1H), 9.33 (br, 1H), 8.94 (br, 1H), 8.19 (s, 1H), 7.88 (s, 1H), 7.75 ( s, 1H), 7.44 (s, 1H), 5.39 (s, 2H), 4.24 (m, 2H), 4.12 (m, 2H), 2.08 (s, 3H), 1.51 (s, 6H), 1.41 (m , 3H), 1.35 (m, 12H) Example 80

 3-tert-butyl-N-cyclopropyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindoline-2 -yl)acetyl]-2-methoxy-benzamide hydrobromide

first step

 5-acetyl-3-tert-butyl-2-hydroxy-benzoic acid

 Dissolve 3-tert-butyl-2-methoxy-benzoic acid 68c (1.60 g, 7.70 mmol) in 20 mL of dichloromethane, add acetyl chloride (0.72 g, 9.23 mmol) and aluminum trichloride (2.55) g, 19.25 mmol), and the reaction was stirred at 40 ° C for 6 hours. 20 mL of ice water was added to the reaction solution, and 100 mL of ethyl acetate was added thereto, and the mixture was separated, and the aqueous layer was extracted with ethyl acetate (20 mL×2). The organic phase was combined and washed with saturated sodium chloride solution (20 mL×3), anhydrous The residue was dried over MgSO4, EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Gray solid), Yield: 62.7%.

 Second step

 5-Acetyl-3-tert-butyl-N-cyclopropyl-2-hydroxy-benzamide 5-O-acetyl-3-tert-butyl-2-hydroxy-benzoic acid 80a (1.20 g, 5.08 mmol) Dissolved in 15 mL of dichloromethane, adding 1-hydroxybenzotriazole (720 mg, 5.33 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.02) g, 5.33 mmol), dissolved by stirring, then added cyclopropylamine (290 mg, 5.08 mmol), and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjj 80b (600 mg, colorless viscous solid), Yield: 42.8%.

 third step

 5-acetyl-3-tert-butyl-N-cyclopropyl-2-methoxy-benzamide 5-acetyl-3-tert-butyl-N-cyclopropyl-2-hydroxy-benzene The amide 80b (275 mg, 1 mmol) was dissolved in 3 mL of acetone, and then potassium carbonate (207 mg, 1.50 mmol) and methylene chloride (0.3 mL, 6 mmol) was added and the reaction was stirred at 40 ° C for 12 hours. Filtration, and the filtrate was concentrated under reduced pressure. -benzamide 80c (230 mg, colorless oil), yield: 79.0%.

MS m/z (ESI): 290.2 [M+l]

the fourth step 5-(2-bromoacetyl)-3-tert-butyl-N-cyclopropyl-2-methoxy-benzamide 5-O-acetyl-3-tert-butyl-N-cyclopropyl-2 -Methoxy-benzamide 80c (230 mg, 0.79 mmol) was dissolved in 3 mL of chloroform, and copper bromide (355 mg, 1.59 mmol) was added, and the reaction was stirred at 40 ° C for 12 hours. Filtration and concentration of the filtrate under reduced pressure. 2-methoxy-benzamide 80d (190 mg, white viscous solid), Yield: 65.0%.

MS m/z (ESI): 369.1 [M+l]

 the fifth step

 3-tert-butyl-N-cyclopropyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindoline-2 -yl)acetyl]-2-methoxy-benzamide hydrobromide

 Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (31.80 mg, 0.12 mmol) in 1 mL of tetrahydrofuran and add 5-(2-bromoacetyl) 3-tert-butyl-N-cyclopropyl-2-methoxy-benzamide 80d (44 mg, 0.12 mmol). Filtration gave a white solid, which was purified eluted eluted elut elut elut elut elut elut -3-imino-U-dimethyl-isoindolin-2-yl)acetyl]-2-methoxy-benzamide hydrobromide 80 (38 mg, white solid), yield: 50.0%.

MS m/z (ESI): 554.3 [M+l]

 1H NMR (400 MHz, DMSO-, ppm): δ 9.26 (s, 1H), 8.96 (s, 1H), 8.51 (d, / = 4.2 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H) , 7.93 (d, J = 2.0 Hz, 1H), 7.45 (s, 1H), 5.41 (s, 2H), 4.26 (m, 2H), 4.13 (m, 2H), 3.83 (s, 3H), 2.89 ( m, 1H), 1.49 (s, 6H), 1.42 (m, 3H), 1.40 (s, 9H), 1.31 (m, 3H), 0.73 (m, 2H), 0.60 (m, 2H) Example 81

 3-tert-butyl-N-cyclopropyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, oxime-iso) Porphyrin]-2'-ylacetyl]-2-methoxy-benzamide hydrobromide

first step 3-tert-butyl-N-cyclopropyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, oxime-iso) Porphyrin]-2'-yl)acetyl]-2-methoxy-benzamide hydrobromide 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane-1 , 3'-Isoporphyrin]-Γ-imine 41g (44.50 mg, 0.17 mmol) was dissolved in 1 mL of tetrahydrofuran, and 5-(2-bromoacetyl)-3-tert-butyl-N-cyclopropane was added. The base 2-methoxy-benzamide 80d (; 62 mg, 0.17 mmol) was stirred for 12 hours. Filtration gave a white solid, which was purified eluted eluted elut elut elut elut elut elut elut '-Fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)acetyl]-2-methoxy-benzamide hydrobromide 81 ( 55 mg, white solid), Yield: 51.6%.

MS m/z (ESI): 552.3 [M+l]

 1H NMR (400 MHz, DMSO-, ppm): δ 9.36 (s, 1H), 9.06 (s, 1H), 8.51 (d, / = 4.3 Hz, 1H), 7.88 (s, 2H), 7.02 (s, (H, 2H) ), 1.40 (m, 3H), 1.38 (s, 9H), 1.30 (m, 3H), 0.72 (m, 2H), 0.60 (m, 2H) Example 82

 3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindoline-2-yl)acetyl

 -N-(2,3-dihydroxypropyl)benzamide hydrochloride

3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)acetyl] -N-(2,3-dihydroxypropyl)benzamide hydrochloride

3-tert-Butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)acetyl Benzyl hydrobromide 73 (104 mg, 0.20 mmol) was dissolved in 4 mL of N,N-dimethylformamide and 3-aminopropane-1,2-diol (36 mg, 0.40 mmol). 2-(7-azobenzotriazole)^^,^,^-tetramethylurea hexafluorophosphate C93 mg, 0.24 mmol) and N-isopropylpropan-2-amine (49 mg, 0.48 mmol), the reaction was stirred for 5 hours. Add 10 mL of saturated sodium chloride solution to the reaction solution and extract with ethyl acetate (15 </ RTI></RTI><RTIgt;</RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; The title product 3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl) was obtained. Acetyl]-N-(2,3-dihydroxypropyl)benzamide hydrochloride 82 (31 mg, white solid), yield: 26.1%. MS m/z (ESI): 558.3 [M+l]

 1H NMR (400 MHz, DMSO-, ppm): δ 9.36 (br, 1H), 8.99 (br, 1H), 8.86 (br, 1H), 8.48 (s, 1H), 8.27 (s, 1H), 8.12 ( s, 1H), 7.45 (s, 1H), 5.54 (s, 2H), 4.93 (s, 1H), 4.64 (s, 1H), 4.29-4.26 (m, 2H), 4.16-4.10 (m, 2H) , 3.69 (s, 1H), 3.48-3.25 (m, 4H), 1.53 (s, 6H), 1.44-1.23 (m, 15H) Example 83

 3-tert-butyl-N-cyclopropyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, oxime-iso) Porphyrin]-2'-yl)acetyl]benzamide hydrochloride

 First step

 3-tert-butyl-fluorene-cyclopropyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'- Isoporphyrin]-2'-yl)acetyl]benzamide hydrochloride

 3-tert-Butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoporphyrin] -2'-yl)acetyl]benzoic acid hydrochloride 76 (51 mg, 0.10 mmol) was dissolved in 2 mL of N,N-dimethylformamide and cyclopropylamine (11 mg, 0.20 mmol) , 2-(7-Azobenzotriazole)-Ν,Ν,Ν',Ν'-tetramethylurea hexafluorophosphate (46 mg, 0.12 mmol) and N-isopropylpropane-2- Amine (24 mg, 0.24 mmol) was stirred for 3 h. To the reaction mixture, 10 mL of a saturated sodium chloride solution, and ethyl acetate (10 mIX3), and the organic phase was combined, washed with a saturated sodium chloride solution (10 mL×3), dried over anhydrous magnesium sulfate and filtered. The resulting residue was purified by EtOAc EtOAc (EtOAc) elut elut -4'-Fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)acetyl]benzamide hydrochloride 83 (48 mg, white solid) , Yield: 87.3%.

MS m/z (ESI): 522.3 [M+l] NMR NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.51 (br, 1H), 9.12 (br, 1H), 8.87 (br, 1H), 8.42 (s, 1H), 8.20 (s, 1H), 8.07 (s, 1H), 7.03 (s, 1H), 5.38 (s, 2H), 4.26-4.21 (m, 2H), 4.15-4.10 (m, 2H), 2.92-2.86 (m, 1H), 1.92- 1.82 (m, 2H), 1.69-1.65 (m, 2H), 1.42-1.38 (m, 3H), 1.37 (s, 9H), 1.33-1.31 (m, 3H), 0.76-0.64 (m, 4H) Example 84

 1-[3-tert-Butyl-5-(morpholin-4-carbonyl)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[ Cyclopropane

 -1,1'-isoporphyrin]-2'-ketoethyl ketone hydrochloride

 First step

 1-[3-tert-butyl-5-(morpholin-4-carbonyl)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[ Cyclopropane

 -1,1'-isoporphyrin]-2'-ketoethyl ketone hydrochloride

 3-tert-Butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoporphyrin] -2'-yl)acetyl]benzoic acid hydrochloride 76 (48 mg, 0.09 mmol) was dissolved in 2 mL of N,N-dimethylformamide, morpholine (16 mg, 0.19 mmol), 2 -(7-azobenzotriazole)- ^,^-tetramethylurea hexafluorophosphate (43 mg, 0.11 mmol) and N-isopropylpropan-2-amine (22 mg, 0.22 mmol) , stir the reaction for 3 hours. To the reaction mixture, 10 mL of a saturated sodium chloride solution, and ethyl acetate (10 mIX3), and the organic phase was combined, washed with a saturated sodium chloride solution (10 mL×3), dried over anhydrous magnesium sulfate and filtered. The resulting residue was purified by EtOAc (EtOAc) elut elut ,6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-ethylethanone hydrochloride 84 (52 mg, White solid), Yield: 96.3%.

 MS m/z (ESI): 552.3 [M+l]

1H NMR (400 MHz, DMSO-, ppm): δ 9.70 (br, 1H), 9.16 (br, 1H), 8.04 (s, 1H), 7.88 (s, 1H), 7.77 (s, 1H), 7.04 ( s, 1H), 5.40 (s, 2H), 4.24 (m, 2H), 4.12 (m, 2H), 3.67-3.38 (m, 8H), 1.98-1.65 (m, 4H), 1.40 (m, 3H) , 1.36 (s, 9H), 1.31 (m, 3H) Example 85

 3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)acetyl] -N- 2-hydroxyethyl)benzamide hydrochloride

 First step

 3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)acetyl] -N-(2-hydroxyethyl)benzamide hydrochloride

 2-Aminoethanol C13 mg, 0.20 mmol) was dissolved in 2 mL dichloromethane, then 4-dimethylaminopyridine (37 mg, 0.30 mmol), 3-tert-butyl-5-[2-(5,6) -diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)acetyl]benzoic acid hydrobromide 73 (52 mg, 0.10 mmol) and Bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride (51 mg, 0.20 mmol) was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure and purified mjjjjjjjjjj Fluoro-3-imino-U-dimethyl-isoindolin-2-yl)acetyl]-N-(2-hydroxyethyl)benzamide hydrochloride 85 (32 mg, white solid) Yield: 57.1%.

MS m/z (ESI): 528.3 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.40 (br, 1H), 8.98 (br, 2H), 8.54 (s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 7.46 (s, 1H), 5.58 (s, 2H), 4.91 (br, 1H), 4.27 (m, 2H), 4.14 (m, 2H), 3.58-3.38 (m, 4H), 1.54 (s, 6H) , 1.43-1.31 (m, 15H) Example 86

 2-[[3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, oxime-isoindole] Porphyrin] -2'-yl) ethyl salt

 HBr

86

 77g 86

 First step

 2-[[3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, oxime-isoindole] -2'-yl)acetyl]phenyl]amino]acetonitrile hydrobromide

 Dissolve 5',6'-diethoxy-7-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (38 mg, 0.15 mmol) in 1 mL of tetrahydrofuran Then, 77 g (45 mg, 0.15 mmol) of 2-[[3-(2-bromoacetyl)-5-tert-butyl-phenyl]amino]acetonitrile was added, and the mixture was stirred for 2 hr. The resulting residue was purified by EtOAc (EtOAc) elut elut elut elut elut elut elut elut 2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)acetyl]benzene Amino]acetonitrile hydrobromide 86 (12 mg, white solid), yield: 14.6%.

 MS m/z (ESI): 512.6 [M+23]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.48 (br, 1H), 9.07 (br, 1H), 7.41 (s, 1H), 7.13 (m, 2H), 7.03 (s, 1H), 6.97 (s, 1H), 6.52 (t, J = 7.2 Hz, 1H), 5.21 (s, 2H), 4.38 (d, J = 7.2 Hz, 2H), 4.23 (m, 2H), 4.12 (m, 2H) ), 1.79 (m, 2H), 1.66 (m, 2H), 1.40 (m, 3H), 1.33 (m, 12H) Example 87

 3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)acetyl- N,N-bis(2-hydroxyethyl)benzamide hydrochloride

first step

3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1, 1-dimethyl-isoindol-2-yl)acetyl] -N,N-bis(2-hydroxyethyl)benzamide hydrochloride 3-tert-Butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)acetyl Hydrobenzoate hydrobromide 73 (104 mg, 0.20 mmol) was dissolved in 4 mL of N,N-dimethylformamide and 2-(2-hydroxyethylamine)ethanol (42 mg, 0.40 mmol). 2-(7-Azobenzotriazole)-Ν,Ν,Ν',Ν'- Tetramethylurea hexafluorophosphate C93 mg, 0.24 mmol), then N-isopropylpropane-2- Amine (; 48 mg, 0.48 mmol) was stirred for 1 hour. To the reaction mixture, 20 mL of a saturated sodium chloride solution was added, and ethyl acetate (10 mL×3) was added, and the organic phase was combined, washed with saturated sodium chloride solution (10 mL×3), dried over anhydrous magnesium sulfate and filtered. The resulting residue was purified by EtOAc EtOAc (EtOAc) elut elut Amino-1,1-dimethyl-isoindolin-2-yl)acetyl]-N,N-bis(2-hydroxyethyl)benzamide hydrochloride 87 (35 mg, white solid) Yield: 28.7%. MS m/z (ESI): 572.3 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.42 (br, 1H), 9.02 (br, 1H), 8.02 (s, 1H), 7.96 (s, 1H), 7.82 (s, 1H), 7.46 (s, 1H), 5.49 (s, 2H), 4.94 (s, 2H), 4.27 (m, 2H), 4.13 (m, 2H), 3.66-3.51 (m, 8H), 1.51 (s, 6H) , 1.41-1.23 (m, 15H) Example 88

 3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline] -2 '-yl)acetyl]-indole-2,3-dihydroxypropyl)benzamide hydrochloride

 First step

 3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline] - 2'-yl)acetyl]-N-(2,3-dihydroxypropyl)benzamide hydrochloride

3-tert-Butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoporphyrin] -2'-yl)acetyl]benzoic acid hydrochloride 76 (70 mg, 0.14 mmol) was dissolved in 3 mL of N,N-dimethylformamide and 3-aminopropane-1,2-diol was added. (25 mg, 0.27 mmol), 2-(7-azobenzotriazole)-indole, hydrazine, hydrazine, Ν'-tetramethylurea hexafluorophosphate (63 mg, 0.16 mmol) and N- Isopropylpropan-2-amine (33 mg, 0.32 mmol) was stirred for 4 hours. Add 10 mL of saturated sodium chloride solution to the reaction solution and extract with ethyl acetate (15 </ RTI></RTI><RTIgt;</RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; The title product 3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindole] was obtained. Phenyl]-2'-yl)acetyl]-N-(2,3-dihydroxypropyl)benzamide hydrochloride 88 (45 mg, white solid), yield: 56.3%. MS m/z (ESI): 556.3 [M+l]

 1H NMR (400 MHz, DMSO-, ppm): δ 9.45 (br, 1H), 9.10 (br, 1H), 8.79 (br, 1H), 8.38 (s, 1H), 8.25 (s, 1H), 8.08 ( s, 1H), 7.03 (s, 1H), 5.30 (s, 2H), 4.90 (s, 1H), 4.64 (s, 1H), 4.24 (m, 2H), 4.13 (m, 2H), 3.67-3.25 (m, 5H), 1.90 (m, 2H), 1.65 (m, 2H), 1.38 (s, 9H), 1.31 (m, 3H), 1.23 (m, 3H) Example 89

 3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline] -2 '-based) acetyl

 First step

 3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline] - 2'-yl)acetyl]-indole-(2-hydroxypropyl)benzamide hydrochloride

3-tert-Butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoporphyrin] -2'-yl)acetyl]benzoic acid hydrochloride 76 (70 _§ , 0.14 11^101) was dissolved in 3 11 m dichloromethane, and 4-dimethylaminopyridine (50 mg, 0.40 mmol) was added. 2-Aminoethanol (16 mg, 0.27 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (69 mg, 0.27 mmol) was added, and the mixture was stirred for 4 hr. The reaction mixture was concentrated under reduced pressure and purified to purified crystals eluted elut elut elut elut eluting 4'-Fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)acetyl]-N-(2-hydroxypropyl)benzamide hydrochloride Salt 89 (20 mg, white solid), Yield: 26.3%.

MS m/z (ESI): 526.3 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.61 (s, 1H), 9.19 (s, 1H), 9.03 (s, 1H), 8.58 (s _: 1H), 8.33 (s, 1H), 8.15 (s, 1H), 7.11 (s, 1H), 5.49 (s, 2H), 4.97 (s, 1H), 4.31 (m, 2H), 4.20 (m, 2H), 3.63 (m, 2H), 3.40 (m, 2H), 1.93 (s, 2H), 1.73 (s, 2H), 1.44 (m, 15H) Example 90

 L-[3-tert-butyl-5-(2-hydroxyethoxy)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[ Cyclopropane

 -1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

first step

 1-[3-tert-butyl-5-(2-hydroxyethoxy)phenyl]ethanone

 Add cuprous iodide (573 mg, 3 mmol), L-valine (690 mg, 6 mmol) and cesium carbonate (19.56 g, 60 mmol) to the reaction flask, 5 mL 1-(3-bromo) -5-tert-Butyl-phenyl)ethanone oxime (2.55 g, 10 mmol) of dimethyl sulfoxide was added to the reaction system, and ethylene glycol (15 mL, 305 mmol) was added thereto, and the reaction was stirred for 12 hours. Pour the reaction solution into 5 mL of saturated ammonium chloride solution, add 20 mL of ethyl acetate and 20 mL of water, and extract the mixture. The aqueous phase is extracted with ethyl acetate (20 mL), and the organic phase is combined with water (20 mL×2) It was washed with a saturated sodium chloride solution (30 mL×2), dried over anhydrous magnesium sulfate, filtered and evaporated. tert-Butyl-5-(2-hydroxyethoxy)phenyl]ethanone 90a (198 mg, brown oil), yield: 8.4%.

 Second step

 2-bromo[3-tert-butyl-5-(2-hydroxyethoxy)phenyl]ethanone 1-[3-tert-butyl-5-(2-hydroxyethoxy)phenyl]B Ketone 90a (198 mg, 0.84 mmol) was dissolved in 7 mL of a mixture of tetrahydrofuran and methanol (V/V = 6:1). Trimethylphenylammonium bromide (404 mg, 0.84 mmol) was added and stirred. hour. The reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjj Ethyl ketone 90b (190 mg, yellow oil), Yield: 71.9%.

 third step

 1-[3-tert-butyl-5-(2-hydroxyethoxy)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[ Cyclopropane

 -1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

Dissolve 5',6'-diethoxy-7-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (85 mg, 0.32 mmol) in 2 mL of tetrahydrofuran , adding 2-bromo-1-[3-tert-butyl-5-(2-hydroxyethoxy)phenyl]B Ketone 90b (100 mg, 0.32 mmol) was stirred for 12 hours. Filtration gave a white solid, which was purified eluted elut elut elut elut '-Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide 90 (42 mg, White solid), Yield: 22.9%.

MS m/z (ESI): 499.3 [M+l]

1H NMR (400 MHz, DMSO-, ppm): δ 9.42 (s, 1H), 9.09 (s, 1H), 7.59 (s, 1H), 7.40 (s _: 1H), 7.30 (s, 1H), 7.04 ( s, 1H), 5.23 (s, 2H), 4.93 (t, J = 5.2 Hz, 1H), 4.25 (m, 2H), 4.12 (m, 2H), 3.77 (m, 2H), 3.40 (m, 2H) ), 1.80 (m, 2H), 1.67 (m, 2H), 1.41 (m, 3H), 1.33 (s, 9H), 1.31 (m, 3H) Example 91

 1-(3-tert-Butyl-5-methanesulfonyl-phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-U-dimethyl-isoindole

first step

 1-(3-tert-butyl-5-methanesulfonyl-phenyl)ethanone

 1-(3-Bromo-5-tert-butyl-phenyl)ethanone oxime (1.53 g, 6 mmol), sodium methanesulfonate (2.45 g, 24 mmol) and copper trifluoromethanesulfonate (I) The benzene (300 mg, 0.40 mmol) was dissolved in 40 mL of dimethyl sulfoxide, and hydrazine, Ν'-dimethylethylenediamine (108 mg, 0.80 mmol) was added dropwise, and the reaction was stirred at 150 ° C for 2.5 hours. Pour 50 mL of water and 50 mL of ethyl acetate into the reaction mixture, and extract the mixture. The aqueous phase was extracted with ethyl acetate (30 mL×2), and the organic phase was combined, washed with water (30 mL×3) and saturated sodium chloride solution (30) The residue was purified by silica gel column chromatography eluting elut elut Phenyl)ethanone 91a (1.16 g, yellow liquid), Yield: 76.1%.

 Second step

 2-bromo-1-(3-tert-butyl-5-methanesulfonyl-phenyl)ethanone

1-(3-tert-Butyl-5-methanesulfonyl-phenyl)ethanone 91a (200 mg, 0.79 mmol) was dissolved in 20 mL of tetrahydrofuran, and trimethylphenylammonium bromide (296 mg, 0.79 mmol), the reaction was stirred for 30 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified to silica gel The product 2-bromo-l-(3-tert-butyl-5-methanesulfonyl-phenyl)ethanone 91b (210 mg, pale yellow liquid), yield: 80.2%.

 MS m/z (ESI): 350.0 [M+18]

 third step

 L-(3-tert-butyl-5-methanesulfonyl-phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-U-dimethyl-isoporphyrin -2-yl)ethanone hydrobromide

 Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (79 mg, 0.30 mmol) in 1.50 mL of tetrahydrofuran and add 2-bromo-1-( 3-tert-Butyl-5-methanesulfonyl-phenyl)ethanone 91b (100 mg, 0.30 mmol) was stirred for 14 hr. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjj 1-(3-tert-butyl-5-methanesulfonyl-phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindole Porphyrin-2-yl)ethanone hydrobromide 91 (30 mg, white solid), yield: 16.8%.

MS m/z (ESI): 519.2 [M+1]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.42 (br, 1H), 9.02 (br, 1H), 8.39 (s, 1H), 8.32 (s, 1H), 8.23 (s, 1H), 7.46 (s, 1H), 5.58 (s, 2H), 4.26 (m, 2H), 4.12 (m, 2H), 3.36 (s, 3H), 1.53 (s, 6H), 1.41 (m, 12H), 1.30 (m, 3H) Example 92

1-(3-tert-Butyl-5-methanesulfonyl-phenyl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1 , Γ- 异

 -2'-yl) ethyl ketone hydrobromide

 First step

1-(3-tert-butyl-5-methanesulfonyl-phenyl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1 ,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

Dissolve 5',6'-diethoxy-7-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (79 mg, 0.30 mmol) in 2 mL of tetrahydrofuran , 2-bromo-1-(3-tert-butyl-5-methanesulfonyl-phenyl)ethanone 91b (100 mg, 0.30 mmol), stirred for 2 hours, and a white solid precipitated. Filtration, washing with tetrahydrofuran (0.5 mL×2), dried in vacuo to give the title product 1- 3-tert-butyl-5-methanesulfonyl-phenyl) -2-(5',6'-diethoxy-4'-Fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 92 (85 mg, white solid), Yield: 47.5% .

MS m/z (ESI): 517.2 [M+l]

 1H NMR (400 MHz, DMSO-, ppm): δ 9.42 (br, 1H), 9.12 (br, 1H), 8.33 (s, 1H), 8.24 (m, 2H), 7.04 (s, 1H), 5.34 ( s, 2H), 4.23 (m, 2H), 4.12 (m, 2H), 3.34 (s, 3H), 1.88 (m, 2H), 1.67 (m, 2H), 1.40 (m, 12H), 1.29 (m , 3H) Example 93

 L-[3-tert-Butyl-5-(2,3-dihydroxypropyloxy)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino - snail

 '-Isoporphyrin]-2'-yl)ethanone hydrobromide

 First step

 1-[3-tert-Butyl-5-(2,3-dihydroxypropoxy)phenyl]ethanone will be cuprous iodide (153 mg, 0.80 mmol), L-valine (184 mg, 1.60) Methyl) and cesium carbonate (5.20 g, 16 mmol) were added to the reaction flask, and 3 mL of N-containing 1-(3-bromo-5-tert-butyl-phenyl)ethanone 77d (1.02 g, 4 mmol) was added. A solution of N-dimethylformamide and 27 mL of glycerol (11 g, 0.12 mol) in N,N-dimethylformamide was stirred at 90 ° C for 48 hours. After cooling to room temperature, the reaction mixture was quenched by the addition of 10 mL of a saturated aqueous solution of ammonium chloride, and then 20 mL of ethyl acetate and 20 mL of water were added, and the organic phase was separated and extracted with ethyl acetate (20 mL). The organic phase was washed with water (30 mL) and EtOAc (EtOAc) The title product 1-[3-tert-butyl-5-(2,3-dihydroxypropoxy)phenyl]ethanone 93a (289 mg, brown liquid) was obtained.

 Second step

2-Bromo-1-[3-tert-butyl-5-(2,3-dihydroxypropoxy)phenyl]ethanone copper bromide (103 mg, 0.46 mmol) suspended in 1.50 mL of ethyl acetate , heated to reflux, and added 2.50 mL of 1-[3-tert-butyl-5-(2,3-dihydroxypropyloxy)phenyl]ethanone 93a (61 mg, 0.23 mmol). The methyl chloride solution was refluxed for 3 hours. After cooling to room temperature, filtration and EtOAcqqqqqjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The product was obtained as a dark brown oil.

 third step

 1-[3-tert-butyl-5-(2,3-dihydroxypropyloxy)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino - Spiro [cyclopropane-1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (84 mg, 0.30 mmol) and crude 2-bromo 1-[3-tert-butyl-5-(2,3-dihydroxypropyloxy)phenyl]ethanone 93b (105 mg, 0.30 mmol) was dissolved in 1.50 mL of THF, stirred for 4 hrs solid. After suction filtration, the filter cake was washed with EtOAc (EtOAc (EtOAc) 5',6'-Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 93 (38 mg, white solid), Yield: 23.7%.

MS m/z (ESI): 529.7 [M+l]

 1H NMR (400 MHz, DMSO-, ppm): δ 9.40 (br, 1H), 9.06 (br, 1H), 7.58 (s, 1H), 7.39 (s, 1H), 7.30 (s, 1H), 7.03 ( s, 1H), 5.21 (s, 2H), 4.98 (m, 1H), 4.71 (m, 1H), 4.23 (m, 2H), 4.11 (m, 3H), 3.97 (m, 1H), 3.82 (m , 1H), 3.60 (m, 1H), 1.80 (m, 2H), 1.66 (m, 2H), 1.40 (m, 3H), 1.33 (m, 12H) Example 94

 3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)acetyl] Benzonitrile hydrobromide

 77d 94a 94b

 First step

 3-acetyl-5-tert-butyl-benzonitrile

Dissolve 1-(3-bromo-5-tert-butyl-phenyl)ethanone 77d (1 g, 3.92 mmol) and copper cyanide (386 mg, 4.31 mmol) in 15 mL of N-methyl-2-pyrrolidone The reaction was stirred at 170 ° C for 2 hours. Add 20 mL of ethyl acetate and 20 mL of water to the reaction solution, add 10 mL of ammonia water, stir for 30 minutes, and extract. The organic phase was extracted with EtOAc (EtOAc (EtOAc) (EtOAc) (EtOAcjjjjjjj The residue was purified by silica gel column chromatography elut elut elut elut elut elut elut elut elut elut

 MS m/z (ESI): 219.1 [M+18]

 Second step

 3-(2-bromoacetyl)-5-tert-butyl-benzonitrile

 Dissolve 3-acetyl-5-tert-butyl-benzonitrile 94a (300 mg, 1.49 mmol) in 15 mL of tetrahydrofuran, add trimethylphenylammonium tribromide (561 mg, 1.49 mmol), stir the reaction 30 minutes. Filtration, the filtrate was concentrated under reduced pressure, and then purified to silicagel. Yellow liquid), Yield: 82.5%.

 MS m/z (ESI): 299.0 [M+18]

 third step

 3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)acetyl] Benzonitrile hydrobromide

 Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (95 mg, 0.36 mmol) in 1.5 mL of tetrahydrofuran and add 3-(2-bromoacetyl) -5-tert-Butyl-benzonitrile 94b (100 mg, 0.36 mmol), stirred for 12 hours. The title product, 3-tert-butyl-5-[2-(5,6-), was obtained as a yellow solid. Diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindolin-2-yl)acetyl]benzonitrile hydrobromide 94 (35 mg, white solid) Yield: 17.9%.

 MS m/z (ESI): 466.3 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.44 (br, 1H), 9.05 (br, 1H), 8.45 (s, 1H), 8.25 (m, 2H), 7.46 (s, 1H), 5.52 (s, 2H), 4.26 (m, 2H), 4.11 (m, 2H), 1.51 (s, 6H), 1.43 (m, 3H), 1.37 (s, 9H), 1.31 (m, 3H) 95

 3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline] -2 '-based) acetyl

3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline] -2 '-yl)acetyl]benzonitrile hydrobromide

 Dissolve 5',6'-diethoxy-7-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (94 mg, 0.36 mmol) in 1.5 mL of tetrahydrofuran 3-(2-Bromoacetyl)-5-tert-butyl-benzonitrile 94b (100 mg, 0.36 mmol) was added, and the mixture was stirred for 12 hr. The solid was filtered, washed with EtOAc (EtOAc (EtOAcjjjjjjj Amino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)acetyl]benzonitrile hydrobromide 95 (100 mg, white solid), yield: 51.5%.

 MS m/z (ESI): 464.2 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.40 (br, 1H), 9.11 (br, 1H), 8.35 (s, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 7.04 (s, 1H), 5.27 (s, 2H), 4.23 (m, 2H), 4.10 (m, 2H), 1.77 (m, 2H), 1.66 (m, 2H), 1.41 (m, 3H), 1.36 (s, 9H), 1.31 (m, 3H) Example 96

 L-[3-tert-butyl-5-(hydroxymethyl)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane- 1,1'-isoporphyrin-2'-yl)ethanone hydrobromide

 First step

 1-(3-bromo-5-tert-butyl-phenyl)formaldehyde

Dissolve 1,3-dibromo-5-tert-butyl-benzene 77c (17 g, 58.40 mmol) in 120 mL of tetrahydrofuran, add n-butyllithium (23.4 mL, 58.40 mmol) at -78 °C, stir. The reaction took 0.5 hours. Then add N, N-two Methylformamide (6.40 g, 87.70 mmol) was stirred for 0.5 h. Add 120 mL of saturated ammonium chloride solution to the reaction solution, and extract with ethyl acetate (50 mL×2). The organic phase is combined, washed with saturated sodium chloride solution (30 mL×3), dried over anhydrous magnesium sulfate, filtered, The residue was purified by silica gel column chromatography elut elut elut elut elut elut elut elut elut elut 80.0%.

 Second step

 (3-bromo-5-tert-butyl-phenyl)methanol

 1-(3-Bromo-5-tert-butyl-phenyl)ethanone 96a (1.20 g, 4.98 mmol) was dissolved in 16 mL of dry ethanol and sodium borohydride (57 mg, 1.49 mmol). The reaction was stirred for 45 minutes. The reaction mixture was quenched by the addition of 20 mL of water, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated. The title compound (3-bromo-5-tert-butyl-phenyl)methanol 96b (1 g, white solid).

 third step

 1-[3-tert-butyl-5-(hydroxymethyl)phenyl]ethanone

 (3-Bromo-5-tert-butyl-phenyl)methanol 96b (790 mg, 3.25 mmol) was dissolved in 15 mL of tetrahydrofuran, and n-butyllithium (5.20 mL, 13 mmol) was added dropwise at -78 °C. The reaction was stirred for 30 minutes, and N,N-dimethylacetamide (850 mg, 9.75 mmol) was added dropwise, and the mixture was stirred for 30 minutes. 60 mL of a saturated ammonium chloride solution was added to the reaction mixture, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (30 mL×2), and the organic phase was combined and washed with saturated sodium chloride solution (60 mL) The title compound 1-[3-tert-butyl-5-(hydroxymethyl)phenyl]B was obtained by chromatography. Ketone 96c (114 mg, colorless liquid), Yield: 17.0%.

MS m/z (ESI): 207.1 [M+l]

 the fourth step

 1-Bromo-[3-tert-butyl-5-(hydroxymethyl)phenyl]ethanone 1-[3-tert-butyl-5-(hydroxymethyl)phenyl]ethanone 96c (107 mg, 0.52 mmol) was dissolved in 3 mL of tetrahydrofuran, trimethylphenylammonium bromide (195 mg, 0.52 mmol) was added, and the reaction was stirred for 1 hour. Filtration, and the filtrate was concentrated under reduced pressure. Ethylketone 96d (90 mg, colorless liquid), Yield: 60.8%.

MS m/z (ESI): 287.0 [M+l]

 the fifth step

 L-[3-tert-butyl-5-(hydroxymethyl)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane- 1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

Dissolve 5',6'-diethoxy-7-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indoleimine 41g (73 mg, 0.28 mmol) in 2 mL of tetrahydrofuran 2-Bromo-1-[3-tert-butyl-5-(hydroxymethyl)phenyl]ethanone 96d (87 mg, 0.30 mmol) was added, and the mixture was stirred for 2.5 hr. The solid was filtered and washed with tetrahydrofuran (0.5 The title product 1-[3-tert-butyl-5-(hydroxymethyl)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3' was obtained in vacuo. -imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 96 (55 mg, white solid), yield: 34.3%.

MS m/z (ESI): 469.3 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.42 (br, 1H), 9.16 (br, 1H), 7.85 (s, 1H), 7.81 (s, 1H), 7.72 (s, 1H), 7.03 (s, 1H), 5.24 (s, 2H), 4.60 (s, 2H), 4.26-4.21 (m, 2H), 4.15-4.10 (m, 2H), 1.86-1.78 (m, 2H), 1.69- 1.63 (m, 2H), 1.42-1.38 (m, 3H), 1.34 (s, 9H), 1.32-1.29 (m, 3H) Example 97

 L-[3-tert-butyl-5-(2-hydroxyethoxy)phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl Base-isoindol-2-yl ethyl ketone hydrobromide

first step

 1-[3-tert-butyl-5-(2-hydroxyethoxy)phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl Iso-oxalin-2-yl)ethanone hydrobromide

 Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (76 mg, 0.29 mmol) in 2 mL of tetrahydrofuran and add 2-bromo-1-[ 3-tert-Butyl-5-(2-hydroxyethoxy)phenyl]ethanone 90b (90 mg, 0.29 mmol). The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj 2-(5,6-Diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindolin-2-yl)ethanone hydrobromide 97 (33 mg, light Yellow solid), Yield: 23.1%.

 MS m/z (ESI): 501.3 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.32 (br, 1H), 8.96 (br, 1H), 7.63 (s, 1H), 7.44

(s, 2H), 7.30 (s, 1H), 5.41 (s, 2H), 4.60 (s, 2H), 4.26 (m, 2H), 4.12 (m, 4H), 3.76 (m,

2H), 1.51 (s, 6H), 1.42 (m, 3H), 1.34 (m, 12H) Example 98

L-[3-tert-butyl-5-(hydroxymethyl)phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-U-dimethyl-isoindole Phenyl-2-ethylethanone hydrobromide

first step

 1-[3-tert-butyl-5-(hydroxymethyl)phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-U-dimethyl-isoindole Phenan-2-yl)ethanone hydrobromide

 Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (90 mg, 0.34 mmol) in 3 mL of tetrahydrofuran and add 2-bromo-1-[ 3-tert-Butyl-5-(hydroxymethyl)phenyl]ethanone 96d (116 mg, 0.41 mmol). After filtration, the filtrate was concentrated under reduced pressure. (5,6-Diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindolin-2-yl)ethanone hydrobromide 98 (30 mg, white solid) , Yield: 16.1%.

MS m/z (ESI): 471.1 [M+l]

 1H NMR (400 MHz, DMSO-, ppm): δ 9.42 (br, 1H), 9.00 (br, 1H), 7.90-7.88 (m, 2H), 7.72 (s, 1H), 7.46 (s, 1H), 5.47-5.44 (m, 2H), 4.61-4.60 (m, 2H), 4.29-4.24 (m, 2H), 4.15-4.10 (m, 2H), 1.53 (s, 3H), 1.51 (s, 3H), 1.43-1.39 (m, 3H), 1.35 (s, 9H), 1.32-1.30 (m, 3H) Example 99

1-[3-tert-Butyl-5-(l-methylpyrazol-4-yl)phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1, 1-dimethyl-isoindolin-2-yl)ethanone hydrobromide

first step

 1-(3-Bromo-5-tert-butyl-phenyl)ethanone 77d (720 mg, 1-[3-tert-butyl-5-0methylpyrazol-4-yl)phenyl]ethanone 2.83 mmol) and tetrakis(triphenylphosphine)palladium

(327 mg, 0.28 mmol) dissolved in 50 mL of dimethyl ether, stirred for 10 min, then added 7 mL of 1-methylpyrazol-4-ylboronic acid (533 mg, 4.23 mmol) and potassium carbonate (1.95 g, 14.10) The aqueous solution of mmol was heated to reflux and stirred for 4 hours. Filtration, 20 mL of ethyl acetate was added to the filtrate, the mixture was evaporated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated evaporated. 3-tert-Butyl-5-(1-methylpyrazol-4-yl)phenyl]ethanone 99a (318 mg, mp.).

MS m/z (ESI): 257.1 [M+l]

 Second step

 2-bromo-l-[3-tert-butyl-5-(l-methylpyrazol-4-yl)phenyl]ethanone 1-[3-tert-butyl-5-(1-methylpyridyl) Zin-4-yl)phenyl]ethanone 99a (300 mg, 1.17 mmol) dissolved in

To 5 mL of chloroform, copper bromide (522 mg, 2.34 mmol) was added, and the mixture was heated to 40 ° C and stirred for 12 hours. Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified to silica gel column chromatography to eluent to afford the title product 2-bromo-1-[3-tert-butyl-5-(1-methylpyrazole- 4-yl)phenyl]ethanone 99b (216 mg, light yellow oil), yield: 55.0%.

 third step

 1-[3-tert-butyl-5-(1-methylpyrazol-4-yl)phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1, 1-dimethyl

 -isoporphyrin-2-yl)ethanone hydrobromide

Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (40 mg, 0.15 mmol) in 1 mL of tetrahydrofuran and add 2-bromo-1-[ 3-tert-Butyl-5-(1-methylpyrazol-4-yl)phenyl]ethanone 99b (51 mg, 0.15 mmol). The solid was filtered, washed with EtOAc (EtOAc (EtOAcjjjjjjj 6-Diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindolin-2-yl)ethanone hydrobromide 99 (40 mg, white solid), yield : 44.0%. MS m/z (ESI): 521.3 [M+l]

1H NMR (400 MHz, DMSO-, ppm): δ 9.33 (br, 1H), 8.95 (br, 1H), 8.36 (s, 1H), 8.09 (s, 1H), 8.06 (s, 1H), 7.95 ( s, 1H), 7.83 (s, 1H), 7.46 (s, 1H), 5.46 (s, 2H), 4.30-4.25 (m _: 2H), 4.17-4.11 (m, 2H), 3.91 (s, 3H) , 1.53 (s, 6H), 1.43 (m, 3H), 1.39 (s, 9H), 1.32 (m, 3H) Example 100

L-[3-tert-butyl-5-(l-methylpyrazol-4-yl)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'- Amino-spiro[cyclopropane

 -1 1'-Isoporphyrin]-2'-yl)ethanone hydrobromide

 First step

 1-[3-tert-butyl-5-(1-methylpyrazol-4-yl)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'- Amino-spiro[cyclopropane

 -1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

 Dissolve 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (51 mg, 0.19 mmol) in 0.5 mL tetrahydrofuran 2-Bromo-1-[3-tert-butyl-5-(1-methylpyrazol-4-yl)phenyl]ethanone 99b C65 mg (0.19 mmol) was added, and the mixture was stirred for 12 hr. The reaction mixture was concentrated to give crystals crystals crystals crystals crystals -(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide Salt 100 (11 mg, white solid), Yield: 10.0%.

MS m/z (ESI): 519.1 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.59 (br, 1H), 9.13 (br, 1H), 8.37 (s, 1H), 8.07 (s, 1H), 8.05 (s, 1H), 7.94 (s, 1H), 7.79 (s, 1H), 7.05 (s, 1H), 5.37 (s, 2H), 4.27-4.22 (m _: 2H), 4.16-4.11 (m, 2H), 3.90 (s, 3H), 1.78 (m, 2H), 1.68 (m, 2H), 1.41 (m, 3H), 1.38 (s _: 9H), 1.32 (m, 3H) Example 101

L-(3-tert-butyl-5-isopropyl-phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindole Porphyrin -2- ethyl ketone hydrobromide

 First step

 1-bromo-3-tert-butyl-5-isopropyl-benzene

 Zinc chloride (3.64 g, 26.70 mmol) was dissolved in 20 mL of tetrahydrofuran, 13.3 mL of 2 M isopropylmagnesium chloride was added, and the reaction was stirred at 50 ° C for 3 hours. Add 1,3-dibromo-5-tert-butyl-benzene 77c (5.20 g, 17.80 mmol) to another reaction vial, add cuprous iodide (203 mg, 1.07 mmol), 1, Γ-bis (two Benzylphosphine dichloride diferric iron palladium (651 mg, 0.89 mmol) and 20 mL of tetrahydrofuran were added dropwise to the cooled reaction mixture, and the reaction was stirred for 36 hours in the dark. Filtration, the filter cake was washed with EtOAc (EtOAc EtOAc (EtOAc) The product 1-bromo-3-tert-butyl-5-isopropyl-benzene 101a (433 mg, yellow oil), yield: 95.0%.

 Second step

 1-(3-tert-butyl-5-isopropyl-phenyl)ethanone

 Dissolve 1-bromo-3-tert-butyl-5-isopropyl-benzene 101a (730 mg, 2.86 mmol) in 5 mL of tetrahydrofuran, and add 2.50 M n-butyllithium (1.37 mL, dropwise at -78 °C. 3.44 mmol), the reaction was stirred for 2 hours, then N,N-dimethylacetamide (0.37 mL, 4.29 mmol) was added dropwise, and the mixture was stirred for 30 minutes. The reaction mixture was quenched by the addition of 20 mL of a saturated aqueous solution of ammonium chloride, and then 5 mL of water and 20 mL of ethyl acetate, and the organic phase was separated, washed with a saturated sodium chloride solution (5 mL), dried over anhydrous magnesium sulfate. Filtration, and the filtrate was concentrated under reduced pressure. Mg, colorless liquid), Yield: 60.8%.

MS m/z (ESI): 219.1 [M+l]

 third step

 2-bromo-l-(3-tert-butyl-5-isopropyl-phenyl)ethanone

Dissolve 1-(3-tert-butyl-5-isopropyl-phenyl)ethanone 101b (326 mg, 1.50 mmol) in 3 mL of tetrahydrofuran and add trimethylphenylammonium bromide (562 mg, 1.50 mmol), stir the reaction for 1 hour. Filtration, and the filtrate was concentrated under reduced pressure. 101c (207 mg, colorless liquid), yield: 46.0%. MS m/z (ESI): 299.9 [M+l]

 the fourth step

 L-(3-tert-butyl-5-isopropyl-phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindole Porphyrin

 -2-yl)ethanone hydrobromide

 Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (49 mg, 0.18 mmol) in

To 0.5 mL of tetrahydrofuran, 2-bromo-1-(3-tert-butyl-5-isopropyl-phenyl)ethanone 101c (55 mg, 0.18 mmol) was added, and the mixture was stirred for 12 hr. The reaction mixture was concentrated under reduced pressure. mjjjjjjjjj 6-Diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindolin-2-yl)ethanone hydrobromide 101 (20 mg, white solid), yield : 19.0%.

 MS m/z (ESI): 483.5 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 7.86 (s, 1H), 7.77 (s, 1H), 7.65 (s, 1H), 7.44 (s _: 1H), 5.40 (s, 2H), 4.27-4.26 (m, 2H), 4.16-4.11 (m, 2H), 3.04 (m, 1H), 1.52 (s, 6H), 1.43 (m, 3H), 1.36 (s, 9H), 1.34-1.27 ( m, 9H) Example 102

 1-C3-tert-butyl-5-isopropyl-phenyl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, 1'- 异3⁄4

 '-yl) ethyl ketone hydrobromide

 First step

 1-C3-tert-butyl-5-isopropyl-phenyl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, 1'-isoporphyrin]-2'-yl)ethanone hydrobromide

Dissolve 5',6'-diethoxy-7-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indoleimine 41g (50 mg, 0.19 mmol) in 0.5 mL of tetrahydrofuran 2-Bromo-1-(3-tert-butyl-5-isopropyl-phenyl)ethanone 101c (56 mg, 0.19 mmol) was added, and the mixture was stirred for 12 hr. The solid was filtered, washed with EtOAc (EtOAc) (EtOAcjjjjjjjjj -4'-Fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 102 (30 mg, white solid), yield : 28.0%. MS m/z (ESI): 481.6 [M+l]

 1H NMR (400 MHz, DMSO-, ppm): δ 9.39 (br, 1H), 9.06 (br, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.66 (s, 1H), 7.04 ( s, 1H), 5.23 (s, 2H), 4.27-4.22 (m, 2H), 4.16-4.11 (m, 2H), 3.04-2.99 (m, 1H), 1.83 (m, 2H), 1.67 (m, 2H), 1.41 (m, 3H), 1.35 (s, 9H), 1.32 (m, 3H), 1.25 (d, / = 9.3 Hz, 1H) Example 103

 L-[3-tert-butyl-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]-2-(5',6'-diethoxy-4'-fluoro -3'-imino-1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

 First step

 1-bromo-3-tert-butyl-5-(1,1-dimethoxyethyl)benzene

 1-(3-Bromo-5-tert-butyl-phenyl)ethanone oxime (2.30 g, 9 mmol) was dissolved in 3 mL of methanol, followed by trimethoxymethane (2.88 g, 27 mmol) and camphor. Acid (105 mg, 0.45 mmol) was stirred for 12 hours. Add 500 mg of potassium carbonate to the reaction solution, stir for 10 minutes, add 10 mL of water and 10 mL of n-hexane, extract the liquid, extract the aqueous phase with n-hexane (10 mL×2), combine the organic phase, and wash with saturated sodium chloride solution. (10 mL), dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2.70 g, light yellow oil). The product was taken to the next step without purification.

 Second step

 1-[3-tert-butyl-5-(1,1-dimethoxyethyl)phenyl]piperazine

The crude 1-bromo-3-tert-butyl-5-(1,1-dimethoxyethyl)benzene 103a (2.70 g, 9 mmol) was placed in a reaction flask, followed by 2-dicyclohexylphosphine- 2-(N,N-Dimethylamino)biphenyl (177 mg, 0.45 mmol), tris(dibenzylideneacetone)dipalladium (270 mg, 10%), sodium tert-butoxide (2.60 g, 27 mmol And piperazine (1.50 g, 18 Methyl), finally 40 mL of dioxane was added and the reaction was stirred at 60 ° C for 3 hours. 50 mL of water and 20 mL of ethyl acetate were added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (20 mL×4). The organic phase was combined and washed with saturated sodium chloride (30 mL×l), anhydrous magnesium sulfate Drying, filtration, and EtOAc~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The product was directly subjected to the next reaction without purification.

 third step

 1-(3-tert-butyl-5-piperazin-1-yl-phenyl)ethanone

 Dissolve the crude 1-[3-tert-butyl-5-(1,1-dimethoxyethyl)phenyl]piperazine 103b (2 g, 6.50 mmol) in 30 mL of 2 M hydrogen chloride dioxane The reaction was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. The title product was obtained as a crude title compound (1, 3-t-butyl-5-piperazine-i-yl-phenyl)ethanone 103c (1.45 g, yellow oil).

 MS m/z (ESI): 261.1 [M+l]

 the fourth step

 1-[3-tert-Butyl-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]ethanone crude 1-(3-tert-butyl-5-piperazine-1 -yl-phenyl)ethanone 103c (1.40 g, 5.38 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by 2-chloroethanol (694 mg, 8.60 mmol) and potassium carbonate (1.48 g) , 10.76 mmol), the reaction was heated to 70 ° C and stirred for 12 hours. After adding 30 mL of water to the reaction mixture, ethyl acetate (30 mL×4), EtOAc (EtOAc m. Column chromatography was carried out to purify the obtained residue to afford the title product 1-[3-tert-butyl-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]ethanone. 103d (630 mg, yellow oil), Yield: 39.3%.

MS m/z (ESI): 305.1 [M+l]

 the fifth step

 2-bromo-[3-tert-butyl-5-[4-(2-hydroxyethyl)piperazine yl]phenyl]ethanone 1-[3-tert-butyl-5-[4-(2) -hydroxyethyl)piperazin-1-yl]phenyl]ethanone 103d (103 mg, 0.34 mmol) was dissolved in 2 mL of glacial acetic acid, tribromopyridinium salt (108 mg, 0.34 mmol) was added, and the reaction was stirred. hour. 5 mL of water was added to the reaction mixture, the pH was adjusted to 7-8 with sodium bicarbonate, extracted with ethyl acetate (10 mL×4), and the organic phase was combined and washed with saturated sodium chloride (10 mL), anhydrous magnesium sulfate The mixture was dried, filtered, and the filtrate was evaporated,jjjjjjjjjjjjjjj Hydroxyethyl)piperazin-1-yl]phenyl]ethanone 103e (38 mg, white solid), yield: 29.2%.

MS m/z (ESI): 385.1 [M+l]

 Step 6

L-[3-tert-butyl-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]-2-(5',6'-diethoxy-4'-fluoro -3'-imino- Spiro [cyclopropane-1, hydrazine-isoporphyrin]-2'-yl)ethanone hydrobromide

 Dissolve 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (26 mg, 0.10 mmol) in 1 mL of tetrahydrofuran Add 2-bromo-1-[3-tert-butyl-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]ethanone 103e (38 mg, 0.10 mmol), stir Reaction for 4 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj Pyrazin-1-yl]phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoporphyrin] -2'-yl)ethanone hydrobromide 103 (28 mg, white solid), yield: 43.7%.

MS m/z (ESI): 566.1 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 8.69 (s, 1H), 7.92 (s, 1H), 7.88 (s, 1H), 7.04 (s _: 1H), 5.32 (s, 2H), 4.25 (m, 2H), 4.14 (m, 2H), 3.60 (m, 2H), 3.27 (m, 2H), 2.71 (m, 2H), 2.64 (m, 2H), 1.69 (m, 2H), 1.38 (m, 2H), 1.37 (s, 9H), 1.31 (m, 6H) Example 104

 1-C3-tert-butyl-5-cyclopropyl-phenyl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, Γ-isoporphyrin]-2'-yl)ethanone hydrobromide

 104a 104b 104

 First step

 1-(3-tert-butyl-5-cyclopropyl-phenyl)-ethanone

 1-(3-Bromo-5-tert-butyl-phenyl)ethanone oxime (1 g, 3.90 mmol) and tetrakistriphenylphosphine palladium (450 mg,

0.39 mmol) dissolved in 60 mL of dioxane, stirred for 10 minutes, and then added 10 mL of an aqueous solution containing cyclopropylboronic acid (500 mg, 5.90 mmol) and cesium carbonate (6.30 g, 19.50 mmol) to the reaction system. The reaction was stirred at 90 ° C for 5 hours. After cooling to room temperature, the mixture was filtered, and 50 mL of ethyl acetate and 10 mL of water were added to the filtrate. The organic phase was separated, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous magnesium sulfate and filtered. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut elut ), Yield: 71.2%.

MS m/z (ESI): 217.1 [M+l]

Second step 2-bromo-l-(3-tert-butyl-5-cyclopropyl-phenyl)-ethanone

 Dissolve 1-(3-tert-butyl-5-cyclopropyl-phenyl)-ethanone 104a (540 mg, 2.50 mmol) in 7.5 mL of tetrahydrofuran and add trimethylphenylammonium tribromide (940 mg) , 2.50 mmol), stir the reaction for 2 hours. Filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified to silica gel column chromatography to afford to afford the title product 2-bromo-1-(3-tert-butyl-5-cyclopropyl-phenyl)-B Ketone 104b (510 mg, colorless liquid), Yield: 68.9%.

 third step

 1-C3-tert-butyl-5-cyclopropyl-phenyl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, 1'-isoporphyrin]-2'-yl)ethanone hydrobromide

 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (82 mg, 0.31 mmol) and B 2-bromo 1-(3-tert-butyl-5-cyclopropyl-phenyl)-ethanone 104b (92 mg, 0.31 mmol) was dissolved in 1 mL of THF, and the mixture was stirred for 12 hr. Filtration, the filter cake was washed with EtOAc (EtOAc (EtOAc) (EtOAcjjjjjjj —4'-Fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 104 (139 mg, white solid), yield : 80.0%.

 MS m/z (ESI): 479.1 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.36 (br, 1H), 9.05 (br, 1H), 7.75 (s, 1H), 7.53 (s, 1H), 7.48 (s, 1H), 7.03 (s, 1H), 5.20 (s, 2H), 4.27-4.22 (m, 2H), 4.16-4.11 (m, 2H), 2.08-2.05 (m, 1H), 1.80 (m, 2H), 1.66 ( m, 2H), 1.41 (m, 3H), 1.33 (s, 9H), 1.32 (m, 3H), 1.03 (m, 2H), 0.78 (m, 2H)

L-(3-tert-Butyl-5-cyclopropyl-phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-U-dimethyl-isoporphyrin

 -2-yl)ethanone hydrobromide

 Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (62 mg, 0.21 mmol) in 1 mL of tetrahydrofuran and add 2-bromo-1-( 3-tert-Butyl-5-cyclopropyl-phenyl)-ethanone 104b (56 mg, 0.21 mmol). Filtration, and the filtrate was concentrated under reduced pressure. 5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindolin-2-yl)ethanone hydrobromide 105 (72 mg, white solid) Yield: 61.0%.

MS m/z (ESI): 481.1 [M+l]

1H NMR (400 MHz, DMSO-, ppm): δ 7.78 (s, 1H), 7.55 (s, 1H), 7.51 (s, 1H), 7.44 (s 1H), 5.39 (s, 2H), 4.29-4.23 (m, 2H), 4.15-4.10 (m, 2H), 2.07 (m, 1H), 1.50 (s, 6H), 1.42 (m, 3H), 1.34 (s, 9H), 1.30 (m, 3H), 1.02 (m, 2H), 0.80 (m, 2H) Example 106

 L-[3-tert-butyl-5-(trifluoromethyl)-phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-U-dimethyl-iso Porphyrin-2-yl)ethanone hydrobromide

3-tert-butyl-5-(trifluoromethyl)benzoic acid

Dissolve 3-bromo-5-(trifluoromethyl)benzoic acid 106a (5 g, 18.60 mmol) and cuprous iodide (178 mg, 0.93 mmol) in 50 mL of tetrahydrofuran at -78 ° C, then add tert-Butylmagnesium chloride (27.30 mL, 46.50 mmol) was stirred for 1 hour. Quench the reaction by adding 20 mL of saturated ammonium chloride solution to the reaction solution, adding 20 mL of ethyl acetate and 20 mL of water, and adjusting the pH to 2-3 with 1 M hydrogen chloride solution. The mixture was extracted with ethyl acetate (30 mL×3). EtOAc (EtOAc m. The residue obtained was purified to silica gel elut elut elut elut elut elut elut elut elut elut elut

MS m/z (ESI): 245.0 [M-l]

 Second step

 3-tert-Butyl-N-methoxy-5-(trifluoromethyl)benzamide Dissolving 3-tert-butyl-5-(trifluoromethyl)benzoic acid 106b (3.71 g, 15.08 mmol) The reaction was stirred at 85 ° C for 2 hours in 25 mL of thionyl chloride. The reaction mixture was concentrated. At 0 ° C, 30 mL dichloromethane was added, then N-methoxymethylamine (2.34 g, 23.98 mmol) was added, and N,N-diisopropylethylamine (5.84 g) was added dropwise. , 45.24 mmol), the reaction was stirred at room temperature for 12 hours. Add 30 mL of water to the reaction solution, extract the liquid, extract the aqueous phase with dichloromethane (15 mL×3), combine the organic phases, wash with water (15 mL><3) and saturated sodium chloride solution (15 mL×3), no The aqueous solution was dried over sodium sulfate, filtered, and evaporated, evaporated, evaporated,462462462462462462462462462462462462462462462462462462462462 Benzoylamide 106c (985 mg, yellow liquid), Yield: 22.6%.

MS m/z (ESI): 290.0 [M+l]

 third step

 L-[3-tert-butyl-5-(trifluoromethyl)-phenyl]ethanone

 Dissolve 3-tert-butyl-N-methoxy-5-(trifluoromethyl)benzamide 106c (900 mg, 3.10 mmol) in 15 mL of tetrahydrofuran at 0 ° C, then add methyl magnesium chloride ( 2.10 mL, 6.23 mmol), and the reaction was stirred at room temperature for 2 hours. The reaction mixture was quenched by the addition of 20 mL of a saturated aqueous solution of ammonium chloride, and then 15 mL of ethyl acetate and 10 mL of water were added to extract the mixture. The aqueous phase was extracted with ethyl acetate (15 mL×3). The residue was purified by silica gel column chromatography eluting with eluent system B to afford title product 1- [3-tert-Butyl-5-(trifluoromethyl)-phenyl]ethanone 106d (720 mg, yellow liquid), yield: 94.7%.

 the fourth step

 2-bromo small [3-tert-butyl-5-(trifluoromethyl)-phenyl]ethanone

 1-[3-tert-Butyl-5-(trifluoromethyl)-phenyl]ethanone 106d (300 mg, 1.23 mmol) was dissolved in 15 mL of tetrahydrofuran, and trimethylphenyltribromide bromide was added ( 462 mg, 1.23 mmol), and the reaction was stirred for 1 hour. Filtration, and the filtrate was concentrated under reduced pressure. Ethyl ketone 106e (290 mg, yellow liquid), yield: 73.0%.

 the fifth step

 1-[3-tert-butyl-5-(trifluoromethyl)-phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-U-dimethyl-iso Porphyrin-2-yl)ethanone hydrobromide

Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (115 mg, 0.43 mmol) in To 5 mL of tetrahydrofuran, 2-bromo-l-[3-tert-butyl-5-(trifluoromethyl)-phenyl]ethanone 106e (140 mg, 0.43 mmol) was added, and the mixture was stirred for 1 hour. 5 mL of water and 5 mL of ethyl acetate were added to the reaction mixture, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (5 mL×2), and the organic phase was combined, washed with water (10 mL×2) and saturated sodium chloride solution (10 mL×2) The residue was dried over anhydrous sodium sulfate (MgSO4). -Phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)ethanone hydrobromide 106 (24 mg, yellow solid), Yield: 9.4%.

MS m/z (ESI): 509.1 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.60 (br, 1H), 8.97 (br, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 7.45 (s, 1H), 5.56 (s, 2H), 4.26 (m, 2H), 4.11 (m, 2H), 1.52 (s, 6H), 1.40 (m, 12H), 1.32 (m, 3H) 107

 1-[3-tert-Butyl-5-(trifluoromethyl)-phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[ring] Propane-1,1'-'-yl)ethanone hydrobromide

 106e 107

1-[3-tert-butyl-5-(trifluoromethyl)-phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclo] Propane-1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

 Dissolve 5',6'-diethoxy-7-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (57 mg, 0.22 mmol) in 1 mL of tetrahydrofuran 2-Bromo-1-[3-tert-butyl-5-(trifluoromethyl)-phenyl]ethanone 106e (70 mg, 0.22 mmol) was added, and the mixture was stirred for 1 hour. The solid was filtered, washed with EtOAc (EtOAc (EtOAcjjjjjjjj Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 107 (75 mg, white solid ), Yield: 59.1%.

MS m/z (ESI): 507.1 [M+l]

1H NMR (400 MHz, DMSO-, ppm): δ 9.38 (br, 1H), 8.09 (br, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 8.05 (s, 1H), 7.03 (s, 1H), 5.29 (s, 2H), 4.23 (m, 2H), 4.12 (m, 2H), 1.86 (m _: 2H), 1.66 ( m, 2H), 1.39 (m, 12H), 1.31 (m, 3H) Example 108

 2-[3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoporphyrin) ] -2'-yl)acetyl]phenyl]-2-methyl-propionitrile hydrobromide

 First step

 1-(bromoethyl)-3-tert-butyl-5-methyl-benzene

 1-tert-Butyl-3,5-dimethyl-benzene 108a (5 g, 30.81 mmol), azobisisobutyronitrile (50 mg, 0.30 mmol) and N-bromosuccinimide (4.39 g) , 24.65 mmol) was dissolved in 50 mL of carbon tetrachloride and stirred at 80 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The title product was obtained as a crude title product: 1-(bromoethyl)-3-tert-butyl-5-methyl-benzene 108b (6.10 g, as colorless oil).

 Second step

 2-(3-tert-butyl-5-methyl-phenyl)acetonitrile

 The crude 1-(bromoethyl)-3-tert-butyl-5-methyl-benzene 108b (482 mg, 2 mmol) and tetrabutylamine cyanide (805 mg, 3 mmol) were dissolved in 5 mL of N. The reaction was stirred at 60 ° C for 1.5 hours in N-dimethylformamide. 10 mL of water was added to the reaction mixture, and the mixture was combined with EtOAc (EtOAc) The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:

 third step

2-(3-tert-butyl-5-methyl-phenyl)-2-methyl-propanenitrile Dissolve potassium tert-butoxide C198 mg, 1.76 mmol) in 5 mL of tetrahydrofuran at -78 ° C, and add 5 mL of 2-(3-tert-butyl-5-methyl-phenyl)acetonitrile 108c (150) A solution of mg, 0.80 mmol) and iodomethane (342 mg, 2.40 mmol) in tetrahydrofuran was stirred for 0.5 hour and allowed to react at room temperature for 3 hours. After adding 5 mL of water, the mixture was extracted with ethyl acetate (5 mL×2), EtOAcjjjjjjjjj -(3-tert-Butyl-5-methyl-phenyl)-2-methyl-propanenitrile 108d (151 mg, yellow oil).

 the fourth step

 3-tert-butyl-5-(1-cyano-1-methyl-ethyl)benzoic acid

 The crude product 2-0 tert-butyl-5-methyl-phenyl)-2-methyl-propanenitrile 108d (150 mg, 0.69 mmol) was dissolved in 1.3 mL of acetic acid, and 0.1 mL concentrated sulfuric acid and chromium oxide (206) Mg, 2.07 mmol), stirred for 2 hours. 20 mL of water and 10 mL of ethyl acetate were added to the reaction mixture, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (5 mL×3). The organic phase was combined and washed sequentially with water (10 mL×2) and saturated sodium chloride solution (10 mL) Drying over anhydrous magnesium sulfate, EtOAc (EtOAc m. Oily), the product was directly subjected to the next reaction without purification.

 the fifth step

 3-tert-Butyl-5-(1-cyano-1-methyl-ethyl)-N-methoxy-N-methyl-benzamide The crude 3-tert-butyl-5-0 cyano group -1-Methyl-ethyl)benzoic acid 108e (154 mg, 0.62 mmol) was dissolved in 2 mL of chlorosulfoxide and stirred at 80 ° C for 2 hr. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc m.) Ethylamine (240 mg, 1.86 mmol) was stirred for 0.5 h. 5 mL of water was added to the reaction mixture, and the mixture was combined with EtOAc EtOAc (EtOAc) The residue obtained was purified by column chromatography eluting to afford the title product 3-t-butyl-5-(1-cyano-1-methyl-ethyl)-N-methoxy-N-methyl -benzamide 108f (100 mg, yellow oil), Yield: 55.2%

MS m/z (ESI): 289.1 [M+l]

 Step 6

 2- 3-acetyl-5-tert-butyl-phenyl)-2-methyl-propanenitrile

 Dissolve 3-tert-butyl-5-(1-cyanomethyl-ethyl)-N-methoxy-N-methyl-benzamide 108f (100 mg, 0.34 mmol) in an ice bath In 2 mL of tetrahydrofuran, 3 M methylmagnesium chloride (0.23 mL, 0.68 mmol) was added, and the reaction was stirred for 2 hours. 5 mL of water was added to the reaction solution, and the pH was adjusted with 2 mL of M hydrogen chloride solution, extracted with ethyl acetate (5 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous magnesium sulfate Filtration, and the filtrate was concentrated under reduced pressure to give the crude title product 2-(3-acetyl-5-tert-butyl-phenyl)-2-methyl-propanonitrile 108 g (75 mg, white solid) Purification proceeds directly to the next reaction.

MS m/z (ESI): 261.2 [M+l 8]

Seventh step 2-[3-(2-bromoacetyl)-5-tert-butyl-phenyl]-2-methyl-propanenitrile

 The crude product 2-0 acetyl-5-tert-butyl-phenyl)-2-methyl-propanenitrile 108 g (75 mg, 0.30 mmol) was dissolved in 10 mL of tetrahydrofuran, and trimethylphenylammonium bromide was added. (115 mg, 0.30 mmol), stirred for 1.5 h. Filtration, and the filtrate was concentrated under reduced pressure. -2-Methyl-propionitrile 108 h (72 mg, colorless liquid), Yield: 74.2%.

 MS m/z (ESI): 341.1 [M+18]

 Eighth step

 2-[3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoporphyrin) ] -2'-yl)acetyl]phenyl]-2-methyl-propionitrile hydrobromide

 Dissolve 5',6'-diethoxy-7-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (40 mg, 0.15 mmol) in 0.5 mL of tetrahydrofuran 2-[3-(2-Bromoacetyl)-5-tert-butyl-phenyl]-2-methyl-propanenitrile 108h (49 mg, 0.15 mmol) was added, and the mixture was stirred for 3 hr. The solid was filtered, washed with EtOAc (EtOAc (EtOAcjjjjjjjj '-Imino-spiro[cyclopropane-1,1'-isoporphyrin]-2'-yl)acetyl]phenyl]-2-methyl-propionitrile hydrobromide 108 (33 mg, white Solid), Yield: 44.0% o

 MS m/z (ESI): 506.1 [M+l]

1H NMR (400 MHz, DMSO-, ppm): δ 7.97 (s, 1H), 7.93 (s, 1H), 7.88 (s, 1H), 7.04 (s _: 1H), 5.27 (s, 2H), 4.23 ( m, 2H), 4.12 (m, 2H), 1.67 (s, 6H), 1.43 (m, 2H), 1.39 (m, 2H) _: 1.38 (s, 9H), 1.33 (m, 6H) Example 109

 2-[3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl) Acetyl]

 -2-methyl-propionitrile hydrobromide

 First step

1-[3-tert-butyl-5-(2-hydroxyethoxy)phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl Base-different Porphyrin-2-yl)ethanone hydrobromide

 Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (106 mg, 0.40 mmol) in 5 mL of tetrahydrofuran and add 2-[3-(2 -Bromoacetyl)-5-tert-butyl-phenyl]-2-methyl-propanenitrile 108h (129 mg, 0.40 mmol). The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjj 2-(5,6-Diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindolin-2-yl)ethanone hydrobromide 109 (86 mg, white Solid), Yield: 36.5%.

MS m/z (ESI): 508.3 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 8.01 (s, 1H), 7.98 (s, 1H), 7.88 (s, 1H), 7.45 (s _: 1H), 5.48 (s, 2H), 4.28 (m, 2H), 4.12 (m, 2H), 1.78 (s, 6H), 1.44 (s, 6H), 1.40 (m, 3H), 1.38 0, 9H), 1.31 (m, 3H) Example 110

 3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline] -2 '-based) acetyl

 -N,N-bis(2-hydroxyethyl)benzamide hydrochloride

 76 110

 First step

 3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline] -2 '-yl)acetyl]-indole, fluorene-bis(2-hydroxyethyl)benzamide hydrochloride

3-tert-Butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoporphyrin] -2'-yl)acetyl]benzoic acid hydrochloride 76 (350 mg, 0.68 mmol) and 2-(2-hydroxyethylamino)ethanol (142 mg _: 1.35 mmol) dissolved in 3 mL of N, N-dimethyl In the formamide, 2-(7-azobenzotriazine) is added.

Oxazole) - hydrazine, hydrazine, hydrazine, Ν'-tetramethylurea hexafluorophosphate (308 mg, 0.81 mmol), and the reaction was stirred for 2 hours. 5 mL of a saturated sodium chloride solution was added, and the mixture was extracted with ethyl acetate (20 mL×2), and the organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue gave the title product 3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'- Isoporphyrin] -2'- Acetyl]-N,N-bis(2-hydroxyethyl)benzamide hydrochloride 110 (110 mg, pale yellow solid), yield: 22.3%.

 MS m/z (ESI): 570.1 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 7.99 (s, 1H), 7.96 (s, 1H), 7.88 (s, 1H), 7.82 (s 1H), 6.97 (s, 1H), 5.16 (s, 2H), 4.87 (m, 2H), 4.23-4.15 (m, 2H), 4.13-4.09 (m, 2H), 3.66 (m, 2H), 3.56 (m, 2H), 3.51 (m, 2H) ), 3.32 (m, 2H), 1.76 (m, 2H), 1.58 (m, 2H), 1.40 (m, 3H), 1.36 (s, 9H), 1.29 (m, 3H) Example 111

 3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline] -2 '-yl)acetyl]-N-[2-hydroxy-1 -(hydroxymethyl)ethyl]benzamide hydrochloride

first step

3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline] - 2'-yl)acetyl]-N-[2-hydroxy-1 -(hydroxymethyl)ethyl]benzamide hydrochloride 3-tert-butyl-5-[2-(5',6' -diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)acetyl]benzoic acid hydrochloride 76 (150 Mg, 0.29 mmol) and 2-aminopropyl-1,3-diol (53 mg, 0.58 mmol) dissolved in 1 mL of N,N-dimethylformamide and added 2-(;7-azobenzene Trinitrogen

Iridazole, hydrazine, hydrazine, hydrazine, Ν'-tetramethyluronium hexafluorophosphate (132 mg, 0.35 mmol), stirred for 2 hours. 5 mL of a saturated sodium chloride solution was added, and the mixture was extracted with ethyl acetate (20 mL×2), and the organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue gave the title product 3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'- Isoporphyrin] -2'-yl)acetyl]-N-[2-hydroxysuccinyl(hydroxymethyl)ethyl]benzamide hydrochloride 111 (120 mg, pale yellow solid), Yield: 70.0 %.

 MS m/z (ESI): 556.2 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 9.47 (br, 1H), 9.03 (br, 1H), 8.45-8.42 (m, 2H), 8.25 (s, 1H), 8.08 (s, 1H), 7.02 (s, 1H), 5.36 (s, 2H), 4.77 (m, 2H), 4.25 (m, 2H), 4.13 (m, 2H) ), 3.59 (m, 4H), 1.84 (m, 2H), 1.65 (m, 2H), 1.41 (m, 3H), 1.39 (s, 1H), 1.32 (m, 3H) Example 112

1-[3-tert-Butyl-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]-2-(5,6-diethoxy-4-fluoro-3- Imino-1,1-

 First step

 1-[3-tert-butyl-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]-2-(5,6-diethoxy-4-fluoro-3- Imino-1,1-dimethyl-isoindol-2-yl)ethanone hydrobromide

 Dissolve 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindolamine 24d (56 mg, 0.20 mmol) in 5 mL of tetrahydrofuran and add 2-bromo-1-[ 3-tert-Butyl-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]ethanone 1036 (80 13⁄4, 0.20 1^^1) and triethylamine (80 13⁄4, 0.20) 1^^) 1), the reaction was stirred for 48 hours. The reaction mixture was concentrated under reduced pressure.

1-[3-tert-butyl-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]-2-(5,6-diethoxy-4-fluoro-3- Imino-1,1-dimethyl-isoindolin-2-yl)ethanone hydrobromide 112 (21 mg, yellow solid), yield: 16.2%.

 MS m/z (ESI): 569.7 [M+l]

1H NMR (400 MHz, DMSO-, ppm): δ 7.22 (s, 1H), 6.93 (s, 1H), 6.74 (s, 1H), 5.48 (s _:

2H), 4.27 (m, 2H), 4.12 (m, 2H), 3.62 (m, 2H), 3.44 (m, 4H), 3.22 (m, 4H), 2.53 (m,

2H), 1.32 (m, 6H), 1.35 (s, 9H), 1.27 (s, 6H) Example 113

 L-[3-tert-Butyl-5-(l,2-dihydroxyethyl)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino- Spirulin

-1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

first step

 L-(3-tert-butyl-5-vinyl-phenyl)ethanone

 Dissolve 1-(3-bromo-5-tert-butyl-phenyl)ethanone oxime (360 mg, 1.41 mmol) and tetrakis(triphenylphosphine)palladium (163 mg, 0.14 mmol) in 4 mL of dioxane After stirring for 10 minutes in the ring, tri-n-butyl (;vinyl)tin (492 mg, 1.55 mmol) and cesium fluoride (428 mg, 2.82 mmol) were added, and the reaction was stirred at 90 ° C for 2 hours. 5 mL of water and 10 mL of ethyl acetate were added to the reaction mixture, and the mixture was separated. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude title product 1-(3-tert-butyl-5-vinyl-phenyl)ethanone 113a (407 mg, m.

MS m/z (ESI): 203.1 [M+l]

 Second step

 1-[3-tert-Butyl-5-(l,2-dihydroxyethyl)phenyl]ethanone crude 1-(3-tert-butyl-5-vinyl-phenyl)ethanone 113a (404 Mg, 2 mmol) was dissolved in 10 mL of tert-butanol, and N-methyl-N-oxidized morpholine (257 mg, 2.20 mmol) and osmium tetroxide (25 mg, 0.10 mmol) were added in that order, and the reaction was stirred for 1 hour. 10 mL of 5% sodium thiosulfate solution and 20 mL of ethyl acetate were added to the reaction mixture, and the organic phase was washed with saturated sodium chloride solution (5 mL×2), dried over anhydrous magnesium sulfate and filtered. The residue obtained was purified by silica gel column chromatography elutd elut elut elut elut , colorless oil), Yield: 38.0%.

 MS m/z (ESI): 237.1 [M+l]

 third step

 2-bromo[3-tert-butyl-5-(l,2-dihydroxyethyl)phenyl]ethanone 1-[3-tert-butyl-5-(1,2-dihydroxyethyl) Phenyl]ethanone 113b (180 mg, 0.76 mmol) was dissolved in

To 2 mL of tetrahydrofuran, trimethylphenylammonium tribromide (287 mg, 0.76 mmol) was added, and the reaction was stirred for 4 hours. Filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified to silica gel column chromatography to afford to afford the title product 2-bromo-1-[3-tert-butyl-5-(1,2-dihydroxyethyl) Phenyl]ethanone 113c (30 mg, colorless liquid), Yield: 12.5%. the fourth step

 1-[3-tert-Butyl-5-(l,2-dihydroxyethyl)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino- Spirulin

 -1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide

 Dissolving 5',6'-diethoxy-7-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (25 mg, 0.10 mmol) in 0.5 mL of tetrahydrofuran 2-Bromo-1-[3-tert-butyl-5-(1,2-dihydroxyethyl)phenyl]ethanone 118c C 30 mg (0.10 mmol) was added, and the mixture was stirred for 12 hr. After suction filtration, the solid was washed with EtOAc (EtOAc (EtOAc) (EtOAcjjjjjjj (1,2-dihydroxyethyl)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-iso Porphyrin]-2'-yl)ethanone hydrobromide 113 (10 mg, white solid), Yield: 18.0%.

 MS m/z (ESI): 499.2 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 7.87 (s, 1H), 7.83 (s, 1H), 7.73 (s, 1H), 7.01 (s 1H), 5.49 (s, 1H), 5.25 (s, 2H), 4.88 (s, 1H), 4.22 (m, 2H), 4.12 (m, 2H), 3.49 (m, 2H), 1.76 (m, 2H), 1.62 (m, 2H), 1.40 ( m, 3H), 1.34 (s, 9H), 1.31 (m, 3H) Example 114

 2-[3-tert-Butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoporphyrin) ] -2'-yl) acetylphenyl]-2-methyl-propionic acid hydrobromide

first step

2-(3-Acetyl-5-tert-butyl-phenyl)-2-methyl-propionic acid methyl ester 1-(3-bromo-5-tert-butyl-phenyl)ethanone 77d (4.27 g , 17 mmol), bis(dibenzylideneacetone)palladium (96 mg, 0.17 mmol) and zinc fluoride (866 mg, 8.37 mmol) dissolved in 40 mL of N,N-dimethylformamide, add 1- Methoxy-2-methyl-small (trimethylsiloxy)propene (4.35 g, 25 mmol) and tri-tert-butylphosphine (1.69 g, 0.84 mmol) were stirred at 100 ° C for 16 hours. 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL×3), and the organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue gave the title product 2-(3-acetyl-5-tert-butyl- Phenyl)-2-methyl-propionic acid methyl ester 114a (1.68 g, brownish yellow oil), yield: 36.2%.

 Second step

 2-[3-(2-Bromoacetyl)-5-tert-butyl-phenyl]-2-methyl-propionic acid methyl ester 2-(3-acetyl-5-tert-butyl-phenyl) Methyl 2-methyl-propionate 114a (276 mg, 1 mmol) was dissolved in 5 mL of tetrahydrofuran, phenyltrimethylammonium bromide (376 mg, 1 mmol) was added, and the reaction was stirred for 1 hour. Filtration, the filter cake was washed with EtOAc (EtOAc)EtOAc. -Bromoacetyl)-5-tert-butyl-phenyl]-2-methyl-propionic acid methyl ester 114b C154 mg, pale yellow liquid), Yield: 43.4%.

 third step

 2-[3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindole] Porphyrin] -2'-yl)acetyl]phenyl]-2-methyl-propionic acid hydrobromide

 Dissolve 5',6'-diethoxy-7-fluoro-spiro[cyclopropane-1,3'-isoindoline]-indole-imine 41g (92 mg, 0.35 mmol) in 3 mL of tetrahydrofuran Add 2-[3-(2-bromoacetyl)-5-tert-butyl-phenyl]-2-methyl-propionic acid methyl ester 114b (124 mg, 0.35 mmol) and triethylamine (0.5 mL, 0.35 mmol), the reaction was stirred for 8 hours. The reaction mixture was concentrated under reduced pressure. '-Fluoro-3'-imino-spiro[cyclopropane-1,1'-isoporphyrin]-2'-yl)acetyl]phenyl]-2-methyl-propionic acid hydrobromide 114 (13 mg, yellow solid), Yield: 6.2%.

MS m/z (ESI): 525.2 [M+l]

1H NMR (400 MHz, DMSO-J ₆ , ppm): δ 10.98 (br, 1H), 8.19 (br, 1H), 8.02 (br, 1H), 7.48 (m, 2H), 7.30 (s, 1H), 6.88 (m, 1H), 5.24 (s, 2H), 4.16 (m, 2H), 4.02 (m, 2H), 1.90 (m, 2H), 1.55 (m, 2H), 1.53 (s, 6H), 1.40 -1.23 (m, 15H) Example 115

L-[3-tert-Butyl-5-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]-2-(5',6'-diethoxy-4'-fluoro- 3'-imino-snail

 [Ring '-iso 3⁄4 I porphyrin] -2'-yl) ethyl ketone hydrobromide

first step

 2-[3-tert-butyl-5-(1,1-dimethoxyethyl)phenyl]-2-methyl-propionic acid methyl ester 2-(3-acetyl-5-tert-butyl -Phenyl)-2-methyl-propionic acid methyl ester 114a (600 mg, 2.17 mmol) was dissolved in 5 mL of methanol and added trimethoxymethane (714 uL, 6.51 mmol) and camphorsulfonic acid (50 mg, 0.22) Methyl), the reaction was stirred for 3 hours. 50 mL of water and 40 mg of potassium carbonate were added to the reaction mixture, and extracted with ethyl acetate (30 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (100 mL×2), dried over anhydrous magnesium sulfate Concentration by pressure gave the crude title product 2-[3-tert-butyl-5-(1,1-dimethoxyethyl)phenyl]-2-methyl-propionic acid methyl ester 115a (676 mg, brown Red oil), the product was directly subjected to the next reaction without purification.

 Second step

 1-[3-tert-butyl-5-(2-hydroxy-U-dimethyl-ethyl)phenyl]ethanone crude 2-[3-tert-butyl-5-(1,1-dimethyl Methyl oxyethyl)phenyl]-2-methyl-propionate 115a (670 mg, 2.08 mmol) was dissolved in 5 mL of tetrahydrofuran, and then added with lithium aluminum hydrogen (87 mg, 2.29 mmol). Reaction for 10 minutes. 50 mL of water was added to the reaction mixture, and the mixture was combined with ethyl acetate (50 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution (100 mL×2), dried over anhydrous magnesium sulfate, filtered, 4 mL of 1.60 M hydrogen chloride in dioxane solution was stirred for 5 minutes. 50 mL of water was added to the reaction mixture, and the mixture was combined with ethyl acetate (30 mL?), and the organic phase was combined, washed with a saturated sodium chloride solution (100 mL×2), dried over anhydrous magnesium sulfate, filtered, The title product is 1-[3-tert-butyl-5-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]ethanone 115b (471 mg, brown-broil). Go directly to the next step.

 third step

 2-bromo[3-tert-butyl-5-(2-hydroxy-U-dimethyl-ethyl)phenyl]ethanone crude 1-[3-tert-butyl-5-(2-hydroxy- 1,1-Dimethyl-ethyl)phenyl]ethanone 115b (471 mg, 1.90 mmol) was dissolved in 10 mL of tetrahydrofuran, and phenyltrimethylammonium bromide (713 mg, 1.90 mmol) was added and stirred. 0.5 hours. Filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified to silica gel column chromatography to afford to afford the title product 2-bromo-1-[3-ter-butyl-5-(2-hydroxy-U-dimethyl Base-ethyl)phenyl]ethanone 115c (170 mg, pale yellow liquid), Yield: 27.4%.

MS m/z (ESI): 327.0 [M+l]

the fourth step L-[3-tert-Butyl-5-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]-2-(5',6'-diethoxy-4'-fluoro- 3'-Imino-spiro[cyclopropane-1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide 5',6'-diethoxy-7'-fluoro- Spirulina [cyclopropane-1,3'-isoindoline]-indole-imine 41g (120 mg, 0.46 mmol) was dissolved in 1 mL of tetrahydrofuran and 2-bromo-1-[3-tert-butyl-5 was added. -(2-Hydroxy-1,1-dimethyl-ethyl)phenyl]ethanone 115c (164 mg, 0.50 mmol). Filtration, the filter cake was washed with EtOAc (1 mL) and dried in vacuo to give the title product 1-[3-ter-butyl-5-(2-hydroxy-U-dimethyl-ethyl)phenyl]-2-( 5',6'-Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 115 (190 mg, white solid), Yield: 70.6%.

MS m/z (ESI): 511.2 [M+l]

1H NMR (400 MHz, DMSO-, ppm): δ 9.41 (br, 1H), 9.10 (br, 1H), 7.82 (s, 1H), 7.80 (s, 1H), 7.76 (s, 1H), 7.04 ( s, 1H), 5.25 (s, 2H), 4.23 (m, 2H), 4.12 (m, 2H), 3.49 (m, 2H), 1.76 (m, 2H), 1.66 (m, 2H), 1.40 (m , 3H), 1.35 (s, 9H), 1.31 (m, 3H), 1.28 (m, 6H) Test example:

 Biological evaluation Example 1 Calcium ion transport inhibition experiment

 The following method can be used to determine the inhibitory effect of the compounds of the invention on PARI-mediated calcium transport. By using Chinese hamster ovary cell CHO-K1 (purchased from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, catalog number GNHa 7), Fluo-4 NW calcium assay kit (invitrogen Cat. No F36206) and PARI agonistic polypeptide thrombin receptor Activator peptide 6 (Sigma, T1573-5MG) was used to determine the effect of the inventive compounds on PARI-mediated calcium transport.

 The probenecid stock solution and loading buffer required for the experiment can be prepared according to the instructions of the Fluo-4 NW calcium assay kit. Experimental steps:

CHO-K1 cells were treated with DEME medium (Gibco) with 10% fetal bovine serum as complete medium, and seeded at a concentration of 25,000 cells/well into 96-well cell culture plates at 37 ° C, 5% carbon dioxide. Cultivate until confluent. Subsequently, the medium was discarded, and 100 μ of the configured loading buffer was added to each well of the plate, and incubated at 37 ° C, 5% carbon dioxide for 45 minutes. The test compound was first dissolved in dimethyl sulfoxide and then diluted to the desired concentration for the experiment using an assay buffer (; containing IX HBSS, 20 mM HEPES, 2.5 mM probenecid). Then, 100 μL of the diluted test compound sample was added to each well of the test group on the 96-well plate, and the negative control group was added with the same volume of the assay buffer. The plates were then incubated for 30 minutes at room temperature, and then 25 μ of thrombin receptor activator peptide 6 diluted to 20 μΜ with buffer (IX HBSS, 20 mM HEPES) was added to each well. In The relative fluorescence intensity of each well was measured at an excitation wavelength of 485 nm and an emission wavelength of 525 nm. The inhibition rate of PIR-mediated calcium transport was calculated.

The inhibition rate of the test compound to PARI is calculated by the following formula:

F _NC : fluorescence intensity of negative control wells

F _TC : Fluorescence intensity of test compound pores

The half-inhibitory concentration IC _{5Q of the} test compound can be calculated from the inhibition rates at different concentrations.

90 0.01

 93 0.013

96 0.033

97 0.035

100 0.058

101 0.077

102 0.038

103 0.046

104 0.03

108 0.029

109 0.042

115 0.025

116 0.003

120 0.014 Conclusion: The value of the calcium flux inhibition rate of the test compound of the present invention is 0.006 to 0.099 μΜ, and the compound of the present invention has a significant inhibitory effect on PARI-mediated calcium ion transport. Example 2 In vitro platelet aggregation experiment

 The following method can be used to determine the inhibitory activity of the compounds of the present invention on platelet aggregation. The experimental method is briefly described as follows:

ACD was used as an anticoagulant to obtain whole blood samples from healthy male Chinese guinea pigs (purchased from Shanghai Shengwang Experimental Animal Farm X weight 450~600 g) by venipuncture. Platelet-rich plasma was then obtained by centrifugation at 200 X g for 20 minutes at room temperature. The plasma was then centrifuged at 800 X g for 10 minutes to obtain platelet pellets. Tyrode's buffer (containing 140 mM NaCl, 2.7 mM KC1, 12 mM NaHC0 ₃ , 0.76 mM NaHP04, 5.5 mM Glucose, 5 mM HEPES, 2 mg/mL bovine serum albumin, and pH 7.4, 20)

Apyrase) After washing twice, resuspend the platelet pellet and calculate it, and finally dilute to 2~3x10 ⁸ /mL for use.

 The agglutination experiment was carried out at room temperature. First add 90 \, platelet suspension to each well of a 96-well plate. After the test compound was dissolved in dimethyl sulfoxide to prepare the concentration required for the experiment, 8 \, compound was added to each test group well, and the negative control group was replaced with the same volume of DMSO. Compounds and platelets were pre-incubated at 37 °C for 6 minutes, then 2 μΐ, 20 μΜ of the thrombin agonist polypeptide TRAP was added to each well, and 96 wells were shaken vigorously on a shaker to initiate the agglutination process. The agglutination rate was obtained by measuring the transmittance of each well at 405 nm. The platelet aggregation rate of the test compound is calculated by the following formula:

AR = (Tc -T0) / (T100-T0) Tc: test the transmittance of the compound pores

TO: transmittance of negative control wells

T100: Platelet-inhibiting agglutination IC _5Q values of light-transmitting compounds in blank wells can be calculated from agglutination rates at different concentrations.

 Conclusion: The test compound of the present invention has a significant inhibitory effect on platelet aggregation in guinea pigs. Pharmacokinetic evaluation Test example 1 Pharmacokinetic test of the compound of the present invention

 1, abstract

 The concentration of the drug in plasma at various times after the compounds of Examples 24, 35, 40, 44 and 108 of the present invention were studied. The pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.

 2. Test plan

2.1 Test drugs

 Examples 24, 35, 40, 44 and 108 compounds

2.2 Test animals

 Healthy adult SD rats, 20 males and females, divided into 5 groups, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2008-0016.

2.3 Drug preparation

 Weigh the appropriate amount of the drug, add 0.5% sodium carboxymethylcellulose to grind until the sample is evenly suspended, and the sample concentration is 2.0 mg/mL.

2.4 Administration

 SD rats were intragastrically administered overnight after fasting, and the dose was 20.0 mg/kg (in the form of alkali base), and the administration volume was 10 mL/kg.

2.5 Sample Collection

 Animals of each group were collected from the orbital helium by 0.1 mL before and after administration, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 24.0, 36.0, 48.0 hours, and centrifuged at 3500 rpm for 10 minutes. Plasma was separated and stored at -20 °C. Eat 2 hours after administration.

3. Operation

Take 20 L of rat plasma at each time after administration, and add internal standard solution (100 ng/mL, methanol) 50 μ, methanol 95 μL, vortex for 3 minutes, centrifuge for 10 minutes (13500 rpm), and take 10 μL of the supernatant for LC-MS/MS analysis. The main pharmacokinetic parameters were calculated using DAS 2.0 software.

 4, pharmacokinetic parameters results

 The pharmacokinetic parameters of the compounds of the invention are as follows:

 Conclusion: The compounds tested in the present invention have higher plasma concentrations and exposure levels in rats, and have obvious pharmacokinetic advantages. Pharmacodynamic test

Purpose:

The effect of the PAR-1 inhibitor Example 44 compound on TARP-induced platelet aggregation in guinea pigs was determined. Experimental drugs:

Example 44 compound; Prostaglandin I ₂ , TRAP were supplied by Sigma.

experimental method:

 The drug dose was 50 mg/kg (2.5 ml/kg), and a suspension was prepared with 0.5% sodium carboxymethylcellulose plus 5% Tween-80. Male guinea pigs weighing 250 g to 350 g were randomly divided into groups. After intragastric administration, after returning to the original cage for 2 hours, it was anesthetized with 20% urethane. The abdominal aorta of the guinea pig was bled with a disposable plastic syringe containing 3.8% sodium citrate (1:10 volume, one 枸). Citrate and nine parts of blood anticoagulation).

Preparation of platelet-rich plasma: The abdominal aorta blood of guinea pigs was centrifuged at 200 g for 10 minutes (22 ° C), and 1.5 mL of the upper platelet-rich plasma was taken out. Platelet washing method: Tyrode's buffer 'solution (NaCl 129 mM, KC1 2.8 mM, KH ₂ P0 ₄ 0.8 mM, MgCl ₂ 0.8 mM, NaHC0 ₃ 8.9 mM, HEPEs 10 mM, glucose 5.5 mM) was used.

Platelet aggregation assay: using platelet aggregometer, add platelet buffer 291 to a clear plastic cuvette, add 3 buffer and 6 calcium chloride (50 μΜ) to the cuvette, and add a magnetic stirrer at 37°. The pre-incubation bath was carried out for 2 minutes in C, and then 40 μΜ of the platelet aggregation-inducing agent TRAP was added, and the rate of change in aggregation within 5 minutes (1 minute, 3 minutes, 5 minutes, maximum aggregation rate) was continuously measured to evaluate the inhibitory effect of the drug on platelet aggregation. Experimental results:

 The compound of Example 44 had a strong inhibitory effect on TRAP-induced platelet aggregation in guinea pigs within 5 minutes, and the percentage of aggregation of the compound of Example 85 (10 mg/kg) decreased at 3 minutes and 5 minutes compared with the blank control group. 47.47% and 45.21% (P<0.05, P<0.05); SHR130362 (30 mg/kg) decreased the percentage of aggregation at 5 minutes and 5 minutes by 57.63% and 48.57% (P<0.05, P<0.05). SHR130362 (50 mg/kg) showed a reduction in aggregation percentages of 69.96%, 82.55%, and 78.51% at 1 minute, 3 minutes, and 5 minutes (P < 0.05, P < 0.001, P < 0.001). Therefore, the compound of Example 44 has a preferred anticoagulant effect.

Claims

Claims:

A compound of the formula (I) or a pharmaceutically acceptable salt thereof,

(I)

 among them:

Ar is selected from aryl or heteroaryl, wherein said aryl or heteroaryl is optionally further substituted with one or more substituents of R ^a ;

Y is selected from -CR ¹² - or N atom;

L is selected from -CR ¹³ R ¹⁴ - or -(CH ₂ ) _m -;

RR ² and R ³ are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a nitro group, an alkoxy group, an alkyl group, an alkenyl group, a blocked group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ wherein the alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkane Oxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC(0) Substituted by a substituent of NR ¹⁶ R ¹⁷ or -C(0)NR ¹⁶ R ¹⁷ ;

R ¹ and R ² or R ² and R ³ together with the carbon atom to which they are attached form an aryl group, wherein said aryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy Alkyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0)pR ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ Substituted by a substituent of R ¹⁷ , —C(0)NR ¹⁶ R ¹⁷ or —S(0)ONR ¹⁶ R ¹⁷ ;

R ⁴ and R ⁵ are each independently selected from cyano, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, hetero The cyclo, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, aryl, heteroaryl, -C(0)OR ¹⁵ , -OC ( 0) R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S (0) Substituting a substituent of _p R ¹⁵ , —NR ¹⁶ R ¹⁷ , —OC(0)NR ¹⁶ R ¹⁷ , —C(0)NR ¹⁶ R ¹⁷ or —S(0)ONR ¹⁶ R ¹⁷ ;

Alternatively, R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cycloalkyl group, wherein said cycloalkyl group is optionally further further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, alkane Substituted by an oxy group, a cycloalkyl group, a heterocyclic group or a substituent of -NR ¹⁶ R ¹⁷ ;

R ^{6 is} selected from the group consisting of a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, an aryl group, a heteroaryl group, -C(0)OR ¹⁵ , -C(0)R ¹⁵ or -C(0)NR ¹⁶ R ¹⁷ , wherein the alkyl, alkoxy, cycloalkyl, aryl or heteroaryl group is further optionally further selected from one or more halogens Substituted with a substituent of a hydroxyl group, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group or a heterocyclic group;

R ^a may be the same or different and each independently selected from a hydrogen atom, a hydroxyl group, a halogen, a cyano group, a nitro group, a silane group, an alkoxy group, an alkyl group, an alkenyl group, a blocked group, a cycloalkyl group, a heterocyclic group, an aryl group. , heteroaryl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C (0) R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or - S(0)ONR ¹⁶ R ¹⁷ , wherein the silane group, alkoxy group, alkyl group, alkenyl group, blocked group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further one or more Selected from halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyalkyl, -C(0)OR ¹⁵ , -OC ( 0) R ¹⁵ -0(CH ₂ ) _n C(0)OR ¹⁵ -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0 Substituting _p R ¹⁵ -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ ;

R ^{12 is} selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a nitro group, an alkoxy group, an alkyl group, an alkenyl group, a aryl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -C(0) OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0 R ¹⁵ , -S(0) _p R ¹⁵ -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ , where The alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C Substituting (0) a substituent of NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ ;

R ¹³ and R ¹⁴ are each independently selected from alkyl or halo, wherein said alkyl group is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano or nitro;

R ^{15 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further Substituted by one or more substituents selected from halogen, hydroxy, cyano, nitro, alkoxy or alkyl;

R ¹⁶ and R ¹⁷ are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group Or a heterocyclic group, an aryl group or a heteroaryl group, optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, hetero Aryl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0 R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ -NR ¹⁸ R ¹⁹ , -OC(0)NR ¹⁸ R ¹⁹ , -C(0)NR ¹⁸ R ¹⁹ or -S(0 Substituted by a substituent of ONR ¹⁸ R ¹⁹ ;

Alternatively, R ¹⁶ and R ¹⁷ form a heterocyclic group with a nitrogen atom to which the ring is bonded, wherein the heterocyclic group contains one or more N, 0 or S(0) _p heteroatoms, and the heterocyclic group is Further selected by one or more of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyalkyl, -C(0)OR ¹⁵ -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ , -NR ¹⁸ R ¹⁹ , -OC(0)NR ¹⁸ R ¹⁹ , -C(0)NR ¹⁸ R ¹⁹ or -S(0)ONR ¹⁸ R ¹⁹ Substituted by a substituent;

R ¹⁸ and R ¹⁹ are each independently selected from a hydrogen atom, a halogen, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group;

 m is selected from 1, 2 or 3;

 n is selected from 1, 2 or 3;

 p is selected from 0, 1 or 2.

2. A compound of the formula (A) or a pharmaceutically acceptable salt thereof,

Its towel _:

Y is selected from -CR ¹² - or N atom;

L is selected from -CR ¹³ R ¹⁴ - or -(CH ₂ ) _m -;

I ¹ , R ² and R ³ are each independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a nitro group, an alkoxy group, an alkyl group, an alkenyl group, a blocked group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heterocyclic group. Aryl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0 R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S( 0) ONR ¹⁶ R ¹⁷ wherein the alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, and nitrate Alkyl, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ -0(CH ₂ ) _n C(0) OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC( 0) Substituted by a substituent of NR ¹⁶ R ¹⁷ or -C(0)NR ¹⁶ R ¹⁷ ;

R ¹ and R ² or R ² and R ³ together with the carbon atom to which they are attached form an aryl group, wherein said aryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy Alkyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0)pR ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ Substituted by a substituent of R ¹⁷ , —C(0)NR ¹⁶ R ¹⁷ or —S(0)ONR ¹⁶ R ¹⁷ ;

R ⁴ and R ⁵ are each independently selected from cyano, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, hetero The cyclo, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, aryl, heteroaryl, -C(0)OR ¹⁵ , -OC ( 0) R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S (0) Substituting a substituent of _p R ¹⁵ , —NR ¹⁶ R ¹⁷ , —OC(0)NR ¹⁶ R ¹⁷ , —C(0)NR ¹⁶ R ¹⁷ or —S(0)ONR ¹⁶ R ¹⁷ ;

Alternatively, R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cycloalkyl group, wherein said cycloalkyl group is optional Further substituted with one or more substituents selected from halogen, hydroxy, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl or -NR ¹⁶ R ¹⁷ ;

R ^{6 is} selected from a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, an aryl group, a heteroaryl group, -C(0)OR ¹⁵ , -C(0)R ¹⁵ or -C(0)NR ¹⁶ R ¹⁷ wherein the alkyl, alkoxy, cycloalkyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, alkoxy Substituted by a substituent of a cycloalkyl or heterocyclic group;

R ⁷ , R ⁸ , R ⁹ , R ^1Q and R ¹¹ are each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a halogen, a cyano group, a nitro group, a silane group, an alkoxy group, an alkyl group, an alkenyl group, a block group, and a cycloalkyl group. , heterocyclic group, aryl, heteroaryl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C( 0) OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0)pR ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0) NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ wherein the silane group, alkoxy group, alkyl group, alkenyl group, blocked group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group Further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyalkyl, -C(0) OR ¹⁵ , -OC(0)R ¹⁵ -0(CH ₂ ) _n C(0)OR ¹⁵ -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ substituted by a substituent of R ¹⁷ ;

Alternatively, R ⁹ and R ^1Q together with the carbon atom to which they are attached form a heterocyclic group, aryl or heteroaryl group, wherein said heterocyclic group, aryl or heteroaryl group is further optionally further selected from one or more selected from one or more Halogen, hydroxy, cyano, nitro, silyl, alkoxy, alkyl, alkenyl, aryl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)OR ¹⁵ , - OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ substituted;

R ^{12 is} selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a nitro group, an alkoxy group, an alkyl group, an alkenyl group, a aryl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -C(0) OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0 R ¹⁵ , -S(0) _p R ¹⁵ -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ , where The alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , -S(0) _p R ¹⁵ -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C Substituting (0) a substituent of NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ ;

R ¹³ and R ¹⁴ are each independently selected from alkyl or halo, wherein said alkyl group is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano or nitro;

R ^{15 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further Substituted by one or more substituents selected from halogen, hydroxy, cyano, nitro, alkoxy or alkyl;

R ¹⁶ and R ¹⁷ are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group , heterocyclic, aryl or heteroaryl One step or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)OR ¹⁵ , -OC (0) R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ¹⁵ , - Substituted by a substituent of S(0)pR ¹⁵ , -NR ¹⁸ R ¹⁹ , -OC(0)NR ¹⁸ R ¹⁹ , -C(0)NR ¹⁸ R ¹⁹ or -S(0)ONR ¹⁸ R ¹⁹ ;

Alternatively, R ¹⁶ and R ¹⁷ together with the nitrogen atom are attached form a heterocyclic group containing one or more N, 0 or S (0) _p hetero atoms in the heterocyclic group, and wherein any heterocyclyl group Further selected by one or more of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyalkyl, -C(0)OR ¹⁵ -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ^{15, -S (0) pR 15} , -NR 18 R 19, -OC (0) NR 18 R 19, -C (0) NR 18 R 19 or -S (0) ONR ¹⁸ R ¹⁹ group substituted with a substituent ;

R ¹⁸ and R ¹⁹ are each independently selected from a hydrogen atom, a halogen, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group;

 m is selected from 1, 2 or 3;

 n is selected from 1, 2 or 3;

 p is selected from 0, 1 or 2.

The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein Ar is selected from a 5- or 6-membered heteroaryl group, preferably a pyrrolyl group or a pyridyl group. The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁴ and R ^{5 are} selected from an alkyl group or an aryl group.

The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁴ and R ⁵ together with the carbon atom to be bonded form a cyclopropyl group.

The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁶ is a hydrogen atom.

The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ^{12 is} selected from a hydrogen atom or a halogen.

The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein L is selected from -(CH2) _m- , m is 1. The compound of the formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound is selected from the group consisting of:

OSSC.0/llOZN3/X3d 9ε60 /ΐΐΟΖ OAV

OSSC.0/llOZN3/X3d 9ε60 /ΐΐΟΖ OAV 90Z

OSSC.0/llOZN3/X3d 9ε60 /ΐΐΟΖ OAV

207

The compound of the formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound of the formula (I) is present in the form of a free or pharmaceutically acceptable acid addition salt, The acid addition salt includes a hydrochloride, a hydrobromide, a methanesulfonate, a sulfate, a phosphate, a maleate, a malate, a citrate, an acetate or a trifluoroacetate, preferably Hydrobromide and hydrochloride. The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the salt of the compound is selected from the group consisting of:

Oil

OSSC.0/llOZN3/X3d 9ε60 /ΐΐΟΖ OAV

211

12. A method of preparing a compound of formula (I), the method comprising:

 a compound of the formula (IA) or IB)

Against the compound of formula (IC)

 (IC)

 Its towel:

 X is selected from a halogen, preferably a chlorine atom or a bromine atom;

Wherein: L, Y, ^ to ¹¹ as defined in the _c claimed in claim 1~8

A compound represented by the formula (IA) or (IB) or a pharmaceutically acceptable salt thereof, which is an intermediate for the preparation of a compound of the formula (I),

 (IA) (IB)

Wherein R ¹ , R ² , R ³ and Y are as defined in claim 1;

R ⁴ and R ⁵ are each independently selected from cyano, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably alkyl or aryl, wherein said alkyl, alkane The oxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, aryl, heteroaryl, -C ( 0) OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC (0) R ¹⁵ , -S(0)pR ¹⁵ , -NR ¹⁶ R ¹⁷ , -OC(0)NR ¹⁶ R ¹⁷ , -C(0)NR ¹⁶ R ¹⁷ or -S(0)ONR ¹⁶ R ¹⁷ Substituted by a substituent;

Alternatively, R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cycloalkyl group, preferably a cyclopropyl group, wherein said cycloalkyl group is optionally further further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyanogen Base, alkyl, alkoxy Substituted by a substituent of a cycloalkyl group, a heterocyclic group or -NR ¹⁶ R ¹⁷ ;

R ^{6 is} selected from a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, an aryl group, a heteroaryl group, -C(0)OR ¹⁵ , -C(0)R ¹⁵ or -C(0)NR ¹⁶ R ¹⁷ , preferably a hydrogen atom, wherein the alkyl, alkoxy, cycloalkyl, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkane Substituted by a substituent of a group, an alkoxy group, a cycloalkyl group or a heterocyclic group.

R ^{15 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further Substituted by one or more substituents selected from halogen, hydroxy, cyano, nitro, alkoxy or alkyl;

R ¹⁶ and R ¹⁷ are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group Or a heterocyclic group, an aryl group or a heteroaryl group, optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, hetero Aryl, -C(0)OR ¹⁵ , -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0 R ¹⁵ , -NHC(0)R ¹⁵ , -S(0)pR ¹⁵ , -NR ¹⁸ R ¹⁹ , -OC(0)NR ¹⁸ R ¹⁹ , -C(0)NR ¹⁸ R ¹⁹ or -S(0 Substituted by a substituent of ONR ¹⁸ R ¹⁹ ;

Alternatively, R ¹⁶ and R ¹⁷ together with the nitrogen atom are attached form a heterocyclic group containing one or more N, 0 or S (0) _p hetero atoms in the heterocyclic group, and wherein any heterocyclyl group Further selected by one or more of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyalkyl, -C(0)OR ¹⁵ -OC(0)R ¹⁵ , -0(CH ₂ ) _n C(0)OR ¹⁵ , -(CH ₂ ) _n C(0)OR ¹⁵ , -C(0)R ¹⁵ , -NHC(0)R ^{15, -S (0) pR 15} , -NR 18 R 19, -OC (0) NR 18 R 19, -C (0) NR 18 R 19 or -S (0) ONR ¹⁸ R ¹⁹ group substituted with a substituent ;

R ¹⁸ and R ¹⁹ are each independently selected from a hydrogen atom, a halogen, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group;

 n is selected from 1, 2 or 3;

 p is selected from 0, 1 or 2.

The compound of the formula (IA) or (IB) or a pharmaceutically acceptable salt thereof, according to claim 12, wherein the compound is selected from the group consisting of:

A method of preparing a general formula (; IA ) or (; IB compound, the method comprising:

The compound of the formula (III) is reacted with cuprous cyanide in the presence of a catalyst to obtain a compound of the formula (IA) or (IB); wherein the catalyst is preferably

Alternatively, a compound of the formula (IV) is obtained by formulating a compound of the formula (IA) or (IB);

 (V)

Alternatively, reacting a compound of the formula (V) with concentrated aqueous ammonia to obtain a compound of the formula (IA) or (IB);

 (VI)

Alternatively, the compound of the formula (VI) is reacted in water to give a compound of the formula (1) or (IB) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Y are as defined in claim 1.

16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Use of the compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, or the pharmaceutical composition according to claim 13 for the preparation of a calcium ion transport inhibitor.

18. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15 for the preparation of a thrombin receptor antagonist.

The use according to claim 18, wherein the thrombin receptor antagonist is a PARI receptor antagonist Agent.

The use of the compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, or the pharmaceutical composition according to claim 13, for the preparation of a platelet aggregation inhibitor.

The use of the compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, or the pharmaceutical composition according to claim 13, for the preparation of a smooth muscle cell proliferation inhibitor.

The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, or the pharmaceutical composition according to claim 15 for the preparation of a medicament for treating a thrombin receptor-related disease Use in.

The use according to claim 22, wherein the thrombin receptor-related disease is selected from the group consisting of thrombosis, vascular restenosis, deep venous thrombosis, pulmonary embolism, cerebral infarction, heart disease, sowing blood vessel. Internal blood coagulation syndrome, hypertension, inflammatory disease, rheumatism, asthma, glomerulonephritis, osteoporosis, neurological disease and/or malignancy.