CN103664996B - Indole derivatives and preparation method thereof - Google Patents

Abstract

The present invention relates to a new class of antibacterial compounds, namely a class of indole derivatives, their stereoisomers or their pharmaceutically acceptable salts or solvates or hydrates; methods for preparing these compounds, pharmaceutical compositions containing these compounds, Use of these compounds in the preparation of antibacterial drugs.

Description

Indole derivatives and their preparation methods

technical field

The present invention relates to a new class of antibacterial compounds, namely a class of indole derivatives, their stereoisomers or their pharmaceutically acceptable salts or solvates or hydrates; methods for preparing these compounds, pharmaceutical compositions containing these compounds, Use of these compounds in the preparation of antibacterial drugs, the antibacterial drugs are preferably directed against bacillus or gram, more preferably against mycobacterium tuberculosis or gram-negative bacteria or gram-positive bacteria.

Background technique

The resistance of drug-resistant strains to antibiotics, especially multidrug resistance, seriously endangers the treatment of anti-infective diseases and has become one of the important public health problems of global concern. In recent years, infections caused by drug-resistant strains have been one of the main causes of high mortality from infectious diseases, such as methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE), penicillin-resistant Streptococcus pneumoniae (PRSP) and vancomycin-resistant enterococci (VRE) have greatly limited the use of antibacterial drugs, or even ineffective. The clinical demand for new effective antibacterial drugs is very urgent, and people are sparing no effort to actively search for and develop various new drugs that can resist drug-resistant bacteria.

Nonovocycin is an antibacterial antibiotic with a new chemical structure produced by a strain of actinomycetes isolated from the soil in Jinan, Shandong Province, my country. It has inhibitory effects on some Gram-positive and negative bacteria, and its toxicity is very low. For mice infected with Shigella or Escherichia coli, intraperitoneal or oral administration has a protective effect. In clinical practice, noveltymycin has good curative effect on sepsis and urinary system infection caused by Escherichia coli. The molecular structure of β-methylindole propionic acid of desulfurized cvnovycin does not have the thiopyran ring in cvnovycin, and its antibacterial activity against E.coli B is the same as that of cvnovycin. Qi Tianqing et al. studied the antibacterial effect and primary antibacterial effect of desulfonovamycin on E.coli B. The results showed that both desulfuronovycin and desulfuronovycin produced antibacterial activity by inhibiting the biosynthesis of bacterial tryptophan. The mechanism of antibacterial action is to antagonize and inhibit the synthesis of tryptophan pathway enzymes (Qi Changqing et al. Antibiotics 1984, 9 (5): 401). This result indicated that it seems that the thiopyran ring in the noveltymycin molecule is not an essential group. The structure of noveltymycin is novel, and its main core is a new heterocyclic ring system in chemistry. However, it has not been used clinically since its discovery. The reason is that in addition to the high cost of fermentation and production, it also has a narrow antibacterial spectrum, can only be taken orally, and cannot be injected intramuscularly, and its antibacterial activity is lower than other antibacterial drugs in clinical practice. Therefore, scientists have carried out a lot of structural modifications on the noveltymycin. According to the chemical structure characteristics of the noveltycin, Su Shenghui et al. carried out the following modifications: synthesized several carboxylic acid derivatives, including esters and amides; synthesized several Derivatives substituted on the NH of indole; several substitutions are made throughout the ring system. Tests on these derivatives showed that, except for N-formyl cvnovycin, which had an antibacterial effect close to that of cvnovycin, the other derivatives had no obvious antibacterial effect [Su Shenghui et al. Pharmaceutical Industry, 1984, 139 (2): 17)].

Therefore, there is a need in the art for new antimicrobial compounds.

Contents of the invention

The main technical problem to be solved by the present invention is to screen and synthesize a new class of antibacterial compounds through the structure-activity research on noveltymycin derivatives. The compounds not only have significant antibacterial activity, but also have the advantages of small molecular weight, simple synthesis, and small toxic and side effects.

The present invention also provides a synthesis method of the indole derivative or a pharmaceutically acceptable salt thereof. The compound can be obtained by selecting the reaction route.

The present invention also provides the application of the indole derivative or its pharmaceutically acceptable salt in antibacterial aspects, and studies have shown that it has significant antibacterial activity, and further provides an antibacterial pharmaceutical composition using the indole derivative as an active ingredient. The present invention also provides the use of the compound of the present invention in the preparation of antibacterial drugs, the antibacterial drugs are preferably directed against Bacillus or Gram, more preferably against Mycobacterium tuberculosis or Gram-negative bacteria or Gram-positive bacteria.

In one aspect, the present invention provides indole derivatives having the general formula (I), their stereoisomers, or their pharmaceutically acceptable salts or solvates or hydrates:

in,

R is H, C _{1-6 alkyl, C 1-6 alkanoyl or C 1-6 alkylamino ;}

R ₂ is H, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 alkanoyl, halogen, cyano, nitro, CF ₃ , amino, N( R ₅ ) ₂ , COR ₆ , CO ₂ R ₆ , or CON(R ₆ ) ₂ ;

R ₃ is H, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 alkanoyl, halogen, cyano, nitro, CF ₃ , amino, N( R ₅ ) ₂ , COR ₆ , CO ₂ R ₆ , or CON(R ₆ ) ₂ ;

R ₄ is H, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 alkanoyl, halogen, cyano, nitro, CF ₃ , amino, N( R ₅ ) ₂ , COR ₆ , CO ₂ R ₆ , or CON(R ₆ ) ₂ ;

Each R ₅ is independently H, C _1-6 alkyl, or COCH ₂ N(R ₇ ) ₂ ;

Each R ₆ is independently H, or C _1-6 alkyl;

Each R ₇ is independently H, or C _1-6 alkyl;

A, B, and D are independently carbon or nitrogen atoms;

X is NH, O, S or absent;

Y is OR ₈ or N(R ₈ ) ₂ ;

Each R ₈ is independently selected from

(1) H or C _1-6 alkyl,

The wavy line represents the bond,

R ₁₁ represents H or C _1-6 alkyl;

R ₁₂ stands for

i) C _1-6 alkyl that is unsubstituted or substituted by 1-3 R ₉ ;

ii) C _3-8 cycloalkyl that is unsubstituted or substituted by halogen, C _1-6 alkyl, C 1-6 alkylamino, hydroxyl or C _1-6 alkoxy;

iii) 6 to 18 membered aryl or 5 to 14 membered heteroaryl unsubstituted or substituted by 1-3 R ₁₀ ;

iv) adamantyl;

Each R ₈ can be independently replaced by 1-3 R ₉ ,

Each R ₉ is independently selected from halogen, C _1-6 alkyl, C _1-6 alkylamino, di(C _1-6 alkyl)amino, hydroxyl, hydroxy C _1-6 alkyl, amino, amino C _1-6 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkylcarbonyloxy, aminosulfonyl, carbamoyl, C _1-6 alkylcarbamoyl, C _3-8 cycloalkyl; 6- to 18-membered arylcarbonyloxy; 6- to 18-membered aryl or 5- to 14-membered heteroaryl, or 6- to 18-membered aryl or 5- to 14-membered heteroaryl substituted with R ₁₀ ; containing 5 or 6 A non-aromatic heterocyclic group of ring atoms; butyrolactam-1-yl; and a phosphoric acid group;

R ₁₀ is selected from halogen, hydroxyl, amino, C _1-6 alkylcarbonyl, C _1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and C _1-6 alkylcarbonyloxy;

Provided that said compound of formula (I) does not include the following compounds:

The substituents of the above formula are shown in the table below

2) Compounds of the following formula 3

Formula 3

R ₁ is methyl and R ₂ is hydroxyl; or

R ₁ is methyl and R ₂ is ethoxy; and

3) Compounds of formula 4

Formula 4

_R1 is methyl and _R2 is hydroxyl.

In a preferred embodiment, the compound of formula (I) has the following general formula (II):

R ₁ , R ₂ , R ₃ , R ₄ , A, B, D, X, Y are as defined in general formula (I).

In another preferred embodiment, _R3 is substituted on A.

In another preferred embodiment, _R3 is substituted on B.

In another preferred embodiment, _R is substituted on D.

In another preferred embodiment, the compound of formula (I) has the following general formula XV

R ₁ , R ₂ , R ₃ , R ₄ , A, B, D, and Y are as defined in the general formula (I).

In another preferred embodiment, in the compound of formula (I) or formula (II),

A, B and D are all carbon atoms;

B and D are carbon atoms, and A is a nitrogen atom;

D is a carbon atom, A and B are nitrogen atoms;

A and D are carbon atoms, and B is a nitrogen atom;

A and B are carbon atoms and D is a nitrogen atom; or

B is a carbon atom, and A and D are nitrogen atoms.

In another preferred embodiment, in the compound of formula (I) or formula (II),

R ₁ is H, C _1-4 alkyl, C _1-4 alkanoyl or C _1-4 alkylamino;

R ₂ is H, C _1-4 alkyl, C _3-4 cycloalkyl, C _1-4 alkoxy, C _1-4 alkanoyl, halogen, cyano, nitro, CF ₃ , amino, N( R ₅ ) ₂ , COR ₆ , CO ₂ R ₆ , or CON(R ₆ ) ₂ ;

R ₃ is H, C _1-4 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-4 alkanoyl, halogen, cyano, nitro, CF ₃ , amino, N( R ₅ ) ₂ , COR ₆ , CO ₂ R ₆ , or CON(R ₆ ) ₂ ;

R ₄ is H, C _1-4 alkyl, C _3-4 cycloalkyl, C _1-4 alkoxy, C _1-4 alkanoyl, halogen, cyano, nitro, CF ₃ , amino, N( R ₅ ) ₂ , COR ₆ , CO ₂ R ₆ , or CON(R ₆ ) ₂ ;

Each R ₅ is independently H, C _1-4 alkyl, or COCH ₂ N(R ₇ ) ₂ ;

Each R ₆ is independently H, C _1-4 alkyl;

Each R ₇ is independently H, C _1-4 alkyl;

A, B, D are carbon or nitrogen atoms;

X is NH, O, S or absent;

Y is OR ₈ or N(R ₈ ) ₂ ;

Each R ₈ is independently selected from

(1) H or C _1-6 alkyl,

The wavy line represents the bond,

R ₁₁ represents H or C _1-6 alkyl;

R ₁₂ stands for

i) C _1-6 alkyl that is unsubstituted or substituted by 1-3 R ₉ ;

ii) C _3-8 cycloalkyl that is unsubstituted or substituted by halogen, C _1-6 alkyl, C 1-6 alkylamino, hydroxyl or C _1-6 alkoxy;

iii) 6 to 18 membered aryl or 5 to 14 membered heteroaryl unsubstituted or substituted by 1-3 R ₁₀ ;

iv) adamantyl;

Each R ₈ can be independently replaced by 1-3 R ₉ ,

Each R ₉ is independently selected from halogen, C _1-6 alkyl, C _1-6 alkylamino, di(C _1-6 alkyl)amino, hydroxyl, hydroxy C _1-6 alkyl, amino, amino C _1-6 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkylcarbonyloxy, aminosulfonyl, carbamoyl, C _1-6 alkylcarbamoyl, C _3-8 cycloalkyl; 6- to 18-membered arylcarbonyloxy, 6- to 18-membered aryl or 5- to 14-membered heteroaryl, or 6- to 18-membered aryl or 5- to 14-membered heteroaryl substituted with R ₁₀ ; containing 5 or 6 Non-aromatic heterocyclic groups of ring atoms; butyrolactam-1-yl and phosphoric acid groups;

R ₁₀ is selected from halogen, hydroxy, amino, C _1-6 alkylcarbonyl, C _1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and C _1-6 alkylcarbonyloxy.

In another preferred embodiment, Y is OR ₈ , R ₈ is C _1-6 alkyl, each R ₈ can be independently substituted by 1-3 R ₉ , each R ₉ is independently selected from halogen, C _1-6 alkyl, C _1-6 alkylamino, di(C _1-6 alkyl) amino, hydroxyl, hydroxy C _1-6 alkyl, amino, amino C _1-6 alkyl, C _1-6 alkane C 1-6 alkylcarbonyloxy, C _1-6 alkylcarbonyloxy, aminosulfonyl, carbamoyl, C _1-6 alkylcarbamoyl, C _3-8 cycloalkyl; 6 to 18 membered arylcarbonyloxy, 6 to 18-membered aryl or 5- to 14-membered heteroaryl, or R ₁₀ -substituted 6- to 18-membered aryl or 5- to 14-membered heteroaryl; non-aromatic heterocyclic group containing 5 or 6 ring atoms; but Lactam-1-yl and phosphate groups.

In another preferred embodiment, Y is OR ₈ , R ₈ is C _1-6 alkyl, each R ₈ can be independently substituted by 1-3 R ₉ , each R ₉ is independently selected from 6 to 18 Member arylcarbonyloxy.

In another preferred embodiment, in the compound of formula (I) or formula (II), R ₁₂ represents unsubstituted C _3-8 cycloalkyl, and each R ₈ can be independently replaced by 1-3 R ₉ Substituted, each R ₉ is independently selected from hydroxyl, and C _1-6 alkylamino, preferably, R ₉ is substituted on R ₁₂ .

In another preferred embodiment, the present invention relates to an indole derivative represented by formula (I) or its stereoisomer, or their pharmaceutically acceptable salt or solvate or hydrate:

in,

R is H, C _{1-6 alkyl, or C 1-6 alkanoyl} ;

R ₂ is H, C _1-6 alkyl or halogen;

R ₃ is H, C _1-6 alkyl, C _1-6 alkoxy, halogen, CF ₃ , or N(R ₅ ) ₂ ;

R ₄ is C _1-6 alkyl;

Each R ₅ is independently H, or C _1-6 alkyl;

A, B, and D are independently carbon or nitrogen atoms;

X is O, S, or absent;

Y is OR ₈ , or N(R ₈ ) ₂ ;

Each R ₈ is independently selected from

(1) H, or C _1-6 alkyl,

The wavy line represents the bond,

R ₁₁ represents H or C _1-6 alkyl;

R ₁₂ stands for

i) unsubstituted or C _1-6 alkyl substituted by 1-3 R ₉ ;

ii) C _3-8 cycloalkyl unsubstituted or substituted by halogen, C _1-6 alkyl, C _1-6 alkylamino, hydroxyl or C _1-6 alkoxy;

iii) 6- to ₁₈ -membered aryl that is unsubstituted or substituted by 1-3 R,

iv) adamantyl;

v) unsubstituted 5 to 14 membered heteroaryl;

Each R ₈ can be independently replaced by 1-3 R ₉ ,

Each R ₉ is independently selected from halogen, C _1-6 alkyl, C _1-6 alkylamino, di(C _1-6 alkyl)amino, hydroxyl, 6 to 18 membered arylcarbonyloxy, containing 5 Or a non-aromatic heterocyclic group with 6 ring atoms, butyrolactam-1-yl, and a phosphoric acid group;

R ₁₀ is selected from halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy, C _1-6 alkylamino and C _1-6 alkylamino;

Provided that said compound of formula (I) does not include the following compounds:

1) Compound of formula 2

Formula 2

The substituents of the above formula are shown in the table below

2) Compounds of the following formula 3

Formula 3

R ₁ is methyl and R ₂ is hydroxyl; or

R ₁ is methyl and R ₂ is ethoxy; and

3) Compounds of the following formula 4

Formula 4

_R1 is methyl and _R2 is hydroxyl.

In another preferred embodiment, R ₁ is H, C _1-6 alkyl, or C _1-6 alkanoyl.

In another preferred embodiment, R ₂ is H, C _1-6 alkyl or halogen.

In another preferred embodiment, R ₃ is H, C _1-6 alkyl, C _1-6 alkoxy, halogen, CF ₃ , or N(R ₅ ) ₂ .

In another preferred embodiment, R ₄ is C _1-6 alkyl.

In another preferred embodiment, each R ₅ is independently H, or C _1-6 alkyl.

In another preferred embodiment, A, B, D are independently carbon or nitrogen atoms.

In another preferred embodiment, X is O, S, or absent.

In another preferred embodiment, Y is OR ₈ , or N(R ₈ ) ₂ ,

Each R ₈ is independently selected from

(1) H, or C _1-6 alkyl,

The wavy line represents the bond,

R ₁₁ represents H or C _1-6 alkyl.

In another preferred embodiment, R ₁₂ represents

i) unsubstituted or C _1-6 alkyl substituted by 1-3 R ₉ ;

ii) C _3-8 cycloalkyl unsubstituted or substituted by halogen, C _1-6 alkyl, C _1-6 alkylamino, hydroxyl or C _1-6 alkoxy;

iii) 6- to ₁₈ -membered aryl that is unsubstituted or substituted by 1-3 R,

iv) adamantyl;

v) Unsubstituted 5- to 14-membered heteroaryl.

_In another preferred embodiment, each R is independently selected from

(1) H, or C _1-6 alkyl,

The wavy line represents the bond,

R ₁₁ represents H or C _1-6 alkyl.

In another preferred embodiment, _R represents

i) unsubstituted or C _1-6 alkyl substituted by 1-3 R ₉ ;

ii) C _3-8 cycloalkyl that is unsubstituted or substituted by halogen, C _1-6 alkyl, C _1-6 alkylamino, hydroxyl or C _1-6 alkoxy;

iii) 6- to ₁₈ -membered aryl that is unsubstituted or substituted by 1-3 R,

iv) adamantyl;

v) Unsubstituted 5- to 14-membered heteroaryl.

_In another preferred embodiment, each R is independently selected from

(1) H, or C _1-6 alkyl,

The wavy line represents the bond,

R ₁₁ represents H or C _1-6 alkyl;

R ₁₂ stands for

i) unsubstituted or C _1-6 alkyl substituted by 1-3 R ₉ ;

ii) C _3-8 cycloalkyl unsubstituted or substituted by halogen, C _1-6 alkyl, C _1-6 alkylamino, hydroxyl or C _1-6 alkoxy;

iii) 6- to ₁₈ -membered aryl that is unsubstituted or substituted by 1-3 R,

iv) adamantyl;

v) Unsubstituted 5- to 14-membered heteroaryl.

In another preferred embodiment, each R ₈ can be independently substituted by 1-3 R ₉ , each R ₉ is independently selected from halogen, C _1-6 alkyl, C _1-6 alkylamino, di (C _1-6 alkyl)amino, hydroxyl, 6- to 18-membered arylcarbonyloxy, non-aromatic heterocyclic group having 5 or 6 ring atoms, butyrolactam-1-yl, and phosphoric acid. In preferred aspects, _R9 is substituted on _R12 .

In another preferred embodiment, R ₁₀ is selected from halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy, C _1-6 alkylamino and C _{1-6 6} Alkylamino.

In another preferred embodiment, the compound of formula (I) has the structure of formula VIII

Wherein R ₁ , R ₂ , R ₃ , R ₄ , A, B, D are as defined in formula (I), and X is NH, O or S.

In another preferred embodiment, the compound of formula (I) has the structure of formula IX

Wherein R ₁ , R ₂ , R ₃ , R ₄ , A, B, and D are as defined in formula (I).

In another preferred embodiment, the compound of formula (I) has the structure of formula X

Wherein, Z is O or N, and R ₈ is C _1-6 alkyl that is unsubstituted or substituted by 1-3 R ₉ , R ₄ , R ₉ , A, B, D are as defined in formula I, X It is NH, O or S.

In another preferred embodiment, the compound of formula (I) has the structure of formula XI

Wherein, Z is O or N, and R ₈ is C _1-6 alkyl that is unsubstituted or substituted by 1-3 R ₉ , and R ₄ , R ₉ , A, B, and D are as defined in formula I.

In another preferred embodiment, the compound of formula (I) has the structure of formula XIII

Wherein, R ₁ , R ₂ , R ₃ , R ₄ , R ₁₁ , R ₁₂ , A, B, D and X are as defined in formula I.

In another preferred embodiment, the compound of formula (I) has the structure of formula XIV

Wherein, R ₁ , R ₂ , R ₃ , R ₄ , R ₁₁ , R ₁₂ , A, B and D are as defined in formula I.

Preferred compounds of the present invention are the compounds or stereoisomers in Table 1 and Table 2 below and their pharmaceutically acceptable salts and solvates or hydrates.

Table 1

Table 2

The relevant definitions of terms in the present invention are as follows.

The term "alkyl" used in this application means a saturated straight-chain or branched hydrocarbon group, especially a straight-chain or branched alkyl group with 1-6 carbon atoms. Specific examples include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl base, isohexyl. Preferred is methyl, ethyl or propyl. Substituted alkyl groups may be dihalo or trihaloalkyl groups such as trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, tribromomethyl, tribromoethyl, and the like.

The terms "halogen", "halo" and "halo" mean F, Cl, Br or I.

The term "cycloalkyl" refers to a non-aromatic monocyclic carbocyclic ring, which may be saturated, having from 3 to 8 ring carbon atoms. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The terms "heterocyclyl" or "heterocycle" as used herein refer to aromatic and non-aromatic cyclic groups having at least one heteroatom as a ring member. Preferred heterocyclic groups are those containing at least one heteroatom containing 5 or 6 ring atoms, more preferably 5 or 6 membered heterocyclic groups containing 1 nitrogen atom and 1 oxygen atom, or containing 1 A 5- or 6-membered heterocyclic group containing 1 nitrogen atom or 1 oxygen atom, or a 5- or 6-membered non-aromatic heterocyclic group containing 1 nitrogen atom and 1 oxygen atom, or a 1 nitrogen atom or 1 oxygen atom Atoms of 5 or 6 membered non-aromatic heterocyclic groups, and the "heterocyclic group" includes: cyclic amine groups, such as morpholino, preferably morpholino, piperidinyl, preferably piperidino, pyrrolidinyl, preferably pyrrolidino and the like; and cyclic ether groups such as tetrahydrofuryl, tetrahydropyranyl and the like. Aromatic heterocyclic groups, also known as "heteroaryls", are mono-cyclic hetero-aromatic groups which may contain 1-3 heteroatoms, for example pyrrole, furan, thiophene, imidazole, oxazole, thiazole, tris Azole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine groups, etc. The term "heteroatom" as used herein includes nitrogen atoms, oxygen atoms and sulfur atoms. The term heteroaryl as used herein also includes polycyclic hetero-aromatic systems with two or more rings in which two atoms are common to two adjacent rings (the rings are "fused"), Where at least one of the rings is heteroaryl, for example the other rings may be cycloalkyl, cycloalkenyl, aryl, heterocycle and/or heteroaryl. Heteroaryl includes 5 or 6 membered mono-cyclic hetero-aromatic groups containing 1 or 2 nitrogen, oxygen or sulfur atoms. Polycyclic hetero-aromatic systems with two rings include benzo five-membered heteroaryls containing one nitrogen, oxygen or sulfur atom. Examples of polycyclic heteroaromatic systems include quinoline, isoquinoline, tetrahydroisoquinoline, quinoxaline, benzimidazole, benzofuran, purine, imidazopyridine, benzotriazole, and the like. Examples of heteroaryl also include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, Azolyl, iso Azolyl, Oxadiazolyl, thiazolyl, isothiazolyl or thiadiazolyl, including for example, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3 -different Azolyl, 4-iso Azolyl, 5-iso Azolyl, 2- Oxadiazolyl, 5- Oxadiazolyl, 2- Azolyl, 4- Azolyl, 5- Azolyl, 3-pyrazolyl, 4-pyrazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-triazolyl, 5-triazolyl, tetrazolyl, 2-thiophene Base, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuryl, indolyl, benzotriazolyl, benzothiazolyl, benzo Azolyl, benzimidazolyl, isoquinolyl, indolyl, isoindolyl, acridinyl, benziso Azolyl, isothiazolyl, 1,2,3- Oxadiazolyl, 1,2,5- Oxadiazolyl, 1,2,4- Diazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, Pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g. 2-quinolinyl, 3-quinolinyl, 4-quinolinyl) and isoquinolinyl (e.g. 1-isoquinolinyl , 3-isoquinolinyl or 4-isoquinolinyl).

The term "phosphate" as used in the application means -PO(OH) ₂ .

The term "alkoxy" as used in this application denotes an alkyl group, as defined above, attached to the molecule through an oxygen ("alkoxy" eg -O-alkyl) atom. Specific examples include, but are not limited to, methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, Isopentyloxy, n-hexyloxy, isohexyloxy, etc., when they are substituted alkoxy groups, the substituents may be, for example, halogen or amino.

The term "alkanoyl" means -C(O)R, where R is alkyl as defined herein. Specific examples include, but are not limited to, formyl, acetyl, isopropyl acyl, n-propyl acyl, n-butyryl acyl, isobutyryl acyl, sec-butyryl acyl, tert-butyryl acyl, n-pentyl acyl, isopentyl acyl Acyl, n-hexyl, isohexyl, etc.

The term "aryl" refers to a carbocyclic aromatic ring group. The carbocyclic aromatic ring groups have only carbon ring atoms (generally 6-18) and include monocyclic aromatic rings such as phenyl and fused polycyclic aromatic ring systems in which one carbocyclic aromatic ring Fused to one or more aromatic rings, where the radical or point of attachment is on the carbocyclic aromatic ring. Examples include 1-naphthyl, 2-naphthyl, 1-anthracenyl and 2-anthracenyl. As used in this application, the term "carbocyclic aromatic ring" also includes within its scope groups in which an aromatic ring is fused to one or more non-aromatic rings (carbocyclic or heterocyclic), such as in indene Hydronyl, phthalimide, naphthimidyl, phenanthridinyl or tetrahydronaphthyl, wherein the group or point of attachment is on a carbocyclic aromatic ring.

The term DMAP is 4-dimethylaminopyridine.

The term DIC is N,N-diisopropylcarbodiimide.

The term DMF is dimethylformamide.

The term "racemic mixture" means an equimolar mixture of two or more enantiomeric species that is optically inactive. The present invention includes all stereoisomers of the compounds described herein.

The present invention includes salts or solvates of the compounds described herein, including combinations thereof, such as solvates of salts. The compounds of the present invention may exist in solvated forms (eg, hydrated forms) as well as unsolvated forms, and the present invention includes all such forms.

Usually, but not always, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salt" mean non-toxic salts of compounds of the invention.

Examples of suitable pharmaceutically acceptable salts include inorganic acid addition salts such as hydrochloride, bromate, sulfate, phosphate and nitrate; organic acid addition salts such as acetate, galactaric acid salt, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate and Ascorbate; salts with acidic amino acids, such as aspartate and glutamate; alkali metal salts, such as sodium and potassium; alkaline earth metal salts, such as magnesium and calcium; ammonium salts; salts of organic bases , such as trimethylamine salts, triethylamine salts, pyridinium salts, picoline salts, dicyclohexylamine salts, and N,N'-dibenzylethylenediamine salts; and salts with basic amino acids, such as Lysine and Arginine. In some cases, the salt may be a hydrate or an ethanol solvate.

The modifier "about" used with a quantity is inclusive of the stated value and has the meaning dictated by the context (eg, includes the degree of error associated with measurement of the particular quantity).

The present invention also provides a synthesis method of the compound of formula (I).

The method can be reacted according to the following scheme to prepare the compound of formula (I).

Wherein, the definitions of R ₁ , R ₂ , R ₃ , A, B, D, and Y are as defined above for formula (I), wherein each R' ₁ is independently -COR ₄ , and R ₄ is as in formula (I) As defined, X is NH, O or S.

The method of the present invention can be reacted according to the following scheme, and the formula (I) compound with the formula VIII structure is converted into the formula (I) compound with the formula IX structure

Wherein, the definitions of R ₁ , R ₂ , R ₃ , R ₄ , A, B, and D are as defined in formula (I).

The method of the present invention can also be reacted according to the following scheme, thereby converting the compound of formula VIII into the compound of formula X

Wherein, Z is O or N, and R ₈ is C _1-6 alkyl unsubstituted or substituted by 1-3 R ₉ , R ₁ , R ₂ , R ₃ , R ₄ , R ₉ , A , B, D are as defined in formula (I), X is NH, O or S.

The method of the present invention can also be reacted according to the following scheme, thereby the compound of formula IX is converted into the compound of formula XI

Wherein, Z is O or N, and R ₈ is C _1-6 alkyl unsubstituted or substituted by 1-3 R ₉ , R ₁ , R ₂ , R ₃ , R ₄ , R ₉ , A, B , D as defined in formula (I).

The method of the present invention can also be reacted according to the following scheme, thereby converting the compound of formula VIII into the compound of XIII

Wherein, R ₁ , R ₂ , R ₃ , R ₄ , R ₁₁ , R ₁₂ , A, B and D are as defined in formula (I), and X is NH, O or S.

The method of the present invention can also be reacted according to the following scheme, thereby converting the compound of formula IX into the compound of XIV

Wherein, R ₁ , R ₂ , R ₃ , R ₄ , R ₁₁ , R ₁₂ , A, B and D are as defined in formula (I).

The method of the present invention may comprise the steps of:

Step 1) make the compound of formula III

Reaction with formula 1 compound,

(R' ₁ ) ₂ O Formula 1

Thereby generating the compound of formula IV,

wherein each R' ₁ is independently -COR ₄ , R ₁ , R ₂ , R ₃ , R ₄ , A, B, D are as defined in formula (I), and R ₁₃ is halogen or nitro;

Step 2) reacting the compound of formula IV with HXCH ₂ COY' to obtain the compound of formula V,

Wherein Y' is C _1-6 alkoxy, R ₁ , R ₂ , R ₃ , R ₄ , A, B, D are as defined in formula (I), X is NH, O or S;

Step 3) reacting the compound of formula V with acid and its salt to obtain the compound of formula VI

Wherein Y' is as defined in formula V, R ₁ , R ₂ , R ₃ , R ₄ , A, B, D are as defined in formula (I), X is NH, O or S;

Step 4) hydrogenating the compound of formula VI to obtain the compound of formula VII

Wherein Y' is as defined in formula V, R ₁ , R ₂ , R ₃ , R ₄ , A, B, D are as defined in formula (I), X is NH, O or S;

Step 5) reacting the compound of formula VII with a base to obtain the compound of formula (I), which has the structure of formula VIII

Wherein R ₁ , R ₂ , R ₃ , R ₄ , A, B, D are as defined in formula (I), and X is NH, O or S.

The method of the present invention may also comprise the steps of:

Step 6) In the presence of a catalyst, the compound of formula (I) with the structure of formula VIII

Converted to a compound of formula (I) having the structure of formula IX

Wherein R ₁ , R ₂ , R ₃ , R ₄ , A, B, and D are as defined in formula (I).

The method of the present invention may also comprise the steps of:

Step 7) In the presence of a suitable base, the compound of formula VIII

Reaction with R ₈ ZH gives the compound of formula X

Wherein, Z is O or N, and R ₈ is C _1-6 alkyl unsubstituted or substituted by 1-3 R ₉ , R ₁ , R ₂ , R ₃ , R ₄ , R ₉ , A, B , D as defined in formula (I), X is NH, O or S.

The method described in the present invention can also comprise the steps:

Step 8) Compound of formula IX

Reaction with R ₈ ZH affords compounds of formula XI.

Wherein, Z is O or N, and R ₈ is C _1-6 alkyl unsubstituted or substituted by 1-3 R ₉ , R ₁ , R ₂ , R ₃ , R ₄ , R ₉ , A, B , D as defined in formula (I).

The method of the present invention may also comprise the steps of:

Step 9) Compound of formula VIII

and Reaction, obtain formula XIII compound

Wherein, R ₁ , R ₂ , R ₃ , R ₄ , R ₁₁ , R ₁₂ , A, B, D and X are as defined in formula (I).

The method of the present invention may also comprise the steps of:

Step 10) Compound of formula IX

and Reaction, obtain formula XIV compound

Wherein, R ₁ , R ₂ , R ₃ , R ₄ , R ₁₁ , R ₁₂ , A, B and D are as defined in formula (I).

In one embodiment of the method of the present invention, step 1) is carried out in the presence of an inert gas, preferably nitrogen, in an organic solvent, preferably dichloromethane, in a catalyst, preferably tin tetrachloride, and/or nitro Compounds of formula III are reacted with compounds of formula 1 in the presence of methane, preferably at room temperature, to form compounds of formula IV.

In one embodiment of the method of the present invention, step 2) is carried out as follows, in the presence of an inert gas, preferably nitrogen, the compound of formula IV, HXCH ₂ COY' and a suitable base, such as anhydrous pyridine, in a suitable solvent, such as In anhydrous methanol, preferably react at a suitable temperature, such as about 90°C, for a suitable time, such as 48 hours, to obtain the compound of formula V.

In one embodiment of the method of the present invention, step 3) is carried out as follows, in the presence of an inert gas, preferably nitrogen, reacting the compound of formula V with an acid and its salt, preferably ammonium acetate and glacial acetic acid, to obtain the compound of formula VI.

In one embodiment of the method of the present invention, step 4) is carried out as follows, in the presence of a catalyst, such as 10% Pd-C, in an organic solvent, such as ethyl acetate, preferably at a suitable pressure, such as 45 atmospheres, Hydrogenation of compounds of formula VI affords compounds of formula VII.

In one embodiment of the method of the present invention, step 5) is carried out by mixing the compound of formula VII and a suitable base, such as sodium hydroxide, in a suitable solvent, such as ethanol, water and/or tetrahydrofuran, preferably at an appropriate temperature, For example, reacting at room temperature for an appropriate time, such as 5 h, to obtain the compound of formula (I), which has the structure of formula VIII.

In one embodiment of the method of the present invention, described method also comprises following step 6):

In the presence of a catalyst, such as Raney nickel, preferably in a suitable base, such as sodium hydroxide, in a suitable solvent, such as water, the compound of formula (I) having the structure of formula VIII is converted into the compound of formula (I) having the structure of formula IX compound.

In one embodiment of the method of the present invention, described method also comprises following step 7):

Compounds of formula X are obtained by reacting compounds of formula VIII with R ₈ ZH in the presence of DIC and DMAP.

In one embodiment of the method of the present invention, described method also comprises following step 8):

Reaction of compounds of formula IX with R ₈ ZH in the presence of an inert gas such as nitrogen, a suitable base such as triethylamine in a suitable solvent such as DMF affords compounds of formula XI.

In one embodiment of the method of the present invention, described method also comprises following step 9):

In the presence of an inert gas, preferably nitrogen, in the presence of a suitable base such as triethylamine, in a suitable solvent such as DMF, preferably at a suitable temperature such as room temperature for a suitable time such as 5min, the compound of formula VIII and reaction to obtain the compound of formula XIII.

In one embodiment of the method of the present invention, described method also comprises following step 10):

In the presence of an inert gas, preferably nitrogen, in the presence of a suitable base, such as triethylamine, in a suitable solvent, such as DMF, preferably at a suitable temperature, such as room temperature, the compound of formula IX and React for an appropriate time such as 5 min to obtain the compound of formula XIV.

Preparation of Stereoisomers

Stereoisomers of the compounds of the present invention can be prepared by referring to the conventional technical means of the prior art, for example, the exploration of the total synthetic route of chuangmycin and the research on its stereoisomers by Guo Xialing et al. (Acta Pharmacologica Sinica, 1987, 22 (9) :671-678). Specifically, stereoisomers of the compounds in Table 1 having stereoconfigurations as described in formula (II) or XV, especially the compounds in Table 2, were prepared according to the above methods.

Those skilled in the art know how to prepare salts or solvates of the compounds described herein.

The present invention also provides an antibacterial composition containing the compound of formula (I) defined above or a pharmacodynamically acceptable salt thereof as an active ingredient. The weight ratio of the indole derivative contained in the pharmaceutical composition is 0.7-99.9% in the composition, and the weight ratio of the pharmaceutically acceptable carrier in the composition is 0.1-99.9%. The pharmaceutical compositions are in the form of formulations suitable for pharmaceutical use. Pharmaceutical formulations can be tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, capsules, hard capsules, soft capsules, sustained-release capsules, oral liquids, mixtures , oral preparations, granules, granules, pills, powders, ointments, pills, suspensions, solutions, injections, powder injections, freeze-dried powder injections, cachets, suppositories, ointments, plasters, creams , sprays, aerosols, drops, patches.

In the pharmaceutical composition of the present invention, as a preparation form, the effective amount of the compound of the invention contained in each dose is 0.1-1000mg, and each dose refers to each preparation unit, such as each tablet, each capsule, It can also refer to each dosage, such as 100 mg each time.

When the pharmaceutical composition of the present invention is prepared into solid or semisolid pharmaceutical preparations in the form of powder, tablet, dispersible powder, capsule, cachet, suppository and ointment, a solid carrier can be used. The solid carrier that can be used is preferably one or more substances selected from diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, swelling agents, etc., or can be encapsulated substances. In powder formulations, the carrier contains from 5% to 70% of the micronized active ingredient. Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sucrose, lactose, fructose, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, a low boiling wax, cocoa butter, and the like. Because of their ease of administration, tablets, powders, cachets and capsules represent the most advantageous oral solid formulations.

Liquid formulations of the invention include solutions, suspensions and emulsions. For example, the injection preparation for parenteral administration can be in the form of water or water-propylene glycol solution, and its isotonicity, pH, etc. are adjusted to make it suitable for the physiological conditions of the living body; liquid preparations can also be prepared in polyethylene glycol, In solution form in aqueous solution. Oral aqueous solutions can be prepared by dissolving the active ingredient in water and adding appropriate amount of coloring, flavoring, stabilizing and thickening agents. Aqueous suspensions suitable for oral administration can be prepared by dispersing the micronized active ingredient in viscous material, such as natural and synthetic gums, methylcellulose, sodium carboxymethylcellulose, and other known suspending agents.

It is especially advantageous to formulate the aforementioned pharmaceutical preparations in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form of formulation refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect. Such dosage unit form may be in packaged form, such as a tablet, capsule or powder in a vial or vial, or an ointment, gel or cream in a tube or bottle.

While the amount of active ingredient contained in dosage unit forms may vary, it will generally be adjusted within the range of 1-800 mg, depending on the potency of the active ingredient chosen.

When the active compound of formula (I) of the present invention is used as a drug for the treatment of bacterial infections, it is preferably administered in an amount of 6-14 mg/kg body weight. However, the dosage administered will vary with the needs of the patient, the severity of the infection to be treated, the compound selected, and the like.

Those skilled in the art can routinely determine the preferred dosage for a particular situation. Generally, the initial treatment dose is lower than the optimum dose of the active ingredient, and then the dose is gradually increased until the optimum therapeutic effect is achieved. For convenience, the total daily dosage may be divided and administered in divided doses.

detailed description

The present invention is described in further detail below by the examples, and these examples can make those skilled in the art understand the present invention more comprehensively, but the implementation of the present invention is not limited to these examples, and these examples can not limit the present invention in any way . Corresponding NMR, mass spectral data and other related data are written below the corresponding products, and the title compound in the form of a racemic mixture has the same nuclear magnetic and mass spectral data as its corresponding specific isomer. The specific isomer structure related to the title compound mentioned in the preparation examples below is the compound represented in Table 2, and the number of the title compound and its corresponding specific isomer is designated as follows: the number of the title compound Add "'" to the upper right corner to obtain the specific isomer number corresponding to the title compound. For example, the specific isomer number of Compound 1 is Compound 1'.

Example 1: 2-Carboxylic acid-3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole (compound C)

Step 1) Under nitrogen protection, slowly add tin tetrachloride (4.5ml, 36mmol) to a solution of 4-iodoindole (7.5g, 30mmol) in dichloromethane (75ml) at 0°C, react at room temperature for 30min, and then Add Ac ₂ O (2.9g, 30mmol) and nitromethane (46.5ml), react at room temperature for 1h, quench with ice water, filter, wash the filter cake with a small amount of ether, extract the organic layer with ethyl acetate, anhydrous Na ₂ SO ₄ was dried, the solvent was spin-dried, and the compound 3-acetyl-4-iodoindole (6.9 g, 78%) was obtained after recrystallization with ethyl acetate and petroleum ether.

¹ HNMR(500MHz,DMSO-d6)δ:12.07(s,1H),8.32(d,J=3.0Hz,1H),7.67(dd,J=7.5Hz,1.0Hz,1H),7.49(dd,J =8.0Hz, 1.0Hz, 1H), 6.92(t, J=8.0Hz, 1H), 2.49(s, 3H). MS (ESI ⁺ ) m/z: 286.0 [M+H] ⁺ .

Step 2) Under nitrogen protection, mix 3-acetyl-4-iodoindole (2.85g, 10mmol), ethyl thioglycolate (3.84g, 16mmol) and anhydrous pyridine (2.61g, 17mmol) in anhydrous methanol (100ml ) solution was reacted at 90°C for 48 hours. After the reaction, methanol was evaporated to dryness, and 100ml ethyl acetate was added to dissolve the residue. The ethyl acetate layer (80ml×3) was washed with water, and the ethyl acetate layer was dried with anhydrous Na ₂ SO ₄ . The solvent was spin-dried and recrystallized from ethyl acetate and petroleum ether to obtain the compound 3-acetyl-4-ethoxycarbomethylthioindole (1.93 g, 70%).

¹ HNMR (500MHz, DMSO-d6) δ: 12.00(s, 1H), 8.28(s, 1H), 7.24(d, J=8.0Hz, 1H), 7.14(t, J=8.0Hz, 1H), 6.96 (d, J=8.0Hz, 1H), 4.08(q, J=7.5Hz, 2H), 3.80(s, 2H), 2.45(s, 3H), 1.13(t, J=7.5Hz, 3H). MS (ESI ⁺ ) m/z: 278.1 [M+H]+.

Step 3) Under nitrogen protection, 3-acetyl-4-ethoxycarbomethylthioindole (2.63g, 10mmol), ammonium acetate (3.51g, 46mmol) and glacial acetic acid (5.54g, 93mmol) were mixed at 110°C React for 15 hours, add water after the reaction, extract the water layer (80ml×3) with ethyl acetate, wash the ethyl acetate layer (80ml×3), dry the ethyl acetate layer with anhydrous Na ₂ SO ₄ , spin to dry the solvent After separation by petroleum ether and ethyl acetate column chromatography, the compound 3-methyl-5H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid ethyl ester (1.23g, 50%) was obtained .

¹ HNMR (500MHz, DMSO-d6) δ: 11.20(s, 1H), 7.32(s, 1H), 6.84(d, J=8.0Hz, 1H), 6.77(t, J=8.0Hz, 1H), 6.44 (d, J=7.0Hz, 1H), 4.18(q, J=7.5Hz, 2H), 2.49(s, 3H), 1.24(t, J=7.5Hz, 3H). MS (ESI ⁺ ) m/z: 259.1 [M] ⁺ .

Step 4) To a solution of ethyl 3-methyl-5H-thiopyrano[4,3,2-cd]indole-2-carboxylate (1.23g, 5mmol) in ethyl acetate (50ml) was added 10 % Pd-C (324mg, 0.30mmol), then catalytic hydrogenation reaction at 45 atmospheres for 20h, after the reaction was completed, it was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, and the filtrate was concentrated with petroleum ether and ethyl acetate The compound 3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid ethyl ester (0.74 g, 60%) was obtained through column chromatography separation. ¹ HNMR (500MHz, DMSO-d6) δ: 12.85(s, 1H), 10.80(s, 1H), 7.15(d, J=2.0Hz, 1H), 7.12(d, J=8.0Hz, 1H), 6.92 (t,J=7.5Hz,1H),6.73(d,J=7.0Hz,1H),4.29(d,J=3.0Hz,1H),4.16(q,J=7.5Hz,2H),3.66(dq ,J=3.5Hz,7.0Hz,1H),1.23(t,J=7.0Hz,3H). MS (ESI ⁺ ) m/z: 261.3 [M] ⁺ .

Step 5) Ethyl 3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylate (0.5 g, 2 mmol) and sodium hydroxide (1.21g, 30mmol) in ethanol (30ml), water (18ml) and tetrahydrofuran (80ml) was reacted at room temperature for 5h. After the reaction, add brine to the reaction solution for dilution, then add 2M hydrochloric acid solution (20ml), extract with dichloromethane (80ml×3), dry over anhydrous magnesium sulfate, wash the filter cake with ethyl acetate, spin dry the solvent and use Recrystallization from dichloromethane and toluene afforded a racemic mixture of 2-carboxylic acid-3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole (0.30 g, 66 %).

The racemic mixture 2-carboxylic acid-3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole (0.3 g) obtained above was dissolved in anhydrous methanol ( 8ml), heated to boiling, dropwise added (—)-α-phenylethylamine (0.18ml), filtered while hot, and precipitated (S)-α-phenylethylamine (2R,3S)-2-carboxylic acid- 3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole, white rod crystal 0.20g. The mother liquor is kept. The crystals were recrystallized twice with anhydrous methanol and weighed 0.17 g.

The mixture of the crystals and H ₂ O (9 ml) was treated with 49% H ₂ SO ₄ —H ₂ O, extracted with ether, washed with water to pH 5, and dried over anhydrous MgSO ₄ . Concentrate and recrystallize once from chloroform-ether to obtain (2R,3S)-2-carboxylic acid-3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole 0.1g, white amorphous crystal. The relevant data are as follows:

¹ HNMR (500MHz, DMSO-d6) δ: 12.99(s, 1H), 10.89(s, 1H), 7.14(d, J=2.0Hz, 1H), 7.09(d, J=8.0Hz, 1H), 6.98 (t,J=7.5Hz,1H),6.77(d,J=7.0Hz,1H),4.24(d,J=3.0Hz,1H),3.66(dq,J=3.5Hz,7.0Hz,1H), 1.21(d,J=7.0Hz,3H). MS (ESI ⁺ ) m/z: 233.1 [M] ⁺ .

Example 2: Benzoyloxymethyl 3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylate (CV2)

Under nitrogen protection, the racemic mixture 2-carboxylic acid-3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole or (2R,3S)-2 -Carboxylic acid-3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole (0.23g, 1mmol) and triethylamine (0.10g, 1mmol) dissolved In DMF solution (6ml), react at room temperature for 5min, then add chloromethyl benzoate (0.17g, 1mmol), react at room temperature for 24h, add ethyl acetate 50ml after the reaction, wash the ethyl acetate layer (80ml×3 ), the ethyl acetate layer was dried with anhydrous Na ₂ SO ₄ , the solvent was spin-dried and recrystallized with ethanol and petroleum ether to obtain a racemic mixture of 3-methyl-3,5-dihydro-2H-thiopyrano[ 4,3,2-cd]indole-2-carboxylic acid benzoyloxymethyl ester or (2R,3S)-3-methyl-3,5-dihydro-2H-thiopyrano[4, 3,2-cd] Indole-2-carboxylic acid benzoyloxymethyl ester (0.22g, 60%), the relevant data are as follows:

¹ HNMR (500MHz, DMSO-d6) δ: 10.91(s, 1H), 7.94(d, J=7.5Hz2H), 7.71(d, J=7.5Hz, 2H), 7.56(t, J=7.5Hz, 1H ),7.18(s,1H),7.11(d,J=8.5Hz,1H),6.98(t,J=7.5Hz,1H),6.76(d,J=7.0Hz,1H),6.01(t,J =6.5Hz,1H),5.94(d,J=6.5Hz,1H),4.42(d,J=3.5Hz,1H),3.61(dd,J=3.5Hz,6.5Hz,1H),1.23(d, J=7.0Hz, 3H). MS (ESI ⁺ ) m/z: 367.1 [M+H] ⁺ .

Example 3: 3-(Indol-3-yl)-butyric acid (Compound 20)

Sodium hydroxide (0.19g, 4.8mmol) was dissolved in water (50ml), and the racemic mixture 2-carboxylic acid-3-methyl-3,5-dihydro-2H-thiopyrano[ 4,3,2-cd]indole or (2R,3S)-2-carboxylic acid-3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole Indole (1g, 4.3mmol), add freshly prepared Raney nickel (Raney nickel) (10g, wet weight, containing absolute ethanol) and water (50ml) to it, heat and reflux for 1 hour, cool and filter, and use 0.02% Wash with sodium hydroxide solution (20ml×2), combine the washing solution with the filtrate, add 0.2 g of activated carbon for decolorization, filter, acidify the filtrate with concentrated hydrochloric acid and extract with ether (20ml×3), wash the ether extract with water (10ml×3) , dried over night over anhydrous sodium sulfate, concentrated solvent and recrystallized with diethyl ether and petroleum ether to obtain yellow crystals, which is a racemic mixture of 3-(indol-3-yl)-butyric acid or (S)-3-(indol Indol-3-yl)-butyric acid (0.46g, 52%), the relevant data are as follows:

¹ HNMR (400MHz, DMSO-d6) δ: 12.00(s, 1H), 10.76(s, 1H), 7.53(d, J=8.0Hz, 1H), 7.31(d, J=8.0Hz, 1H), 7.09 (d,J=2.4Hz,1H),7.04(t,J=7.2Hz,1H),6.95(t,J=7.2Hz,1H),3.42(m,1H),2.65(m,1H),2.46 (m,1H),1.31(d,J=6.8Hz,3H). MS (ESI ⁺ ) m/z: 204.3 [M+H] ⁺ .

Example 4: 3-(indol-3-yl)-benzoyloxymethyl butyrate (compound DSCV)

Under nitrogen protection, the racemic mixture 3-(indol-3-yl)-butyric acid or (S)-3-(indol-3-yl)-butyric acid (0.20g, 1mmol) and triethylamine ( 0.10g, 1mmol) was dissolved in DMF solution (6ml), reacted at room temperature for 5min, then added chloromethyl benzoate (0.17g, 1mmol), reacted at room temperature for 24h, after the reaction was completed, added 50ml of ethyl acetate, washed ethyl acetate with water The ester layer (80ml×3), the ethyl acetate layer was dried with anhydrous Na ₂ SO ₄ , the solvent was spin-dried and the column was separated to obtain the target compound 3-(indol-3-yl)-butyric acid benzoyloxy Methyl ester (0.23 g, 70%), which is a racemic mixture or (S) isomer, the relevant data are as follows:

¹ HNMR (400MHz, DMSO-d6) δ: 10.79(s, 1H), 7.90(d, J=8.4Hz, 1H), 7.69(t, J=7.6Hz, 1H), 7.53(t, J=7.6Hz ,1H),7.16(d,J=8.0Hz,1H),7.12(d,J=2.4Hz,1H),7.03(m,1H),6.93(m,1H),5.92(q,2H),3.45 (m,1H),2.84(m,1H),2.69(m,1H),1.30(d,J=6.8Hz,3H). MS (ESI ⁺ ) m/z: 338.1 [M+H] ⁺ .

Example 5: 2-Carboxylic acid-3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]-6-azaindole (compound 1)

Starting from 4-iodo-1H-pyrrolo[3,2-c]pyridine, the title compound was prepared in a manner similar to that of Example 1, which was a racemic mixture or (2R,3S) isomer, relevant data as follows:

¹ H NMR (500MHz, chloroform) δ11.73(s,1H),7.63(s,1H),7.31(s,1H), 6.93(s,1H),6.37(s,1H),4.04(s,1H ), 3.50(m,1H), 1.44(d,J=6.5Hz,3H). MS (ESI ⁺ ) m/z: 234.05[M] ⁺ .

Example 6: 2-Carboxylic acid-3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]-6,7-diazaindole (compound 2)

Starting from 4-iodo-1H-pyrrolo[3,2-d]pyridazine, the title compound was prepared in a similar manner to Example 1 as a racemic mixture or (2R,3S) isomer, related Data are as follows:

¹ H NMR (500MHz, chloroform) δ11.77(s,1H),8.96(s,1H),7.92(s,1H),6.37(s,1H),4.04(s,1H),3.50(m,1H ), 1.46 (d, J=6.5Hz, 3H). MS (ESI ⁺ ) m/z: 235.04[M] ⁺ .

Example 7: 2-Carboxylic acid-3-methyl-3,5-dihydro-2H-pyrano[4,3,2-cd]-6,7-diazaindole (compound 3)

Starting from 4-iodo-1H-pyrrolo[3,2-d]pyridazine, the title compound was prepared by a method similar to Example 1 as a racemic mixture or (2R,3S) isomer, relevant data as follows:

¹ H NMR (500MHz, chloroform) δ11.78(s,1H),8.90(s,1H),7.88(s,1H),6.37(s,1H),4.47(s,1H),3.70(m,1H ), 1.53 (d, J=6.5Hz, 3H). MS (ESI ⁺ ) m/z: 219.06[M] ⁺ .

Example 8: 3-Methyl-6-methoxy-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (Compound 4)

Starting from 4-iodo-7-methoxy-1H-indole, the title compound was prepared by a method similar to Example 1, which was a racemic mixture or (2R,3S) isomer, and the relevant data were as follows:

¹ H NMR (500MHz, chloroform) δ12.53(s,1H),11.68(s,1H),9.82(s,1H),7.15(s,1H),6.89(s,1H),4.13(s,1H ), 4.07(s,3H), 3.50(m,1H), 1.41(d,J=6.5Hz,3H). MS (ESI ⁺ ) m/z: 263.06[M] ⁺ .

Example 9: 3-Methyl-6-methylamino-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (Compound 5)

Starting from 4-iodo-N-methyl-1H-indol-7-amine, the title compound was prepared by a method similar to Example 1 as a racemic mixture or (2R,3S) isomer, related Data are as follows:

¹ H NMR (500MHz, chloroform) δ12.78(s,1H),11.31(s,1H),9.86(s,1H),7.02(s,1H),6.97(s,1H),4.04(s,1H ), 3.50(m,1H), 2.88(s,3H), 1.54(d,J =6.5Hz,3H). MS (ESI ⁺ ) m/z: 262.08[M] ⁺ .

Example 11: 2-carboxylic acid-3,4-dimethyl-7-trifluoromethyl-3,5-dihydro-2H-pyrano[4,3,2-cd]indole (compound 7 )

Starting from 2-methyl-4-iodo-6-(trifluoromethyl)-1H-indole, the title compound was prepared as a racemic mixture or (2R,3S) by a method analogous to Example 1 Isomers, the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ12.17(s,1H),11.86(s,1H),8.37(s,1H),6.92(s,1H),4.47(s,1H),3.70(m,1H ), 2.49(s,3H), 1.45(d,J=6.5Hz,3H). MS (ESI ⁺ ) m/z: 299.08[M] ⁺ .

Example 12: 3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (3'-morpholino)propyl ester (compound 75)

2-Carboxylate-3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole or (2R,3S)-2-carboxylate-3-methyl Base-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole (2.55g, 11mmol) was dissolved in dichloromethane (50ml), and DIC (1.51g, 11.98mmol) was added , stirred at room temperature for 1 h, added DMAP (0.24 g, 1.96 mmol) and 3-morpholino-propanol (1.59 g, 10.95 mmol), heated to reflux for 6 h, washed the reaction solution with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered After evaporation to dryness, ethyl acetate petroleum ether system was recrystallized to obtain 3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (3 '-morpholino)propyl ester or (2R,3S)-3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid ( 2.97g (75%) of 3'-morpholino)propyl ester, the relevant data are as follows:

1H NMR (500MHz, chloroform) δ11.86(s,1H),9.65(s,1H),7.18(s,1H),7.11(s,1H),7.02(s,1H),4.18(m,2H) ,4.00(s,1H),3.81(m,1H),3.69(m,2H),2.62(m,2H),2.49(s,2H),2.39(m,2H),1.78(s,2H), 1.57(d,J=6.5Hz,3H). MS (ESI ⁺ ) m/z: 360.15[M]+.

Example 13: 3-Methyl-7-fluoro-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (2'-morpholino) Ethyl ester (Compound 76)

Using compound 2-morpholinoethanol and 2-carboxylic acid-3-methyl-7-fluoro-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole as raw materials, It is a racemic mixture or (2R, 3S) isomer. The title compound was prepared according to a method similar to Example 12, which is a racemic mixture or (2R, 3S) isomer. The relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.84(s,1H),9.79(s,1H),7.02(s,1H),6.89(s,1H),4.27(s,2H),4.00(s,1H ), 3.81(m,1H), 3.71(m,4H), 2.83(m,4H), 2.59(m,2H), 1.52(d,J=6.5Hz,3H). MS (ESI ⁺ ) m/z: 364.13[M] ⁺ .

Example 14: 3-methyl-3,5-dihydro-2H-pyrano[4,3,2-cd]indole-2-carboxylic acid (2'-morpholino) ethyl ester (compound 77 )

Starting from the compound 2-morpholinoethanol and 2-carboxylic acid-3-methyl-3,5-dihydro-2H-pyrano[4,3,2-cd]indole, which is racemic Mixture or (2R, 3S) isomer, the title compound was prepared according to a method similar to Example 12, which is a racemic mixture or (2R, 3S) isomer, and the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.36(s,1H),9.80(s,1H),7.18(s,1H),7.02(s,1H),6.80(s,1H),4.31(s,2H ),4.30(s,1H),4.01(m,1H),3.70(m,4H),2.86(s,4H),2.82(m,2H),1.40(d,J=6.5Hz,3H). MS (ESI ⁺ ) m/z: 330.16[M] ⁺ .

Example 15: 3-methyl-7-methoxy-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (2'-dimethyl Amino) ethyl ester (compound 78)

Starting from the compound 2-methylaminoethanol and 2-carboxylic acid-3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole, which is racemic Mixture or (2R, 3S) isomer, react according to the method similar to Example 12 to prepare the title compound, which is a racemic mixture or (2R, 3S) isomer, the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.66(s,1H),9.78(s,1H),7.02(s,1H),6.79(s,1H),4.23(m,2H),4.00(s,1H) ), 3.88(s,3H), 3.81(m,1H), 3.16(m,2H), 2.81(s,6H), 1.41(d,J=6.0Hz,3H). MS (ESI ⁺ ) m/z: 334.14[M] ⁺ .

Example 16: 3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]-6,8-diazaindole-2-formyl (2'- Dimethylaminoethyl)amine (Compound 79)

With the compound N,N-dimethylethylenediamine and 2-carboxylic acid-3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]-6,8- Diazaindole is the starting material, which is a racemic mixture or (2R, 3S) isomer, and the title compound is prepared according to a method similar to Example 12, which is a racemic mixture or (2R, 3S) isomer , the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.53(s,1H),9.05(s,1H),7.30(s,1H), 4.11(s,1H),3.48(s,1H),3.40(m,1H ), 3.35(m,2H), 2.64(m,2H), 2.32(s,6H), 1.61(d,J=6.5Hz,3H). MS (ESI ⁺ ) m/z: 305.13[M] ⁺ .

Example 17: 2-(3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]-8-azaindole-2-carbonyloxy)ethyl Phosphonic acid (compound 80)

2-Carboxylic acid-3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]-8-azaindole or (2R,3S)-2-carboxy Acid-3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]-8-azaindole (2.57g, 11mmol) dissolved in dichloromethane (50ml) , add DIC (1.51g, 11.98mmol), stir at room temperature for 1h, add DMAP (0.24g, 1.96mmol) and dimethyl hydroxyethyl phosphonate (1.84g, 10.95mmol), after heating to reflux for 6h, water and saturated salt The reaction solution was washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness, recrystallized from ethyl acetate petroleum ether system to obtain 3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2- cd]-8-azaindole-2-carboxylic acid (2'-phosphonic acid dimethyl) ethyl ester 3.50g, dissolve it in dichloromethane (50ml), add trimethylbromosilane (9.85g, 64.8mmol) stirred at room temperature for 3h, terminated the reaction with methanol, and evaporated to dryness to obtain the product 2-(3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]-8- Azaindole-2-carbonyloxy)ethylphosphonic acid 2.53g (68%), which is a racemic mixture or (2R,3S) isomer, the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.58(s,1H),8.12(s,1H),7.21(s,1H),6.37(s,1H),4.31(m,2H),4.00(s,1H ), 3.81(m,3H), 2.02(m,2H), 1.42(d,J=6.0Hz,3H). MS (ESI ⁺ ) m/z: 342.04[M] ⁺ .

Example 18: Methyl N-methyl-3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]-7-azaindole-2-carboxylate (Compound 8)

Starting from 4-iodo-1-methyl-1H-pyrrolo[3,2-c]pyridine, the title compound was prepared as a racemic mixture or (2R,3S ) isomers, the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ7.71(s,1H),6.90(s,1H),6.29(s,1H),5.32(m,1H),4.00(s,1H),3.78(m,1H ), 3.62(s,3H), 1.42(d,J=6.5Hz,3H). MS (ESI ⁺ ) m/z: 262.08[M] ⁺ .

Example 19: Ethyl N-acetyl-3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]-7-azaindole-2-carboxylate (Compound 9)

Starting from 1-(4-iodo-1H-pyrrolo[2,3-c]pyridin-1-yl)ethanone, the title compound was prepared as a racemic mixture by a method analogous to Examples 1 and 12 Or (2R,3S) isomers, the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ8.65(s,1H),8.30(s,1H),7.12(s,1H),4.12(m,2H),4.01(s,1H),3.81(m,1H ), 2.70(s,3H), 1.54(d,J=6.5Hz,3H), 1.01(m,3H). MS (ESI ⁺ ) m/z: 304.09[M] ⁺ .

Example 20: 3-methyl-3,5-dihydro-2H-pyrano[4,3,2-cd]-6,7-diazaindole-2-carboxylic acid ethyl ester (compound 10 )

Starting from 4-iodo-1H-pyrrolo[3,2-d]pyridazine, the title compound was prepared as a racemic mixture or (2R,3S) isomer by a method similar to that of Examples 1 and 12 , the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.32(s,1H),8.88(s,1H),6.28(s,1H),4.15(m,2H),3.98(s,1H),3.84(m,1H ), 1.53(d, J=6.5Hz, 3H), 0.99(m, 3H). MS (ESI ⁺ ) m/z: 247.10 [M] ⁺ .

Example 21: Ethyl 3-methyl-3,5-dihydro-2H-pyrano[4,3,2-cd]-7-azaindole-2-carboxylate (Compound 11)

Starting from 4-iodo-1H-pyrrolo[2,3-c]pyridine, the title compound was prepared as a racemic mixture or (2R,3S) isomer by a method analogous to Examples 1 and 12, The relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.33(s,1H),8.86(s,1H),8.36(s,1H),6.37(s,1H),4.43(s,1H),4.26(m,2H ), 4.01(m, 1H), 1.42(d, J=6.5Hz, 3H), 1.30(m, 3H). MS (ESI ⁺ ) m/z: 246.10 [M] ⁺ .

Example 22: 3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]-6,7-diazaindole-2-formylethylamide (compound 12)

Starting from 4-iodo-1H-pyrrolo[3,2-d]pyridazine, the title compound was prepared as a racemic mixture or (2R,3S) isomer by a method similar to that of Examples 1 and 12 , the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.43(s,1H),8.32(s,1H),7.83(s,1H),6.37(s,1H),4.43(s,1H),4.26(m,2H ), 4.01(m, 1H), 1.42(d, J=6.5Hz, 3H), 1.30(m, 3H). MS (ESI ⁺ ) m/z: 262.09[M] ⁺ .

Example 23: tert-butyl 3-methyl-7-fluoro-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylate (Compound 13)

Starting from 4-iodo-6-fluoro-1H-indole, the title compound was prepared by a method similar to Examples 1 and 12, which was a racemic mixture or (2R,3S) isomer, and the relevant data were as follows:

¹ H NMR (500MHz, chloroform) δ11.36(s,1H),8.95(s,1H),7.36(s,1H),6.37(s,1H),3.56(s,1H),3.48(m,1H ), 1.40(s,9H), 1.34(d,J=6.5Hz,3H). MS (ESI ⁺ ) m/z: 307.10 [M] ⁺ .

Example 24: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-formyl tert-butylamine (Compound 14)

Starting from 4-iodo-1H-indole, the title compound was prepared by a method similar to Examples 1 and 12, which was a racemic mixture or (2R,3S) isomer, and the relevant data were as follows:

¹ H NMR (500MHz, chloroform) δ11.66(s,1H),9.79(s,1H),8.00(s,1H),7.02(s,1H),6.90(s,1H),6.85(s,1H ), 4.00(s,1H), 3.81(m,1H), 1.50(s,9H), 1.34(d,J=6.5Hz,3H). MS (ESI ⁺ ) m/z: 288.13[M] ⁺ .

Example 25: 3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]-6,8-diazaindole-2-carboxamide (compound 15)

Starting from 4-iodo-7H-pyrrolo[2,3-d]pyrimidine, the title compound was prepared as a racemic mixture or (2R,3S) isomer by a method similar to that of Examples 1 and 12, The relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.75(s,1H),9.80(s,1H),8.21(s,1H),7.02(s,1H),4.11(s,1H),3.48(m,1H ), 1.53(s,3H), 1.29(d,J=6.5Hz,3H). MS (ESI ⁺ ) m/z: 248.07[M] ⁺ .

Example 26: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]-6-azaindole-2-carboxylethylamide (Compound 16)

Starting from 4-iodo-1H-pyrrolo[3,2-c]pyridine, the title compound was prepared as a racemic mixture or (2R,3S) isomer by a method similar to that of Examples 1 and 12, The relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.66(s,1H),9.05(s,1H),8.03(s,1H),7.43(s,1H),6.37(s,1H),4.11(s,1H ), 3.48(m,1H), 2.92(m,2H), 1.34(d, J=6.5Hz,3H), 1.20(s,3H). MS (ESI ⁺ ) m/z: 261.09[M] ⁺ .

Example 27: 3-methyl-3,5-dihydro-2H-pyrano[4,3,2-cd]-6,7-diazaindole-2-formyl isopropylamide (compound 17 )

Starting from 4-iodo-1H-pyrrolo[3,2-d]pyridazine, the title compound was prepared as a racemic mixture or (2R,3S) isomer by a method similar to that of Examples 1 and 12 , the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.88(s,1H),8.92(s,1H),8.02(s,1H),6.01(s,1H),6.37(s,1H),4.11(s,1H ), 3.84(m,1H), 1.31(d,J=6.5Hz,3H), 1.07(s,6H). MS (ESI ⁺ ) m/z: 260.13 [M] ⁺ .

Example 30: 3-(1-Methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)butanoic acid (Compound 21)

Starting from 1-methyl-4-iodo-1H-pyrrolo[2,3-c]pyridine, the title compound was prepared as a racemic mixture or (S) iso Construct, the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.78(s,1H),8.45(s,1H),8.28(d,J=6.5Hz,1H),,7.22(d,J=6.5Hz,1H),6.45 (s,1H),3.36(s,1H),3.20(m,1H),2.51(m,2H),1.39(d,J=6.5Hz,3H). MS (ESI ⁺ ) m/z: 218.11[M] ⁺ .

Example 32: 3-(7-Methoxy-1-methyl-1H-pyrrolo[3,2-c]pyridin-3-yl)butanoic acid (Compound 22)

Starting from 4-iodo-7-methoxy-1-methyl-1H-pyrrolo[3,2-c]pyridine, the title compound was prepared as racemic Mixture or (S) isomer, the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.06(s,1H),7.98(s,1H),7.85(s,1H),6.14(s,1H),3.91(s,3H),3.66(s,1H ), 3.20(m,1H), 2.50(m,2H), 1.39(d,J=6.5Hz,3H). MS (ESI ⁺ ) m/z: 248.12[M] ⁺ .

Example 33: 3-(7-Fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)butanoic acid (Compound 23)

Starting from 4-iodo-7-fluoro-1H-pyrrolo[2,3-c]pyridine, the title compound was prepared as a racemic mixture or (S) isomer by a method analogous to Examples 1 and 3 Body, the relevant data are as follows

¹ H NMR (500MHz, chloroform) δ11.36(s,1H),10.55(s,1H),8.00(s,1H),7.58(s,1H),6.83(s,1H),3.20(m,1H ),2.51(m,2H),1.40(d,J=6.5Hz, 3H). MS (ESI ⁺ ) m/z: 222.08[M] ⁺ .

Example 34: Ethyl 3-(7-fluoro-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)butanoate (Compound 24)

Starting from 1-methyl-4-iodo-7-fluoro-1H-pyrrolo[2,3-c]pyridine, the title compound was prepared as racemic by a method analogous to Examples 1, 3 and 12 Mixture or (S) isomer, the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ7.96(s,1H),7.50(s,1H),6.27(s,1H),4.01(m,2H),3.84(s,3H),3.51(m,1H ), 2.54(m, 2H), 1.39(d, J=6.5Hz, 3H), 1.15(m, 3H). MS (ESI ⁺ ) m/z: 264.13[M] ⁺ .

Example 35: N-ethyl-3-(5-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)butyrylethylamide (Compound 25)

Starting from 4-iodo-5-methyl-1H-pyrrolo[2,3-c]pyridine, the title compound was prepared as a racemic mixture or (S ) isomers, the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.39(s,1H),8.29(s,1H),7.32(s,1H),6.84(s,1H),3.26(m,2H),3.18(m,1H ), 2.66(m,2H), 2.57(s,3H), 2.49(s,1H), 1.39(d,J=6.5Hz,3H), 1.08(m,3H). MS (ESI ⁺ ) m/z: 245.15 [M] ⁺ .

Example 36: tert-butyl 3-(7H-pyrrolo[2,3-c]pyridazin-5-yl)butanoate (Compound 26)

Starting from 4-iodo-7H-pyrrolo[2,3-c]pyridazine, the title compound was prepared by a method similar to Example 12, which was a racemic mixture or (S) isomer, and the relevant data were as follows :

¹ H NMR (500MHz, chloroform) δ9.08(s,1H),7.57(s,2H),6.38(s,1H),3.51(m,1H),2.54(m,2H),1.40(d,J =6.5Hz, 3H), 1.36(s, 9H). MS (ESI ⁺ ) m/z: 261.15 [M] ⁺ .

Example 37: tert-butyl 3-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)butanoate (Compound 27)

Starting from 4-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine, the title compound was prepared as a racemic mixture or (S ) isomers, the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ9.25(s,1H),8.52(s,1H),6.15(s,1H),3.78(s,3H),3.51(m,1H),2.53(m,2H ), 1.38(d, J=6.0Hz, 3H), 1.33(s, 9H). MS (ESI ⁺ ) m/z: 275.16[M] ⁺ .

Example 38: N-Ethyl-3-(5-(methylamino)-1H-indol-3-yl)butanamide (Compound 28)

Starting from 4-iodo-5-(methylamino)-1H-indole, the title compound was prepared as a racemic mixture or (S) isomer by methods analogous to Examples 1, 3 and 12, The relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.30(s,1H),9.52(s,1H),8.03(s,1H),7.26(s,1H),7.17(s,1H),6.50(s,1H ),6.37(s,1H),3.27(m,2H),3.18(m,1H),2.80(s,3H),2.55(m,2H),1.39(d,J=6.0Hz,3H),1.05 (m,3H). MS (ESI ⁺ ) m/z: 259.17[M] ⁺ .

Example 39: Isopropyl 3-(1-Acetyl-6-methyl-1H-indol-3-yl)butanoate (Compound 29)

Starting from 1-acetyl-4-iodo-6-methyl-1H-indole, the title compound was prepared as a racemic mixture or (S) isomer by methods analogous to Examples 1, 3 and 12 Body, the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ7.68(s,1H),7.37(s,1H),7.00(s,1H),6.98(s,1H),4.92(m,1H),3.51(m,1H ), 2.70(s,3H), 2.50(m,1H), 2.27(m,2H), 2.20(s,3H), 1.42(d,J=6.0Hz,3H), 1.15(s,6H). MS (ESI ⁺ ) m/z: 301.17[M] ⁺ .

Example 40: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (4'-methylcyclohexanecarbonyloxy ) methyl ester (compound 30)

The title compound was prepared by a method similar to Example 2, which was a racemic mixture or (2R, 3S) isomer, and the relevant data were as follows:

¹ H NMR (500MHz, chloroform) δ9.65(s, 1H), 7.11(d, J=7.0Hz, 3H), 6.04(d, J=6.5Hz, 1H), 5.91(t, J=6.5Hz, 1H),4.00(s,1H),3.81(m,1H),2.28(m,1H),1.66(m,3H),1.56(m,3H),1.38(d,J=6.0Hz,3H), 1.26(m,4H),1.01(m,3H). MS (ESI ⁺ ) m/z: 387.15 [M] ⁺ .

Example 41: (3-Methyl-7-fluoro-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid 4-methoxycyclohexane Alkylcarbonyloxy)methyl ester (compound 31)

Starting from 4-iodo-6-fluoro-1H-indole, the title compound was prepared by a method similar to Examples 1 and 2, which was a racemic mixture or (2R,3S) isomer, and the relevant data were as follows:

¹ H NMR (500MHz, chloroform) δ9.79(s,1H),7.02(s,1H),6.89(s,2H),6.52(d,J=6.5Hz,1H),6.05(d,J=6.5 Hz,1H),4.00(s,1H),3.81(m,1H),3.45(s,3H),2.97(m,1H),2.02(m,4H),1.50(m,2H),1.40(m ,3H), 1.38(d,J=6.0Hz,3H). MS (ESI ⁺ ) m/z: 421.14[M] ⁺ .

Example 42: 3-Methyl-7-methoxy-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (cyclopropanecarbonyloxy ) methyl ester (compound 32)

Starting from 4-iodo-6-methoxy-1H-indole, the title compound was prepared by a method similar to Examples 1 and 2 as a racemic mixture or (2R,3S) isomer, relevant data as follows:

¹ H NMR (500MHz, chloroform) δ9.64(s,1H),7.02(s,1H),6.78(s,2H),6.05(d,J=6.5Hz,1H),5.93(d,J=6.5 Hz,1H),4.10(s,1H),3.83(m,1H),3.73(s,3H),1.43(m,1H),1.38(d,J=6.0Hz,3H),1.11(m,2H ), 0.83(m,2H). MS (ESI ⁺ ) m/z: 361.10 [M] ⁺ .

Example 43: 3-Methyl-3,5-dihydro-2H-pyrano[4,3,2-cd]-6,8-diazaindole-2-carboxylic acid (cyclopentane acyloxy)methyl ester (compound 33)

Starting from 4-iodo-7H-pyrrolo[2,3-d]pyrimidine, the title compound was prepared as a racemic mixture or (2R,3S) isomer by a method analogous to Examples 1 and 2, The relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.98(s,1H),9.05(s,1H),7.36(s,1H),6.37(d,J=6.5Hz,1H),5.73(d,J=6.5 Hz,1H),4.00(s,1H),3.81(m,1H),2.57(m,1H),2.10(m,2H),1.84(m,2H),1.75(m,2H),1.69(m ,2H), 1.46(d,J=6.0Hz,3H). MS (ESI ⁺ ) m/z: 361.11 [M] ⁺ .

Example 44: 3-Methyl-3,5-dihydro-2H-pyrano[4,3,2-cd]-8-azaindole-2-carboxylic acid (cyclobutanecarboxy ) methyl ester (compound 34)

Starting from 4-iodo-1H-pyrrolo[2,3-b]pyridine, the title compound was prepared as a racemic mixture or (2R,3S) isomer by a method analogous to Examples 1 and 2, The relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ8.45(s,1H),7.63(s,1H),6.57(d,J=6.5Hz,1H),6.49(s,1H),5.92(d,J=6.5 Hz,1H),3.82(s,2H),3.74(m,1H),2.91(m,1H),2.50(m,2H),2.35(m,2H),2.16(m,2H),1.38(d ,J=6.0Hz, 3H). MS (ESI ⁺ ) m/z: 346.10 [M] ⁺ .

Example 45: 3-Methyl-3,5-dihydro-2H-pyrano[4,3,2-cd]-8-azaindole-2-carboxylic acid (4'-hydroxycyclohexane Formyloxy)methyl ester (compound 35)

Starting from 4-iodo-1H-pyrrolo[2,3-b]pyridine, the title compound was prepared as a racemic mixture or (2R,3S) isomer by a method analogous to Examples 1 and 2, The relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ8.23(s,1H),7.40(s,1H),6.67(d,J=6.0Hz,1H),6.37(s,1H),5.82(d,J=6.0 Hz,1H),4.00(s,1H),3.81(m,1H),3.25(m,1H),2.90(s,1H),2.76(m,2H),2.27(s,2H),1.95(m ,2H), 1.63(m,2H), 1.42(m,2H), 1.38(d,J=6.5Hz,3H). MS (ESI ⁺ ) m/z: 390.12[M] ⁺ .

Example 46: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (1'-methylcyclohexanecarbonyloxy ) methyl ester (compound 36)

The title compound was prepared by a method similar to Example 2, which was a racemic mixture or (2R,3S) isomer, and the relevant data were as follows

¹ H NMR (500MHz, chloroform) δ9.80(s,1H),7.12(s,1H),7.02(s,1H),6.67(d,J=6.0Hz,1H),5.82(d,J=6.0 Hz,1H),4.00(s,1H),3.83(m,1H),2.07(m,2H),1.66(m,4H),1.56(m,3H),1.44(d,J=6.5Hz,3H ), 1.35(m,1H), 1.09(s,3H). MS (ESI ⁺ ) m/z: 387.15 [M] ⁺ .

Example 47: 3-Methyl-7-(methylamino)-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (4'- Methoxycyclohexanecarbonyloxy)methyl ester (compound 37)

Starting from 4-iodo-N-methyl-1H-indol-6-amine, the title compound was prepared as a racemic mixture or (2R,3S) isomer by a method analogous to Examples 1 and 2 , the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ7.02(s,1H),6.75(d,J=6.0Hz,1H),6.45(s,1H),6.24(s,1H),5.83(d,J=6.0 Hz,1H),4.02(s,1H),3.84(m,1H),3.47(s,3H),2.84(s,3H),2.79(m,1H),2.57(m,1H),2.21(m ,3H), 1.82(m,3H), 1.50(m,4H), 1.38(d,J=6.5Hz,3H). MS (ESI ⁺ ) m/z: 432.17[M] ⁺ .

Example 48: 3,6-Dimethyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (4'-methylcyclohexane Carbonyloxy) methyl ester (compound 38)

Starting from 4-iodo-7-methyl-1H-indole, the title compound was prepared by a method similar to Examples 1 and 2, which was a racemic mixture or (2R,3S) isomer, and the relevant data were as follows :

¹ H NMR (500MHz, chloroform) δ8.80(s,1H),7.08(s,1H),7.02(s,1H),6.75(d,J=6.0Hz,1H),5.83(d,J=6.0 Hz,1H),4.02(s,1H),3.83(m,1H),2.84(s,3H),2.57(m,1H),1.85(m,2H),1.73(m,4H),1.53(m ,1H), 1.52(m,4H), 1.38(d,J=6.5Hz,3H), 1.02(m,3H). MS (ESI ⁺ ) m/z: 401.17[M] ⁺ .

Example 49: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]-6,8-diazaindole-2-carboxylic acid (4'- Methoxycyclohexanecarbonyloxy) methyl ester (compound 39)

Starting from 4-iodo-7H-pyrrolo[2,3-d]pyrimidine, the title compound was prepared as a racemic mixture or (2R,3S) isomer by a method analogous to Examples 1 and 2, The relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ9.05(s, 1H), 6.76(d, J=6.0Hz, 1H), 6.37(s, 1H), 5.88(d, J=6.0Hz, 1H), 4.00( s,1H),3.81(m,1H),3.47(s,3H),2.84(m,1H),2.37(m,1H),2.36(m,3H),2.25(m,2H),2.07(m ,2H), 1.65(m,2H), 1.56(m,2H), 1.47(d,J=6.5Hz,3H). MS (ESI ⁺ ) m/z: 405.14[M] ⁺ .

Example 50: 3-Methyl-3,5-dihydro-2H-pyrano[4,3,2-cd]-8-azaindole-2-carboxylic acid (4'-hydroxycyclohexane Carbonyloxy) methyl ester (compound 40)

Starting from 4-iodo-1H-pyrrolo[2,3-b]pyridine, the title compound was prepared as a racemic mixture or (2R,3S) isomer by a method analogous to Examples 1 and 2, The relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ8.16(s,1H),6.96(s,1H),6.86(d,J=6.0Hz,1H),6.64(s,1H),5.78(d,J=6.0 Hz,1H),4.81(s,1H),4.01(s,1H),3.68(m,1H),3.42(m,2H),2.66(m,2H),1.95(m,2H),1.71(m ,2H), 1.52(m,3H), 1.43(d,J=6.5Hz,3H). MS (ESI ⁺ ) m/z: 374.15 [M] ⁺ .

Example 51: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]-6,8-diazaindole-2-carboxylic acid (4'- Hydroxycyclohexanecarbonyloxy)methyl ester (compound 41)

Starting from 4-iodo-1H-pyrrolo[2,3-b]pyrimidine, the title compound was prepared as a racemic mixture or (2R,3S) isomer by a method similar to that of Examples 1 and 2, The relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.20(s,1H),8.23(s,1H),7.26(s,1H),6.86(d,J=6.0Hz,1H),5.78(d,J=6.0 Hz,1H),4.05(s,1H),3.81(m,1H),3.75(s,1H),2.90(m,1H),2.76(m,2H),2.06(m,2H),1.75(m ,2H), 1.55(m,3H), 1.39(d,J=6.5Hz,3H). MS (ESI ⁺ ) m/z: 390.12[M] ⁺ .

Example 52: 3-Methyl-8-methoxy-3,5-dihydro-2H-pyrano[4,3,2-cd]indole-2-carboxylic acid (4'-methylcyclo Hexanecarbonyloxy)methyl ester (compound 42)

Starting from 4-iodo-5-methoxy-1H-indole, the title compound was prepared by a method similar to Examples 1 and 2 as a racemic mixture or (2R,3S) isomer with the following data :

¹ H NMR (500MHz, chloroform) δ11.23(s,1H),7.02(s,1H),6.88(s,1H),6.80(s,1H),6.56(d,J=6.0Hz,1H), 5.68(d,J=6.0Hz,1H),4.81(s,1H),4.01(m,1H),3.91(s,3H),2.52(m,2H),1.67(m,2H),1.53(t , J=5.5Hz, 3H), 1.40(m, 2H), 1.34(d, J=6.5Hz, 3H), 1.03(m, 2H). MS (ESI ⁺ ) m/z: 401.18[M] ⁺ .

Example 53: 3-Methyl-3,5-dihydro-2H-pyrano[4,3,2-cd]indole-2-carboxylic acid (4-fluorocyclohexanecarbonyloxy)methyl Esters (Compound 43)

The title compound was prepared by a method similar to Example 2, which was a racemic mixture or (2R, 3S) isomer, and the relevant data were as follows:

¹ H NMR (500MHz, chloroform) δ11.31(s,1H),7.14(s,1H),7.02(s,1H),6.98(s,1H),6.82(s,1H),6.66(d,J =6.0Hz,1H),5.73(d,J=6.0Hz,1H),4.81(s,1H),4.49(m,1H),2.69(m,2H),1.51(m,3H),1.49(m ,4H), 1.34(d,J=6.5Hz,3H). MS (ESI ⁺ ) m/z: 375.15 [M] ⁺ .

Example 54: 3,7-Dimethyl-3,5-dihydro-2H-pyrano[4,3,2-cd]indole-2-carboxylic acid (4'-chlorocyclohexanecarbonyloxy base) methyl ester (compound 44)

Starting from 4-iodo-6-methyl-1H-indole, the title compound was prepared by a method similar to Examples 1 and 2, which was a racemic mixture or (2R,3S) isomer, and the relevant data were as follows :

¹ H NMR (500MHz, chloroform) δ11.28(s,1H),6.82(s,1H),6.38(s,1H),6.14(s,1H),6.06(d,J=6.0Hz,1H), 5.83(d,J=6.0Hz,1H),4.33(s,1H),3.88(m,1H),3.11(m,1H),2.38(s,3H),2.23(m,4H),1.75(m ,3H), 1.35(m,2H), 1.26(d,J=6.5Hz,3H). MS (ESI ⁺ ) m/z: 405.13[M] ⁺ .

Example 55: 3-Methyl-3,5-dihydro-2H-pyrano[4,3,2-cd]-6,8-diazaindole-2-carboxylic acid (4'-methyl Aminocyclohexanecarbonyloxy)methyl ester (compound 45)

Starting from 4-iodo-7H-pyrrolo[2,3-d]pyrimidine, the title compound was prepared as a racemic mixture or (2R,3S) isomer by a method similar to that of Examples 1 and 2, The relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.19(s,1H),9.12(s,1H),6.37(s,1H),6.26(d,J=6.0Hz,1H),5.83(d,J=6.0 Hz,1H),4.03(s,1H),3.98(m,1H),2.48(s,3H),2.12(m,1H),1.82(m,3H),1.56(m,3H),1.43(m ,3H), 1.26(d,J=6.5Hz,3H). MS (ESI ⁺ ) m/z: 386.20 [M] ⁺ .

Example 56: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (isobutyryloxy)methyl ester (compound 46)

The title compound was prepared by a method similar to Example 2, which was a racemic mixture or (2R, 3S) isomer, and the relevant data were as follows:

¹ H NMR (500MHz, chloroform) δ11.21(s,1H),8.66(s,1H),7.17(s,1H),7.05(s,1H),7.02(s,1H),6.86(d,J =6.0Hz,1H),5.63(d,J=6.0Hz,1H),4.00(s,1H),3.81(m,1H),2.66(m,1H),1.41(d,J=6.5Hz,3H ), 1.15(s,6H). MS (ESI ⁺ ) m/z: 333.10 [M] ⁺ .

Example 57: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (pivaloyloxy)methyl ester (compound 47)

The title compound was prepared by a method similar to Example 2, which was a racemic mixture or (2R, 3S) isomer, and the relevant data were as follows:

¹ H NMR (500MHz, chloroform) δ11.80(s,1H),8.60(s,1H),7.56(m,1H),7.16(m,1H),7.02(s,1H),6.36(d,J =6.0Hz,1H),5.23(d,J=6.0Hz,1H),4.06(s,1H),3.83(m,1H),1.46(d,J=6.5Hz,3H),1.27(s,9H ). MS (ESI ⁺ ) m/z: 347.12[M] ⁺ .

Example 58: 3,7-Dimethyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (pivaloyloxy)methyl Esters (Compound 48)

Starting from 4-iodo-6-methyl-1H-indole, the title compound was prepared by a method similar to Examples 1 and 2, which was a racemic mixture or (2R,3S) isomer, and the relevant data were as follows :

¹ H NMR (500MHz, chloroform) δ11.77(s,1H),7.65(s,1H),7.01(s,1H),6.37(s,1H),6.29(d,J=6.0Hz,1H), 5.73(d,J=6.0Hz,1H),3.85(s,1H),3.71(m,1H),2.47(s,3H),1.40(d,J=6.5Hz,3H),1.26(s,9H ). MS (ESI ⁺ ) m/z: 361.13 [M] ⁺ .

Example 59: 3-Methyl-6-fluoro-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (1'-(pivaloyl Oxy)) ethyl ester (compound 49)

Starting from 4-iodo-7-fluoro-1H-indole, the title compound was prepared by a method similar to Examples 1 and 2, which was a racemic mixture or (2R,3S) isomer, and the relevant data were as follows:

¹ H NMR (500MHz, chloroform) δ11.69(s,1H),7.94(s,1H),7.11(s,1H),7.02(s,1H),6.87(m,1H),4.08(s,1H ), 3.80(m,1H), 1.74(m,3H), 1.46(d,J=6.5Hz,3H), 1.27(s,9H). MS (ESI ⁺ ) m/z: 379.13[M] ⁺ .

Example 60: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]-6,8-diazaindole-2-carboxylic acid (1'- (pivaloyloxy))ethyl ester (compound 50)

Starting from 4-iodo-7H-pyrrolo[2,3-d]pyrimidine, the title compound was prepared as a racemic mixture or (2R,3S) isomer by a method similar to that of Examples 1 and 2, The relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.51(s,1H),9.05(s,1H),7.34(s,1H),6.37(m,1H),3.89(s,1H),3.71(m,1H ), 1.75(s,3H), 1.47(d,J=6.5Hz,3H), 1.26(s,9H). MS (ESI ⁺ ) m/z: 363.13[M] ⁺ .

Example 61: 3-Methyl-6-methoxy-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (1'-(propane Acyloxy)) ethyl ester (compound 51)

Using compound 4 as raw material, the title compound was prepared by a method similar to Example 2, which is a racemic mixture or (2R,3S) isomer, and the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.28(s,1H),7.94(s,1H),7.13(s,1H),7.02(s,1H),6.67(s,1H),4.10(s,3H ), 4.01(s,1H), 3.81(s,1H), 2.54(m,2H), 1.75(m,3H), 1.41(d,J=6.5Hz,3H), 1.28(m,3H). MS (ESI ⁺ ) m/z: 363.11[M] ⁺ .

Example 62: 3-Methyl-3,5-dihydro-2H-pyrano[4,3,2-cd]-6,8-diazaindole-2-carboxylic acid (1'-( pivaloyloxy)) ethyl ester (compound 52)

The title compound was prepared by a method similar to Example 43 as a racemic mixture or (2R,3S) isomer, and the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.30(s,1H),9.02(s,1H),6.57(s,1H),6.39(d,J=6.0Hz,1H),5.63(d,J=6.0 Hz, 1H), 4.43(s, 1H), 4.01(m, 1H), 1.54(d, J=6.5Hz, 3H), 1.28(s, 9H). MS (ESI ⁺ ) m/z: 333.13[M] ⁺ .

Example 65: Benzoyloxymethyl 3-methyl-3,5-dihydro-2H-pyrano[4,3,2-cd]indole-2-carboxylate (Compound 55)

The title compound was prepared by a method similar to Example 2, which was a racemic mixture or (2R, 3S) isomer, and the relevant data were as follows:

¹ H NMR (500MHz, chloroform) δ11.39(s,1H),7.89(m,2H),7.71(m,2H),7.28(s,1H),7.10(m,2H),6.80(m,2H ),6.12(d,J=6.0Hz,1H),5.82(d,J=6.0Hz,1H),4.40(s,1H),3.81(m,1H),1.26(d,J=7.0Hz,3H ). MS (ESI ⁺ ) m/z: 351.35 [M] ⁺ .

Example 66: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (4'-methoxybenzoyloxy ) methyl ester (compound 56)

Starting from compound C, which is a racemic mixture or (2R, 3S) isomer, the title compound, which is a racemic mixture or (2R, 3S) isomer, was prepared by a method similar to Example 2, The relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.33(s,1H),9.80(s,1H),7.14(m,2H),7.04(m,2H),6.93(m,4H),6.89(d,J =6.0Hz,1H),5.83(d,J=6.0Hz,1H),3.89(s,3H),3.77(s,1H),3.64(m,1H),1.22(d,J=7.0Hz,3H ). MS (ESI ⁺ ) m/z: 397.10 [M] ⁺ .

Example 67: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (4'-methylbenzoyloxy) Methyl ester (Compound 57)

Starting from compound C, which is a racemic mixture or (2R, 3S) isomer, the title compound, which is a racemic mixture or (2R, 3S) isomer, was prepared by a method similar to Example 2, The relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ7.98(m,2H),7.75(m,2H),7.13(m,2H),7.13(m,3H),6.81(d,J=6.0Hz,1H), 5.76(d, J=6.0Hz, 1H), 3.96(s, 1H), 3.81(m, 1H), 2.47(s, 3H), 1.28(d, J=7.0Hz, 3H). MS (ESI ⁺ ) m/z: 381.10 [M] ⁺ .

Example 68: 3-Methyl-7-fluoro-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (3'-fluorobenzoyl Oxy) methyl ester (compound 58)

The title compound was prepared by a method similar to Example 41 as a racemic mixture or (2R,3S) isomer, and the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.71(s,1H),7.77(m,3H),7.37(m,1H),6.92(m,3H),7.09(d,J=6.0Hz,1H), 5.80(d, J=6.0Hz, 1H), 3.86(s, 1H), 3.81(m, 1H), 1.26(d, J=7.0Hz, 3H). MS (ESI ⁺ ) m/z: 403.07[M] ⁺ .

Example 69: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (4'-methylaminobenzoyloxy ) methyl ester (compound 59)

Starting from compound C, which is a racemic mixture or (2R, 3S) isomer, the title compound, which is a racemic mixture or (2R, 3S) isomer, was prepared by a method similar to Example 2, The relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.82(s,1H),8.36(m,1H),7.78(m,2H),7.12(m,2H),7.09(m,2H),6.68(m,2H ),6.79(d,J=6.0Hz,1H),5.63(d,J=6.0Hz,1H),4.21(s,1H),4.00(m,1H),2.90(s,3H),1.31(d , J=7.0Hz, 3H). MS (ESI ⁺ ) m/z: 396.11 [M] ⁺ .

Example 70: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (4'-hydroxybenzoyloxy)methanol base ester (compound 60)

The title compound was prepared by a method similar to Example 2, which was a racemic mixture or (2R, 3S) isomer, and the relevant data were as follows:

¹ H NMR (500MHz, chloroform) δ11.61(s,1H),7.87(s,2H),7.14(m,2H),6.93(m,4H),6.64(d,J=6.0Hz,1H), 5.57(d, J=6.0Hz, 1H), 4.13(s, 1H), 3.84(s, 1H), 3.81(m, 1H), 1.42(d, J=7.0Hz, 3H). MS (ESI ⁺ ) m/z: 383.42 [M] ⁺ .

Example 71: 3-Methyl-3,5-dihydro-2H-pyrano[4,3,2-cd]indole-2-carboxylic acid (4'-methylbenzoyloxy)methanol base ester (compound 61)

Starting from compound C, which is a racemic mixture or (2R, 3S) isomer, the title compound, which is a racemic mixture or (2R, 3S) isomer, was prepared by a method similar to Example 2, The relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.83(s,1H),7.89(m,2H),7.21(m,2H),7.13(m,2H),6.80(m,2H),6.72(d,J =6.0Hz,1H),5.62(d,J=6.0Hz,1H),4.01(s,1H),3.81(m,1H),2.47(s,3H),1.28(d,J=7.0Hz,3H ). MS (ESI ⁺ ) m/z: 365.38[M] ⁺ .

Example 72: 3-Methyl-7-methoxy-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (1'-(4 ''-methylbenzoyloxy))ethyl ester (compound 62)

Starting from 4-iodo-6-methoxy-1H-indole, the title compound was prepared by a method similar to Examples 1 and 2 as a racemic mixture or (2R,3S) isomer, relevant data as follows:

¹ H NMR (500MHz, chloroform) δ11.81(s,1H),7.89(m,2H),7.20(m,2H),6.80(s,1H),6.68(m,2H),6.58(m,1H ),4.00(s,1H),3.88(s,3H),3.81(m,1H),2.46(s,3H),1.81(m,3H),1.52(d,J=7.0Hz,3H). MS (ESI ⁺ ) m/z: 425.13[M] ⁺ .

Example 73: 3-Methyl-7-methoxy-3,5-dihydro-2H-thiopyrano[4,3,2-cd]-6,8-diazaindole-2- Carboxylic acid (1'-(4''-ethylbenzoyloxy)) ethyl ester (compound 63)

Starting from 2-methoxy-4-iodo-7H-pyrrolo[2,3-d]pyrimidine, the title compound was prepared as a racemic mixture or (2R, 3S) isomer, relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ7.94(m,2H),7.53(m,2H),6.61(m,1H),6.28(s,1H),4.38(s,1H),3.87(m,1H ), 3.74(s,3H), 2.71(s,3H), 1.82(m,3H), 1.26(d,J=7.0Hz,3H), 1.19(m,3H). MS (ESI ⁺ ) m/z: 441.14[M] ⁺ .

Example 74: 3,7-Dimethyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]-8-azaindole-2-carboxylic acid (1'- (4''-Methoxybenzoyloxy))ethyl ester (Compound 64)

Starting from 4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridine, the title compound was prepared as a racemic mixture or (2R,3S ) isomers, the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.77(s,1H),7.94(m,2H),7.19(s,1H),6.92(m,2H),6.61(m,1H),6.28(s,1H ),4.13(s,1H),3.84(m,1H),3.81(s,3H),1.78(m,3H),1.54(d,J=7.0Hz,3H). MS (ESI ⁺ ) m/z: 426.12[M] ⁺ .

Example 75: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]-7,8-diazaindole-2-carboxylic acid (1'- Benzoyloxy)ethyl ester (compound 65)

Starting from 4-iodo-7H-pyrrolo[2,3-c]pyridazine, the title compound was prepared as a racemic mixture or (2R,3S) isomer by a method similar to Examples 1 and 2 , the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.77(s,1H),9.16(m,1H),8.01(m,2H),7.60(m,3H),6.65(m,1H),6.22(s,1H ), 4.38(s,1H), 3.79(m,1H), 1.80(m,3H), 1.34(d,J=7.0Hz,3H). MS (ESI ⁺ ) m/z: 383.09[M] ⁺ .

Example 76: 3,7-Dimethyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]-6,8-diazaindole-2-carboxylic acid ( 1'-benzoyloxy)ethyl ester (compound 66)

Starting from 2-methyl-4-iodo-7H-pyrrolo[2,3-d]pyrimidine, the title compound was prepared as a racemic mixture or (2R,3S ) isomers, the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.81(s,1H),8.01(m,2H),7.72(m,2H),7.57(s,2H),6.54(m,1H),6.37(m,1H ), 4.86(s,1H), 3.81(m,1H), 2.48(s,3H), 1.81(m,3H), 1.29(d,J=7.0Hz,3H). MS (ESI ⁺ ) m/z: 397.11 [M] ⁺ .

Example 77: 3-Methyl-7-fluoro-3,5-dihydro-2H-pyrano[4,3,2-cd]indole-2-carboxylic acid (3'-fluorobenzoyloxy base) methyl ester (compound 67)

The title compound was prepared by a method similar to Example 41 as a racemic mixture or (2R,3S) isomer, and the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ7.71(m,2H),7.38(m,2H),6.80(s,1H),6.64(d,J=6.0Hz,1H),6.59(s,1H), 6.51(s, 2H), 5.57(d, J=6.0Hz, 1H), 4.81(s, 1H), 4.01(m, 1H), 1.24(d, J=7.0Hz, 3H). MS (ESI ⁺ ) m/z: 387.09[M] ⁺ .

Example 78: 3-Methyl-3,5-dihydro-2H-pyrano[4,3,2-cd]indole-2-carboxylic acid (4'-methoxybenzoyloxy) Methyl ester (compound 68)

Starting from 4-iodo-1H-indole, the title compound was prepared by a method similar to Examples 1 and 2, which was a racemic mixture or (2R,3S) isomer, and the relevant data were as follows:

¹ H NMR (500MHz, chloroform) δ11.75(s,1H),7.98(m,2H),7.13(m,1H),6.98(m,3H),6.75(m,2H),6.72(d,J =6.0Hz,1H),5.65(d,J=6.0Hz,1H),4.43(s,1H),4.01(m,1H),3.87(s,3H),1.55(d,J=7.0Hz,3H ). MS (ESI ⁺ ) m/z: 381.12 [M] ⁺ .

Example 79: (3-(1H-indol-3-yl)butyryloxy)methyl benzoate (Compound 69)

The title compound was prepared by a method similar to Example 4, which was a racemic mixture or (2R, 3S) isomer, and the relevant data were as follows:

¹ H NMR (500MHz, chloroform) δ11.68(s,1H),8.04(m,2H),7.59(m,4H),7.29(m,2H),6.97(m,1H),6.80(s,1H ),6.62(d,J=6.0Hz,1H),5.83(d,J=6.0Hz,1H),3.51(m,1H),2.64(m,2H),1.38(d,J=7.0Hz,3H ). MS (ESI ⁺ ) m/z: 337.13[M] ⁺ .

Example 80: (3-(1H-indol-3-yl)butyryloxy)methyl 4-methylbenzoate (Compound 70)

The title compound was prepared by a method similar to Example 4, which was a racemic mixture or (2R, 3S) isomer, and the relevant data were as follows:

¹ H NMR (500MHz, chloroform) δ11.81(s,1H),7.89(m,2H),7.49(m,2H),7.25(m,3H),6.97(m,1H),6.80(s,1H ),6.72(d,J=6.5Hz,1H),5.63(d,J=6.5Hz,1H),3.58(m,1H),2.43(m,2H),1.30(d,J=7.0Hz,3H ). MS (ESI ⁺ ) m/z: 351.15 [M] ⁺ .

Example 81: (3-(1H-indol-3-yl)butyryloxy)methyl 4-methoxybenzoate (Compound 71)

The title compound was prepared by a method similar to Example 4, which was a racemic mixture or (2R, 3S) isomer, and the relevant data were as follows:

H NMR (500MHz, chloroform) δ11.90(s,1H),7.98(m,2H),7.44(m,2H),7.20(m,2H),6.90(m,2H),6.80(s,1H) ,6.68(d,J=6.5Hz,1H),5.59(d,J=6.5Hz,1H),3.56(m,1H),2.37(m,2H),2.11(m,3H),1.32(d, J=7.0Hz, 3H). MS (ESI ⁺ ) m/z: 367.14[M] ⁺ .

Example 82: (3-(6-Methyl-1H-indol-3-yl)butyryloxy)methyl 4-methoxycyclohexanecarboxylate (Compound 72)

Starting from 2-iodo-6-methyl-1H-indole, the title compound was prepared by a method analogous to Examples 1, 3 and 4 as a racemic mixture or (2R,3S) isomer, related Data are as follows:

¹ H NMR (500MHz, chloroform) δ11.69(s,1H),7.72(s,1H),6.98(m,2H), 6.80(m,1H),6.74(d,J=6.5Hz,1H), 5.62(d,J=6.5Hz,1H),3.51(m,1H),3.45(s,3H),2.83(m,2H),2.35(m,3H),1.93(m,2H),1.88(m ,3H), 1.66(m,4H), 1.45(m,2H), 1.39(d,J=7.0Hz,3H). MS (ESI ⁺ ) m/z: 387.20 [M] ⁺ .

Example 83: (3-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)butyryloxy)methyl cyclohexanecarboxylate (Compound 73)

Starting from 6-iodo-7H-pyrrolo[2,3-d]pyrimidine, the title compound was prepared as a racemic mixture or (2R,3S) isomer by methods analogous to Examples 1, 3 and 4 Body, the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.39(s,1H),9.25(s,1H),8.74(s,1H),6.73(s,1H),6.34(d,J=6.5Hz,1H), 5.53(d,J=6.5Hz,1H),3.51(m,1H),2.48(m,3H),1.92(m,2H),1.72(m,2H),1.48(m,6H),1.35(d , J=7.0Hz, 3H). MS (ESI ⁺ ) m/z: 345.17[M] ⁺ .

Example 84: 3-(7H-Pyrrolo[2,3-d]pyrimidin-5-yl)butanoic acid (pivaloyloxy)methyl ester (Compound 74)

The title compound was prepared by a method similar to Example 83 as a racemic mixture or (2R,3S) isomer, and the relevant data are as follows:

¹ H NMR (500MHz, chloroform) δ11.53(s,1H),9.25(s,1H),8.71(s,1H),6.79(s,1H),6.29(d,J=6.5Hz,1H), 5.33(d, J=6.5Hz, 1H), 3.51(m, 1H), 2.52(m, 2H), 1.39(d, J=7.0Hz, 3H), 1.11(s, 9H). MS (ESI ⁺ ) m/z: 319.15[M] ⁺ .

Example 85: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (pyridin-2-ylformyloxy)methanol base ester (compound 81)

The title compound was prepared by a method similar to Example 2, which was a racemic mixture or (2R, 3S) isomer, and the relevant data were as follows:

1H NMR (500MHz, chloroform) δ11.91(s,1H),9.65(s,1H),8.27(m,2H),8.04(s,1H),7.14(m,2H),7.92(m,2H) ,6.29(d,J=6.5Hz,1H),5.33(d,J=6.5Hz,1H),4.00(s,1H),3.81(m,1H),1.18(d,J=7.0Hz,3H) . MS (ESI ⁺ ) m/z: 368.08[M]+.

Example 86: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (benzofuran-2-ylformyloxy ) methyl ester (compound 82)

The title compound was prepared by a method similar to Example 2, which was a racemic mixture or (2R, 3S) isomer, and the relevant data were as follows:

1H NMR (500MHz, chloroform) δ11.09(s,1H),7.49(m,4H),7.12(m,3H),7.04(m,2H),6.65(d,J=6.5Hz,1H),5.53 (d, J=6.5Hz, 1H), 4.86(s, 1H), 3.81(m, 1H), 1.46(d, J=7.0Hz, 3H). MS (ESI ⁺ ) m/z: 407.08[M] ⁺ .

Example 87: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (indol-3-ylformyloxy) Methyl ester (compound 83)

The title compound was prepared by a method similar to Example 2, which was a racemic mixture or (2R, 3S) isomer, and the relevant data were as follows:

1H NMR (500MHz, chloroform) δ11.81(s,1H),9.90(m,1H),8.84(s,1H),7.92(s,1H),7.44(m,2H),7.11(m,3H) ,7.02(m,2H),6.72(d,J=6.5Hz,1H),5.65(d,J=6.5Hz,1H),4.00(s,1H),3.81(m,1H),1.18(d, J=7.0Hz, 3H). MS (ESI ⁺ ) m/z: 406.10[M] ⁺ .

Example 88: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-formyl(2'-morpholinoethyl)amine ( Compound 84)

Starting from compound 2-morpholino-ethylamine and compound C, which is a racemic mixture or (2R, 3S) isomer, the title compound was prepared according to a method similar to Example 12, which was a racemic mixture or (2R,3S) isomer, the relevant data are as follows:

¹ H NMR (400MHz,DMSO)δ10.88(s,1H),7.87(s,1H),7.15(d,J=2.0Hz,1H),7.09(d,J=8.0Hz,1H),6.99( t,J=7.6Hz,1H),6.76(d,J=7.2Hz,1H),4.10(d,J=3.6Hz,1H),3.59(m,1H),3.54(t,J=4.4Hz, 4H), 3.29(m, 1H), 3.11(m, 1H), 2.32(t, J=2.4Hz, 6H), 1.26(d, J=6.4Hz, 3H). MS (ESI ⁺ ) m/z: 346.2 [M+H] ⁺ .

Example 89: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (2'-morpholino)ethyl ester (Compound 85)

Starting from compound 2-morpholino-ethanol and compound C, which is a racemic mixture or (2R, 3S) isomer, the title compound was prepared according to a method similar to Example 12, which was a racemic mixture or ( 2R,3S) isomers, the relevant data are as follows:

¹ H NMR(400MHz,DMSO)δ10.91(s,1H),7.17(d,J=2.0Hz,1H),7.11(d,J=8.4Hz,1H),7.00(t,J=7.6Hz, 1H),6.78(d,J=7.2Hz,1H),4.29(d,J=3.6Hz,1H),4.12(m,2H),3.55(m,1H),3.52(m,4H),2.39( m, 2H), 2.31 (m, 4H), 1.27 (d, J=6.8Hz, 3H). MS (ESI ⁺ ) m/z: 347.2 [M+H] ⁺ .

Example 90: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-formyl(3'-dimethylaminopropyl)amine ( Compound 86)

Starting from N,N-dimethyl-1,3-propylenediamine and compound C, which is a racemic mixture or (2R,3S) isomer, the title compound was prepared according to a method similar to Example 12, which is Racemic mixture or (2R,3S) isomer, the relevant data are as follows:

¹ H NMR(400MHz,DMSO)δ10.87(s,1H),8.07(t,J=3.6Hz,1H),7.14(d,J=2.0Hz,1H),7.09(d,J=8.0Hz, 1H),6.98(t,J=7.6Hz,1H),6.75(d,J=7.2Hz,1H),4.11(d,J=3.6Hz,1H),3.59(m,1H),3.16(m, 1H), 3.04(m, 1H), 2.19(t, J=7.2Hz, 2H), 2.11(s, 6H), 1.53(m, 2H), 1.19(d, J=6.8Hz, 3H). MS (ESI ⁺ ) m/z: 318.2 [M+H] ⁺ .

Example 91: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-formyl(2'-dimethylaminoethyl)amine ( Compound 87)

Starting from N,N-dimethylethylenediamine and compound C, which is a racemic mixture or (2R,3S) isomer, the title compound was prepared according to a method similar to Example 12, which is a racemic mixture Or (2R,3S) isomers, the relevant data are as follows:

¹ H NMR (400MHz,DMSO)δ10.87(s,1H),7.95(s,1H),7.14(d,J=2.0Hz,1H),7.09(d,J=8.0Hz,1H),6.98( t,J=7.6Hz,1H),6.75(d,J=7.2Hz,1H),4.11(d,J=3.2Hz,1H),3.58(m,1H),3.22(m,1H),3.09( m, 1H), 2.26(t, J=6.8Hz, 2H), 2.10(d, J=3.6Hz, 6H), 1.19(d, J=6.8Hz, 3H). MS (ESI ⁺ ) m/z: 304.1 [M+H] ⁺ .

Example 92: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (4'-fluorobenzoyloxy)methanol base ester (compound 88)

Using chloromethyl 4-fluorobenzoate and compound C as raw materials, which are racemic mixtures or (2R, 3S) isomers, the title compound was prepared according to a method similar to Example 2, which was a racemic mixture or (2R,3S) isomers, the relevant data are as follows:

¹ H NMR (400MHz,DMSO)δ10.92(s,1H),7.99(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,2H),7.16(s,1H),7.12( d,J=8.0Hz,1H),7.00(t,J=7.6Hz,1H),6.77(d,J=7.2Hz,1H),6.00(d,J=6.0Hz,1H),5.92(d, J=6.0Hz, 1H), 4.42(d, J=3.6Hz, 1H), 3.62(m, 1H), 1.24(d, J=6.8Hz, 3H). MS (ESI ⁺ ) m/z: 408.1 [M+Na] ⁺ , 424.0 [M+Ka] ⁺ .

Example 93: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (adamantane-1-formyloxy)methanol base ester (compound 89)

Using amantadin-1-ylcarboxylic acid chloromethyl ester and compound C as raw materials, which are racemic mixtures or (2R, 3S) isomers, the title compound was prepared according to a method similar to Example 2, which was racemic Rotary mixture or (2R,3S) isomer, the relevant data are as follows:

¹ H NMR(400MHz,DMSO)δ10.93(s,1H),7.18(d,J=1.2Hz,1H),7.13(d,J=8.0Hz,1H),7.00(t,J=7.6Hz, 1H),6.77(d,J=7.2Hz,1H),5.73(d,J=5.6Hz,1H),5.67(d,J=5.6Hz,1H),4.34(d,J=4.0Hz,1H) ,3.58(m,1H),1.97(s,3H),1.77(d,J=2.4Hz,6H),1.66(m,6H),1.27(d,J=6.8Hz,3H). MS (ESI ⁺ ) m/z: 448.2 [M+Na] ⁺ , 464.1 [M+Ka] ⁺ .

Example 94: 3-methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid cyclohexanecarbonyloxymethyl ester (Compound 90 )

Starting from chloromethyl cyclohexanecarboxylate and compound C, which is a racemic mixture or (2R, 3S) isomer, the title compound was prepared by a method similar to Example 2, which was a racemic mixture or (2R,3S) isomer, the relevant data are as follows:

¹ H NMR (400MHz,DMSO)δ10.93(s,1H),7.18(s,1H),7.13(d,J=8.4Hz,1H),7.00(t,J=7.6Hz,1H),6.78( d,J=7.2Hz,1H),5.73(d,J=6.0Hz,1H),5.67(d,J=6.0Hz,1H),4.35(d,J=3.6Hz,1H),3.59(m, 1H), 2.31(m, 1H), 1.79(m, 2H), 1.67(m, 2H), 1.57(d, J=10.4Hz, 1H), 1.26(m, 8H). MS (ESI ⁺ ) m/z: 396.1 [M+Na] ⁺ , 412.1 [M+Ka] ⁺ .

Example 95: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (1'-benzoyloxy)ethyl Esters (Compound 91)

Starting from 1-chloroethyl benzoate and compound C, which is a racemic mixture or (2R, 3S) isomer, the title compound was prepared by a method similar to Example 2, which was a racemic mixture or (2R,3S) isomer, the relevant data are as follows:

¹ H NMR(400MHz,DMSO)δ10.85(s,1H),8.01(d,J=8.0Hz,2H),7.66(t,J=7.2Hz,1H),7.55(d,J=8.0Hz, 2H),7.16(s,1H),7.12(d,J=8.0Hz,1H),7.00(t,J=7.6Hz,1H),6.77(d,J=7.2Hz,1H),6.76(m, 1H), 4.34(d, J=4.0Hz, 1H), 3.58(m, 1H), 1.40(m, 3H), 1.24(d, J=6.8Hz, 3H). MS (ESI ⁺ ) m/z: 404.1 [M+Na] ⁺ , 420.1 [M+Ka] ⁺ .

Example 96: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (1'-cyclohexanecarbonyloxy)ethyl base ester (compound 92)

Starting from chloroethyl 1-cyclohexanecarboxylate and compound C, which is a racemic mixture or (2R,3S) isomer, the title compound was prepared by a method similar to Example 2, which was racemic Mixture or (2R,3S) isomer, relevant data are as follows:

H NMR(400MHz,DMSO)δ10.92(s,1H),7.18(s,1H),7.13(d,J=8.4Hz,1H),7.00(t,J=7.6Hz,1H),6.78(d ,J=7.2Hz,1H),6.76(m,1H),2.31(m,3H),1.40(m,14H). MS (ESI ⁺ ) m/z: 410.1 [M+Na] ⁺ , 426.1 [M+Ka] ⁺ .

Example 97: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-formyl (3'-imidazol-1-ylpropyl) Amine (Compound 93)

Starting from compound 3-imidazol-1-ylpropylamine and compound C, which is a racemic mixture or (2R, 3S) isomer, the title compound was prepared according to a method similar to Example 12, which was a racemic mixture or (2R,3S) isomer, the relevant data are as follows:

¹ H NMR (400MHz,DMSO)δ10.88(s,1H),8.19(t,J=3.2Hz,1H),7.60(s,1H),7.15(t,J=3.6Hz,2H),7.09( d,J=8.0Hz,1H),6.98(t,J=7.6Hz,1H),6.89(s,1H),6.76(d,J=7.2Hz,1H),4.14(d,J=3.6Hz, 1H), 3.96(t, J=7.6Hz, 2H), 3.63(m, 1H), 3.09(m, 1H), 3.01(m, 1H), 1.84(m, 2H), 1.19(d, J=6.8 Hz, 3H). MS (ESI ⁺ ) m/z: 341.1 [M+H] ⁺ , 363.1 [M+Na] ⁺ .

Example 98: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-formyl (3'-butyrolactam-1-ylpropane base) amine (compound 94)

Starting from compound 3-butyrolactam-1-ylpropylamine and compound C, which is a racemic mixture or (2R, 3S) isomer, the title compound was prepared according to a method similar to Example 12, which was racemic Mixture or (2R,3S) isomer, relevant data are as follows:

¹ H NMR (400MHz,DMSO)δ10.87(s,1H),8.13(t,J=4.8Hz,1H),7.14(s,1H),7.08(d,J=8.0Hz,1H),6.98( t,J=7.6Hz,1H),6.75(d,J=7.2Hz,1H),4.12(d,J=3.2Hz,1H),3.61(m,1H),3.23(m,3H),3.06( m, 1H), 2.20(t, J=8.0Hz, 2H), 1.92(m, 2H), 1.57(t, J=6.8Hz, 2H), 1.18(d, J=6.8Hz, 3H). MS (ESI ⁺ ) m/z: 358.2[M+H] ⁺ , 380.2[M+Na] ⁺ .

Example 99: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (2-benzoyloxy)ethyl ester (compound 95)

Starting from 2-chloroethyl benzoate and compound C, which is a racemic mixture or (2R, 3S) isomer, the title compound was prepared by a method similar to Example 2, which was a racemic mixture or (2R,3S) isomer, the relevant data are as follows:

¹ H NMR(400MHz,DMSO)δ10.90(s,1H),7.97(d,J=7.2Hz,1H),7.68(t,J=7.6Hz,1H),7.54(t,J=7.7Hz, 2H),7.12(m,2H),6.96(t,J=7.2Hz,1H),6.76(d,J=7.2Hz,1H),4.45(m,2H),4.36(d,J=3.6Hz, 1H), 3.63 (m, 1H), 1.22 (d, J=6.8Hz, 3H). MS (ESI ⁺ ) m/z: 404.2[M+Na] ⁺ , 420.0[M+Ka] ⁺ .

Example 100: 3-Methyl-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid (3-benzoyloxy)propyl ester (compound 96)

Starting from 3-chloropropyl benzoate and compound C, which is a racemic mixture or (2R, 3S) isomer, the title compound was prepared by a method similar to Example 2, which was a racemic mixture or (2R,3S) isomers, the relevant data are as follows:

¹ H NMR (400MHz,DMSO)δ10.92(s,1H),7.97(m,2H),7.65(d,J=7.4Hz,1H),7.53(t,J=7.7Hz,2H),7.13( dd,J=9.5,4.9Hz,2H),6.96(m,1H),6.78(d,J=7.1Hz,1H),4.32(d,J=3.7Hz,1H),4.24(dd,J=13.7 ,7.5Hz,4H),3.63(m,1H),2.00(t,J=6.2Hz,2H),1.23(d,J=6.8Hz,3H). MS(ESI ⁺ )m/z:418.0[M+Na] ⁺ ,434.0[M+Ka] ⁺

Example 101: 3-Methyl-4,7,8-tribromo-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylic acid benzoyl Oxymethyl ester (compound 97)

With the compound chloromethyl benzoate and 2-carboxylate-3-methyl-4,7,8-tribromo-3,5-dihydro-2H-thiopyrano[4,3,2-cd] Indole is a raw material, which is a racemic mixture or (2R, 3S) isomer, and the title compound is prepared according to a method similar to Example 2, which is a racemic mixture or (2R, 3S) isomer, relevant data as follows

¹ H NMR (400MHz,DMSO)δ12.34(s,1H),8.01(d,J=8.0Hz,1H),7.74(m,2H),7.53(m,3H),5.85(q,J=5.9 Hz, 2H), 4.49(d, J=4.0Hz, 1H), 3.57(m, 1H), 1.23(d, J=8.0Hz, 3H). MS (ESI ⁺ ) m/z:, 622.9 [M+Na] ⁺ .

Example 102: Benzoyloxymethyl 3-methyl-4-bromo-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole-2-carboxylate (compound 98)

Starting from the compounds chloromethyl benzoate and 2-carboxylic acid-3-methyl-4-bromo-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indole, It is a racemic mixture or (2R, 3S) isomer, and the title compound is prepared according to a method similar to Example 2, which is a racemic mixture or (2R, 3S) isomer, and the relevant data are as follows

¹ H NMR(400MHz,DMSO)δ11.68(s,1H),7.80(dd,J=8.3,1.2Hz,2H),7.69(d,J=7.5Hz,1H),7.53(t,J=7.8 Hz,2H),7.04(dd,J=8.1,0.7Hz,1H),6.98(m,1H),6.78(dd,J=7.1,0.7Hz,1H),5.84(s,2H),4.28(d ,J=2.2Hz,1H),3.55(m,1H),1.26(d,J=6.9Hz,3H). MS (ESI ⁺ ) m/z:, 523.9 [M+H] ⁺ .

Activity Test of Compounds of the Invention

The antibacterial activity of the compounds of the present invention is determined by measuring the minimum inhibitory concentration (MlC, mg/L) of its standard strains, clinically isolated strains and drug-resistant strains of some antibacterial agents: in this experiment, the latest Tigecycline (Tige), a listed glycinecycline antibiotic, was used as the control drug. The minimum inhibitory concentration is determined as follows: add 1ml of the drug solution to a sterile plate, then add 14ml of melted 50°C MH medium, mix well, so that the final concentration of the drug contained in each plate is 128, 64, 32 , 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, 0.03 mg/L; after cooling, use a multi-point inoculator (DenleyA400, England) to inoculate Gram bacteria, preferably Gram-negative bacteria or For Gram-positive bacteria, the inoculum amount is about 10 ⁵ CFU/ml, and the dish is covered. The above-mentioned bacterial strains are placed in a 35-37° C. incubator and cultivated for 18-20 hours, and the results are observed and recorded; the minimum concentration of the drug contained in the aseptic growth plate is the minimum inhibitory concentration (MIC).

Table 3 lists the in vitro antibacterial activity of representative compounds of the formula (I) compounds of the present application against Gram bacteria strains, and compares them with tigecycline, a newly listed glycinecycline antibiotic. As can be seen from Table 3, the in vitro activity of the formula (I) compound of the present invention to these Gram bacteria is better than the newly listed glycinecycline antibiotic tigecycline recently, or is equivalent thereto, and the formula (I) compound of the present invention is to Clinically increasing MRSA (methicillin-resistant Staphylococcus aureus) and MRSE (methicillin-resistant Staphylococcus aureus) also showed good activity. For fungi, especially Gram, preferably Gram-negative or Gram-positive bacteria.

Table 3 The preferred compounds of the present invention have an in vitro antibacterial activity (MIC μg/ml) to clinically isolated Gram bacteria

The applicant also used the above-mentioned method to conduct a comparative test with cvcv (CD) and desulfocvc (DSC, corresponding to compound No. 20 in the present invention) as positive controls, and the results are shown in Table 4-8.

Table 4

table 5

Table 6

Table 7

As mentioned above, the compound of the present invention has stronger antibacterial activity and broad antibacterial spectrum against various pathogenic microorganisms including Gram-negative bacteria and Gram-positive bacteria. The antibacterial activity of the compound of the present invention to Gram strains, especially to Staphylococcus genus including MRSA and MRSE is better than or equivalent to tigecycline, a recently listed glycinecycline antibiotic. The compound of the present invention is to Gram strain, especially to including Staphylococcus aureus MRSA12-1, ATCC25923, MSSE12-8, Klebsiella pneumoniae E-12-1, Pseudomonas aeruginosa 12-20, Streptococcus pneumoniae 10- The antibacterial activity of 11 was better than that of positive control cvnovmycin and desulfurcnovmycin.

The antibacterial activity of the compounds of the present invention against bacillus, preferably anti-tuberculosis bacillus is determined by measuring its minimum inhibitory concentration (MlC, mg/L) to standard bacterial strain H37Rv: in this experiment, use rifampicin (RFP) as contrast medicine. The minimum inhibitory concentration was determined as follows: 200 μl sterilized water was added to each well of a 96-well plate to prevent the components of each experimental well from evaporating during the cultivation process, and 1 mg of each compound was accurately weighed, and 1 ml of sterilized distilled water was added to prepare 1000μg/ml stock solution; RFP was dissolved in dimethylformamide; filtered through a 0.22μm microporous membrane. Dilute with 7H9 medium (without Tween 80) to the required double concentration respectively, add 100 μl of 96-well plate, and the final concentration of the test drug (the compound of the present invention, especially the compound of Table 1 or Table 2) is: 128.0 , 64.0, 32.0, 16.0, 8.0, 4.0, 2.0, 1.0, 0.5, 0.25, 0.125, 0.0625 μg/ml. The final concentrations of the control drug RFP were: 32.0, 16.0, 8.0, 4.0, 2.0, 1.0, 0.5, 0.25, 0.125, 0.0625, 0.032 μg/ml. Select cultures of various strains that grow vigorously on the improved Roche medium to make a bacterial suspension, inoculate it into 7H9 liquid medium, and incubate at 37°C for 10-14 hours to grow until the turbidity is McFarland1 (equivalent to 107 CUF /ml), inoculate 100 μl per well after dilution, the final concentration of bacterial solution Set up 2 growth control wells without antibacterial drugs and incubate at 37°C. Add 20 μl to growth control wells after day 5 Blue (Setotec company product) and 5% Tween 8050 μ l mixed solution, 37 ℃ incubation 24h, if the color changes from blue to pink, then add the above-mentioned amount of AlamarBlue and Tween 80 mixed solution in the hole of each test drug, Incubate at 37°C for 24h, record the color of each well, and define MIC as the lowest drug concentration that prevents the color change (from blue to pink). The results show that the compound of the present invention has obvious effect on antibacterial, preferably Mycobacterium tuberculosis.

Table 8 lists the in vitro antibacterial activity of the representative compound CV2 among the compounds of formula (I) of the present application against bacillus, preferably Mycobacterium tuberculosis, and compares it with rifampicin. It can be seen from Table 4 that the in vitro activity of the compound of formula (I) of the present invention on bacillus, preferably Mycobacterium tuberculosis is equivalent to that of rifampicin. The in vitro activity MIC of the compound of formula (I) of the present invention, especially the compound of table 1, is 0.25-8 μ g/ml to bacillus, preferably mycobacterium tuberculosis, and the compound of table 1 with the specific stereo configuration shown in formula (II) or formula XV Stereoisomers, especially the compounds in Table 2, have an in vitro activity MIC of 0.125-4 μg/ml against bacilli, preferably Mycobacterium tuberculosis. Compared with cvcnovycin (CD) and desulfocvcvc (DSC, corresponding to the compound No. 20 in the present invention), the compound of the present invention has better antibacterial activity.

The in vitro antibacterial activity (MIC μ g/ml) of table 8 compound to Mycobacterium tuberculosis

Compound number active Compound number active Compound number active Compound number active RFP 0.108 57 0.90 12' 2.62 70' 1.26 cd 6.00 58 0.72 13' 2.90 71' 1.20 CV2 0.78 59 0.70 14' 2.86 72' 1.34 1 3.62 60 0.71 15' 2.17 73' 1.38 2 3.54 61 2.48 16' 2.43 74' 1.52 3 4.21 62 1.01 17' 2.95 75' 1.84 4 3.84 63 1.32 20' 4.00 76' 1.80 5 4.38 64 1.42 twenty one' 3.51 77' 3.39 7 4.86 65 1.58 twenty two' 2.62 78' 1.95 8 5.23 66 1.60 twenty three' 2.69 79' 2.11 9 5.06 67 3.07 twenty four' 4.18 80' 1.64 10 4.82 68 2.40 25' 4.14 81' 0.48 11 3.82 69 2.38 26' 4.19 82' 0.64 12 5.23 70 2.52 27' 4.26 83' 0.58 13 5.80 71 2.40 28' 3.83 84' 1.88 14 5.72 72 2.68 29' 3.83 85' 1.86 15 4.33 73 2.76 30' 0.42 86' 2.01 16 4.85 74 3.04 31' 0.39 87' 1.93 17 5.90 75 3.68 32' 1.13 88' 0.39 20 8.00 76 3.60 33' 0.63 89' 0.58 twenty one 7.02 77 6.77 34' 0.99 90' 0.40 twenty two 5.23 78 3.89 35' 0.40 91' 0.54 twenty three 5.37 79 4.22 36' 0.54 92' 0.56 twenty four 8.35 80 3.28 37' 0.38 93' 1.94 25 8.28 81 0.96 38' 0.61 94' 1.91 26 8.37 82 1.28 39' 0.37 95' 0.46 27 8.52 83 1.16 40' 1.19 96' 0.52 28 7.66 84 3.76 41' 0.45 97' 1.17 29 7.66 85 3.72 42' 1.27 98' 0.84 30 0.83 86 4.01 43' 1.19 31 0.78 87 3.85 44' 1.71 32 2.25 88 0.78 45' 1.28 33 1.26 89 1.16 46' 0.63 34 1.98 90 0.80 47' 0.69 35 0.80 91 1.08 48' 0.84 36 1.08 92 1.12 49' 0.65 37 0.76 93 3.87 50' 0.68 38 1.22 94 3.82 51' 0.94 39 0.74 95 0.92 52' 0.73 40 2.38 96 1.03 55' 1.18 41 0.90 97 2.33 56' 0.36 42 2.54 98 1.68 57' 0.45 43 2.38 58' 0.36

44 3.42 CV2' 0.39 59' 0.35 45 2.55 1' 1.81 60' 0.36 46 1.26 2' 1.77 61' 1.24 47 1.38 3' 2.11 62' 0.51 48 1.67 4' 1.92 63' 0.66 49 1.29 5' 2.19 64' 0.71 50 1.35 7' 2.43 65' 0.79 51 1.88 8' 2.62 66' 0.80 52 1.46 9' 2.53 67' 1.54 55 2.36 10' 2.41 68' 1.20 56 0.72 11' 1.91 69' 1.19

Tests for Toxicity and Side Effects

Acute toxicity test: use ICR mice, body weight: 18-22g, half male and half male, administer the compound of the present invention, preferably the compound of Table 1 and 2. A total of 20 animals. The compounds were administered intragastrically according to the doses, and the abnormal reactions and the number of dead animals within 14 days were recorded. The test results showed that compound CV2 was administered to mice at 2 g/kg once, and no animal died, and the LD50 of CV2 administered to ICR mice was greater than 2.0 g/kg. With the exception of compound CV2, the compounds of the invention, preferably the compounds of Tables 1 and 2, have an LD50 comparable to compound CV2.

Claims (45)

1. A kind of indole derivative shown in formula (I) or its stereoisomer, or their pharmaceutically acceptable salt: in, R is H, C _{1-6 alkyl or C 1-6 alkanoyl} ; R2 is H _; R ₃ is H, C _1-6 alkyl, or C _1-6 alkoxy; R ₄ is C _1-6 alkyl; B and D are carbon atoms, and A is a nitrogen atom; D is a carbon atom, A and B are nitrogen atoms; A and D are carbon atoms, and B is a nitrogen atom; A and B are carbon atoms, and D is a nitrogen atom; A is a carbon atom and B and D are nitrogen atoms; or B is a carbon atom, A and D are nitrogen atoms; X is O, or S; Y is OR ₈ ; R ₈ is H or C _1-6 alkyl, said R ₈ can be independently substituted by 1-3 R ₉ , each R ₉ is a phosphoric acid group; or _R8 is The wavy line represents the bond, R ₁₁ represents H or C _1-6 alkyl; R ₁₂ stands for ii) C _3-8 cycloalkyl that is unsubstituted or substituted by C _1-6 alkylamino, hydroxyl or C _1-6 alkoxy, said cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl base or cyclohexyl; iii) a 6-membered aryl group that is unsubstituted or substituted by 1-3 R ₁₀ ; R ₁₀ is selected from C _1-6 alkyl and C _1-6 alkoxy; the stereoisomer has the following general formula (II) R ₁ , R ₂ , R ₃ , R ₄ , A, B, D, X, Y are as defined in general formula (I), With the proviso that the compound of formula (I) does not include the following compounds: 1) Compounds of the following formula 4 _R1 is methyl and _R2 is hydroxyl. 2. A kind of indole derivative shown in formula (I) or its stereoisomer, or their pharmaceutically acceptable salt: in, _R1 is H, _R2 is H, _R3 is H, R ₄ is C _1-6 alkyl; B and D are carbon atoms, and A is a nitrogen atom; D is a carbon atom, A and B are nitrogen atoms; A and D are carbon atoms, and B is a nitrogen atom; A and B are carbon atoms, and D is a nitrogen atom; A is a carbon atom and B and D are nitrogen atoms; or B is a carbon atom, A and D are nitrogen atoms; X is O, or S; Y is N(R ₈ ) ₂ , The R ₈ is H and C _1-6 alkyl, and the C _1-6 alkyl is unsubstituted or substituted by 1-3 R ₉ , Each R ₉ is C _1-6 alkylamino; The stereoisomer has the following general formula (II) R ₁ , R ₂ , R ₃ , R ₄ , A, B, D, X, Y are as defined in general formula (I). 3. A kind of indole derivative shown in formula (I) or its stereoisomer, or their pharmaceutically acceptable salt: in, _R1 is H, _R2 is H, or halogen, R ₃ is H, C _1-6 alkyl, C _1-6 alkoxy, halogen or N(R ₅ ) ₂ , R ₄ is C _1-6 alkyl, each R ₅ is independently H or C _1-6 alkyl, A, B and D are all carbon atoms; X is O, or S; Y is OR ₈ , Each R ₈ is independently selected from (1) C _1-6 alkyl, which is substituted by one R ₉ , each R ₉ is a non-aromatic heterocyclic group containing 6 ring atoms, and the non-aromatic heterocyclic group is morpholinyl; (2) The wavy line represents the bond, R ₁₁ represents H or C _1-6 alkyl; R ₁₂ stands for i) unsubstituted or C _1-6 alkyl substituted by 1-3 R _9' ; ii) C _3-8 cycloalkyl that is unsubstituted or substituted by C _1-6 alkyl, halogen or C _1-6 alkoxy, the cycloalkyl is cyclopropyl or cyclohexyl; iii) 6-membered aryl or 5 to 14-membered heteroaryl that is unsubstituted or substituted by 1 R ₁₀ , said heteroaryl is pyridine, benzofuryl, indolyl, or isoindolyl; iv) adamantyl; each R _9' is 6-membered arylcarbonyloxy, R ₁₀ is selected from halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkylamino; The stereoisomer has the following general formula (II) R ₁ , R ₂ , R ₃ , R ₄ , A, B, D, X, Y are as defined in general formula (I). 4. A kind of indole derivative shown in formula (I) or its stereoisomer, or their pharmaceutically acceptable salt: in, _R1 is H, _R2 is H, R ₃ is C _1-6 alkoxyl, R ₄ is C _1-6 alkyl, A, B and D are all carbon atoms; X is O, or S; Y is OR ₈ , R ₈ is C _1-6 alkyl, which is substituted by 1 R ₉ , each R ₉ is di(C _1-6 alkyl)amino. 5. A kind of indole derivative shown in formula (I) or its stereoisomer, or their pharmaceutically acceptable salt: in, _R1 is H, _R2 is H, _R3 is H, R ₄ is C _1-6 alkyl, A, B and D are all carbon atoms; X is O, or S; Y is N(R ₈ ) ₂ , The R ₈ is H and C _1-6 alkyl, and the C _1-6 alkyl is substituted by 1-3 R ₉ , Each R is independently selected from C _1-6 alkylamino, morpholinyl, imidazole and butyrolactam- ₁ -yl, The stereoisomer has the following general formula (II) R ₁ , R ₂ , R ₃ , R ₄ , A, B, D, X, Y are as defined in general formula (I). 6. A kind of indole derivative shown in formula (I) or its stereoisomer, or their pharmaceutically acceptable salt: in _R1 is H, R ₂ is H, or C _1-6 alkyl R ₃ is C _1-6 alkoxy, CF ₃ or N(R ₅ ) ₂ , R ₄ is C _1-6 alkyl, each R ₅ is independently H or C _1-6 alkyl, A, B and D are all carbon atoms; X is O, or S; Y is OR ₈ ; each _R8 is H; The stereoisomer has the following general formula (II) R ₁ , R ₂ , R ₃ , R ₄ , A, B, D, X, Y are as defined in general formula (I). 7. A kind of indole derivative shown in formula (I) or its stereoisomer, or their pharmaceutically acceptable salt: in _R1 is H, _R2 is H, _R3 is halogen, R ₄ is C _1-6 alkyl, A, B and D are all carbon atoms; X is O, or S; Y is OR ₈ ; Each R ₈ is C _1-6 alkyl; The stereoisomer has the following general formula (II) R ₁ , R ₂ , R ₃ , R ₄ , A, B, D, X, Y are as defined in general formula (I). 8. A kind of indole derivative shown in formula (I) or its stereoisomer, or their pharmaceutically acceptable salt: in _R1 is H, _R2 is H, _R3 is H, R ₄ is C _1-6 alkyl, A, B and D are all carbon atoms; X is O, or S; Y is N(R ₈ ) ₂ ; The R ₈ is H and C _1-6 alkyl; The stereoisomer has the following general formula (II) R ₁ , R ₂ , R ₃ , R ₄ , A, B, D, X, Y are as defined in general formula (I). 9. The compound or stereoisomer thereof, or their pharmaceutically acceptable salts as claimed in any one of claims 1 to 2, 6, and 8: in, The C _1-6 alkyl is a C _1-4 alkyl. 10. The compound or its stereoisomer or their pharmaceutically acceptable salt as claimed in claim 3: in, The C _1-6 alkyl is a C _1-4 alkyl. 11. The compound or its stereoisomer, or their pharmaceutically acceptable salts as claimed in claim 5: in, The C _1-6 alkyl is a C _1-4 alkyl. 12. The compound or stereoisomer thereof, or their pharmaceutically acceptable salts as claimed in any one of claims 4 and 7: in, The C _1-6 alkyl is a C _1-4 alkyl. 13. The compound as claimed in claim 1 or its stereoisomer, or their pharmaceutically acceptable salt: Wherein, the C _1-6 alkanoyl is a C _1-4 alkanoyl. 14. The compound according to any one of claims 1 and 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: Wherein, the C _1-6 alkoxy is a C _1-4 alkoxy. 15. The compound or its stereoisomer, or their pharmaceutically acceptable salt as claimed in claim 4: Wherein, the C _1-6 alkoxy is a C _1-4 alkoxy. 16. The compound or stereoisomer thereof, or their pharmaceutically acceptable salts as claimed in claim 3: Wherein, the C _1-6 alkoxy is a C _1-4 alkoxy. 17. The compound or stereoisomer thereof, or their pharmaceutically acceptable salts as claimed in claim 3: Wherein, the halogen is selected from F, Cl, or Br. 18. The compound or its stereoisomers, or their pharmaceutically acceptable salts as claimed in claim 7: Wherein, the halogen is selected from F, Cl, or Br. 19. Compounds or stereoisomers thereof, or pharmaceutically acceptable salts thereof, as claimed in any one of claims 1 to 2, 6 and 8: in, The alkyl group is selected from methyl, ethyl, isopropyl, n-propyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. 20. The compound or stereoisomer thereof, or their pharmaceutically acceptable salts as claimed in claim 3: in, The alkyl group is selected from methyl, ethyl, isopropyl, n-propyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. 21. The compound or stereoisomer thereof, or their pharmaceutically acceptable salts as claimed in claim 5: in, The alkyl group is selected from methyl, ethyl, isopropyl, n-propyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. 22. The compound according to any one of claims 4 and 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in, The alkyl group is selected from methyl, ethyl, isopropyl, n-propyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. 23. The compound according to any one of claims 10, 16 and 20, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: Wherein, the halogen is selected from F, Cl, or Br. 24. The compound or stereoisomer thereof, or their pharmaceutically acceptable salts as claimed in claim 12: Wherein, the halogen is selected from F, Cl, or Br. 25. The compound or stereoisomer thereof, or their pharmaceutically acceptable salts as claimed in claim 22: Wherein, the halogen is selected from F, Cl, or Br. 26. Compounds or stereoisomers thereof, or pharmaceutically acceptable salts thereof, as claimed in any one of claims 10, 16, 17 and 20: in, The heterocyclic group is selected from morpholino. 27. A compound which is a compound selected from the following table 28. A method for preparing the compound according to any one of claims 1 to 27 and its pharmaceutically acceptable salt, or an isomer thereof, characterized in that the method comprises the following steps: Step 1) make formula III compound Reaction with formula 1 compound, (R' ₁ ) ₂ O Formula 1 Thereby generating the compound of formula IV, wherein each R' ₁ is independently -COR ₄ , R ₁ , R ₂ , R ₃ , R ₄ , A, B, and D are as defined in formula (I) described in any one of 1 to 19, and R ₁₃ is halogen; Step 2) reacting the compound of formula IV with HXCH ₂ COY' to obtain the compound of formula V, Wherein Y' is a C _1-6 alkoxy group, R ₁ , R ₂ , R ₃ , R ₄ , A, B, D are as defined in formula (I) described in any one of 1 to 19, and X is O or S; Step 3) react the compound of formula V with acid and salt thereof to obtain the compound of formula VI wherein Y' is as defined in formula V, R ₁ , R ₂ , R ₃ , R ₄ , A, B, D are as defined in formula (I) described in any one of 1 to 19, and X is O or S; Step 4) hydrogenating the compound of formula VI to obtain the compound of formula VII wherein Y' is as defined in formula V, R ₁ , R ₂ , R ₃ , R ₄ , A, B, D are as defined in formula (I) described in any one of 1 to 19, and X is O or S; and Step 5) reacting the compound of formula VII with a base to obtain the compound of formula (I), which has the structure of formula VIII wherein R ₁ , R ₂ , R ₃ , R ₄ , A, B, and D are as defined in formula (I) described in any one of 1 to 19, and X is O or S. 29. The method of claim 28, further comprising the steps of: Step 7) In the presence of DIC and DMAP, the compound of formula VIII Reaction with R ₈ ZH gives the compound of formula X Wherein, Z is O or N, and R ₈ is C _1-6 alkyl unsubstituted or substituted by 1-3 R ₉ , R ₁ , R ₂ , R ₃ , R ₄ , R ₉ , A, B , D is as defined in formula (I) described in any one of 1 to 19, X is O or S. 30. The method of claim 28, further comprising the steps of: Step 9) compound of formula VIII and Reaction, obtain formula XIII compound Wherein, R ₁ , R ₂ , R ₃ , R ₄ , R ₁₁ , R ₁₂ , A, B, D and X are as defined in formula (I) described in any one of 1 to 19. 31. The method of any one of claims 28 to 30, wherein, step 1) is carried out as follows, in the presence of an inert gas, in an organic solvent, in the presence of a catalyst, the compound of formula III reacts with the compound of formula 1, thereby generating the compound of formula IV compound. 32. The method of claim 31, wherein, step 1) is carried out as follows, in the presence of nitrogen, in dichloromethane, in the presence of tin tetrachloride, and/or nitromethane, at room temperature, the formula III compound and Compounds of formula 1 are reacted to produce compounds of formula IV. 33. The method according to any one of claims 28 to 30, wherein, step 2) is carried out as follows, in the presence of an inert gas, the formula IV compound, HXCH ₂ COY' and anhydrous pyridine, in anhydrous methanol, at 90 °C for 48 hours to obtain the compound of formula V. 34. The method of claim 33, wherein, step 2) is carried out as follows, in the presence of nitrogen, react the compound of formula IV, HXCH ₂ COY' and anhydrous pyridine in anhydrous methanol at 90°C for 48h to obtain formula V compound. 35. The method according to any one of claims 28 to 30, wherein step 3) is carried out by reacting the compound of formula V with an acid and a salt thereof in the presence of an inert gas to obtain a compound of formula VI. 36. The method of claim 28, wherein step 3) is carried out by reacting the compound of formula V with ammonium acetate and glacial acetic acid in the presence of nitrogen to obtain the compound of formula VI. 37. The method according to any one of claims 28 to 30, wherein step 4) is carried out by hydrogenating the compound of formula VI in the presence of a catalyst in an organic solvent at 45 atmospheres to obtain the compound of formula VII. 38. The method of claim 37, wherein step 4) is carried out by hydrogenating the compound of formula VI in the presence of 10% Pd-C in ethyl acetate at 45 atmospheres to obtain the compound of formula VII. 39. The method according to any one of claims 28 to 30, wherein step 5) is carried out as follows, the compound of formula VII and sodium hydroxide are reacted at room temperature for 5h in ethanol, water and/or tetrahydrofuran to obtain formula (I ) compound having the structure of formula VIII. 40. The method of claim 30, wherein, The method step 9) is carried out as follows: in the presence of an inert gas, in the presence of triethylamine, in DMF, react at room temperature for 5min, the compound of formula VIII and reaction to obtain the compound of formula XIII. 41. The method of claim 40, wherein, The method step 9) is carried out as follows: in the presence of nitrogen, in the presence of triethylamine, in DMF, react at room temperature for 5min, the compound of formula VIII and reaction to obtain the compound of formula XIII. 42. A pharmaceutical composition, which contains a therapeutically effective amount of any one of claims 1 to 27 indole derivatives, their stereoisomers, or their pharmaceutically acceptable salts, and one or more pharmaceutical acceptable carrier. 43. Use of the indole derivatives according to any one of claims 1 to 27, their stereoisomers, or their pharmaceutically acceptable salts in the preparation of antibacterial drugs. 44. The use according to claim 43, wherein the antibacterial drug is an antibacterial or Gram drug. 45. The application according to claim 43, wherein the antibacterial drug is an anti-tuberculosis or Gram-negative bacteria or Gram-positive bacteria drug.