CN110818609A - Preparation method and application of 3-acetyl indole BRPF1 inhibitor - Google Patents

Preparation method and application of 3-acetyl indole BRPF1 inhibitor Download PDF

Info

Publication number
CN110818609A
CN110818609A CN201810937871.4A CN201810937871A CN110818609A CN 110818609 A CN110818609 A CN 110818609A CN 201810937871 A CN201810937871 A CN 201810937871A CN 110818609 A CN110818609 A CN 110818609A
Authority
CN
China
Prior art keywords
acetyl
methyl
indole
alkyl
carboxylic acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201810937871.4A
Other languages
Chinese (zh)
Inventor
焦宇
刘勇
陆涛
彭琪
陈亚东
唐伟方
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
China Pharmaceutical University
Original Assignee
China Pharmaceutical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by China Pharmaceutical University filed Critical China Pharmaceutical University
Priority to CN201810937871.4A priority Critical patent/CN110818609A/en
Publication of CN110818609A publication Critical patent/CN110818609A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention relates to a 3-acetyl indole compound shown as a formula (I) with a novel structure, a medicinal salt, a prodrug and a hydrate thereofOr a solvate thereof, to processes for their preparation, to pharmaceutical compositions containing a therapeutically effective amount of said compounds and to their use as protein tyrosine kinase inhibitors, especially as inhibitors of bromodomain-containing PHD zinc finger protein 1(BRPF1), in the prevention or treatment of diseases where inhibition of BRPF1 is beneficial.

Description

Preparation method and application of 3-acetyl indole BRPF1 inhibitor
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a compound taking 3-acetyl indole as a mother nucleus or a salt thereof, a preparation method thereof, a medicinal composition containing the compound and application of the compound as a bromine-containing PHD zinc finger protein 1(BRPF1) inhibitor in preventing or treating diseases benefiting from BRPF1 inhibition.
Background
The genome of a eukaryote is highly organized within its nucleus. The long strand of double-stranded DNA is wrapped around a histone octamer (typically composed of two molecules each of histones H2A, H2B, H3 and H4) to form a nucleosome. Then, the basic building block of nucleosomes is further compressed by polymerization and folding into a highly compressed chromatin structure. Chromatin structure may undergo a series of different degrees of compaction, with tightness varying with the cell cycle, with the most compact during cell division. Chromatin structure plays an important role in regulating gene transcription, but highly compressed chromatin is not able to efficiently regulate gene transcription. Histone structure is controlled by a series of post-translational modifications to histones, especially to histones H3 and H4, most commonly modifications to the histone tails extending beyond the nucleosome core. These modifications include acetylation, methylation, phosphorylation, ubiquitination, SUMO, and many others. These epigenetic marks are "written" and "erased" by specific enzymes, which are located at specific residues on the tail of the histone protein, thereby forming an epigenetic code that is then interpreted by the cell as allowing gene-specific regulation of chromatin structure for transcription.
Histone acetylation is often associated with activation of gene transcription, such as altering the electrostatic property to loosen the interaction of DNA and histone octamers. In addition to this physical change, the binding of a particular protein to acetyl lysine in histones can read the epigenetic code. Bromodomains are small (about 110 amino acids), common domains in proteins that typically bind to, but are not limited to, the acetyl lysine residues of histones. About 50 amino acids are known to contain bromodomains, which have various functions in cells.
BRPF1 (also known as peregrin or Br140 protein) is a bromodomain-containing protein that has been shown to bind to acetyl lysine residues of histone tails (including H2AK5ac, H4K12ac and H3K14ac) (Poplawski et al, J.mol.biol., 2014426: 1661-one 1676). BRPF1 also contains other domains normally found in chromatin-associated factors, including 1 dual plant homeodomain (PHD domain) and zinc finger domain (ZnF domain) module (PZP) and 1 chromo/Tudor-associated Pro-Trp-Pro (pwwp) domain. BRPF1 forms 1 tetrameric complex with monocyte leukemia zinc finger protein (MOZ, also known as KAT6A or MYST3), growth inhibitory factor (ING5) and Esa1 related factor (hEAF6) homologues. In humans, MOZ (monocytic leukemia zinc finger protein, also known as KAT6A or MYST3) translocation of t (8; 16) (p 11; p13) is associated with and contributes to the development of acute myeloid leukemia subtypes. (Borrow et al, nat. Genet., 199614: 33-41). The BRPF1 bromodomain helps recruit the MOZ complex to different sites of active chromatin, and is therefore thought to play an important role in the regulation of translation, hematopoiesis, leukemia pathogenesis and other developmental processes by the MOZ complex (Ullah et al, mol. cell. biol., 200828: 6828-6843; Perez-Campo et al, Blood, 2009113: 4866-4874). Demont et al (Demont et al, ACS med. chem. lett., (2014) (dx. doi. org/10.1021/ml5002932) disclose certain 1, 3-dimethyl benzimidazolones as potent and selective BRPF1 bromodomain inhibitors.
Disclosure of Invention
The invention designs and synthesizes a series of compounds with brand new structures containing 3-acetyl indole parent nucleus by virtual screening after researching the crystal structure of BRPF1 protein. The pharmacological test result shows that: the compound of the invention has good BRPF1 protein inhibition activity.
The technical scheme of the invention is as follows:
1. a compound of formula (I) and isomers, diastereomers, enantiomers, tautomers, and salts thereof:
Figure BSA0000169032640000021
wherein:
x, Y, Z is N or C
L, M is-CONH-, -CONHCO-, -NHCONH-, -NHCO-, -NHCOCH-, -NHCOCH2-、-CONHCH2-、-SO-、-SO2-、-SO2NH-、 -CO-、-CO2-、-NHCH2-or a chemical bond;
R1represents hydrogen, alkyl;
R2represents hydrogen, alkyl;
R3，R4is C1-C12Alkyl radical, C3-C8-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aralkyloxy, C1-C12-alkoxy, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, -SO2R3、-OR3、-SOR3、-COR3、-CO2R3、NCOR3，-NR5R6Or 3-7 membered nitrogen-containing aliphatic heterocyclic ring, which may have 0-2 unsaturated bonds, and may have hydrogen, halogen, hydroxyl or C1-C6-alkyl substitution; or is aryl or heteroaryl which may optionally be substituted in one or more positions in the same or different manner by: hydrogen, halogen, hydroxy, nitro, cyano, C1-C12Alkyl radical, C3-C8-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aralkyloxy, C1-C12-alkoxy, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, -SO2R3、-OR3、-SOR3、-COR3、-CO2R3、NCOR3，-NR5R6Or 3-7 membered nitrogen-containing aliphatic heterocyclic ring, which may have 0-2 unsaturated bonds, hydrogen or halogenElement, hydroxy or C1-C6-alkyl substitution;
R5and R6Independently of one another are hydrogen, C1-C12Alkyl radical, C3-C8-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aralkyloxy, C1-C12-alkoxy, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, -SO2R3、-OR4、-SOR5、-COR3、-CO2R3，-NR1R2Or 3-7 membered nitrogen-containing aliphatic heterocyclic ring, which may have 0-2 unsaturated bonds in the ring, and may have hydrogen, halogen, hydroxy or C1-C6-alkyl substitution;
aryl and heteroaryl groups are selected from: pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, imidazole, indole, quinoline, purine, benzo five-membered heterocycle, five-membered heterocycle six-membered heterocycle.
2. Preferred embodiments of the present invention are compounds of formula (II) and isomers, diastereomers, enantiomers, tautomers and salts thereof:
Figure BSA0000169032640000031
wherein:
l, M is-CONH-, -CONHCO-, -NHCONH-, -NHCO-, -NHCOCH-, -NHCOCH2-、、-SO-、-SO2-、-SO2NH-、-CO-、 -CO2-、-NHCH2-or a bond;
R1represents hydrogen, C1-C6Alkyl radical, C3-C8-cycloalkyl, halo-C1-C6-an alkyl group;
R2represents hydrogen, C1-C6Alkyl radical, C3-C8-cycloalkyl, halo-C1-C6-an alkyl group;
R3，R4is C1-C12Alkyl radical, C3-C8-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aralkyloxy, C1-C12-alkoxy, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, -SO2R3、-OR3、-SOR3、-COR3、-CO2R3、NCOR3，-NR5R6Or 3-7 membered nitrogen-containing aliphatic heterocyclic ring, which may have 0-2 unsaturated bonds, and may have hydrogen, halogen, hydroxyl or C1-C6-alkyl substitution; or is aryl or heteroaryl which may optionally be substituted in one or more positions in the same or different manner by: hydrogen, halogen, hydroxy, nitro, cyano, C1-C12Alkyl radical, C3-C8-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aralkyloxy, C1-C12-alkoxy, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, -SO2R3、-OR3、-SOR3、-COR3、-CO2R3、NCOR3，-NR5R6Or 3-7 membered nitrogen-containing aliphatic heterocyclic ring, which may have 0-2 unsaturated bonds, and may have hydrogen, halogen, hydroxyl or C1-C6-alkyl substitution
R5And R6Independently of one another are hydrogen, C1-C12Alkyl radical, C3-C8-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aralkyloxy, C1-C12-alkoxy, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, -SO2R3、-OR4、-SOR5、-COR3、-CO2R3，-NR1R2Or 3-7 membered nitrogen-containing aliphatic heterocyclic ring, which may have 0-2 unsaturated bonds in the ring, and may have hydrogen, halogen, hydroxy or C1-C6-alkyl substitution;
aryl and heteroaryl groups are selected from: pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, imidazole, indole, quinoline, purine, benzo five-membered heterocycle, five-membered heterocycle six-membered heterocycle.
R1Represents hydrogen, methyl;
R2represents hydrogen, methyl;
R3represents 2-methoxybenzenesulphonylamino, 4-methoxybenzenesulphonylamino, methoxycarbonyl, phenylcarbamoyl, 2-methoxybenzenecarbamoyl,
2-thiazolecarbamoyl, cyclopentylcarbamoyl, phenyl, 3-pyridyl;
R4represents ethoxycarboxamido, benzenesulfonylamino, 2-methoxybenzenesulfonylamino, N- (propylsulfonyl) acetylamino, N- (benzenesulfonyl) benzenesulfonylamino, benzoylamino, 2-methoxybenzoylamino, butyrylamino, phenylureido, 2-methoxybenzoylureido, 3-trifluoromethylphenylureido, ethylureido, N- (acetyl) ethoxycarboxamido, amino, pyrrolidinyl.
3. The compounds of formula 1 are preferably compounds of the following structure:
n- (3-acetyl-2-methyl-1H-indol-5-yl) -2-methoxybenzenesulphonamide (I-1)
N- (3-acetyl-2-methyl-1H-indol-5-yl) -4-methoxybenzenesulphonamide (I-2)
3-acetyl-2-methyl-7- (phenylsulfonylamino) -1H-indole-5-carboxylic acid methyl ester (I-3)
3-acetyl-7- ((2-methoxyphenyl) sulfonylamino) -1H-indole-5-carboxylic acid methyl ester (I-4)
3-acetyl-2-methyl-7- (N- (propylsulfonyl) acetylamino) -1H-indole-5-carboxylic acid methyl ester (I-5)
3-acetyl 2-methyl-7- (N- (phenylsulfonyl) phenylsulfonylamino) -1H-indole-5-carboxylic acid methyl ester (I-6)
2-methyl-3-acetyl-7-benzoylamino-1H-indole-5-carboxylic acid methyl ester (I-7)
3-acetyl-7- (2-methoxybenzoylamino) -2-methyl-1H-indole-5-carboxylic acid methyl ester (I-8)
3-acetyl-7-butyrylamino-2-methyl-1H-indole-5-carboxylic acid methyl ester (I-9)
3-acetyl-2-methyl-7- (3-phenylureido) -1H-indole-5-carboxylic acid methyl ester (I-10)
3-acetyl-7- (3- (2-methoxyphenyl) ureido) -2-methyl-1H-indole-5-carboxylic acid methyl ester (I-11)
3-acetyl-2-methyl-7- (3- (3- (trifluoromethyl) phenyl) ureido) -1H-indole-5-carboxylic acid methyl ester (I-12)
3-acetyl-7- (3-ethylureido) -2-methyl-1H-indole-5-carboxylic acid methyl ester (I-13)
3-acetyl-7- ((ethoxycarbonyl) amino) -2-methyl-1H-indole-5-carboxylic acid methyl ester (I-14)
3-acetyl-7- ((ethoxycarbonyl) amino) -1, 2-dimethyl-1H-indole-5-carboxylic acid methyl ester (I-15)
3-acetyl-7- (N- (ethoxycarbonyl) acetylamino) -1, 2-dimethyl-1H-indole-5-carboxylic acid methyl ester (I-16)
3-acetyl-7- ((ethoxycarbonyl) amino) -1H-indole-5-carboxylic acid methyl ester (I-17)
(3-acetyl-2-methyl-5- (phenylcarbamoyl) -1H-indol-7-yl) carbamic acid ethyl ester (I-18)
(3-acetyl-5- ((2-methoxyphenyl) carbamoyl) -2-methyl-1H-indol-7-yl) carbamic acid ethyl ester (I-19)
(3-acetyl-2-methyl-5- ((thiazol-2-yl) carbamoyl) -1H-indol-7-yl) carbamic acid ethyl ester (I-20)
(3-acetyl-5- (cyclopentylcarbamoyl) -2-methyl-1H-indol-7-yl) carbamic acid ethyl ester (I-21)
(3-acetyl-2-methyl-5- (methylcarbamoyl) -1H-indol-7-yl) carbamic acid ethyl ester (I-22)
(3-acetyl-5-benzoyl-2-methyl-1H-indol-7-yl) carbamic acid ethyl ester (I-23)
(3-acetyl-2-methyl-5-phenyl-1H-indol-7-yl) carbamic acid ethyl ester (I-24)
(3-acetyl-2-methyl-5- (pyridin-3-yl) -1H-indol-7-yl) carbamic acid tert-butyl ester (I-25)
3-acetyl-2-methyl-7- (pyrrolidin-1-yl) -1H-indole-5-carboxylic acid methyl ester (I-26)
3-acetyl-N- (2-methoxyphenyl) -2-methyl-7- (pyrrolidin-1-yl) -1H-indole-5-carboxamide (I-27)
1- (7-amino-5-benzoyl-2-methyl-1H-indol-3-yl) ethyl-1-one (I-28)
2-methyl-3-acetyl-N- (piperidin-4-yl) -5- (pyridin-3-yl) -1H-indol-7-amine (I-29)
The specific structure is shown in the following table:
Figure BSA0000169032640000051
Figure BSA0000169032640000052
Figure BSA0000169032640000061
according to the invention, pharmaceutically acceptable salts include the acid addition salts of the compounds of formula (I) with the following acids: hydrochloric, hydrobromic, sulphuric, phosphoric, methanesulphonic, benzenesulphonic, p-toluenesulphonic, naphthalenesulphonic, citric, tartaric, lactic, pyruvic, acetic, maleic or succinic, fumaric, salicylic, phenylacetic, mandelic acid. Also included are acid salts of inorganic bases such as: contains alkali metal cation, alkaline earth metal cation, and ammonium cation salt. The invention further relates to a pharmaceutical composition which comprises a therapeutically effective amount of a compound of the invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.
The invention further relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same for the preparation of a medicament for the treatment of a Bromodomain dependent disorder.
The invention further relates to application of the compound shown in the general formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the compound in preparation of a medicament for inhibiting BRPF1 protein.
The invention further relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same for the manufacture of a medicament for the treatment of cancer or a tissue proliferative disorder, wherein the cancer is selected from melanoma, papillary thyroid tumors, cholangiocarcinomas, colon cancer, ovarian cancer, midline carcinoma, non-small cell lung cancer, malignant lymphomas, carcinomas and sarcomas of the liver, kidney, bladder, prostate, breast, pancreas, and primary and recurrent solid tumors of the skin, colon, thyroid, lung and ovary or leukemia.
The preparation method of the invention
In order to achieve the preparation purpose of the invention, the invention adopts the following preparation technical scheme:
a process for the preparation of a compound of the invention of formula (I) comprising the steps of:
method 1-1:
Figure BSA0000169032640000081
Reagents and conditions：(a)i)Sat.NaNO2(aq)，conc.HCl，0℃，30min；ii)0.5MSO2in DCM，CuCl，0℃，30 min；r.t.，1h；(b)ICl，conc.HCl，H2O，r.t.，3h；(c)2，4-pentanedione，Cu2O，Cs2CO3，DMF/H2O(v/v，3/1)，100℃， 5h；(d)Raney Ni，hydrazinehydrate，CH3OH，0℃，1h；(e)A1 or 4-Methoxybenzenesulfonyl chloride， anhydrouspyridine，anhydrous DCM，r.t.，2h.
method 1-2:
Figure BSA0000169032640000082
Figure BSA0000169032640000091
Figure BSA0000169032640000092
Reagents and conditions：(a)CH3OH，SOCl2，reflux，overnight；(b)ammoniumhydroxide，Et(i-Pr)2N，DCM，r.t.， overnight；(c)Ag2SO4，I2，CH3OH，r.t.，12h；(d)(CF3CO)2O，anhydrous Et3N，anhydrous DCM，0℃，5min；r.t.，2h；(e)propargyl alcohol，PdCl2(PPh3)2，CuI，Et(i-Pr)2N，(i-Pr)2NH，DMF，N2，r.t.，12h；(f)ethyl chloroformate，anhydrous pyridine，DMAP，anhydrous DCM，0℃，5min；r.t.，2h；(g)Pd(PPh3)4，anhydrousEt3N，HCO2H， CH3CN，N2，80℃，1h；(h)Pd/C，H2，CH3OH/THF(v/v，1/1)，r.t.，5h；(i)acylchloride，DMAP，anhydrous Et3N， anhydrous DCM，0℃，5min；r.t.，2h；or sulfurylchloride，anhydrous pyridine，r.t.，2h；or isocyanate，anhydrous DCM，r.t.，overnight；or 2-methoxybenzoic acid，DPPA，anhydrous Et3N，anhydrous THF，reflux，6h；or ethyl chloroformate，Sat.K2CO3(aq)，DCM，r.t.，1h；(j)acetyl chloride，Et2AlCl，AlCl3，N2，anhydrous DCM，0C，5 min；r.t.，5h.
methods 1 to 3:
Figure BSA0000169032640000093
Reagents and conditions：(a)NaH，CH3l，DMF，r.t.，2h；(b)Pd/C，H2，CH3OH/THF(v/v，1/1)，r.t.，5h；(c)ethyl chloroformate，DMAP，anhydrous Et3N，anhydrous DCM，0℃，5min；r.t.，2h；(d)acetyl chloride，Et2AlCl，AlCl3，N2，anhydrous DCM，0℃，5min；r.t.，5h.
methods 1 to 4:
Reagents and conditions：(a)trimethylsilylacetylene，(Ph3P)2PdCl2.CuI，Ph3P，anhydrous Et3N.anhydrous DMF， anhydrous toluene，N2，r.t.，overnight；(b)K2CO3，CH3OH，r.t.，25min；(c)[RhCl(COD)]2， tris(4-fluorophenyl)phosphine，anhydrous DMF，N2，85℃，50min；(d)Pd/C，H2，CH3OH/THF(v/v，1/1)，r.t.，5h； (e)ethylchloroformate，Sat.K2CO3(aq)，DCM，r.t.，1h；(f)acetyl chloride，Et2AlCl，AlCl3，N2，anhydrous DCM， 0℃，5min；r.t.，5h.
method 1-5:
Reagents and conditions：(a)acetic acid，POCl3，reflux，30min；(b)KOH，THF，ethylene glycol，reflux，30min；(c) EDC·HCl，HOBt，Et(i-Pr)2N，DMF，r.t.，overnight；(d)Raney Ni，hydrazine hydrate，MeOH，0℃，1h；(e)ethyl chloroformate，Sat.K2CO3(aq)，DCM，r.t.，1h.
method 1-6:
Figure BSA0000169032640000111
Reagents and conditions：(a)CH3NH2in CH3OH，45℃，22h；(b)acetic acid，POCl3，reflux，30min；(c)Raney Ni， hydrazine hydrate，MeOH，0℃，1h；(d)ethylchloroformate，Sat.K2CO3(aq)，DCM，r.t.，1h.
methods 1 to 7:
Figure BSA0000169032640000121
Reagents and conditions：(a)i)(COCl)2，DMF，r.t.，30min；ii)AlCl3，benzene，r.t.，8h；(b)NH3·H2O，(i-Pr)2NEt， THF，r.t.，24h；(c)Ag2SO4，I2，CH3OH，r.t.，overnight；(d)(CF3CO)2O，anhydrous Et3N，anhydrous DCM，0℃，5 min；r.t.，2h；(e)propargylalcohol，PdCl2(PPh3)2，CuI，anhydrous Et3N，anhydrous DMF，N2，r.t.，12h；(f)ethylchloroformate，anhydrous pyridine，DMAP，anhydrous DCM，0℃，5min；r.t.，2h；(g)Pd(PPh3)4，anhydrous Et3N， HCO2H，CH3CN，N2，80℃，2h；(h)Raney Ni，hydrazine hydrate，MeOH，0℃，1h；(i)ethyl chloroformate，Sat. K2CO3(aq)，DCM，r.t.，1h；or benzylchloroformate，NaOH，r.t.，5h；(j)acetyl chloride，Et2AlCl，AlCl3，N2， anhydrous DCM，0℃，5min；r.t.，5h.
method 1-8:
Reagents and conditions：(a)Ag2SO4，I2，CH3OH，r.t.，overnight；(b)(CF3CO)2O，anhydrous Et3N，anhydrous DCM，0℃，5min；r.t.，2h；(c)propargyl alcohol，PdCl2(PPh3)2，CuI，Et3N，DMF，N2，r.t.，12h；(d)phenylboronic acid or 3-pyridylboronicacid，Pd(Ph3P)4，K2CO3，1，4-dioxane，H2O，100℃，12h；(e)ethyl chloroformate，anhydrous pyridine，0℃，5min；r.t.，2h；(f)Pd(PPh3)4，anhydrous Et3N，HCO2H，CH3CN，N2，80℃，2h；(g) Pd/C，H2，CH3OH/THF(v/v，1/1)，r.t.，5h；(i)ethyl chloroformate，Sat.K2CO3(aq)，DCM，r.t.，1h；(j)acetyl chloride，Et2AlCl，AlCl3，N2，anhydrous DCM，0℃，5min；r.t.，5h.
methods 1 to 9:
Reagents and conditions：(a)1，4-diiodobutane，K2CO3，anhydrous DMF，60℃；(b)acetyl chloride，Et2AlCl，AlCl3， N2，anhydrous DCM，0℃，5min；r.t.，5h.
method 1-10:
Figure RE-GSB0000178510840000142
Reagents and conditions：(a)EtOH，NaBH4，rt，2h；(b)acetyl chloride，Et2AlCl，AlCl3，N2，anhydrous DCM，0℃， 5min；r.t.，5h.
the compound of the invention can be prepared by the preparation method or similar preparation methods, and corresponding raw materials are selected according to different substituents and different positions of the substituents.
Experimental study on binding capacity of BRPF1 protein by part of compounds
BRD4 protein binding Capacity test
The method comprises the following steps: AlphaScreen method
1) Experimental materials and equipment: his-tagged human recombinant BRPF1B bromodomain protein (Reactionbiology, USA); histone H4 peptide acetylated at position K5/8/12/16 (Reaction Biology, USA); streptavidin-coated donor microbeads (PerkinElmer, USA); nickel chelate receptor micro strain (PerkinElmer, USA); DMSO (Sigma, USA); i-1 to I-28 (self-made); biotin (Sigma, USA); multimek full automatic pipettors (NanoScreen, USA); 96 well sample plates (PerkinElmer, USA); 384 well ProxiPlates microplates (PerkinElmer, USA); (iii) Multidrop automatic dispensers (Thermo, USA); EnVision multi-label microplate detector (PerkinElmer, USA).
2) The experimental principle is as follows: donor micro-strains (Streptavidin-coated Donor Beads) and nickel-chelate Acceptor Beads (Ni-chelate Acceptor Beads) coated with Streptavidin were tested. 680nm excitation light (excitation light) causes donor beads (containing xylylene blue) to generate thousands of singlet oxygen molecules per second (ii) ((iii))1O2)，1O2The maximum diffusion distance within its 4. mu.s half-life is 200 nm. When receptor microbeads are present within this diffusion range,1O2the dimethylthiophene derivative on the acceptor microbead is triggered, and then a series of chemical reactions are triggered to finally generate Emission light (Emission light) in the range of 520-620 nm. The interaction between the human recombinant bromodomain protein (His-BRD for short) with the His label and the acetylated histone H4 Peptide (Biotin-Peptide for short) with the K5/8/12/16 position with the Biotin label enables the donor bead and the receptor bead to be close to each other, so as to ensure that the donor bead and the receptor bead are ensured to be close to each other1O2The transfer of (2). After the addition of the Bromodomain inhibitor, the Bromodomain inhibitor and Biotin-Peptide competitively bind His-BRD protein to reduce the emitted light signal, thereby achieving the purpose of testing.
3) The experimental steps are as follows: mu.L of a DMSO solution (10 mM) of the test compound was pipetted from a 96-well sample plate using a Multimek full-automatic pipette, followed by dilution with 1 Xbuffer (consisting of 20mM Tris pH 8.0, 25mM sodium chloride, 2mM dithiothreitol, and 0.05% Tween-20) to give 10 solutions of different concentration gradients (maximum concentration of 2. mu.M or 20. mu.M), each of which was withdrawnmu.L was added to 384-well ProxiPlates plates. To each well was added 9. mu.L of a mixture of His-BRD protein and-Biotin-Peptide in 1 Xbuffer by Multidrop auto-dispenser. After incubation for 30 minutes at room temperature, 2. mu.L of streptavidin-coated donor beads (45. mu.g/mL) and 2. mu.L of nickel-chelate acceptor beads (45. mu.g/mL) were added per well under low light. The plates were read on an EnVision multi-label plate tester after incubation in the dark at room temperature for 30 minutes. The experiment was repeated, taking the average of the data points obtained for each compound concentration, fitting using a GraphPad Prism 5 to plot a four parameter curve, and calculating IC50The value is obtained. The inhibition rate is calculated by the binding rate of the His-BRD protein and the-Biotin-Peptide, and the formula is that the inhibition rate is 1-binding rate.
Experimental results for some preferred compounds
Figure BSA0000169032640000151
Note: ND means not tested.
The biological activity test result shows that the compound provided by the invention has BRD4 inhibition effect.
Detailed Description
The melting point was measured using a RY-1G melting point apparatus (New Tianguan instruments, Tianjin).1H NMR and13c NMR was measured using a BRUKER AVANCE-300 nuclear magnetic resonance apparatus (Brucker, Switzerland) using TMS as an internal standard and the displacement value (. delta.) in ppm; the low resolution mass spectra were determined using a Nicolet model 2000 Fourier transform mass spectrometer and a MAT-212 mass spectrometer (ESI ion source).
EXAMPLE 1 Synthesis of Compound I-1
2-Methoxybenzenesulfonyl chloride (A1)
2-Methoxyaniline (113. mu.L, 1.00mmol) was added to a25 mL eggplant-shaped bottle, followed by 2mL concentrated hydrochloric acid. After stirring for 5 minutes, a saturated aqueous solution of sodium nitrite (75.9mg, 1.10mmol) was added dropwise at 0 ℃ andafter that, the mixture was stirred at 0 ℃ for 30 minutes to obtain a diazonium salt aqueous solution. A further 25mL eggplant-shaped bottle was charged with a solution of sulfur dioxide in methylene chloride (0.5mol/L, 10mL) and cuprous oxide (49.5mg, 0.50mmol), followed by addition of aqueous diazonium salt in portions at 0 ℃. After the addition, the reaction was continued at 0 ℃ for 30 minutes and then at room temperature for 1 hour. After TLC detection of the completion of the reaction, the reaction mixture was poured into 15mL of ice water, extracted with ethyl acetate (8 mL. times.3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered to remove the drying agent, and the filtrate was concentrated to give the crude product. The crude product was isolated by silica gel column chromatography (petroleum ether/ethyl acetate, volume ratio 5: 1) to yield 36.0mg of a white solid in 17% yield. mp: 50-52 ℃;1H NMR(300MHz，Chloroform-d) δ7.92(d，J＝7.9Hz，1H)，7.71(t，J＝7.6Hz，1H)，7.14(d，J＝8.2Hz，1H)，7.11(t，J＝7.8Hz，1H)，3.96(s，2H).
2-iodo-4-nitroaniline (A2)
Iodine monochloride (2.61mL, 52.13mmol) and 22mL of water were put into a 100mL eggplant-shaped bottle, and 9mL of concentrated hydrochloric acid was added at 0 ℃ to obtain an iodine monochloride solution. To a 250mL eggplant-shaped bottle were added 4-nitroaniline (7.20g, 52.13mmol), 59mL of water, and 6.5 mL of concentrated hydrochloric acid, followed by adding an iodine monochloride solution at 0 ℃. After the addition, the reaction solution was allowed to warm for 3 hours. After completion of the TLC detection reaction, the reaction solution was filtered, the filter cake was washed with water (50 mL. times.3), and the filter cake was dried to obtain 13.35g of a yellow-green solid with a yield of 97%. mp: 110-112 ℃;1H NMR(300MHz，DMSO-d6)δ8.40(d，J＝2.6Hz，1H)，7.99(dd，J＝9.1，2.6Hz，1H)，6.78(s，1H)，6.75(s， 2H)；ESI-MS m/z：262.9[M-H]+.
2-methyl-5-nitro-3-acetylindole (A3)
A2(100mg, 378.8. mu. mol), acetylacetone (46.43. mu.L, 454.5. mu. mol), cuprous oxide (5.4mg, 37.9. mu. mol) and cesium carbonate (123.4mg, 378.8. mu. mol) were charged in a10 mL two-necked round-bottomed flask, a mixed solvent of N, N-dimethylformamide (0.75mL) and water (0.25mL) was added, the air in the reaction system was replaced with nitrogen gas for 5 minutes, and then the reaction was carried out at 100 ℃ for 5 hours. After TLC detection reaction, the reaction solution was cooled to room temperature, ethyl acetate (2mL) was added to dilute the reaction solution, and insoluble impurities were filteredThe filtrate was extracted with ethyl acetate (5 mL. times.3), the organic phases were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, the drying agent was filtered, and the filtrate was concentrated to give a residue. Separation by silica gel column chromatography (petroleum ether/ethyl acetate, volume ratio 1: 1) gave 55.0mg of a brown solid in 67% yield. mp: 280 ℃ and 282 ℃;1H NMR(300MHz，DMSO-d6)δ12.44(s，1H)，8.95(s，1H)，8.04(d，J＝7.8Hz，1H)，7.53(d，J＝8.7Hz，1H)， 2.74(s，3H)，2.55(s，3H)；ESI-MS m/z：217.1[M-H]+.
2-methyl-5-amino-3-acetylindole (A4)
A3(200mg, 916.4. mu. mol) was charged into a10 mL two-necked round-bottomed flask equipped with a10 mL constant pressure dropping funnel, and 2mL of methanol was added thereto to dissolve it, followed by addition of Raney nickel (188mg, 3.21mmol), and after substituting the air in the reaction system with nitrogen for 5 minutes, a solution of hydrazine hydrate (80. mu.L, 1.34mmol) in methanol was slowly added dropwise at 0 ℃ and stirring was continued at 0 ℃ for 1 hour. After completion of the TLC detection reaction, the reaction solution was filtered through celite, and the filtrate was concentrated to give 155.0mg of a gray solid in 90% yield and directly fed to the next step without purification. mp: 225-226 ℃;1H NMR(300MHz，DMSO-d6)δ11.41(s，1H)，7.23(s，1H)，7.03(d，J＝8.4Hz，1H)，6.48(d，J＝9.9Hz，1H)， 4.75(s，2H)，2.59(s，3H)，2.43(s，3H)；ESI-MSm/z：187.2[M-H]+，189.2[M+H]+.
n- (3-acetyl-2-methyl-1H-indol-5-yl) -2-methoxybenzenesulphonamide (I-1)
A4(54.7mg, 290.4. mu. mol), pyridine (47. mu.L, 580.8. mu. mol) and 2mL of methylene chloride were put into a10 mL round bottom flask, and after stirring the mixture uniformly, A1(60mg, 290.4. mu. mol) was added and the mixture was stirred at room temperature for 2 hours. After completion of the TLC detection reaction, diluted hydrochloric acid (1mol/L, 5mL) was added, extraction was performed with ethyl acetate (5 mL. times.3), the organic phases were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, the drying agent was filtered, and the filtrate was concentrated to give a residue. Silica gel column chromatography (petroleum ether/ethyl acetate, volume ratio 1: 1) gave 11.9mg of yellow powdery solid in 10% yield. mp: 295-297 ℃;1H NMR(300MHz，DMSO-d6)δ11.74(s，1H)，9.58(s，1H)， 7.82-7.71(m，1H)，7.61(dd，J＝7.8，1.5Hz，1H)，7.55-7.43(m，1H)，7.15(dd，J＝8.3，4.3Hz，2H)，7.02-6.85 (m，2H)，3.96(s，3H)，2.60(s，3H)，2.40(s，3H)；ESI-MS m/z：357.1[M-H]+.
EXAMPLE 2 Synthesis of Compound I-2
N- (3-acetyl-2-methyl-1H-indol-5-yl) -4-methoxybenzenesulphonamide (I-2)
Preparation was carried out in a similar manner to I-1 using 4-methoxybenzenesulfonyl chloride (54.7mg, 290.4. mu. mol) as the sulfonylating agent to give 13.0mg of a yellow powdery solid in 13.0% yield. mp: 257 and 258 ℃;1H NMR(300MHz，DMSO-d6)δ11.76(s，1H)，9.76(s，1H)，7.84- 7.69(m，1H)，7.61(d，J＝8.8Hz，2H)，7.20(d，J＝8.5Hz，1H)，7.00(d，J＝8.8Hz，2H)，6.89(dd，J＝8.5，1.8Hz， 1H)，3.76(s，3H)，2.62(s，3H)，2.40(s，3H)；ESI-MSm/z：357.1[M-H]+.
EXAMPLE 3 Synthesis of Compound I-3
4-fluoro-3-nitrobenzoic acid methyl ester (A5)
4-fluoro-3-nitrobenzoic acid (150mg, 0.81mmol), thionyl chloride (176. mu.L, 2.43mmol) and 10mL of methanol were added to a 50mL eggplant-shaped bottle and reacted overnight under reflux. After completion of TLC detection, the excess solvent was distilled off, 2mL of petroleum ether was added, filtered, the filter cake was washed with water and dried to give 130.0mg of a pale yellow solid in 81% yield. mp: 60-62 ℃;1H NMR(300MHz，DMSO-d6)δ8.58 (dd，J＝7.3，2.2Hz，1H)，8.39-8.29(m，1H)，7.76(dd，J＝11.0，8.8Hz，1H)，3.92(s，3H)；ESI-MS m/z：198.0 [M-H]+.
4-amino-3-nitrobenzoic acid methyl ester (A6)
A5(130mg, 652.82. mu. mol), aqueous ammonia (25%, 111. mu.L, 718.10. mu. mol), N-diisopropylethylamine (135. mu.L, 783.38. mu. mol) and 10mL of methylene chloride were put in a10 mL eggplant-shaped bottle and stirred at room temperature overnight. After completion of the TLC detection reaction, the reaction mixture was washed with water (5 mL. times.2) and 10% sodium carbonate solution (5mL) in this order, dried over anhydrous sodium sulfate, filtered through a drying agent, and the filtrate was concentrated to give 105.2mg of a yellow solid in a yield of 82%, and the reaction mixture was directly used in the next step without purification. mp: 204-205℃；1H NMR(300MHz，DMSO-d6)δ8.56(d，J ＝1.8Hz，1H)，8.01(s，2H)，7.94-7.80(m，1H)，7.06(d，J＝8.9Hz，1H)，3.82(s，3H)；ESI-MS m/z：195.1 [M-H]+.
4-amino-3-iodo-5-nitrobenzoic acid methyl ester (A7)
Iodine (9.70g, 38.23mmol) was put into a 500mL eggplant-shaped bottle, 250mL of methanol was further added to dissolve iodine, and then silver sulfate (11.92g, 38.23mmol) and A6(5.00g, 25.49mmol) were sequentially added thereto, and the mixture was stirred at room temperature for 12 hours. After completion of the TLC detection, the reaction mixture was filtered and the reaction solvent was distilled off. After the residue was diluted with dichloromethane (100mL), a saturated sodium thiosulfate solution (100mL) was added, followed by extraction with dichloromethane (100 mL. times.3), drying over anhydrous sodium sulfate, filtration of the drying agent and concentration to give the crude product. The crude product was separated by silica gel column chromatography (dichloromethane as eluent) to give 8.08g of an orange solid in 98% yield. mp: 135 ℃ and 137 ℃;1H NMR(300MHz， DMSO-d6)δ8.57(d，J＝1.9Hz，1H)，8.41(d，J＝1.9Hz，1H)，7.60(s，2H)，3.83(s，3H)；ESI-MS m/z：321.0 [M-H]+.
3-iodo-5-nitro-4- (2, 2, 2-trifluoroacetylamino) benzoic acid methyl ester (A8)
A7(6.44g, 20.00mmol) was added to a 500mL eggplant-shaped bottle, 200mL of anhydrous dichloromethane was added to dissolve A7, anhydrous triethylamine (5.54mL, 40.00mmol) was added, and trifluoroacetic anhydride (5.07mL, 36.00mmol) was slowly added dropwise at 0 ℃. After dropping, stirring was continued at 0 ℃ for 5 minutes, followed by stirring at room temperature for 2 hours. After completion of TLC detection, the reaction solvent was distilled off, diluted hydrochloric acid (1mol/L, 100mL) was added, extraction was performed with ethyl acetate (100 mL. times.3), and the mixture was washed with saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, filtered, dried over a drying agent, and concentrated to obtain a crude product. The crude product was isolated by silica gel column chromatography (petroleum ether/ethyl acetate 1: 1 by volume) to give 8.25g of a pale yellow solid in 99% yield. mp: 134 ℃ and 135 ℃;1H NMR(300MHz，DMSO-d6)δ12.05(s，1H)，8.71(d，J＝1.8Hz，1H)， 8.49(d，J＝1.8Hz，1H)，3.92(s，3H)；ESI-MS m/z：416.9[M-H]+.
3- (3-Hydroxypropyn-1-yl) -5-nitro-4- (2, 2, 2-trifluoroacetylamino) benzoic acid methyl ester (A9)
A8(624mg, 1.49mmol), bistriphenylphosphine palladium dichloride (52.4mg, 74.63. mu. mol) and cuprous iodide (28.4mg, 149.26. mu. mol) were charged into a25 mL two-necked round-bottomed flask, and after replacing the air in the flask with nitrogen for 5 minutes, anhydrous N, N-dimethylformamide (1.5mL), N-diisopropylethylamine (6mL) and diisopropylamine (3mL) were added, and the air in the reaction system was replaced with nitrogen with stirring for 30 minutes. Then, a mixed solution of propargyl alcohol (104. mu.L, 1.79mmol) and diisopropylamine (3mL) was slowly added dropwise thereto, and the reaction solution was stirred at room temperature for 12 hours. After completion of the TLC detection reaction, the insoluble impurities were removed by filtration through celite, the filter cake was washed with ethyl acetate, the filtrate was washed with a saturated aqueous ammonium chloride solution (15 mL. times.2), dried over anhydrous sodium sulfate, the desiccant was filtered, and the crude product was obtained by concentration under reduced pressure. The crude product was isolated by silica gel column chromatography (petroleum ether/ethyl acetate 1: 1 by volume) to yield 335.0mg of a yellow solid in 65% yield. mp: 210 ℃ and 212 ℃;1H NMR (300MHz，DMSO-d6)δ12.03(s，1H)，8.61(s，1H)，8.55(d，J＝1.4Hz，1H)，6.78(s，1H)，4.71(d，J＝6.0Hz， 2H)，3.91(s，3H).
3- (3- ((ethoxycarbonyl) oxy) propyn-1-yl) -5-nitro-4- (2, 2, 2-trifluoroacetylamino) benzoic acid methyl ester (A10)
A9(2.49g, 7.19mmol) and 4-dimethylaminopyridine (87.8mg, 719.20. mu. mol) were charged into a 250mL eggplant-shaped bottle, and after adding anhydrous dichloromethane (72mL) and anhydrous pyridine (2.32mL, 28.77mmol), ethyl chloroformate (1.37mL, 14.38mmol) was slowly added dropwise at 0 ℃. After dropping, the mixture was stirred at 0 ℃ for 5 minutes and then stirred at room temperature for 2 hours. After the completion of the TLC detection reaction, the reaction mixture was washed with 1mol/L dilute hydrochloric acid (50 mL. times.2) and saturated aqueous sodium chloride (50mL) in this order, dried over anhydrous sodium sulfate, filtered through a drying agent, and concentrated under reduced pressure to give a crude product. The crude product was isolated by silica gel column chromatography (petroleum ether/ethyl acetate 1: 1 by volume) to give 2.88g of a yellow solid in 96% yield. mp: 158 ℃ and 160 ℃;1H NMR(300MHz，DMSO-d6)δ12.43(s，1H)，8.67(s，1H)，8.60(d，J＝1.4Hz，1H)，5.36(s， 2H)，4.17(q，J＝7.1Hz，2H)，3.92(s，3H)，1.23(t，J＝7.1Hz，3H)；ESI-MS m/z：417.1[M-H]+.
2-methyl-7-nitro-1H-indole-5-carboxylic acid methyl ester (A11)
A10(2.33g, 5.57mmol) and tetrakis (triphenylphosphine) palladium (321.9mg, 278.52mmol) were charged in a 100mL three-necked round-bottomed flask, and after adding anhydrous acetonitrile, the air in the reaction system was replaced with nitrogen, and then anhydrous triethylamine (2.31mL, 16.68mmol), formic acid (88%, 477. mu.L, 11.12mmol) were sequentially added, followed by stirring at 80 ℃ for 1 hour. After TLC detection reaction is completed, cooling and concentrating the reaction solution to obtain residue. The residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, volume ratio 8: 1) to give 1.23g of a yellow solid in 94% yield. mp: 186 ℃ and 188 ℃;1H NMR(300MHz，DMSO-d6)δ12.11(s，1H)，8.49(s，2H)，6.59(s，1H)，3.91(s，3H)，2.49(s， 3H)；ESI-MS m/z：233.1[M-H]+.
7-amino-2-methyl-1H-indole-5-carboxylic acid methyl ester (A12)
A11(100.0mg, 426.97. mu. mol), palladium on charcoal (10%, 10mg), and a mixed solvent of tetrahydrofuran and methanol (volume ratio 1: 1, 5mL) were placed in a25 mL two-necked round-bottomed flask, and after replacing the air in the reaction flask with hydrogen gas, the reaction was allowed to proceed overnight at room temperature under hydrogen gas. After completion of the TLC detection reaction, the pad was filtered through celite, the filter cake was washed with methanol and concentrated to give 79.2mg of a gray solid in 91% yield. The reaction is directly carried out in the next step without purification. mp: 155 ℃ and 157 ℃;1H NMR(300MHz，Chloroform-d)δ8.07(s，1H)，7.84(s，1H).7.23(s，1H)， 6.27(s，1H)，3.90(s，3H)，2.44(s，3H)；ESI-MS m/z：203.1[M-H]+.
2-methyl-7- (phenylsulfonylamino) -1H-indole-5-carboxylic acid methyl ester (A13a)
A12(60.0mg, 293.79. mu. mol) and 2mL of anhydrous pyridine were put in a10 mL round bottom flask, and after A12 was completely dissolved, benzenesulfonyl chloride (43. mu.L, 337.86. mu. mol) was added dropwise and the mixture was stirred at room temperature for 2 hours. After TLC detection, the reaction solution was neutralized with 1mol/L hydrochloric acid, extracted with ethyl acetate (15 mL. times.3), washed with saturated sodium chloride solution (15mL), dried over anhydrous sodium sulfate, filtered, dried, and concentrated under reduced pressure to give the crude product. The crude product was chromatographed on a silica gel column (petroleum ether/ethyl acetate, vol.)1: 1) gave 81.0mg of yellow solid in 80% yield. mp: 210 ℃ and 212 ℃;1H NMR(300MHz，DMSO-d6)δ11.11(s，1H)，10.15(s，1H)，8.06(d，J＝6.8Hz，2H)，7.97(d， J＝19.7Hz，2H)，7.70-7.50(m，3H)，6.33(s，1H)，3.85(s，3H)，2.42(s，3H)；ESI-MS m/z：367.1[M+Na]+.
3-acetyl-2-methyl-7- (phenylsulfonylamino) -1H-indole-5-carboxylic acid methyl ester (I-3)
A13a (51.0mg, 148.09. mu. mol) and anhydrous aluminum chloride (29.62mg, 222.14. mu. mol) were charged in a10 mL two-necked round-bottomed flask, and after adding anhydrous methylene chloride (2mL), the air in the reaction system was replaced with nitrogen for 5 minutes, and then a hexane solution of diethylaluminum chloride (1M, 222. mu.L, 222.14. mu. mol) and acetyl chloride (16. mu.L, 222.14. mu. mol) were sequentially added at 0 ℃. After the addition was completed, 0C was further stirred for 5 minutes, and then the reaction was carried out at room temperature for 5 hours. After completion of the TLC detection reaction, ice water (5mL) was added, the organic layer was separated, the aqueous layer was extracted with ethyl acetate (5 mL. times.2), the organic layers were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was isolated by silica gel column chromatography (petroleum ether/ethyl acetate 1: 1 by volume) to give 23.0mg of a pale yellow solid in 60% yield. mp: 265 ℃ and 266 ℃;1H NMR(300MHz，DMSO-d6)δ11.92(s，1H)，10.01(s，1H)，8.68-8.54(m，1H)，7.75-7.67(m，2H)， 7.68-7.58(m，1H)，7.60-7.48(m，2H)，7.17(d，J＝1.3Hz，1H)，3.78(s，3H)，2.75(s，3H)，2.51(s，3H)；ESI-MS m/z：385.1[M-H]+.
EXAMPLE 4 Synthesis of Compound I-4
2-methyl-7- ((2-methoxyphenyl) sulfonylamino) -1H-indole-5-carboxylic acid methyl ester (A13b)
The preparation method is the same as A13a, and 40.1mg of white solid is obtained, with the yield of 36%. mp: 198-200 ℃;1H NMR(300MHz，DMSO-d6)δ 11.02(s，1H)，9.67(s，1H)，7.87-7.77(m，1H)，7.70(dd，J＝7.8，1.6Hz，1H)，7.62-7.49(m，1H)，7.33(d，J＝ 1.3Hz，1H)，7.16(d，J＝8.3Hz，1H)，7.00(t，J＝7.5Hz，1H)，6.25(s，1H)，3.86(s，3H)，3.75(s，3H)，2.41(s，3H)； ESI-MS m/z：397.1[M+Na]+.
3-acetyl-7- ((2-methoxyphenyl) propylsulfonylamino) -1H-indole-5-carboxylic acid methyl ester (I-4)
The preparation method is the same as I-3, and 10.0mg of white solid is obtained, with the yield of 15%. mp: 248-250 ℃;1H NMR(300MHz，DMSO-d6)δ11.86 (s，1H)，9.75(s，1H)，8.49(d，J＝1.4Hz，1H)，7.66(dd，J＝7.9，1.8Hz，1H)，7.62-7.53(m，1H)，7.36(d，J＝1.5 Hz，1H)，7.19(d，J＝8.3Hz，1H)，7.00(t，J＝7.5Hz，1H)，3.88(s，3H)，3.78(s，3H)，2.76(s，3H)，2.51(s，3H)； ESI-MS m/z：415.1[M-H]+.
EXAMPLE 5 Synthesis of Compound I-5
2-methyl-7- (propylsulfonylamino) -1H-indole-5-carboxylic acid methyl ester (A13c)
The preparation method is the same as A13a, and a yellow solid 61.5mg with a yield of 67% is obtained. mp: 167-168 ℃ of reaction;1H NMR(300MHz，DMSO-d6)δ 11.06(s，1H)，9.40(s，1H)，7.96(s，1H)，7.63(d，J＝1.3Hz，1H)，6.33(s，1H)，3.83(s，3H)，3.14-3.03(m，2H)， 2.41(s，3H)，1.75-1.64(m，2H)，0.92(t，J＝7.4Hz，3H).
3-acetyl-2-methyl-7- (N- (propylsulfonylamino) acetylamino) -1H-indole-5-carboxylic acid methyl ester (I-5)
The preparation method is the same as I-3, and white solid 50.3mg with yield of 72% is obtained. mp: 245 ℃ and 246 ℃;1H NMR(300MHz，DMSO-d6)δ12.38 (s，1H)，8.86(s，1H)，7.78(s，1H)，3.89(s，3H)，3.82(d，J＝11.2Hz，2H)，2.77(s，3H)，2.56(s，3H)，1.92(s，3H)， 1.89-1.80(m，2H)，1.04(t，J＝7.3Hz，3H)；ESI-MSm/z：417.1[M+Na]+.
EXAMPLE 6 Synthesis of Compound I-6
2-methyl-7- (N- (phenylsulfonyl) phenylsulfonylamino) -1H-indole-5-carboxylic acid methyl ester (A13d)
A12(30.0mg, 146.89. mu. mol), dimethylaminopyridine (2.7mg, 22.03. mu. mol) and 2mL of anhydrous dichloromethane were added to a10 mL eggplant-shaped bottle, after A12 was completely dissolved, anhydrous triethylamine (75. mu.L, 540.57. mu. mol) was added, and finally benzenesulfonyl chloride was added dropwiseChlorine (38. mu.L, 298.79. mu. mol) was stirred at room temperature for 2 hours. After TLC detection, the reaction solution was neutralized with 1mol/L hydrochloric acid, extracted with ethyl acetate (10 mL. times.3), washed with saturated sodium chloride solution (15mL), dried over anhydrous sodium sulfate, filtered, dried, and concentrated under reduced pressure to give the crude product. The crude product was isolated by silica gel column chromatography (petroleum ether/ethyl acetate 5: 1 by volume) to give 68.0mg of a yellow solid in 96% yield. mp: 225-226 ℃;1H NMR(300MHz，Chloroform-d)δ8.29(s，1H)，7.92-7.83(m，4H)，7.77(s，1H)，7.72-7.65(m，2H)，7.52(t， J＝7.8Hz，4H)，7.37(d，J＝1.3Hz，1H)，6.27(s，1H)，3.87(s，3H)，2.28(s，3H)；ESI-MS m/z：483.2[M-H]+.
3-acetyl 2-methyl-7- (N- (phenylsulfonyl) phenylsulfonylamino) -1H-indole-5-carboxylic acid methyl ester (I-6)
The preparation method is the same as I-3, and 45.2mg of white solid is obtained with the yield of 59%. mp: 233-235 ℃;1H NMR(300MHz，Chloroform-d) δ8.85(s，1H)，8.26(s，1H)，7.90-7.79(m，4H)，7.71(t，J＝7.4Hz，2H)，7.54(t，J＝7.8Hz，4H)，7.42(d，J＝1.2 Hz，1H)，3.90(s，3H)，2.67(s，3H)，2.60(s，3H)；ESI-MSm/z：525.2[M-H]+.
EXAMPLE 7 Synthesis of Compound I-7
7-Benzoylamino-2-methyl-1H-indole-5-carboxylic acid methyl ester (A13e)
A12(60.0mg, 293.79. mu. mol), anhydrous triethylamine (163. mu.L, 1.18mmol) and 2mL anhydrous dichloromethane were added to a10 mL eggplant-shaped bottle, after A12 was completely dissolved, benzoyl chloride (43. mu.L, 367.23. mu. mol) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the TLC detection reaction, the reaction mixture was neutralized with 1mol/L hydrochloric acid, extracted with ethyl acetate (10 mL. times.3), washed with a saturated sodium chloride solution (15mL), dried over anhydrous magnesium sulfate, filtered through a desiccant, and concentrated under reduced pressure to obtain a crude product. The crude product was isolated by silica gel column chromatography (petroleum ether/ethyl acetate 1: 1 by volume) to yield 43.0mg of a yellow solid in 47% yield. mp: 198-200 ℃;1H NMR(300MHz，DMSO-d6)δ11.11(s，1H)， 10.14(s，1H)，8.11-8.03(m，2H)，7.99(s，1H)，7.97-7.89(m，1H)，7.67-7.51(m，3H)，6.33(s，1H)，3.84(s，3H)， 2.42(s，3H)；ESI-MS m/z：307.1[M-H]+.
2-methyl-3-acetyl-7-benzoylamino-1H-indole-5-carboxylic acid methyl ester (I-7)
The preparation method is the same as I-3, and 16.7mg of white solid is obtained with the yield of 49%. mp: 273-275 ℃;1H NMR(300MHz，DMSO-d6)δ11.79 (s，1H)，10.30(s，1H)，8.66(s，1H)，8.08(d，J＝7.0Hz，2H)，7.96(s，1H)，7.68-7.53(m，3H)，3.88(s，3H)，2.74 (s，3H)，2.56(s，3H)；ESI-MS m/z：349.3[M-H]+.
EXAMPLE 8 Synthesis of Compound I-8
7- (2-Methoxybenzoylamino) -2-methyl-1H-indole-5-carboxylic acid methyl ester (A13f)
The preparation method is the same as A13e, and 44.3mg of white solid is obtained with the yield of 59%. mp: 150 ℃ to 152 ℃;1H NMR(300MHz，DMSO-d6)δ 11.09(s，1H)，9.87(s，1H)，8.25-8.14(m，1H)，7.96(s，1H)，7.73(dd，J＝7.5，1.5Hz，1H)，7.62-7.50(m，1H)， 7.22(d，J＝8.3Hz，1H)，7.11(t，J＝7.4Hz，1H)，6.32(s，1H)，3.91(s，3H)，3.84(s，3H)，2.41(s，3H)；ESI-MS m/z：361.2[M+Na]+.
3-acetyl-7- (2-methoxybenzoylamino) -2-methyl-1H-indole-5-carboxylic acid methyl ester (I-8)
The preparation method is the same as I-3, and 24.0mg of white solid is obtained with the yield of 71%. mp: 202-204 ℃;1H NMR(300MHz，DMSO-d6)δ11.79 (s，1H)，9.98(s，1H)，8.68-8.60(m，1H)，8.24-8.16(m，1H)，7.84-7.73(m，1H)，7.62-7.52(m，1H)，7.24(d，J ＝8.3Hz，1H)，7.11(t，J＝7.4Hz，1H)，3.92(s，3H)，3.88(s，3H)，2.73(s，3H)，2.55(s，3H)；ESI-MS m/z：379.1 [M-H]+，403.1[M+Na]+.
EXAMPLE 9 Synthesis of Compound I-9
7-Butylamino-2-methyl-1H-indole-5-carboxylic acid methyl ester (A13g)
The preparation method is the same as A13e, and 42.2mg of white solid is obtained with the yield of 52%. mp: 160 ℃ and 161 ℃;1H NMR(300MHz，DMSO-d6)δ 10.91(s，1H)，9.63(s，1H)，8.10-8.01(m，1H)，7.91(s，1H)，6.30(s，1H)，3.82(s，3H)，2.43(s，3H)，2.38(d，J＝ 7.4Hz，2H)，1.68(h，J＝7.3Hz，2H)，0.97(t，J＝7.4Hz，3H)；ESI-MS m/z：273.1[M-H]+.
3-acetyl-7-butyrylamino-2-methyl-1H-indole-5-carboxylic acid methyl ester (I-9)
The preparation method is the same as I-3, and 12.1mg of white solid is obtained, with the yield of 18%. mp: 220 ℃ and 221 ℃;1H NMR(300MHz，DMSO-d6)δ11.63 (s，1H)，9.75(s，1H)，8.57(s，1H)，8.05(s，1H)，3.86(s，3H)，2.75(s，3H)，2.54(s，3H)，2.41(t，J＝7.4Hz，2H)， 1.67(dt，J＝14.7，7.4Hz，2H)，0.97(t，J＝7.4Hz，3H)；ESI-MS m/z：317.1[M+H]+，339.1[M+Na]+.
EXAMPLE 10 Synthesis of Compound I-10
2-methyl-7- (3-phenylureido) -1H-indole-5-carboxylic acid methyl ester (A13H)
A12(30.0mg, 146.89. mu. mol), anhydrous triethylamine (46. mu.L, 330.51. mu. mol) and 2mL of anhydrous dichloromethane were put in a10 mL eggplant-shaped bottle, after A12 was completely dissolved, phenyl isocyanate (16. mu.L, 146.89. mu. mol) was added thereto, and the mixture was stirred at room temperature overnight. After completion of the TLC detection reaction, the reaction mixture was filtered, and the filter cake was washed with anhydrous dichloromethane and dried to obtain 20.2mg of a white solid with a yield of 21%. mp: 240 ℃ and 241 ℃;1H NMR (300MHz，DMSO-d6)δ10.94(s，1H)，8.81(s，1H)，8.48(s，1H)，7.89(s，1H)，7.72(s，1H)，7.51(d，J＝7.8Hz， 2H)，7.29(t，J＝7.8Hz，2H)，6.98(t，J＝7.3Hz，1H)，6.29(s，1H)，3.83(s，3H)，2.42(s，3H)；ESI-MS m/z：346.4 [M+Na]+.
3-acetyl-2-methyl-7- (3-phenylureido) -1H-indole-5-carboxylic acid methyl ester (I-10)
The preparation method is the same as I-3, and 12.5mg of white solid is obtained with the yield of 18%. mp: 229 ℃ at 230 ℃;1H NMR(300MHz，DMSO-d6)δ11.73 (s，1H)，8.90(s，1H)，8.56(s，2H)，7.80-7.76(m，1H)，7.51(d，J＝8.0Hz，2H)，7.31(t，J＝7.9Hz，2H)，6.98(t，J ＝7.3Hz，1H)，3.86(s，3H)，2.74(s，3H)，2.54(s，3H)；ESI-MS m/z：364.1[M-H]+.
EXAMPLE 11 Synthesis of Compound I-11
7- (3- (2-methoxyphenyl) ureido) -2-methyl-1H-indole-5-carboxylic acid methyl ester (A13i)
A method: 2-methoxybenzoic acid (60.0mg, 396.36. mu. mol), diphenylphosphorylazide (85. mu.L, 396.36. mu. mol), anhydrous triethylamine (109. mu.L, 788.72. mu. mol) and 2mL of anhydrous tetrahydrofuran were put in a10 mL eggplant-shaped bottle and heated under reflux for 1 hour. After cooling, a solution of a12(30.0mg, 146.89 μmol) in tetrahydrofuran (1mL) was added to the reaction flask. After the addition, the reaction was refluxed for 5 hours. After TLC detection reaction, the reaction solution was concentrated, and the obtained residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, volume ratio 2: 1) to obtain 90.1mg of white solid with a yield of 92%. Method B: the preparation method is the same as A13h, and 11.0mg of white solid is obtained with a yield of 21%. mp: 197 ℃ and 199 ℃;1H NMR(300MHz，DMSO-d6)δ10.81(s，1H)，9.13(s，1H)，8.20(s，1H)，8.17(dd，J＝7.8，1.7Hz，1H)，7.88(s， 1H)，7.81(s，1H)，7.12-7.01(m，1H)，7.01-6.84(m，2H)，6.30(s，1H)，3.91(s，3H)，3.83(s，3H)，2.43(s，3H)； ESI-MS m/z：376.1[M+Na]+.
3-acetyl-7- (3- (2-methoxyphenyl) ureido) -2-methyl-1H-indole-5-carboxylic acid methyl ester (I-11)
The preparation method is the same as I-3, and 20.1mg of white solid is obtained with the yield of 33%. mp: 225 ℃ and 227 ℃;1H NMR(300MHz，DMSO-d6)δ11.66 (s，1H)，9.21(s，1H)，8.56(s，1H)，8.27(s，1H)，8.16(dd，J＝7.7，1.4Hz，1H)，7.86-7.78(m，1H)，7.11-7.02(m， 1H)，7.02-6.87(m，2H)，3.91(s，3H)，3.87(s，3H)，2.75(s，3H)，2.54(s，3H)；ESI-MS m/z：418.1[M+Na]+.
EXAMPLE 12 Synthesis of Compound I-12
2-methyl-7- (3- (3- (trifluoromethyl) phenyl) ureido) -1H-indole-5-carboxylic acid methyl ester (A13j)
The preparation method is the same as A13h, and a white solid 41.0mg with a yield of 71% is obtained. mp: 245-5246 ℃;1H NMR(300MHz，DMSO-d6) δ10.97(s，1H)，9.22(s，1H)，8.60(s，1H)，8.05(s，1H)，7.92(s，1H)，7.75-7.61(m，2H)，7.52(t，J＝7.8Hz，1H)， 7.31(d，J＝7.7Hz，1H)，6.30(s，1H)，3.83(s，3H)，2.42(s，3H)；ESI-MS m/z：390.1[M-H]+.
3-acetyl-2-methyl-7- (3- (3- (trifluoromethyl) phenyl) ureido) -1H-indole-5-carboxylic acid methyl ester (I-12)
The preparation method is the same as I-3, and 13.2mg of white solid is obtained with the yield of 39%. mp: 175-177 ℃;1H NMR(300MHz，DMSO-d6)δ11.74 (s，1H)，9.31(s，1H)，8.69(s，1H)，8.59(s，1H)，8.04(s，1H)，7.76(s，1H)，7.67(d，J＝7.9Hz，1H)，7.52(t，J＝7.8 Hz，1H)，7.38-7.26(m，1H)，3.87(s，3H)，2.75(s，3H)，2.54(s，3H)；ESI-MS m/z：432.1[M-H]+，456.2[M+Na]+.
EXAMPLE 13 Synthesis of Compound I-13
7- (3-ethylureido) -2-methyl-1H-indole-5-carboxylic acid methyl ester (A13k)
The preparation method is the same as A13h, and 25.0mg of white solid is obtained, with the yield of 31%. mp: 210 ℃ and 211 ℃;1H NMR(300MHz，DMSO-d6)δ 10.91(s，1H)，8.34(s，1H)，7.79(s，1H)，7.75(s，1H)，6.24(d，J＝5.5Hz，2H)，3.81(s，3H)，3.23-3.11(m，2H)， 2.40(s，3H)，1.09(t，J＝7.1Hz，3H)；ESI-MS m/z：276.2[M+H]+，298.1[M+Na]+.
3-acetyl-7- (3-ethylureido) -2-methyl-1H-indole-5-carboxylic acid methyl ester (I-13)
The preparation method is the same as I-3, and 18.1mg of white solid is obtained with the yield of 26%. mp: 255-256 ℃;1H NMR(300MHz，DMSO-d6)δ11.71 (s，1H)，8.47(s，1H)，8.40(s，1H)，7.80(s，1H)，6.33(t，J＝5.5Hz，1H)，3.85(s，3H)，3.17(p，J＝7.1Hz，2H)， 2.73(s，3H)，2.53(s，3H)，1.09(t，J＝7.2Hz，3H)；ESI-MS m/z：318.2[M+H]+，340.2[M+Na]+.
EXAMPLE 14 Synthesis of Compound I-14
7- ((ethoxycarbonyl) amino) -2-methyl-1H-indole-5-carboxylic acid methyl ester (A13l)
A12(60.0mg, 293.79. mu. mol), potassium carbonate (162.4mg, 1.18mmol) in waterThe saturated aqueous solution and 2mL of anhydrous methylene chloride were put in a10 mL round bottom flask, and after A12 was completely dissolved, ethyl chloroformate (32. mu.L, 352.55. mu. mol) was added thereto and the mixture was stirred at room temperature for 1 hour. After completion of the TLC detection reaction, 5mL of water was added, followed by extraction with ethyl acetate (5 mL. times.3), washing with a saturated sodium chloride solution (10mL), drying over anhydrous magnesium sulfate, filtration of the drying agent, and concentration under reduced pressure to obtain a crude product. The crude product was isolated by silica gel column chromatography (petroleum ether/ethyl acetate 2: 1 by volume) to yield 66.0mg of a white solid in 74% yield. mp: 195-196 deg.C;1HNMR(300MHz，DMSO-d6)δ11.01(s，1H)， 9.26(s，1H)，8.00(s，1H)，7.91-7.83(m，1H)，6.33-6.25(m，1H)，4.18(q，J＝7.1Hz，2H)，3.82(s，3H)，2.40(s， 3H)，1.28(t，J＝7.1Hz，3H)；ESI-MS m/z：299.1[M+Na]+.
3-acetyl-7- ((ethoxycarbonyl) amino) -2-methyl-1H-indole-5-carboxylic acid methyl ester (I-14)
The preparation method is the same as I-3, and the beige solid 35.5mg with the yield of 62 percent is obtained. mp: 200 ℃ and 202 ℃;1H NMR(300MHz，DMSO-d6)δ 11.77(s，1H)，9.35(s，1H)，8.54(d，J＝1.2Hz，1H)，8.04(s，1H)，4.18(q，J＝7.1Hz，2H)，3.86(s，3H)，2.72(s， 3H)，2.53(s，3H)，1.28(t，J＝7.0Hz，3H)；ESI-MS m/z：319.1[M+H]+，341.1[M+Na]+.
EXAMPLE 15 Synthesis of Compound I-15
1, 2-dimethyl-7-nitro-1H-indole-5-carboxylic acid methyl ester (A14)
Sodium hydride (60%, 76.9mg, 1.92mmol) was put in a25 mL eggplant-shaped bottle, and after anhydrous N, N-dimethylformamide (5mL) was added, a solution of A11(300.0mg, 1.28mmol) in anhydrous N, N-dimethylformamide (1mL) was added dropwise. After stirring at room temperature for 30 minutes, methyl iodide (239. mu.L, 3.84mmol) was added dropwise. The reaction solution was stirred for 2 hours at room temperature. After completion of the TLC detection reaction, 10mL of ice water was added, followed by extraction with ethyl acetate (5 mL. times.3), washing with a saturated sodium chloride solution (10mL), drying over anhydrous magnesium sulfate, filtration of the drying agent, and concentration under reduced pressure to obtain a crude product. The crude product was isolated by silica gel column chromatography (petroleum ether/ethyl acetate 5: 1 by volume) to give 300.0mg of a white solid in 94% yield. mp: 203-205 ℃;1H NMR(300MHz，DMSO-d6)δ8.43(s，1H)，8.18(s，1H)，6.71(s，1H)，3.89(s，3H)，3.63(s， 3H)，2.48(s，3H)；ESI-MS m/z：271.1[M+Na]+.
7-amino-1, 2-dimethyl-1H-indole-5-carboxylic acid methyl ester (A15)
The preparation was carried out as described for A12 to give 245.7mg of an off-white solid in 93% yield. mp: 175-177 ℃;1H NMR(300MHz，DMSO-d6) δ7.46(d，J＝1.5Hz，1H)，7.02(d，J＝1.5Hz，1H)，6.23-6.18(m，1H)，5.02(s，2H)，3.93(s，3H)，3.77(s，3H)， 2.33(s，3H)；ESI-MS m/z：218.8[M+H]+.
7- ((ethoxycarbonyl) amino) -1, 2-dimethyl-1H-indole-5-carboxylic acid methyl ester (A16)
The preparation method is the same as A13l, and 11.6mg of yellow solid is obtained, with the yield of 29%. mp: 167-168 ℃ of reaction;1H NMR(300MHz，DMSO-d6)δ 9.24(s，1H)，8.10-7.94(m，1H)，7.41(s，1H)，6.41(s，1H)，4.13(q，J＝6.8Hz，2H)，3.82(s，3H)，3.79(s，3H)， 2.39(s，3H)，1.24(t，J＝6.7Hz，3H)；ESI-MS m/z：313.1[M+Na]+.
3-acetyl-7- ((ethoxycarbonyl) amino) -1, 2-dimethyl-1H-indole-5-carboxylic acid methyl ester (I-15)
The preparation method is the same as I-3, and 21.3mg of white solid is obtained, with the yield of 62%. mp: 194 ℃ and 195 ℃;1H NMR(300MHz，DMSO-d6)δ9.40 (s，1H)，8.68(d，J＝1.4Hz，1H)，7.55(s，1H)，4.14(q，J＝6.8Hz，2H)，3.88(s，3H)，3.86(s，3H)，2.73(s，3H)， 2.59(s，3H)，1.25(t，J＝7.0Hz，3H)；ESI-MS m/z：355.1[M+Na]+.
EXAMPLE 16 Synthesis of Compound I-16
3-acetyl-7- (N- (ethoxycarbonyl) acetylamino) -1, 2-dimethyl-1H-indole-5-carboxylic acid methyl ester (I-16)
The preparation method is the same as I-3, and takes A16 as raw material to obtain 7.5mg of white solid with 22 percent of yield. mp: 156 ℃ and 158 ℃;1HNMR(300MHz， DMSO-d6)δ8.78(d，J＝1.5Hz，1H)，7.63(d，J＝1.5Hz，1H)，4.17(q，J＝7.0Hz，2H)，3.87(s，3H)，3.63(s，3H)， 2.73(s，3H)，2.65(s，3H)，2.61(s，3H)，1.08(t，J＝7.1Hz，3H)；ESI-MS m/z：397.1[M+Na]+.
EXAMPLE 17 Synthesis of Compound I-17
4-amino-3-nitro-5- ((trimethylsilyl) ethynyl) benzoic acid methyl ester (A17)
A7(600.0mg, 1.86mmol), bis triphenylphosphine palladium dichloride (65.4mg, 93.15. mu. mol), cuprous iodide (35.5mg, 186.30. mu. mol) and triphenylphosphine (48.9mg, 186.30. mu. mol) were charged into a25 mL two-necked round-bottomed flask, and after replacing the air in the flask with nitrogen for 5 minutes, anhydrous triethylamine (16mL), anhydrous N, N-dimethylformamide (4mL) and anhydrous toluene (8mL) were added in this order, and the air in the reaction system was replaced with nitrogen with stirring for 30 minutes. Then, a mixed solution composed of trimethylsilylacetylene (395. mu.L, 2.79mmol) and anhydrous N, N-dimethylformamide (4mL) was slowly added dropwise, and the reaction solution was stirred overnight at room temperature. After completion of the TLC detection reaction, the insoluble impurities were removed by filtration through celite, the filter cake was washed with ethyl acetate, the filtrate was washed with a saturated aqueous ammonium chloride solution (45 mL. times.2), dried over anhydrous sodium sulfate, the desiccant was filtered, and the crude product was obtained by concentration under reduced pressure. The crude product was isolated by silica gel column chromatography (petroleum ether/ethyl acetate 10: 1 by volume) to yield 521.5mg as a yellow-green solid in 96% yield. mp: 85-86 ℃;1H NMR(300MHz，DMSO-d6)δ8.55(d，J＝1.9Hz，1H)，7.98(d， J＝1.9Hz，1H)，7.59(s，2H)，3.83(s，3H)，0.29(s，9H)；ESI-MS m/z：291.1[M-H]+.
4-amino-3-ethynyl-5-nitrobenzoic acid methyl ester (A18)
A17(500.0mg, 1.71mmol) and methanol (5mL) were added to a25 mL eggplant-shaped bottle, and potassium carbonate (283.63mg, 2.05 mmol) was added. After stirring at room temperature for 25 minutes, the reaction solvent was distilled off, extracted with dichloromethane (15 mL. times.3) and water (20mL), the organic phases were combined, dried over anhydrous sodium sulfate, the drying agent was filtered, and concentrated under reduced pressure to give the crude product. The crude product was isolated by silica gel column chromatography (petroleum ether/ethyl acetate 10: 1 by volume) to yield 369.0mg of a yellow solid in 98% yield. mp: 173-174 ℃;1H NMR(300MHz，DMSO-d6)δ8.57(d， J＝1.8Hz，1H)，8.02(d，J＝1.8Hz，1H)，7.73(s，2H)，4.85(s，1H)，3.84(s，3H)；ESI-MS m/z：219.1[M-H]+.
7-Nitro-1H-indole-5-carboxylic acid methyl ester (A19)
A18(200.0mg, 908.33. mu. mol), (1, 5-cyclooctadiene) chlororhodium (I) dimer (22.4mg, 45.42. mu. mol) and tris (4-fluorophenyl) phosphine (172.4mg, 545.00. mu. mol) were charged to a25 mL two-necked round bottom flask, and after replacing the air in the flask with argon for 5 minutes, degassed anhydrous N, N-dimethylformamide (5mL) was added. The reaction mixture was reacted at 85 ℃ for 50 minutes. After completion of the TLC detection reaction, the reaction mixture was cooled to room temperature, extracted with ethyl acetate (15 mL. times.3) and water (20mL), and the organic phases were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, dried over a drying agent, and concentrated under reduced pressure to give a crude product. The crude product was isolated by silica gel column chromatography (petroleum ether/ethyl acetate, volume ratio 5: 1) to yield 180.0mg of a pale yellow-green solid in 90% yield. mp: 147 ℃ and 149 ℃;1H NMR(300MHz，DMSO-d6)δ12.29(s，1H)，8.68 (s，1H)，8.58(s，1H)，7.66(t，J＝2.6Hz，1H)，6.98-6.88(m，1H)，3.92(s，2H)；ESI-MS m/z：219.1[M-H]+.
7-amino-1H-indole-5-carboxylic acid methyl ester (A20)
The preparation method is the same as A12, and 79.2mg of gray solid is obtained with the yield of 92%. mp: 150 ℃ and 151 ℃;1H NMR(300MHz，DMSO-d6)δ 10.98(s，1H)，7.62-7.53(m，1H)，7.37(t，J＝2.7Hz，1H)，6.98(s，1H)，6.45(dd，J＝2.9，2.0Hz，1H)，5.28(s， 2H)，3.79(s，3H)；ESI-MS m/z：189.1[M-H]+.
7- ((ethoxycarbonyl) amino) -1H-indole-5-carboxylic acid methyl ester (A21)
The preparation method is the same as A13l, 32.6mg of white solid is obtained, and the yield is 79%. mp: 249-250 ℃;1H NMR(300MHz，DMSO-d6)δ 11.16(s，1H)，9.44(s，1H)，8.10(s，1H)，8.05-7.98(m，1H)，7.46(t，J＝2.7Hz，1H)，6.60(dd，J＝3.0，1.9Hz， 1H)，4.19(q，J＝7.1Hz，2H)，3.84(s，3H)，1.29(t，J＝7.1Hz，3H)；ESI-MS m/z：285.1[M+Na]+.
3-acetyl-7- ((ethoxycarbonyl) amino) -1H-indole-5-carboxylic acid methyl ester (I-17)
The preparation method is the same as I-3, and 12.2mg of light purple solid is obtained with the yield of 35%. mp: 276 ℃ and 278 ℃;1H NMR(300MHz，DMSO-d6)δ 11.90(s，1H)，9.54(s，1H)，8.63(d，J＝1.4Hz，1H)，8.43(s，1H)，8.12(s，1H)，4.20(q，J＝7.1Hz，2H)，3.87(s， 3H)，2.48(s，3H)，1.29(t，J＝7.0Hz，3H)；ESI-MS m/z：327.1[M+Na]+.
EXAMPLE 18 Synthesis of Compound I-18
3-acetyl-2-methyl-7-nitro-1H-indole-5-carboxylic acid methyl ester (A22)
A11(1.00g, 4.27mmol), glacial acetic acid (36.63mL, 640.45mmol) were added to a 250mL thick-walled pressure tube, and after A11 was completely dissolved, phosphorus oxychloride (12.85mL) was added. The reaction mixture was reacted at 120 ℃ for 30 minutes. After the completion of the TLC detection reaction, the reaction solution was slowly poured into ice water (100mL), the pH was adjusted to neutral with saturated sodium bicarbonate solution, followed by extraction with ethyl acetate (80 mL. times.3), washing with saturated sodium chloride solution (100mL), drying over anhydrous magnesium sulfate, filtering the drying agent, and concentrating to obtain a crude product. The crude product was isolated by silica gel column chromatography (petroleum ether/ethyl acetate, volume ratio 2: 1) to give 1.08g of a pale yellow solid in 92% yield. mp: 216 ℃ and 218 ℃;1H NMR(300MHz， DMSO-d6)δ12.58(s，1H)，9.12(d，J＝1.4Hz，1H)，8.54(d，J＝1.4Hz，1H)，3.94(s，3H)，2.86(s，3H)，2.58(s， 3H)；ESI-MS m/z：275.4[M-H]+.
3-acetyl-2-methyl-7-nitro-1H-indole-5-carboxylic acid (A23)
A22(16.0mg, 57.92. mu. mol), tetrahydrofuran (1mL) and ethylene glycol (1mL) were added to a10 mL eggplant-shaped bottle, and after A22 was completely dissolved, potassium hydroxide was added. After the addition, the reaction mixture was refluxed for 30 minutes. After completion of TLC detection, the reaction solvent was distilled off, acidified to pH 1 with 1mol/L hydrochloric acid at 0 deg.C, filtered, the filter cake was washed with water and dried to give 14.0mg of a yellow solid with a yield of 92%. mp: 291-292 deg.c;1H NMR(300MHz，DMSO-d6)δ13.35(s，1H)，12.52(s，1H)，9.11(s，1H)，8.55(s，1H)，2.85(s，3H)，2.58(s，3H)；ESI-MS m/z：275.4[M-H]+.
3-acetyl-2-methyl-7-nitro-N-phenyl-1H-indole-5-carboxylic acid amine (A24a)
A23(30.0mg, 114.41. mu. mol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (54.8mg, 286.03. mu. mol), N-diisopropylethylamine (60. mu.L, 343.22. mu. mol) and anhydrous N, N-dimethylformamide (2mL) were put in a10 mL egg plant flask, stirred for 1 hour, added with 1-hydroxybenzotriazole (38.7mg, 286.03. mu. mol) and aniline (16. mu.L, 171.61. mu. mol), and reacted at room temperature overnight. After completion of the TLC detection, the reaction mixture was extracted with ethyl acetate (10 mL. times.3) and water (10mL), washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, dried over a drying agent, and concentrated to obtain a crude product. The crude product was isolated by silica gel column chromatography (petroleum ether/ethyl acetate 1: 1 by volume) to give 25.0mg of a yellow solid in 65% yield. mp: 215-217 ℃;1H NMR(300MHz，DMSO-d6)δ12.53(s，1H)，10.61(s， 1H)，9.14(s，1H)，8.73(s，1H)，7.80(d，J＝7.9Hz，2H)，7.39(t，J＝7.8Hz，2H)，7.14(t，J＝7.3Hz，1H)，2.87(s， 3H)，2.62(s，3H).
3-acetyl-7-amino-2-methyl-N-phenyl-1H-indole-5-carboxylic acid amine (A25a)
A24a (16.0mg, 47.43. mu. mol) and methanol (2mL) were charged in a10 mL two-necked round bottom flask, Raney nickel (10%, 2.8mg, 4.74. mu. mol) was added, then the air in the reaction system was replaced with nitrogen, and then a methanol solution of hydrazine hydrate (88%, 4. mu.L, 71.15. mu. mol) was added dropwise at 0 ℃. After dropping, the reaction solution was allowed to warm for 1 hour, filtered through celite, and the filtrate was concentrated to give 14.1mg of a gray solid, 97% yield. The next step was carried out without further purification. ESI-MS m/z: 308.4[ M + H]+.
(3-acetyl-2-methyl-5- (phenylcarbamoyl) -1H-indol-7-yl) carbamic acid ethyl ester (I-18)
The preparation method is the same as A13l, and 10.5mg of yellow solid is obtained with the yield of 60%. mp: 194 ℃ and 195 ℃;1H NMR(300MHz，Chloroform-d) δ10.71(s，1H)，8.45(s，1H)，8.19(s，1H)，7.61(d，J＝7.7Hz，2H)，7.42(s，1H)，7.38-7.23(m，3H)，7.08(t，J＝ 7.3Hz，1H)，4.24-4.17(m，2H)，2.68(s，3H)，2.54(s，3H)，1.28(d，J＝7.0Hz，3H)；ESI-MS m/z：308.4[M+H]+.
EXAMPLE 19 Synthesis of Compound I-19
3-acetyl-N- (2-methoxyphenyl) -2-methyl-7-nitro-1H-indole-5-carboxylic acid amine (A24b)
The preparation method is the same as A24a, and 85.2mg of yellow solid is obtained with the yield of 61%. mp: 254 ℃ and 255 ℃;1H NMR(300MHz，DMSO-d6)δ 12.52(s，1H)，9.92(s，1H)，9.13(d，J＝1.4Hz，1H)，8.70(d，J＝1.5Hz，1H)，7.68(dd，J＝7.8，1.5Hz，1H)，7.23 (td，J＝7.9，1.6Hz，1H)，7.12(dd，J＝8.3，1.2Hz，1H)，6.99(td，J＝7.6，1.3Hz，1H)，3.85(s，3H)，2.87(s，3H)， 2.63(s，3H)；ESI-MS m/z：368.3[M+H]+.
3-acetyl-7-amino-N- (2-methoxyphenyl) -2-methyl-1H-indole-5-carboxylic acid amine (A25b)
The preparation method is the same as A25a, 32.1mg of gray solid is obtained, and the yield is 98%. The next step was carried out without further purification. ESI-MS m/z: 336.2 [ M-H ]]+.
(3-acetyl-5- ((2-methoxyphenyl) carbamoyl) -2-methyl-1H-indol-7-yl) carbamic acid ethyl ester (I-19)
The preparation method is the same as A13l, and 10.5mg of yellow solid is obtained with the yield of 60%. mp: 210 ℃ and 212 ℃;1H NMR(300MHz，Chloroform-d) δ10.75(s，1H)，8.69(s，1H)，8.50(d，J＝7.9Hz，2H)，7.47-7.40(m，1H)，7.25-7.17(m，1H)，7.13-6.97(m， 2H)，6.97-6.89(m，1H)，4.29(q，J＝7.1Hz，2H)，3.95(s，3H)，2.77(s，3H)，2.65(s，3H)，1.36(t，J＝7.1Hz，3H)； ESI-MS m/z：410.2[M+H]+.
EXAMPLE 20 Synthesis of Compound I-20
3-acetyl-2-methyl-7-nitro-N- (thiazol-2-yl) -1H-indole-5-carboxylic acid amine (A24c)
The preparation method is the same as A24a, and yellow-green solid 44.0mg is obtained with 34% yield. mp: 301-303 ℃;1H NMR(300MHz，DMSO-d6) δ13.39(s，1H)，11.78(s，1H)，8.75(d，J＝2.5Hz，1H)，8.26(dd，J＝9.2，2.5Hz，1H)，7.65(d，J＝9.2Hz，1H)，7.34(s，1H)，2.47(s，3H)，2.26(s，3H)；ESI-MS m/z：343.3[M-H]+.
3-acetyl-7-amino-2-methyl-N- (thiazol-2-yl) -1H-indole-5-carboxylic acid amine (A25c)
The preparation method is the same as A25a, and 36.5mg of gray solid is obtained with the yield of 98%. The next step was carried out without further purification. ESI-MS m/z: 313.3 [ M-H]+.
(3-acetyl-2-methyl-5- ((thiazol-2-yl) carbamoyl) -1H-indol-7-yl) carbamic acid ethyl ester (I-20)
The preparation method is the same as A13l, and 18.0mg of white solid is obtained with the yield of 40%. mp: 269-271 deg.C;1H NMR(300MHz，DMSO-d6)δ 12.65(s，1H)，11.78(s，1H)，9.34(s，1H)，8.53(d，J＝1.4Hz，1H)，8.04(s，1H)，7.55(d，J＝3.6Hz，1H)，7.25(d， J＝3.6Hz，1H)，4.19(q，J＝7.1Hz，2H)，2.72(s，3H)，2.63(s，3H)，1.28(t，J＝7.1Hz，3H)；ESI-MS m/z：387.2 [M+H]+.
EXAMPLE 21 Synthesis of Compound I-21
3-acetyl-N-cyclopentyl-2-methyl-7-nitro-1H-indole-5-carboxylic acid amine (A24d)
The preparation method is the same as A24a, and yellow-green solid 80.0mg, 64% is obtained. mp: 255 ℃ and 257 ℃;1H NMR(300MHz，DMSO-d6)δ12.43 (s，1H)，9.03(s，1H)，8.68(d，J＝7.1Hz，1H)，8.62(d，J＝1.4Hz，1H)，4.27(hept，J＝7.2Hz，1H)，2.84(s，3H)， 2.60(s，3H)，2.01-1.83(m，2H)，1.83-1.66(m，2H)，1.64-1.51(m，4H)；ESI-MS m/z：328.4[M-H]+.
3-acetyl-7-amino-N-cyclopentyl-2-methyl-1H-indole-5-carboxylic acid amine (A25d)
The preparation method is the same as A25a, and a gray solid 45.5mg is obtained with a yield of 98%. The next step was carried out without further purification. ESI-MS m/z: 300.3 [ M + H]+.
(3-acetyl-5- (cyclopentylcarbamoyl) -2-methyl-1H-indol-7-yl) carbamic acid ethyl ester (I-21)
The preparation method is the same as A13l, and 8.6mg of beige solid is obtained, with the yield of 15%. mp: 223 ℃ to 224 ℃;1H NMR(300MHz，DMSO-d6)δ 11.63(s，1H)，9.26(s，1H)，8.32-8.18(m，2H)，7.75(s，1H)，4.32-4.21(m，1H)，4.16(q，J＝7.1Hz，2H)，2.70(s， 3H)，2.56(s，3H)，1.95-1.82(m，2H)，1.79-1.64(m，2H)，1.61-1.49(m，4H)，1.26(t，J＝6.8Hz，3H)；ESI-MS m/z：372.4[M+H]+.
EXAMPLE 22 Synthesis of Compound I-22
N, 2-dimethyl-7-nitro-1H-indole-5-carboxamide (A26)
A11(300.0mg, 1.28mmol) and methylamine alcohol solution (30%, 22.5mL) were added to a 100mL thick-walled pressure tube and stirred at 45 ℃ for 22 hours. After completion of the TLC detection reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, the residue was dissolved in methylene chloride (40mL), washed with water (20 mL. times.3) and saturated brine (20mL) in this order, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, dried over a drying agent, and concentrated to obtain a crude product. The crude product was purified by recrystallization (ethyl acetate) to yield 270.0mg of a yellow solid in 90% yield. mp: 256-258 ℃;1H NMR(300 MHz，DMSO-d6)δ11.97(s，1H)，8.86-8.62(m，1H)，8.48(d，J＝26.2Hz，2H)，6.53(s，1H)，2.82(d，J＝4.2Hz， 3H)，2.49(s，3H)；ESI-MS m/z：232.1[M+H]+.
3-acetyl-N, 2-dimethyl-7-nitro-1H-indole-5-carboxamide (A27)
The preparation was carried out as described for A22 to give 275.0mg of a brown solid in 93% yield. mp: 209-210 ℃;1H NMR(300MHz，DMSO-d6)δ12.44(s，1H)，9.03(s，1H)，8.78(d，J＝4.3Hz，1H)，8.59(d，J＝1.3Hz，1H)，2.84(s，3H)，2.83(s，3H)，2.61(s， 3H)；ESI-MS m/z：274.2[M-H]+.
3-acetyl-7-amino-N, 2-dimethyl-1H-indole-5-carboxamide (A28)
The preparation method is the same as A25a, and a gray solid 222.3mg is obtained, with the yield of 96%. The next step was carried out without further purification.1HNMR(300MHz， DMSO-d6)δ11.67(s，1H)，8.13(d，J＝4.4Hz，1H)，7.75-7.66(m，1H)，6.94-6.85(m，1H)，5.22(s，2H)，2.76(d，J＝4.5Hz，3H)，2.66(s，3H)，2.53(s，3H).
(3-acetyl-2-methyl-5- (methylcarbamoyl) -1H-indol-7-yl) carbamic acid ethyl ester (I-22)
The preparation method is the same as I-3, and 46.6mg of light yellow solid is obtained, with the yield of 36%. mp: 261 ℃ and 263 ℃;1H NMR(300MHz，DMSO-d6)δ 11.64(s，1H)，9.25(s，1H)，8.39-8.29(m，1H)，8.27(s，1H)，7.80(s，1H)，4.17(q，J＝7.1Hz，2H)，2.79(d，J＝ 4.4Hz，3H)，2.70(s，3H)，2.56(s，3H)，1.27(t，J＝7.0Hz，3H)；ESI-MS m/z：318.3[M+H]+，340.3[M+Na]+.
EXAMPLE 23 Synthesis of Compound I-23
(4-fluoro-3-nitrophenyl) (phenyl) methanone (A29)
4-fluoro-3-nitrobenzoic acid (2.00g, 10.80mmol), anhydrous dichloromethane (30mL) and oxalyl chloride (4.57mL, 54.02mmol) were sequentially added to a 100mL eggplant-shaped bottle, and after 2 drops of N, N-dimethylformamide were added dropwise, the reaction was carried out at room temperature for 30 minutes. And detecting 4-fluoro-3-nitrobenzoic acid by TLC (thin layer chromatography), and concentrating to obtain aryl acyl chloride. In a 100mL three-necked round-bottomed flask, anhydrous aluminum trichloride (7.20g, 54.02mmol) and benzene (30mL, 540.22mmol) were charged, the atmosphere in the reaction system was replaced with nitrogen, and then a benzene solution of aryl acid chloride (20mL) was slowly added dropwise at 0 ℃. After the addition, the reaction was carried out at room temperature for 8 hours. After completion of the TLC detection reaction, the reaction mixture was poured into ice water (50mL), the organic layer was separated, the aqueous layer was extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, dried over anhydrous sodium sulfate, the drying agent was filtered, and the crude product was obtained by concentration under reduced pressure. The crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate 10: 1 by volume) to give 2.45g of a white solid in 92% yield. mp: 58 to 59 ℃;1H NMR(300MHz，DMSO-d6)δ8.41(dd，J＝7.3，2.2Hz，1H)，8.17(ddd，J＝8.6，4.3，2.2Hz，1H)，7.83-7.71 (m，4H)，7.61(t，J＝7.5Hz，2H).
(4-amino-3-nitrophenyl) (phenyl) methanone (A30)
A29(130mg, 530.16. mu. mol), aqueous ammonia (25%, 90. mu.L, 583.18. mu. mol), N-diisopropylethylamine (109. mu.L, 636.19. mu. mol) and tetrahydrofuran (2mL) were put in a10 mL eggplant-shaped bottle and reacted at room temperature for 24 hours. After completion of the TLC detection reaction, the reaction mixture was concentrated to remove the reaction solvent, and 1mol/L hydrochloric acid (15mL) was added thereto, followed by extraction with ethyl acetate (10 mL. times.3)Taking, combining organic phases, drying by anhydrous sodium sulfate, filtering a drying agent, and concentrating under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate 5: 1 by volume) to give 58mg of a yellow solid in 45% yield. mp: 140 ℃ and 142 ℃;1H NMR(300MHz，DMSO-d6)δ8.36(d，J＝2.0Hz，1H)，8.09 (s，2H)，7.86(dd，J＝8.9，2.0Hz，1H)，7.74-7.63(m，3H)，7.61-7.53(m，2H)，7.14(d，J＝8.9Hz，1H).
(4-amino-3-iodo-5-nitrophenyl) (phenyl) methanone (A31)
The preparation method is the same as A7, and 1.40g of yellow solid is obtained with the yield of 92%. mp: 150 ℃ and 151 ℃;1H NMR(300MHz，DMSO-d6)δ8.41 -8.34(m，2H)，7.77-7.63(m，5H)，7.58(t，J＝7.3Hz，2H).
n- (4-benzoyl-2-iodo-6-nitrophenyl) -2, 2, 2-trifluoroacetamide (A32)
The preparation method is the same as A8, and light yellow solid 2.64g is obtained with the yield of 75%. mp: 169 ℃ and 170 ℃;1H NMR(300MHz，DMSO-d6)δ 12.01(s，1H)，8.53(d，J＝1.5Hz，1H)，8.37-8.26(m，1H)，7.83(d，J＝7.3Hz，2H)，7.79-7.70(m，1H)，7.61(t， J＝7.5Hz，2H).
n- (4-benzoyl-2- (3-hydroxypropan-1-yn-1-yl) -6-nitrophenyl) -2, 2, 2-trifluoroacetamide (A33)
The preparation method is the same as A9, triethylamine is used as alkali, yellow solid 727.3mg is obtained, and the yield is 86%. mp: 223 ℃ to 224 ℃;1HNMR(300MHz， DMSO-d6)δ12.03(s，1H)，8.40(d，J＝7.7Hz，2H)，7.78(d，J＝7.4Hz，2H)，7.74-7.67(m，1H)，7.60(t，J＝7.2 Hz，2H)，6.79(s，1H)，4.73(d，J＝5.3Hz，2H).
[3- (5-benzoyl-3-nitro-2- (2, 2, 2-trifluoroacetamido) phenyl) prop-2-yn-1-yl ] ethyl carbonate (A34)
The preparation method is the same as A10, and yellow solid 392.0mg is obtained, with the yield of 83%. mp: 135 ℃ and 136 ℃;1H NMR(300MHz，DMSO-d6)δ 12.44(s，1H)，8.57-8.40(m，2H)，7.86-7.76(m，2H)，7.76-7.66(m，1H)，7.60(t，J＝7.4Hz，2H)，5.37(s，2H)，4.18(q，J＝7.1Hz，2H)，1.24(t，J＝7.1Hz，3H).
(2-methyl-7-nitro-1H-indol-5-yl) (phenyl) methanone (A35)
The preparation method is the same as A11, and 146.0mg of yellow solid is obtained with 92% yield. mp: 135 ℃ and 137 ℃;1H NMR(300MHz，DMSO-d6)δ 12.12(s，1H)，8.33(d，J＝7.1Hz，2H)，7.77(d，J＝7.0Hz，2H)，7.71(t，J＝7.4Hz，1H)，7.60(t，J＝7.4Hz，2H)， 6.62(s，1H)，2.51(s，3H).
(7-amino-2-methyl-1H-indol-5-yl) (phenyl) methanone (A36)
The preparation method is the same as A25a, and 88.0mg of gray solid is obtained with 99 percent of yield. mp: 205 ℃ and 206 ℃;1H NMR(300MHz，DMSO-d6)δ 10.87(s，1H)，7.69-7.61(m，2H)，7.61-7.56(m，1H)，7.51(t，J＝7.2Hz，2H)，7.11(s，1H)，6.82(d，J＝1.3Hz， 1H)，6.15(s，1H)，5.19(s，2H)，2.39(s，3H)；ESI-MS m/z：251.0[M+H]+.
(5-benzoyl-2-methyl-1H-indol-7-yl) carbamic acid ethyl ester (A37a)
The preparation method is the same as A13l, and orange solid 95.0mg with yield of 74% is obtained. mp: 237-239 ℃;1H NMR(300MHz，DMSO-d6) δ11.06(s，1H)，9.28(s，1H)，7.88(s，1H)，7.59(tt，J＝14.5，7.2Hz，5H)，6.30(s，1H)，4.17(q，J＝7.1Hz，2H)， 2.41(s，3H)，1.27(t，J＝7.1Hz，3H)；ESI-MS m/z：323.1[M-H]+.
(3-acetyl-5-benzoyl-2-methyl-1H-indol-7-yl) carbamic acid ethyl ester (I-23)
The preparation method is the same as I-3, and light yellow solid 28.6mg with the yield of 44% is obtained. mp: 200 ℃ and 201 ℃;1H NMR(300MHz，DMSO-d6)δ 11.79(s，1H)，9.38(s，1H)，8.29(s，1H)，7.89(s，1H)，7.78-7.69(m，2H)，7.69-7.61(m，1H)，7.56(t，J＝7.4Hz， 2H)，4.18(q，J＝7.1Hz，2H)，2.74(s，3H)，2.50(s，3H)，1.27(t，J＝7.1Hz，3H)；ESI-MS m/z：387.2[M+Na]+.
EXAMPLE 24 Synthesis of Compound I-24
4-bromo-2-iodo-6-nitroaniline (A38)
The preparation method is the same as A7, and orange solid 7.12g with 89% yield is obtained. mp: 140 ℃ and 141 ℃;1H NMR(300MHz，DMSO-d6)δ8.24 -8.12(m，2H)，7.17(s，2H)；ESI-MS m/z：340.9[M-H]+，342.9[M+H]+.
n- (4-bromo-2-iodo-6-nitrophenyl) -2, 2, 2-trifluoroacetamide (A39)
The preparation method is the same as A8, and the light yellow solid is 5.50g, the yield is 84%. mp: 150 ℃ and 151 ℃;1H NMR(300MHz，DMSO-d6)δ 11.85(s，1H)，8.61(d，J＝2.1Hz，1H)，8.37(d，J＝2.0Hz，1H)；ESI-MS m/z：436.8[M-H]+.
n- (4-bromo-2- (3-hydroxypropan-1-yn-1-yl) -6-nitrophenyl) -2, 2, 2-trifluoroacetamide (A40)
The preparation method is the same as A9, triethylamine is used as base, 4.92g of yellow solid is obtained, and the yield is 53%. mp: 181-183 ℃;1HNMR(300MHz， DMSO-d6)δ11.87(s，1H)，8.22(d，J＝1.5Hz，1H)，8.11(d，J＝1.7Hz，1H)，6.64-6.56(m，1H)，4.69(d，J＝6.0 Hz，2H).
2, 2, 2-trifluoro-N- (3- (3-hydroxypropan-1-yn-1-yl) -5-nitro- [1, 1' -biphenyl ] -4-yl) acetamide (A41a)
A40(100mg, 272.42. mu. mol), phenylboronic acid (49.8mg, 408.63. mu. mol), tetrakis (triphenylphosphine) palladium (31.5mg, 27.24. mu. mol) and potassium carbonate (113.0mg, 817.26. mu. mol) were charged into a25 mL three-necked round bottom flask, and after replacing the air in the reaction system with nitrogen, freshly distilled dioxane (6mL) and deionized water (2mL) were added. The reaction mixture was reacted at 90 ℃ for 12 hours. After completion of the TLC detection reaction, ethyl acetate (5mL) was added for dilution, and insoluble impurities were removed by filtration, extracted with water (10 mL. times.3), dried over anhydrous sodium sulfate, filtered through a drying agent, and concentrated to give a crude product. The crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, volume ratio 2: 1) to give 72.5mg of an orange solid in 73% yield. mp: 169 ℃ and 170 ℃;1H NMR(300MHz，DMSO-d6)δ11.72(s，1H)，8.32(d，J＝1.3 Hz，1H)，8.27(d，J＝1.6Hz，1H)，7.83-7.72(m，2H)，7.51(t，J＝7.5Hz，2H)，7.45-7.35(m，1H)，6.67(d，J＝ 1.9Hz，1H)，4.72(d，J＝6.0Hz，2H).
ethyl (3- (5-nitro-4- (2, 2, 2-trifluoroacetylamino) - [1, 1' -biphenyl ] -3-yl) prop-2-yn-1-yl) carbonate (A42a)
The preparation method is the same as A10, and 854.3mg of yellow solid is obtained, with the yield of 72%. mp: 118 ℃ and 120 ℃;1H NMR(300MHz，DMSO-d6)δ 12.13(s，1H)，8.38(d，J＝1.4Hz，1H)，8.34(d，J＝1.6Hz，1H)，7.82-7.73(m，2H)，7.55-7.46(m，2H)，7.45- 7.36(m，1H)，5.36(s，2H)，4.18(q，J＝7.1Hz，2H)，1.24(t，J＝7.1Hz，3H)；ESI-MS m/z：437.5[M+H]+.
2-methyl-7-nitro-5-phenyl-1H-indole (A43a)
The preparation method is the same as A11, and yellow solid 387.1mg is obtained, with the yield being 89%. mp: 153-155 ℃;1H NMR(300MHz，DMSO-d6)δ 11.79(s，1H)，8.27-8.17(m，2H)，7.81-7.70(m，2H)，7.50(t，J＝7.5Hz，2H)，7.38(t，J＝7.3Hz，1H)，6.49(s， 1H)，2.50(s，3H)；ESI-MS m/z：274.5[M+Na]+.
2-methyl-5-phenyl-1H-indol-7-amine (A44a)
The preparation method is the same as A12, and 88.1mg of gray solid is obtained with the yield of 98%. The next step was performed directly without purification.
(2-methyl-5-phenyl-1H-indol-7-yl) carbamic acid ethyl ester (A45a)
The preparation method is the same as A13l, and 40.0mg of yellow solid is obtained, with the yield of 34%. mp: 141 ℃ and 143 ℃;1H NMR(300MHz，DMSO-d6)δ 10.68(s，1H)，9.22(s，1H)，7.65(s，1H)，7.62-7.54(m，2H)，7.42(t，J＝7.6Hz，3H)，7.28(tt，J＝6.7，1.1Hz，1H)， 6.19(s，1H)，4.18(q，J＝7.1Hz，2H)，2.40(s，3H)，1.29(t，J＝7.1Hz，3H)；ESI-MS m/z：295.4[M+H]+.
(3-acetyl-2-methyl-5-phenyl-1H-indol-7-yl) carbamic acid ethyl ester (I-24)
The preparation method is the same as I-3, and light yellow solid 11.0mg with 32% yield is obtained. mp: 190 ℃ and 192 ℃;1H NMR(300MHz，DMSO-d6)δ 11.54(s，1H)，9.32(s，1H)，8.04(d，J＝1.4Hz，1H)，7.68(s，1H)，7.64-7.56(m，2H)，7.46(t，J＝7.6Hz，2H)， 7.38-7.27(m，1H)，4.19(q，J＝7.1Hz，2H)，2.71(s，3H)，2.55(s，3H)，1.28(t，J＝7.0Hz，3H)；ESI-MS m/z： 337.7[M+H]+.
EXAMPLE 25 Synthesis of Compound I-25
2, 2, 2-trifluoro-N- (2- (3-hydroxypropan-1-yn-1-yl) -6-nitro-4- (pyridin-3-yl) phenyl) acetamide (A41b)
The preparation method is the same as A41a, and 237.0mg of yellow-green solid is obtained with the yield of 80%. mp: 225 ℃ and 227 ℃;1H NMR(300MHz，DMSO-d6) δ11.77(s，1H)，9.00(d，J＝1.8Hz，1H)，8.59(dd，J＝4.7，1.5Hz，1H)，8.40(d，J＝1.3Hz，1H)，8.33(d，J＝1.6 Hz，1H)，8.25-8.16(m，1H)，6.68(d，J＝1.9Hz，1H)，5.35(s，1H)，4.72(s，2H).
ethyl (3- (3-nitro-5- (pyridin-3-yl) -2- (2, 2, 2-trifluoroacetylamino) phenyl) prop-2-yn-1-yl) carbonate (A42b)
The preparation method is improved on the basis of A10, pyridine is used as a base and a solvent, and 429.5mg of yellow solid is obtained with the yield of 98%. mp: 166-168 ℃;1H NMR(300MHz，DMSO-d6)δ12.19(s，1H)，9.05-8.96(m，1H)，8.60(d，J＝4.6Hz，1H)，8.47(s， 1H)，8.40(s，1H)，8.26-8.16(m，1H)，6.86(s，1H)，5.37(s，2H)，4.18(q，J＝7.1Hz，2H)，1.25(t，J＝7.0Hz，3H).
2-methyl-7-nitro-5- (pyridin-3-yl) -1H-indole (A43b)
The preparation method is the same as A11, 153.8mg of yellow solid is obtained, and the yield is 62%. mp: 208-210 ℃;1H NMR(300MHz，DMSO-d6)δ 11.88(s，1H)，8.98(s，1H)，8.59(d，J＝4.6Hz，1H)，8.29(d，J＝11.2Hz，2H)，8.19(d，J＝7.9Hz，1H)，7.51(dd， J＝7.7，4.9Hz，1H)，6.50(s，1H)，2.50(s，3H)；ESI-MS m/z：254.1[M+H]+.
2-methyl-5- (pyridin-3-yl) -1H-indol-7-amine (A44b)
The preparation method is the same as A12, and the obtained product is 44.1mg of off-white solid with the yield of 99 percent. The next step was performed directly without purification. ESI-MS m/z: 224.0 [ M + H]+.
(2-methyl-5- (pyridin-3-yl) -1H-indol-7-yl) carbamic acid ethyl ester (A45b)
The preparation method is the same as A13l, and 33.6mg of beige solid is obtained with the yield of 58%. mp: 199-200 ℃;1H NMR(300MHz，Chloroform-d) δ9.65(s，1H)，8.86(d，J＝1.8Hz，1H)，8.54(dd，J＝4.8，1.3Hz，1H)，7.93(dt，J＝7.9，1.9Hz，1H)，7.50(d，J＝ 1.1Hz，1H)，7.37(dd，J＝7.9，4.8Hz，1H)，7.19(s，1H)，6.93-6.85(m，1H)，6.31-6.23(m，1H)，4.30(q，J＝7.1 Hz，2H)，2.48(s，3H)，1.37(t，J＝7.1Hz，3H)；ESI-MS m/z：296.0[M+H]+.
(3-acetyl-2-methyl-5- (pyridin-3-yl) -1H-indol-7-yl) carbamic acid tert-butyl ester (I-25)
The preparation method is the same as I-3, and light yellow solid 11.0mg with 32% yield is obtained. mp: 215-217 ℃;1H NMR(300MHz，Methanol-d4) δ8.77(d，J＝1.8Hz，1H)，8.43(dd，J＝4.9，1.5Hz，1H)，8.06(d，J＝1.6Hz，1H)，8.05-8.00(m，1H)，7.49(d，J ＝4.8Hz，1H)，7.47-7.41(m，1H)，4.24(q，J＝7.1Hz，2H)，2.68(s，3H)，2.56(s，3H)，1.32(t，J＝7.1Hz，3H)；13C NMR(75MHz，Methanol-d4)δ195.4，155.3，147.1，146.6，145.5，138.2，135.2，131.3，129.4，123.9，115.8， 114.5，61.2，47.3，47.0，46.8，29.5，14.1，13.5；ESI-MS m/z：338.4[M+H]+.
EXAMPLE 26 Synthesis of Compound I-26
2-methyl-7- (pyrrolidin-1-yl) -1H-indole-5-carboxylic acid methyl ester (A46)
A12(50.0mg, 244.82. mu. mol), 1, 4-diiodobutane (48. mu.L, 367.23. mu. mol), potassium carbonate (50.8mg, 367.23. mu. mol) and anhydrous N, N-dimethylformamide (3mL) were put in a10 mL eggplant-shaped bottle and reacted at 60 ℃ for 4 hours with stirring. After TLC detection reaction, filtration was carried out, and the filtrate was concentrated and recrystallized (petroleum ether/ethyl acetate, volume ratio 1: 1) to obtain 60.0mg of white solid with a yield of 95%. mp: 100 ℃ to 102 ℃;1H NMR(300MHz，DMSO-d6)δ10.62(s，1H)，7.63(s，1H)，6.96-6.88(m，1H)，6.21(s，1H)， 3.79(s，3H)，3.40(q，J＝6.0Hz，4H)，2.39(s，3H)，1.96(q，J＝4.8，3.3Hz，4H).
3-acetyl-2-methyl-7- (pyrrolidin-1-yl) -1H-indole-5-carboxylic acid methyl ester (I-26)
The preparation method is the same as I-3, and the beige solid 22.5mg with the yield of 35 percent is obtained. mp: 135 ℃ and 137 ℃;1H NMR(300MHz，DMSO-d6)δ 11.25(s，1H)，8.33(d，J＝1.2Hz，1H)，7.08(d，J＝1.4Hz，1H)，.3.83(s，3H)，3.38(t，J＝6.3Hz，4H)，2.74(s，3H)， 2.02-1.94(m，4H)；ESI-MS m/z：301.5[M+H]+.
EXAMPLE 27 Synthesis of Compound I-27
3-acetyl-N- (2-methoxyphenyl) -2-methyl-7- (pyrrolidin-1-yl) -1H-indole-5-carboxamide (I-27)
The preparation method is the same as A46, and 36.6mg of yellow solid is obtained, with the yield of 35%. mp: 255-256 ℃;1H NMR(500MHz，DMSO-d6)δ 11.22(s，1H)，9.17(s，1H)，8.19(d，J＝1.2Hz，1H)，7.94(dd，J＝7.9，1.4Hz，1H)，7.17(td，J＝7.8，74，1.6Hz， 1H)，7.12(dd，J＝8.2，1.3Hz，1H)，7.07(d，J＝1.3Hz，1H)，7.00(td，J＝7.7，1.4Hz，1H)，3.89(s，3H)，3.45(t，J ＝6.3Hz，4H)，2.77(s，3H)，2.58(s，3H)，2.02(p，J＝3.1Hz，4H)；ESI-MS m/z：392.4[M+H]+.
EXAMPLE 28 Synthesis of Compound I-28
(5-benzoyl-2-methyl-1H-indol-7-yl) carbamic acid benzyl ester (A37b)
The preparation method is the same as A13l, and 55.6mg of yellow solid is obtained with the yield of 41%. mp: 139-140 ℃;1H NMR(300MHz，DMSO-d6)δ 11.07(s，1H)，9.43(s，1H)，7.91(s，1H)，7.70(d，J＝7.0Hz，2H)，7.62(d，J＝8.6Hz，2H)，7.54(t，J＝7.3Hz，2H)， 7.48-7.34(m，5H)，6.31(s，1H)，5.20(s，2H)，2.41(s，3H)；ESI-MS m/z：385.3[M+H]+.
1- (7-amino-5-benzoyl-2-methyl-1H-indol-3-yl) ethyl-1-one (1-28)
The preparation method is the same as I-3, and the solid of the yellowish brown is 19.4mg, and the yield is 44%. mp: 255 ℃ and 257 ℃;1H NMR(300MHz，DMSO-d6)δ 11.69(s，1H)，7.75(d，J＝1.3Hz，1H)，7.71(s，1H)，7.69(t，J＝1.7Hz，1H)，7.67-7.59(m，1H)，7.58-7.50(m， 2H)，6.91(d，J＝1.5Hz，1H)，5.38(s，2H)，2.71(s，3H)，2.45(s，3H)；ESI-MS m/z：293.3[M+H]+，291.4[M-H]+.
EXAMPLE 29 Synthesis of Compound I-29
Tert-butyl 4- ((2-methyl-5 (pyridin-3-yl) -1H-indol-7-yl) amino) piperidine-1-carbonate (A47)
A44a (200.0mg, 896.9. mu. mol), N-Boc-4-piperidone (100.0mg, 1010.1. mu. mol), sodium borohydride and absolute ethanol (3mL) were put in a10 mL eggplant-shaped bottle and reacted at 60 ℃ with stirring for 4 hours. After TLC detection reaction, filtering, concentrating the filtrate, and performing column chromatography (petroleum ether/ethyl acetate, volume ratio of 2: 1) to obtain white solid 290.0mg with yield of 80%. mp: 128-132 ℃;1H NMR(300MHz， DMSO-d6)δ10.69(s，1H)，9.22(s，1H)，7.65(s，1H)，7.62-7.54(m，2H)，7.42(t，J＝7.6Hz，3H)，7.28(tt，J＝ 6.7，1.1Hz，1H)，6.19(s，1H)，3.79(t，J＝6.0Hz，2H)，3.57(t，J＝6.0Hz，2H)，2.40(s，3H)，2.06(t，J＝6.0Hz， 2H)，1.59(t，J＝6.0Hz，2H)，1.47(s，9H)，ESI-MS m/z：406.5[M+H]+，。
2-methyl-3-acetyl-N- (piperidin-4-yl) -5- (pyridin-3-yl) -1H-indol-7-amine (I-29)
The preparation method is the same as I-3, and the light yellow solid is 98.4mg, and the yield is 40%. δ 8.77(d, J ═ 1.8Hz, 1H), 8.43(dd, J ═ 4.9, 1.5Hz, 1H), 8.06(d, J ═ 1.6Hz, 1H), 8.05-8.00(m, 1H), 7.49(d, J ═ 4.8Hz, 1H), 7.47-7.41(m, 1H), 3.49(t, J ═ 6.0Hz, 2H), 3.02(t, J ═ 6.0Hz, 2H), 2.62(s, 3H), 2.50- (s, 3H), 1.56(t, J ═ 6.0Hz, 2H), 1.44(s, 9H),; ESI-MS m/z: 349.4 [ M + H]+。

Claims (6)

1. A compound of formula (I) and isomers, diastereomers, enantiomers, tautomers, and salts thereof:
Figure RE-FSB0000178510830000011
wherein:
x, Y, Z is N or C
L, M is-CONH-, -CONHCO-, -NHCONH-, -NHCO-, -NHCOCH-, -NHCOCH2-、-CONHCH2-、-SO-、-SO2-、-SO2NH-、-CO-、-CO2-、-NHCH2-or a chemical bond;
R1represents hydrogen, alkyl;
R2represents hydrogen, alkyl;
R3，R4is C1-C12Alkyl radical, C3-C8-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aralkyloxy, C1-C12-alkoxy, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, -SO2R3、-OR3、-SOR3、-COR3、-CO2R3、NCOR3，-NR5R6Or 3-7 membered nitrogen-containing aliphatic heterocyclic ring, which may have 0-2 unsaturated bonds, and may have hydrogen, halogen, hydroxyl or C1-C6-alkyl substitution; or is aryl or heteroaryl which may optionally be substituted in one or more positions in the same or different manner by: hydrogen, halogen, hydroxy, nitro, cyano, C1-C12Alkyl radical, C3-C8-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aralkyloxy, C1-C12-alkoxy, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, -SO2R3、-OR3、-SOR3、-COR3、-CO2R3、NCOR3，-NR5R6Or 3-7 membered nitrogen-containing aliphatic heterocyclic ring, which may have 0-2 unsaturated bonds, and may have hydrogen, halogen, hydroxyl or C1-C6-alkyl substitution
R5And R6Independently of one another are hydrogen, C1-C12-alkyl radical、C3-C8-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aralkyloxy, C1-C12-alkoxy, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, -SO2R3、-OR4、-SOR5、-COR3、-CO2R3，-NR1R2Or 3-7 membered nitrogen-containing aliphatic heterocyclic ring, which may have 0-2 unsaturated bonds in the ring, and may have hydrogen, halogen, hydroxy or C1-C6-alkyl substitution;
aryl and heteroaryl groups are selected from: pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, imidazole, indole, quinoline, purine, benzo five-membered heterocycle, five-membered heterocycle six-membered heterocycle.
2. A compound of formula (II) and isomers, diastereomers, enantiomers, tautomers, and salts thereof:
wherein:
l, M is-CONH-, -CONHCO-, -NHCONH-, -NHCO-, -NHCOCH-, -NHCOCH2-、、-SO-、-SO2-、-SO2NH-、-CO-、-CO2-、-NHCH2-or a bond;
R1represents hydrogen, C1-C6Alkyl radical, C3-C8-cycloalkyl, halo-C1-C6-an alkyl group;
R2represents hydrogen, C1-C6Alkyl radical, C3-C8-cycloalkyl, halo-C1-C6-an alkyl group;
R3，R4is C1-C12Alkyl radical, C3-C8-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aralkyloxy, C1-C12-alkoxy, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, -SO2R3、-OR3、-SOR3、-COR3、-CO2R3、NCOR3，-NR5R6Or 3-7 membered nitrogen-containing aliphatic heterocyclic ring, which may have 0-2 unsaturated bonds, and may have hydrogen, halogen, hydroxyl or C1-C6-alkyl substitution; or is aryl or heteroaryl which may optionally be substituted in one or more positions in the same or different manner by: hydrogen, halogen, hydroxy, nitro, cyano, C1-C12Alkyl radical, C3-C8-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aralkyloxy, C1-C12-alkoxy, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, -SO2R3、-OR3、-SOR3、-COR3、-CO2R3、NCOR3，-NR5R6Or 3-7 membered nitrogen-containing aliphatic heterocyclic ring, which may have 0-2 unsaturated bonds, and may have hydrogen, halogen, hydroxyl or C1-C6-alkyl substitution
R5And R6Independently of one another are hydrogen, C1-C12Alkyl radical, C3-C8-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aralkyloxy, C1-C12-alkoxy, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, -SO2R3、-OR4、-SOR5、-COR3、-CO2R3，-NR1R2Or 3-7 membered nitrogen-containing aliphatic heterocyclic ring, which may have 0-2 unsaturated bonds in the ring, and may have hydrogen, halogen, hydroxy or C1-C6-alkyl substitution;
aryl and heteroaryl groups are selected from: pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, imidazole, indole, quinoline, purine, benzo five-membered heterocycle, five-membered heterocycle six-membered heterocycle.
3. The compounds of the general formula (II) are preferably compounds of the following structure:
n- (3-acetyl-2-methyl-1H-indol-5-yl) -2-methoxybenzenesulphonamide (I-1)
N- (3-acetyl-2-methyl-1H-indol-5-yl) -4-methoxybenzenesulphonamide (I-2)
3-acetyl-2-methyl-7- (phenylsulfonylamino) -1H-indole-5-carboxylic acid methyl ester (I-3)
3-acetyl-7- ((2-methoxyphenyl) sulfonylamino) -1H-indole-5-carboxylic acid methyl ester (I-4)
3-acetyl-2-methyl-7- (N- (propylsulfonyl) acetylamino) -1H-indole-5-carboxylic acid methyl ester (I-5)
3-acetyl 2-methyl-7- (N- (phenylsulfonyl) phenylsulfonylamino) -1H-indole-5-carboxylic acid methyl ester (I-6)
2-methyl-3-acetyl-7-benzoylamino-1H-indole-5-carboxylic acid methyl ester (I-7)
3-Acetyl-7- (2-methoxybenzoylamino) -2-methyl-1H-indole-5-carboxylic acid methyl ester (I-8)
3-acetyl-7-butyrylamino-2-methyl-1H-indole-5-carboxylic acid methyl ester (1-9)
3-acetyl-2-methyl-7- (3-phenylureido) -1H-indole-5-carboxylic acid methyl ester (I-10)
3-acetyl-7- (3- (2-methoxyphenyl) ureido) -2-methyl-1H-indole-5-carboxylic acid methyl ester (I-11)
3-acetyl-2-methyl-7- (3- (3- (trifluoromethyl) phenyl) ureido) -1H-indole-5-carboxylic acid methyl ester (I-12)
3-acetyl-7- (3-ethylureido) -2-methyl-1H-indole-5-carboxylic acid methyl ester (I-13)
3-acetyl-7- ((ethoxycarbonyl) amino) -2-methyl-1H-indole-5-carboxylic acid methyl ester (I-14)
3-acetyl-7- ((ethoxycarbonyl) amino) -1, 2-dimethyl-1H-indole-5-carboxylic acid methyl ester (I-15)
3-acetyl-7- (N- (ethoxycarbonyl) acetylamino) -1, 2-dimethyl-1H-indole-5-carboxylic acid methyl ester (I-16)
3-acetyl-7- ((ethoxycarbonyl) amino) -1H-indole-5-carboxylic acid methyl ester (I-17)
(3-acetyl-2-methyl-5- (phenylcarbamoyl) -1H-indol-7-yl) carbamic acid ethyl ester (I-18)
(3-acetyl-5- ((2-methoxyphenyl) carbamoyl) -2-methyl-1H-indol-7-yl) carbamic acid ethyl ester (I-19)
(3-acetyl-2-methyl-5- ((thiazol-2-yl) carbamoyl) -1H-indol-7-yl) carbamic acid ethyl ester (I-20)
(3-acetyl-5- (cyclopentylcarbamoyl) -2-methyl-1H-indol-7-yl) carbamic acid ethyl ester (I-21)
(3-acetyl-2-methyl-5- (methylcarbamoyl) -1H-indol-7-yl) carbamic acid ethyl ester (I-22)
(3-acetyl-5-benzoyl-2-methyl-1H-indol-7-yl) carbamic acid ethyl ester (I-23)
(3-acetyl-2-methyl-5-phenyl-1H-indol-7-yl) carbamic acid ethyl ester (I-24)
(3-acetyl-2-methyl-5- (pyridin-3-yl) -1H-indol-7-yl) carbamic acid tert-butyl ester (I-25)
3-acetyl-2-methyl-7- (pyrrolidin-1-yl) -1H-indole-5-carboxylic acid methyl ester (I-26)
3-acetyl-N- (2-methoxyphenyl) -2-methyl-7- (pyrrolidin-1-yl) -1H-indole-5-carboxamide (I-27)
1- (7-amino-5-benzoyl-2-methyl-1H-indol-3-yl) ethyl-1-one (I-28)
2-methyl-3-acetyl-N- (piperidin-4-yl) -5- (pyridin-3-yl) -1H-indol-7-amine (1-29).
4. A compound of general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, and a compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein said pharmaceutically acceptable salt is an acid addition salt of said compound with: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, benzenesulfonic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, or mandelic acid; or the pharmaceutically acceptable salt is a salt of the compound with an inorganic base selected from: a basic metal cation, an alkaline earth metal cation, or an ammonium cation.
5. A pharmaceutical composition comprising a compound of general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, or comprising a compound of claim 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
6. Use of a compound of general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof and a compound of claim 3 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of diseases associated with BRPF1 inhibitors.
CN201810937871.4A 2018-08-11 2018-08-11 Preparation method and application of 3-acetyl indole BRPF1 inhibitor Pending CN110818609A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810937871.4A CN110818609A (en) 2018-08-11 2018-08-11 Preparation method and application of 3-acetyl indole BRPF1 inhibitor

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810937871.4A CN110818609A (en) 2018-08-11 2018-08-11 Preparation method and application of 3-acetyl indole BRPF1 inhibitor

Publications (1)

Publication Number Publication Date
CN110818609A true CN110818609A (en) 2020-02-21

Family

ID=69547386

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810937871.4A Pending CN110818609A (en) 2018-08-11 2018-08-11 Preparation method and application of 3-acetyl indole BRPF1 inhibitor

Country Status (1)

Country Link
CN (1) CN110818609A (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113248472A (en) * 2020-02-12 2021-08-13 中国药科大学 Anti-osteoporosis compound and derivative thereof, pharmaceutical composition, preparation method and application
CN114213396A (en) * 2022-01-27 2022-03-22 深圳市乐土生物医药有限公司 Indole-2-ketone compound and preparation method and application thereof
WO2023013994A1 (en) 2021-08-02 2023-02-09 주식회사 미토이뮨테라퓨틱스 Novel indole derivative, pharmaceutical composition comprising same, and use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160060260A1 (en) * 2014-08-29 2016-03-03 Board Of Regents, The University Of Texas System Bromodomain inhibitors for treating disease
CN107108614A (en) * 2014-11-10 2017-08-29 基因泰克公司 It is used as the substituted pyrrolopyridine of Bu Luomo domain inhibitor
CN107207493A (en) * 2014-11-10 2017-09-26 基因泰克公司 It is used as the pyrrolopyridine being substituted of Bu Luomo domain inhibitor

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160060260A1 (en) * 2014-08-29 2016-03-03 Board Of Regents, The University Of Texas System Bromodomain inhibitors for treating disease
CN107108614A (en) * 2014-11-10 2017-08-29 基因泰克公司 It is used as the substituted pyrrolopyridine of Bu Luomo domain inhibitor
CN107207493A (en) * 2014-11-10 2017-09-26 基因泰克公司 It is used as the pyrrolopyridine being substituted of Bu Luomo domain inhibitor

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ACS，STN REGISTRY数据库: "RN：1368716-35-1", 《ACS，STN REGISTRY数据库》 *
PAUL BAMBOROUGH等: "GSK6853, a Chemical Probe for Inhibition of the BRPF1 Bromodomain", 《ACS MEDICINAL CHEMISTRY LETTERS》 *
WYLIE S. PALMER等: "Structure-Guided Design of IACS-9571, a Selective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor", 《JOURNAL OF MEDICINAL CHEMISTRY》 *
刘勇,等: "BRPF蛋白的生物学功能及其抑制剂研究进展", 《药学研究》 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113248472A (en) * 2020-02-12 2021-08-13 中国药科大学 Anti-osteoporosis compound and derivative thereof, pharmaceutical composition, preparation method and application
CN113248472B (en) * 2020-02-12 2022-06-28 中国药科大学 Anti-osteoporosis compound and derivative thereof, pharmaceutical composition, preparation method and application
WO2023013994A1 (en) 2021-08-02 2023-02-09 주식회사 미토이뮨테라퓨틱스 Novel indole derivative, pharmaceutical composition comprising same, and use thereof
CN114213396A (en) * 2022-01-27 2022-03-22 深圳市乐土生物医药有限公司 Indole-2-ketone compound and preparation method and application thereof

Similar Documents

Publication Publication Date Title
RU2719583C2 (en) Radiolabelled 2-amino-6-fluoro-n-[5-fluoro-pyridin-3-yl]-pyrazolo [1, 5-a] pyrimidine-3-carboxamide derivatives used as atr kinase inhibitor, preparations based thereon compounds and various solid forms thereof
CN101440092B (en) 2-indazole-4-aza indole-5-amino derivatives, and preparation and use thereof
EP2146986B1 (en) Diphenyl-dihydro-imidazopyridinones
JP2009525350A (en) Pyrrolo [2,3, B] pyridine derivatives useful as RAF kinase inhibitors
CA3133753A1 (en) Novel small molecule inhibitors of tead transcription factors
Sonawane et al. Synthesis of thieno [2, 3-b] quinoline and selenopheno [2, 3-b] quinoline derivatives via iodocyclization reaction and a DFT mechanistic study
WO2011082098A1 (en) Lysine and arginine methyltransferase inhibitors for treating cancer
PL212494B1 (en) Certain chemical entities, compositions, and methods
EP3016950A1 (en) Tricyclic pyrido-carboxamide derivatives as rock inhibitors
JP2021536428A (en) Replacement indole and how to use it
CN110818609A (en) Preparation method and application of 3-acetyl indole BRPF1 inhibitor
TWI811400B (en) Further substituted triazolo quinoxaline derivatives
WO2019141131A1 (en) Bromodomain inhibitor compound and use thereof
JP2022517280A (en) Bruton's tyrosine kinase inhibitor
WO2017162204A1 (en) Manufacturing method of benzofuran analog and intermediate and crystalline form of same
CN112125885A (en) Benzoindole bifunctional molecular derivative and preparation method and application thereof
CN111592522B (en) Arginine methylation transferase 5 small-molecule inhibitor and preparation method and application thereof
CN107879975B (en) Histone deacetylase inhibitor and application thereof
Kato et al. Synthesis of poly-substituted pyrazolo [1, 5-a] quinolines through one-pot two component cascade reaction
JP2006526654A (en) Substituted indoles and methods for preparing substituted indoles
CA2730071A1 (en) Antineoplastic derivatives of 4-oxo-l, 4-dihydro-quinolin?, preparation thereof, and therapeutic use thereof
CN111606888B (en) Pyrrole derivative and preparation method and application thereof
TW201918473A (en) Method for preparing indenoisoquinoline derivatives
CN112441970A (en) 2, 5-disubstituted-3-aminopyridine compound and preparation method and application thereof
KR101035709B1 (en) 2-Sustitutedaminoalkylenyloxy-3-substitutedphenylethynyl-6-aminoquinoxaline derivatives

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20200221