CN109721605B - Immune cell migration inhibitor - Google Patents

Immune cell migration inhibitor Download PDF

Info

Publication number
CN109721605B
CN109721605B CN201711050899.8A CN201711050899A CN109721605B CN 109721605 B CN109721605 B CN 109721605B CN 201711050899 A CN201711050899 A CN 201711050899A CN 109721605 B CN109721605 B CN 109721605B
Authority
CN
China
Prior art keywords
compound
chloro
carboxamido
phenyl
methylsulfonyl
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.)
Active
Application number
CN201711050899.8A
Other languages
Chinese (zh)
Other versions
CN109721605A (en
Inventor
沈旺
丁悦
汪江峰
姜浩
陈福利
吴兴龙
李寸飞
杨立国
胡彪
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.)
Weimu Biotechnology (Zhejiang) Co.,Ltd.
Original Assignee
Vivavision Biopharma Shanghai Co ltd
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 Vivavision Biopharma Shanghai Co ltd filed Critical Vivavision Biopharma Shanghai Co ltd
Priority to CN201711050899.8A priority Critical patent/CN109721605B/en
Priority to PCT/CN2018/087630 priority patent/WO2019085441A1/en
Publication of CN109721605A publication Critical patent/CN109721605A/en
Application granted granted Critical
Publication of CN109721605B publication Critical patent/CN109721605B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/08—Antiseborrheics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The immune cell migration inhibitor provided by the invention is characterized by having a structure shown by the following equation:

Description

Immune cell migration inhibitor
Technical Field
The invention relates to the field of pharmacy, in particular to an immune cell migration inhibitor.
Background
Many local diseases are associated with inflammation, such as irritant contact dermatitis, eczematous dermatitis, seborrheic dermatitis, scarring, atopic dermatitis, psoriasis, etc. in dermatology; alopecia-related macular degeneration; ophthalmic inflammatory or immune diseases such as intraocular inflammation, periocular inflammation, ocular surface inflammation, keratoconjunctivitis sicca (KCS, also known as dry eye syndrome), KCS in Sjogren's syndrome patients, allergic conjunctivitis, uveitis, ocular inflammation caused by contact lens wear, corneal inflammation caused by contact lens wear, periocular tissue inflammation caused by contact lens wear, post-operative ocular inflammation, intraocular inflammation, retinitis, edema, retinopathy, corneal inflammation, Graves' disease (baserow's disease), or Graves' eye disease; in addition, there are Graft Versus Host Disease (GVHD) and the like.
Psoriasis and eczema are associated with a disturbance of the systemic immune system. Thus, when the symptoms are severe, systemic drugs such as TNF-alpha antibody inhibitors (e.g., adalimumab (Humira), infliximab, certolizumab, and golimumab), interleukin IL-12 antibody inhibitor infliximab, interleukin IL-4 antibody inhibitor Dupilumab, T cell inhibitory antibody efalizumab, and the like, are used. These systemic drugs have significant effects, but they also cause side effects due to systemic suppression of the immune system, such as susceptibility to viral and bacterial diseases, allergic reactions, cancer initiation in a few cases, or highly lethal "Progressive Multifocal Leukoencephalopathy (PML)" which is a viral infection.
For the above reasons, topical application is preferred for the treatment of topical dry eye, mild-to-moderate psoriasis and eczema. There are only a few international patients with dry eye syndrome (cyclosporin, Lifitegrast, etc.) but no topical drugs have been approved in china for treating dry eye syndrome, while external drugs for psoriasis and eczema are mainly hormones, cyclopamine, etc., and have strong side effects on skin. Therefore, there is a great need to develop and test drugs for treating local inflammatory diseases with high efficiency and low side effect, which can benefit a large part of patients.
Disclosure of Invention
The present invention aims to overcome the above-mentioned drawbacks and to provide a novel inhibitor of migration of immune cells.
The invention provides an immune cell migration inhibitor which is characterized by having a structure shown in the following equation:
Figure BDA0001453142600000011
R1selected from aryl, heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl;
R2halogen, alkyl, cyano, alkoxy and nitro which are substituted on any or several aromatic rings;
R3selected from aryl, heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl;
x is selected from CR4R5、NR6O, CO (i.e.,
Figure BDA0001453142600000021
)、SOn；
y is selected from CR7、N；
Z is selected from CR8R9、(CR8R9)2CO (i.e.,
Figure BDA0001453142600000022
)；
u is selected from C, N;
w is selected from CR10、N、NR11、O；
V is selected from CR12、N、NR13、O；
I is selected from CR14R15CO (i.e.,
Figure BDA0001453142600000023
)；
wherein n is selected from 0,1 and 2;
m is selected from 0 and an integer (e.g., 1,2, 3.);
R4，R5，R6，R7，R8，R9，R14，R15selected from hydrogen, alkyl, substituted alkyl;
R10，R12selected from hydrogen, alkyl, halogen, cyano, alkoxy;
R11，R13selected from hydrogen, alkyl;
X-Y, Z-U, U-W, W-V are connected through a single bond or a double bond;
Y-Z are connected by single bond or double bond, or Y-Z has no chemical bond (i.e. non-cyclic structure).
The alkyl group may be a straight-chain alkyl group, a branched-chain alkyl group, a cyclic alkyl group, a heterocyclic alkyl group, etc., and the above alkyl group is preferably an alkyl group having not more than 6 carbon atoms, such as: methyl, ethyl, propyl, isopropyl, N-butyl, isobutyl, cyclopentyl, N-heterocyclopentyl
Figure BDA0001453142600000024
Cyclohexyl, N-heterocycloalkyl
Figure BDA0001453142600000025
The alkenyl group may be a straight alkenyl group, a branched alkenyl group, a cycloalkenyl group, a heterocyclic alkenyl group, or the like, and the above alkenyl group is preferably an alkenyl group having not more than 6 carbon atoms, such as: vinyl, propenyl, allyl, butenyl, cis-butadienyl, cyclohexenyl, N-heterocyclohexenyl
Figure BDA0001453142600000026
The substituted alkyl is preferably substituted by aryl, heteroaryl, cyano or hydroxyl on one or more hydrogen atoms on an alkane chain with the carbon chain length of not more than 6; such as: benzyl, 4-hydroxy-benzyl, 2-phenyl-ethyl, acetonitrile, hydroxymethyl, and the like;
the substituted alkenyl is preferably substituted by aryl, heteroaryl, cyano or hydroxyl on one or more hydrogen atoms in an olefin chain with a carbon chain length of not more than 6; such as: 2-phenyl-vinyl, 2- (4-hydroxy-phenyl) -vinyl, and the like;
the above alkoxy group may be a linear alkoxy group, a branched alkoxy group, etc., such as: methoxy, ethoxy, propoxy;
the aryl is selected from aromatic systems consisting of one or more five-membered, six-membered and seven-membered aromatic rings, one or more hydrogens on the aromatic rings can be substituted by alkyl, aryl, cyano, nitro, amino, hydroxyl, halogen and the like, and is preferably selected from phenyl, naphthyl, anthryl, 2-hydroxyphenyl, 6-methyl-naphthyl and the like;
the heteroaryl is selected from aromatic systems consisting of one or more five-membered, six-membered and seven-membered aromatic rings, wherein one or more carbon atoms on the aromatic rings are substituted by nitrogen, oxygen and sulfur, and one or more hydrogens on the aromatic rings are substituted by alkyl, aryl, cyano, nitro, amino, hydroxyl, halogen and the like, and is preferably selected from N-pyridyl, quinolyl, p-hydroxypyridinyl, 2-methyl-quinolyl and the like.
Furthermore, the immune cell migration inhibitor provided by the invention also has the characteristics that: i.e. compounds preferably selected from G1, G2, G3, G4, G5;
wherein, the G1 compound has a structure shown in the following equation:
Figure BDA0001453142600000031
the compounds of the above G2 class have the structure shown in the following equation:
Figure BDA0001453142600000032
the compounds of the above G3 class have the structure shown in the following equation:
Figure BDA0001453142600000033
the compounds of the above G4 class have the structure shown in the following equation:
Figure BDA0001453142600000034
the compounds of the above G5 class have the structure shown in the following equation:
Figure BDA0001453142600000035
furthermore, the immune cell migration inhibitor provided by the invention also has the characteristics that: i.e., (S) -2- (8-chloro-2- (benzofuran-6-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazoline-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid;
(S) -2- (8-chloro-2- (pyrazolo [1,5-a ] pyridine-2-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid;
(S) -2- (8-chloro-2- (1H-indole-6-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid;
(S) -2- (8-chloro-2- (1H-indole-2-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid;
(S) -2- (8-chloro-2- (1H-indole-4-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid;
(S) -2- (8-chloro-2- (3-hydroxyphenyl-1-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid;
(S) -2- (8-chloro-2- (3-methyl-1H-indene-2-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid;
(S, E) -2- (8-chloro-2- (3- (2-hydroxyphenyl) acryloyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid;
(S, E) -2- (8-chloro-2- (3- (furan-3-yl) acryloyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid;
(S, E) -2- (8-chloro-2- (3- (furan-2-yl) acryloyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid;
(S, E) -2- (8-chloro-2- (3- (thiophen-2-yl) acryloyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid;
(S) -2- (8-chloro-2- (naphthalene-2-formyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid;
(S) -2- (8-chloro-2- (benzofuran-2-formyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid;
(S) -2- (5-chloro-7- ((3-hydroxybenzyl) carbamoyl) -1H-indole-4-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid;
(S) -2- (8-chloro-2- (benzofuran-6-carbonyl) -2,3,5, 6-tetrahydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid;
(S) -2- (8-chloro-2- (1H-indole-6-carbonyl) -2,3,5, 6-tetrahydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid;
(S) -2- (8-chloro-2- (3-hydroxybenzyl) -1-oxo-2, 3,5, 6-tetrahydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid;
(S) -2- (8-chloro-2- (3-hydroxybenzyl) -3-oxo-2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid.
Furthermore, the immune cell migration inhibitor provided by the invention also has the characteristics that: namely, the preparation method of the G1 compound comprises the following steps:
performing halogenation reaction on 2-amido dimethyl terephthalate to obtain an intermediate product I;
obtaining an intermediate product II through bromination or iodination and alkynylation reaction of the intermediate product;
the intermediate product II is subjected to cyclization reaction to form an intermediate product III;
the intermediate product III is subjected to hydrolysis, reduction and amination reactions in sequence to obtain an intermediate product IV;
performing cyclization reaction on the intermediate product IV to obtain an intermediate product V;
the intermediate product is hydrolyzed and amidated to obtain intermediate product VI;
carrying out deprotection, amidation and hydrolysis reactions on the intermediate product six to obtain a target product G1;
wherein, the intermediate product I is 5-site and/or 6-site halogenated-2-amino dimethyl terephthalate, and the structure thereof is shown as follows:
Figure BDA0001453142600000051
alkyl is alkyl, preferably methyl;
the intermediate product II is a compound shown in the following structure:
Figure BDA0001453142600000052
LG1as leaving group, preference is given to, for example: macromolecules such as TMS;
the intermediate product III is a five-membered benzo nitrogen-containing heterocycle, and the structure of the intermediate product is shown as follows:
Figure BDA0001453142600000053
the intermediate product IV is a compound shown in the following structure:
Figure BDA0001453142600000054
the intermediate product V is a compound shown in the following structure:
Figure BDA0001453142600000055
pro is an amino protecting group;
the intermediate product six is a compound shown in the following structure:
Figure BDA0001453142600000056
LG2as leaving group, preference is given to, for example: macromolecules such as Bn; the specific equation for the above step is as follows:
Figure BDA0001453142600000061
furthermore, the immune cell migration inhibitor provided by the invention also has the characteristics that: that is, the preparation method of the G2 compound is as follows:
carrying out reduction, deprotection, amidation and hydrolysis reactions on the compound A to obtain a target product;
wherein the compound A is a compound shown in the following structure:
Figure BDA0001453142600000062
pro is an amino protecting group, LG2Is a leaving group.
The specific equation for the above step is as follows:
Figure BDA0001453142600000063
furthermore, the immune cell migration inhibitor provided by the invention also has the characteristics that: that is, the preparation method of the G3 compound is as follows:
carrying out amidation, hydrolysis, amidation and hydrolysis reactions on the compound B-1 to obtain a target product;
wherein the compound B-1 is a compound shown in the following structure:
Figure BDA0001453142600000071
alkyl is an alkyl group, preferably methyl.
The specific equation for the above step is as follows:
Figure BDA0001453142600000072
furthermore, the immune cell migration inhibitor provided by the invention also has the characteristics that: that is, the preparation method of the G4 compound is as follows:
carrying out amidation, hydrolysis, amidation and hydrolysis reactions on the compound B-2 to obtain a target product;
the preparation method of the G5 compound is as follows:
carrying out amidation, reduction, cyclization, hydrolysis, amidation and hydrolysis reactions on the compound B-2 to obtain a target product;
wherein the compound B-2 is a compound shown in the following structure:
Figure BDA0001453142600000073
alkyl is an alkyl group, preferably methyl.
The specific equation for the above step G4 is as follows:
Figure BDA0001453142600000074
the specific equation for the above step G5 is as follows:
Figure BDA0001453142600000081
in the above-mentioned preparation of the compounds G1-G5, the starting materials are all dialkyl ester compounds, preferably dimethyl ester compounds.
Furthermore, the immune cell migration inhibitor provided by the invention also has the characteristics that: namely, the above immunocyte migration inhibitor is used for relieving and treating dry eye disease, eczematous dermatitis and psoriasis.
In addition, the invention also provides a preparation for preparing the immune cell migration inhibitor, which is characterized by comprising the following steps:
step one, uniformly mixing the immune cell migration inhibitor, sterile physiological saline and alkali;
step two, adding a buffer solution until the pH value of the system is 6.75-7.25;
step three, continuously adding sterile normal saline, bubbling nitrogen into the system for 0.5-3 hours, and then packaging;
wherein in the first step, the mass ratio of the immune cell migration inhibitor, the sterile physiological saline to the alkali is 1:10-25: 0.01-0.5;
the mass ratio of the sterile normal saline in the first step and the third step is 1: 0.01-0.5.
In addition, the invention also provides another preparation made of the immune cell migration inhibitor, which is characterized by being prepared by mixing the following components in parts by mass:
Figure BDA0001453142600000082
the invention has the following functions and effects:
the immune cell migration inhibitor provided by the invention has balanced hydrophily and lipophilicity, and can be easily developed into eye drops and externally applied ointment. Has strong ability of inhibiting immune cell migration, and can relieve dry eye syndrome, eczematous dermatitis and psoriasis. The mechanism is that the migration of T immune cells to an inflammation part is locally inhibited, and the T immune cells are activated, so that the side effect is far smaller than that of corticosteroid hormone and high-toxicity cyclic bracteine drugs.
Detailed Description
Examples 1,
Figure BDA0001453142600000091
(S) -2- (8-chloro-2- (benzofuran-6-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazoline-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid
The specific reaction equation is as follows:
Figure BDA0001453142600000092
step A: 2-amino-5-chloroterephthalic acid dimethyl ester (Compound 1-1)
To a vigorously stirred solution of dimethyl 2-aminoterephthalate (10g,48mmol) in isopropanol (1.5L) was added NCS (7.34g,55mmol) over a period of 5 minutes at room temperature. After the addition was complete, the reaction mixture was heated to reflux and reacted for 48 hours. Cooled to room temperature, the solvent was concentrated and the residue was purified by flash chromatography, eluting with petroleum ether in 5% ethyl acetate to give the desired product as a pale yellow crystalline solid (6.4g, 55%). LCMS ESI (+) M/z 244(M + 1).1H NMR(600MHz,CDCl3)δ7.92(s,1H),7.10(s,1H),5.71(brs,2H),3.92(s,3H),3.90(s,3H).
And B: 2-amino-3-bromo-5-chloroterephthalic acid dimethyl ester (Compound 1-2)
NBS (5.09g,28.6mmol) was added to a vigorously stirred solution of dimethyl 2-amino-5-chloroterephthalate (6.4g,26mmol) in methanol (85mL) at room temperature over a period of 5 minutes. After the addition was complete, the reaction mixture was heated to 40 ℃ for 3 hours. After cooling to room temperature, the solvent was concentrated and the residue was purified by flash chromatography eluting with petroleum ether in 10% ethyl acetate to give the desired product as a yellow crystalline solid (8.1g, 97%). LCMS ESI (+) M/z:323(M + 1).1H NMR(600MHz,CDCl3)δ7.92(s,1H),6.48(brs,2H),3.99(s,3H),3.91(s,3H).
And C: 2-amino-3- (trimethylsilylethynyl) -5-chloroterephthalic acid dimethyl ester (compound 1-3)
Pd (PPh) under nitrogen protection3)2Cl2(1.75g,2.5mmol), CuI (950mg,5mmol) and trimethylsilylacetylene (10.6mL,75mmol) were added to a vigorously stirred solution of dimethyl 2-amino-3-bromo-5-chloroterephthalate (8.1g,25mmol) in TEA (62mL), and the reaction mixture was heated to 90 ℃ for 16 hours. After cooling to room temperature. Filtration through celite, washing of the filter cake with DCM (200mL), concentration of the filtrate and purification of the residue by flash chromatography eluting with petroleum ether 10% ethyl acetate afforded the desired product as a dark yellow oil (7.9g, 93%). LCMS ESI (+) M/z:340(M + 1).1H NMR(600MHz,DMSO)δ7.80(s,1H),6.88(brs,2H),3.87(s,3H),3.84(s,4H),0.24(s,9H).13C NMR(151MHz,DMSO)δ166.00,165.36,149.66,140.57,131.70,113.44,111.11,107.42,106.28,96.57,52.91,52.34,-0.35.
Step D: 5-chloro-1H-indole-4, 7-dicarboxylic acid methyl ester (Compound 1-4)
CuI (5.24g,27.6mmol) was added to a vigorously stirred solution of dimethyl 2-amino-3- (trimethylsilylethynyl) -5-chloroterephthalate (7.9g,23mmol) in DMF (60mL) under nitrogen and the reaction mixture was heated to 100 ℃ for 5 h. After cooling to room temperature. Filtration through celite, washing of the filter cake with ethyl acetate (400mL), washing of the filtrate with water (50mL),1M aqueous HCl (50mL), saturated brine (50mL), drying of the organic phase over anhydrous sodium sulfate, filtration, concentration of the filtrate, purification of the residue by flash chromatography, eluting with petroleum ether of 20% ethyl acetate, afforded the desired product as a white solid (3.93g,14.7mmol 64%). LCMS ESI (+) M/z 268(M + 1).1H NMR(600MHz,DMSO)δ11.64(s,1H),7.76(s,1H),7.61(s,1H),6.62(s,1H),3.97(s,6H).
Step E.5-chloro-4- (methoxycarbonyl) -1H-indole-7-carboxylic acid (Compound 1-5)
Aqueous LiOH (1M,17mL) was added to a stirred solution of methyl 5-chloro-1H-indole-4, 7-dicarboxylate (3.93g,14.7mmol) in THF (73mL) and after stirring at room temperature for 5 hours, the reaction was acidified with aqueous HCl (2M) topH3, diluted with ethyl acetate (200mL), the aqueous phase extracted with ethyl acetate, the combined organic phases washed with brine, the organic phase dried over anhydrous sodium sulfate, filtered and the filtrate concentrated to give the desired product as a pale red solid (3.54g,14mmol 95%). LCMS ESI (+) M/z:254(M + 1).1H NMR(400MHz,DMSO)δ13.77(brs,1H),11.53(s,1H),7.74(s,1H),7.54(t,J＝2.8Hz,1H),6.59(dd,J＝2.9,1.9Hz,1H),3.96(s,3H).
Step F: 5-chloro-7- (hydroxymethyl) -1-hydro-indole-4-carboxylic acid methyl ester (Compound 1-6)
Under the protection of nitrogen, BH is added3(1M in THF, 28mL) was added dropwise to a vigorously stirred solution of 5-chloro-4- (methoxycarbonyl) -1H-indole-7-carboxylic acid (3.54g,14mmol) in THF (70mL) at 0 deg.C, and after completion of the addition, the reaction mixture was allowed to warm to room temperature for 2H. Quench with methanol (20 mL). The solvent was concentrated and the residue was dissolved in ethyl acetate and washed successively with 1M aqueous HCl (20mL), saturated brine (20mL), the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated and the residue was purified by flash chromatography eluting with 50% ethyl acetate in petroleum ether to give the desired product as a white solid (2.68g,11.2mmol 80%). LCMS ESI (+) M/z:240(M + 1).1H NMR(600MHz,DMSO)δ11.46(s,1H),7.50(t,J＝2.7Hz,1H),7.20(s,1H),6.60–6.50(m,1H),5.45(t,J＝5.7Hz,1H),4.81(d,J＝5.7Hz,2H),3.92(s,3H).
Step G: 5-chloro-7- (azidomethyl) -1H-indole-4-carboxylic acid methyl ester (Compound 1-7)
DPPA (4g,14.56mmol), DBU (3.4g,22.4mmol) were added dropwise to a vigorously stirred solution of methyl 5-chloro-7- (hydroxymethyl) -1-hydro-indole-4-carboxylate (2.68g,11.2mmol) in THF (56mL) under nitrogen, and after completion of the addition, the reaction mixture was reacted at room temperature for 16 h. Ethyl acetate (200mL) was added, washed successively with 1M aqueous HCl (30mL), saturated brine (20mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by flash chromatography eluting with 30% ethyl acetate in petroleum ether to give the desired product as a white solid (2.37g,9mmol 80%). LCMS ESI (+) M/z 265(M + 1).1H NMR(600MHz,DMSO)δ11.82(s,1H),7.60(t,J＝2.6Hz,1H),7.28(s,1H),6.60(s,1H),4.79(s,2H),3.93(s,3H).
Step H: 5-chloro-7- (aminomethyl) -1-hydro-indole-4-carboxylic acid methyl ester (Compound 1-8)
A solution of PPh3(2.59g,9.9mmol) in THF (24mL) was added dropwise to a vigorously stirred solution of 5-chloro-7- (azidomethyl) -1-hydro-indole-4-carboxylic acid methyl ester (2.37g,9mmol) in THF (24mL) under nitrogen, the reaction mixture was allowed to react at room temperature for 16H and then H was added2O (1.6mL), the mixture was stirred at room temperature for 2 hours, ethyl acetate (200mL) was added, the organic phase was dried over anhydrous sodium sulfate, after filtration, the filtrate was concentrated, the residue was purified by flash chromatography, after removal of the triphenylphosphine oxide by elution with ethyl acetate, and then with dichloromethane in 5% methanol to give the desired product as a white solid (1.82g,7.65mmol 85%). LCMS ESI (+) M/z:239(M + 1).1H NMR(600MHz,DMSO)δ7.50(d,J＝3.0Hz,1H),7.25(s,1H),6.57(d,J＝3.0Hz,1H),4.03(s,2H),3.91(s,3H)
Step I: 2-tert-butyl 7-methyl 8-chloro-1H-pyrrolo [3,2,1-ij ] quinazoline-2, 7(3H) -dicarboxylate (compound 1-9)
K2CO3(2.11g,15.3mmol) and paraformaldehyde (252mg,8.42mmol) were added to a vigorously stirred solution of methyl 5-chloro-7- (aminomethyl) -1-hydro-indole-4-carboxylate (1.82g,7.65mmol) in methanol (76mL), the reaction mixture was reacted at 40 ℃ for 48 hours, di-tert-butyl dicarbonate (5g,22.9mmol) and triethylamine (1.53g,15.3mmol) were added, the mixture was stirred at room temperature for 16 hours and then the reaction mixture was concentrated, the residue was dissolved in ethyl acetate (200mL), washed successively with water (30mL), saturated brine (20mL), the organic phase was dried over anhydrous sodium sulfate, after filtration, the filtrate was concentrated, the residue was purified by flash chromatography, eluting with 30% ethyl acetate in petroleum ether to give the desired product as a white solid (1.87g,5.36mmol 70%). LCMS ESI (+) M/z 351(M + 1). 1H NMR (600MHz, CDCl3) δ 7.23(s,1H),7.03(s,1H),6.69(d, J ═ 2.6Hz,1H),5.65(s,2H),4.86(s,2H),4.00(s,3H),1.46(s,9H).
Step J: 2-Boc 8-chloro-2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxylic acid (Compound 1-10)
Aqueous NaOH (2M,5.36mL,10.72mmol) was added to a vigorously stirred solution of 2-tert-butyl 7-methyl 8-chloro-1H-pyrrolo [3,2,1-ij]Of quinazoline-2, 7(3H) -dicarboxylate (1.87g,5.36mmol)Methanol (53mL) solution, the reaction mixture at 80 ℃ for 3 hours, after cooling to room temperature, the reaction was diluted with dichloromethane (200mL), the reaction was adjusted to pH3 with 10% aqueous citric acid, the aqueous phase was extracted with dichloromethane, the combined organic phases were washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, after filtration, the filtrate was concentrated to give the desired product as a white solid (1.71g,5.09mmol 95%). LCMS ESI (+) M/z 337(M + 1).1H NMR(600MHz,MeOD)δ7.44(d,J＝3.0Hz,1H),7.08(s,1H),6.67(d,J＝3.0Hz,1H),5.72(s,2H),4.90(s,2H),1.48(s,9H).
Step K: (S) -2- (8-chloro-2- (tert-butoxycarbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid benzyl ester (Compound 1-11)
HATU (1.15g,3mmol) and DIPEA (1.12g,8.63mmol) were added to a vigorously stirred 2-tert-butoxycarbonyl 8-chloro-2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] under nitrogen blanket]And quinazoline-7-carboxylic acid (968mg,2.875mmol) in DMF (14mL), the reaction mixture was reacted at room temperature for 1 hour, then a solution of (S) benzyl 2-amino-3- (3- (methylsulfonyl) phenyl) propionate hydrochloride (1.17g,3.16mmol) in DMF (6mL) was added, the mixture was stirred at room temperature for an additional 2 hours, ethyl acetate (200mL) was added, washed with water (30mL), saturated brine (20mL) in sequence, the organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated, the residue was purified by flash chromatography eluting with 50% ethyl acetate in petroleum ether to give the desired product as a white solid (1.69g,2.59mmol 90%). LCMS ESI (+) M/z 652(M + 1).1H NMR(600MHz,DMSO)δ8.92(d,J＝8.0Hz,1H),7.95(s,1H),7.90(s,1H),7.80(d,J＝7.8Hz,1H),7.69(d,J＝7.6Hz,1H),7.58(t,J＝7.7Hz,1H),7.44(d,J＝3.0Hz,1H),7.42–7.32(m,5H),7.00(s,1H),5.94(d,J＝2.9Hz,1H),5.65(q,J＝12.0Hz,2H),5.21(s,2H),4.96(ddd,J＝10.7,8.1,4.9Hz,1H),4.81(s,2H),3.35(dd,J＝14.2,4.9Hz,1H),3.12(dd,J＝10.7,14.2Hz,1H),3.10(s,3H),1.38(s,9H).
Step L: benzyl (S) -2- (8-chloro-2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] oxoquinazoline-7-carbonylamino) -3- (3- (methylsulfonyl) phenyl) propanoate (Compounds 1-12)
TFA (2mL) was added to a vigorously stirred solution of benzyl (S) -2- (8-chloro-2- (tert-butoxycarbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoate (1.3g,2mmol) in dichloromethane (10mL), the reaction mixture was reacted at room temperature for 3 hours, and the reaction was concentrated to give the desired product as a pale red solid (1.3g,2mmol 100%, TFA salt). The product was used directly in the subsequent reaction without purification. LCMS ESI (+) M/z:552(M + 1).
Step M: (S) -2- (8-chloro-2- (benzofuran-6-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazoline-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid benzyl ester (Compound 1-13)
HATU (418mg,1.1mmol) and DIPEA (390mg,3mmol) were added to a vigorously stirred solution of benzofuran-6-carboxylic acid (178mg,1.1mmol) in DMF (5mL) under nitrogen, the reaction mixture was reacted at room temperature for 1 hour and (S) -2- (8-chloro-2, 3-dihydro-1H-pyrrole [3,2, 1-ij) was added]And benzyl quinazoline-7-carbonylamino) -3- (3- (methylsulfonyl) phenyl) propionate trifluoroacetate (649mg,1mmol), the mixture is stirred at room temperature for an additional 2 hours, ethyl acetate (100mL) is added, the mixture is washed successively with water (20mL), saturated brine (20mL), the organic phase is dried over anhydrous sodium sulfate, the filtrate is concentrated, the residue is purified by flash chromatography, eluting with 50% ethyl acetate in petroleum ether, to give the desired product as a white solid (661mg,0.95mmol 95%). LCMS ESI (+) M/z:696(M + 1).1H NMR(600MHz,DMSO)δ8.95(d,J＝8.0Hz,1H),8.16(d,J＝2.0Hz,1H),7.90(s,1H),7.79(d,J＝7.8Hz,1H),7.77(d,J＝8.0Hz,1H),7.69(d,J＝8.2Hz,1H),7.69(s,1H),7.58(t,J＝7.7Hz,1H),7.43–7.32(m,5H),7.28(d,J＝7.6Hz,1H),7.08(s,1H),7.05–6.82(m,1H),5.95(s,1H),5.98–5.68(m,2H),5.21(s,2H),5.14–4.96(m,2H),4.98–4.92(m,1H),3.35(dd,J＝14.6,5.3Hz,1H),3.13(dd,J＝12.5,9.5Hz,1H),3.11(s,3H).
And step N: (S) -2- (8-chloro-2- (benzofuran-6-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid (compounds 1-14)
LiOH (0.8mL,0.5M aqueous solution) was added to vigorously stirred (S) -2- (8-chloro-2- (benzofuran-6-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2, 1-ij)]Quinazoline-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid benzylAfter the reaction mixture had reacted at room temperature for 1 hour in THF (3.6mL) the ester (250mg,0.359mmol) was added aqueous HCl (2M,0.3mL) and the reaction mixture was isolated by preparative HPLC to give the desired product as a white solid (130mg,0.215mmol 60%). LCMS ESI (+) M/z:606(M + 1).1H NMR(600MHz,DMSO)δ13.15(brs,1H),8.84(d,J＝8.3Hz,1H),8.21(d,J＝2.1Hz,1H),7.94(s,1H),7.84(t,J＝8.9Hz,2H),7.76(d,J＝8.1Hz,1H),7.75(s,1H),7.65(t,J＝7.7Hz,1H),7.60–7.40(m,1H),7.35(d,J＝7.7Hz,1H),7.14(d,J＝1.2Hz,1H),7.10–6.90(m,1H),6.18(s,1H),5.92(brs,2H),5.08(brs,2H),4.93–4.76(m,1H),3.39(dd,J＝14.2,4.2Hz,1H),3.18(s,3H),3.13(dd,J＝13.9,11.2Hz,1H).
Example 2
Figure BDA0001453142600000121
(S) -2- (8-chloro-2- (1H-indole-6-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid
The title compound was prepared according to the method of example 1 steps M and N, using 1H-indole-6-carboxylic acid instead of the compound benzofuran-6-carboxylic acid to give a white solid. LCMS ESI (+) M/z 605(M + 1).1H NMR(600MHz,DMSO)δ12.89(brs,1H),11.39(s,1H),8.78(d,J＝8.2Hz,1H),7.89(s,1H),7.79(d,J＝7.8Hz,1H),7.70(d,J＝7.5Hz,1H),7.63(d,J＝8.1Hz,1H),7.59(t,J＝7.7Hz,1H),7.52(s,1H),7.53–7.46(m,1H),7.46(s,1H),7.04(d,J＝8.2Hz,1H),7.03–6.93(m,1H),6.52(s,1H),6.13(s,1H),5.99–5.78(m,2H),5.14–4.95(m,2H),4.85–4.69(m,1H),3.30–3.26(m,1H),3.12(s,3H),3.10–3.03(m,1H).
Example 3
Figure BDA0001453142600000131
(S) -2- (8-chloro-2- (pyrazolo [1,5-a ] pyridine-2-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid
The procedure is as in example 1, Steps M and N, using pyrazole [1,5-a ]]The title compound was prepared from pyridine-2-carboxylic acid instead of benzofuran-6-carboxylic acid as a white solid. LCMS ESI (+) M/z:606(M + 1).1H NMR(600MHz,DMSO)δ12.89(brs,1H),8.76(d,J＝8.0Hz,1H),8.75(d,J＝6.5Hz,1H),7.88(s,1H),7.79(d,J＝8.3Hz,1H),7.77(d,J＝10.1Hz,1H),7.69(d,J＝7.6Hz,1H),7.58(t,J＝7.7Hz,1H),7.63–7.40(m,1H),7.33(t,J＝7.7Hz,1H),7.10–7.01(m,1H),7.15–6.92(m,1H),6.90(s,1H),6.30–6.18(m,1H),6.17–6.06(m,1H),,6.06–5.93(m,1H),5.44–5.31(m,1H),5.23–5.08(m,1H),4.82–4.74(m,1H),3.32(dd,J＝14.3,4.3Hz,1H),3.11(s,3H),3.05(dd,J＝13.5,11.4Hz,1H).
Example 4
Figure BDA0001453142600000132
(S) -2- (8-chloro-2- (1H-indole-2-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid
The title compound was prepared according to the method of example 1 steps M and N, using 1H-indole-2-carboxylic acid instead of the compound benzofuran-6-carboxylic acid to give a white solid. LCMS ESI (+) M/z 605(M + 1).1H NMR(600MHz,DMSO)δ12.88(brs,1H),11.70(s,1H),8.76(d,J＝8.3Hz,1H),7.88(s,1H),7.79(d,J＝7.8Hz,1H),7.73–7.65(m,2H),7.63–7.52(m,2H),7.42(d,J＝8.2Hz,1H),7.23(t,J＝7.6Hz,1H),7.12–7.06(m,2H),6.95(s,1H),6.13(d,J＝2.4Hz,1H),6.16–5.99(m,2H),5.40–5.08(m,2H),4.84–4.70(m,1H),3.31–3.28(m,1H),3.11(s,3H),3.08–3.02(m,1H).
Example 5
Figure BDA0001453142600000141
(S) -2- (8-chloro-2- (1H-indole-4-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid
The title compound was prepared according to the method of example 1 steps M and N, using 1H-indole-4-carboxylic acid instead of the compound benzofuran-6-carboxylic acid to give a white solid. LCMS ESI (+) M/z 605(M + 1).1H NMR(600MHz,DMSO)δ12.92(brs,1H),11.42(s,1H),8.78(d,J＝8.2Hz,1H),7.89(s,1H),7.79(d,J＝7.8Hz,1H),7.70(d,J＝7.6Hz,1H),7.59(t,J＝7.7Hz,1H),7.56(d,J＝8.6Hz,1H),7.45(t,J＝2.6Hz,1H),7.39–7.19(m,1H),7.16(t,J＝7.7Hz,1H),6.99(d,J＝7.2Hz,1H),6.94–6.66(m,1H),6.24(s,1H),6.11(s,1H),6.06–5.50(m,2H),5.34–4.83(m,2H),4.83–4.75(m,1H),3.33(dd,J＝14.0,4.2Hz,1H),3.12(s,3H),3.07(dd,J＝13.9,11.2Hz,1H).
Example 6
Figure BDA0001453142600000142
(S) -2- (8-chloro-2- (3-hydroxyphenyl-1-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid
The title compound was prepared according to the method of example 1 steps M and N, using 3-hydroxybenzoic acid instead of the compound benzofuran-6-carboxylic acid to give a white solid. LCMS ESI (+) M/z:582(M + 1).1H NMR(600MHz,DMSO)δ12.92(brs,1H),9.81(s,1H),8.77(s,1H),7.88(s,1H),7.79(d,J＝7.9Hz,1H),7.70(d,J＝7.9Hz,1H),7.59(t,J＝7.7Hz,1H),7.52–7.36(m,1H),7.29(t,J＝7.8Hz,1H),7.17–6.95(m,1H),6.91(d,J＝8.4Hz,1H),6.78–6.74(m,1H),6.71(s,1H),6.12(s,1H),6.04–5.57(m,2H),5.20–4.82(m,2H),4.82–4.72(m,1H),3.47–3.42(m,1H),3.12(s,3H),3.07(dd,J＝13.5,11.5Hz,1H).
Example 7
Figure BDA0001453142600000143
(S) -2- (8-chloro-2- (3-methyl-1H-indene-2-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid
The title compound was prepared according to the method of example 1 steps M and N, using 3-methyl-1H-indene-2-carboxylic acid instead of the compound benzofuran-6-carboxylic acid to give a white solid. LCMS ESI (+) M/z 618(M + 1).1H NMR(600MHz,DMSO)δ12.89(brs,1H),8.78(d,J＝8.3Hz,1H),7.89(s,1H),7.79(d,J＝7.8Hz,1H),7.70(d,J＝7.6Hz,1H),7.59(t,J＝7.7Hz,1H),7.55–7.43(m,3H),7.38(t,J＝7.5Hz,1H),7.31(t,J＝7.4Hz,1H),7.15–6.95(m,1H),6.13(brs,1H),6.04–5.75(m,2H),5.18–4.90(m,2H),4.86–4.74(m,1H),3.56(s,2H),3.33(dd,J＝14.1,4.2Hz,1H),3.12(s,3H),3.08(dd,J＝13.9,11.2Hz,1H),2.05(s,3H).
Example 8
Figure BDA0001453142600000151
(S, E) -2- (8-chloro-2- (3- (2-hydroxyphenyl) acryloyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid
The title compound was prepared according to the method of example 1 steps M and N, using (E) -3- (2-hydroxyphenyl) acrylic acid instead of the compound benzofuran-6-carboxylic acid to give a white solid. LCMS ESI (+) M/z 608(M + 1).1H NMR(600MHz,DMSO)δ12.88(brs,1H),10.08(s,1H),8.73(d,J＝8.2Hz,1H),7.87(s,1H),7.83(d,J＝15.5Hz,1H),7.79(d,J＝7.8Hz,1H),7.75(d,J＝7.6Hz,1H),7.69(d,J＝7.6Hz,1H),7.58(t,J＝7.7Hz,1H),7.56–7.43(m,1H),7.32(d,J＝14.6Hz,1H),7.22(t,J＝7.7Hz,1H),7.03(brs,1H),6.89(d,J＝8.1Hz,1H),6.85(t,J＝7.5Hz,1H),6.11(s,1H),6.07–5.79(m,2H),5.31–4.94(m,2H),4.82–4.73(m,1H),3.32(dd,J＝14.1,4.2Hz,1H),3.11(s,3H),3.05(dd,J＝13.9,11.1Hz,1H).
Example 9
Figure BDA0001453142600000152
(S, E) -2- (8-chloro-2- (3- (furan-3-yl) acryloyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid
The title compound was prepared according to the method of example 1 steps M and N, using (E) -3- (furan-3-yl) acrylic acid instead of the compound benzofuran-6-carboxylic acid to give a white solid. LCMS ESI (+) M/z:582(M + 1).1H NMR(600MHz,DMSO)δ12.91(brs,1H),8.73(s,1H),8.05(s,1H),7.87(s,1H),7.79(d,J＝7.8Hz,1H),7.76(s,1H),7.69(d,J＝7.7Hz,1H),7.58(t,J＝7.7Hz,1H),7.59–7.45(m,1H),7.49(t,J＝14.8Hz,1H),7.21–6.96(m,2H),7.03(s,1H),6.11(s,1H),6.09–5.80(m,2H),5.27–4.93(m,2H),4.81–4.71(m,1H),3.32–3.27(m,1H),3.11(s,3H),3.05(dd,J＝13.8,11.1Hz,1H).
Example 10
Figure BDA0001453142600000161
(S, E) -2- (8-chloro-2- (3- (furan-2-yl) acryloyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid
The title compound was prepared according to the method of example 1 steps M and N, using (E) -3- (furan-2-yl) acrylic acid instead of the compound benzofuran-6-carboxylic acid to give a white solid. LCMS ESI (+) M/z:582(M + 1).1H NMR(600MHz,DMSO)δ12.91(brs,1H),8.75(d,J＝8.3Hz,1H),7.87(s,1H),7.85(s,1H),7.79(d,J＝7.8Hz,1H),7.69(d,J＝7.7Hz,1H),7.58(t,J＝7.7Hz,1H),7.56–7.48(m,1H),7.40(d,J＝15.1Hz,1H),7.16–7.06(m,1H),7.06(s,1H),6.91(d,J＝3.0Hz,1H),6.67–6.60(m,1H),6.10(s,1H),6.08–5.80(m,2H),5.25–4.93(m,2H),4.84–4.71(m,1H),3.32(dd,J＝14.0,4.3Hz,1H),3.11(s,3H),3.04(dd,J＝14.0,11.2Hz,1H).
Example 11
Figure BDA0001453142600000162
(S, E) -2- (8-chloro-2- (3- (thiophen-2-yl) acryloyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid
The title compound was prepared according to the method of example 1 steps M and N, using (E) -3- (thiophen-2-yl) acrylic acid instead of the compound benzofuran-6-carboxylic acid to give a white solid. LCMS ESI (+) M/z:598(M + 1).1H NMR(600MHz,DMSO)δ12.89(brs,1H),8.74(d,J＝8.2Hz,1H),7.88(s,1H),7.79(d,J＝7.7Hz,1H),7.74–7.66(m,3H),7.58(t,J＝7.7Hz,1H),7.52(d,J＝3.2Hz,1H),7.56–7.46(m,1H),7.14(dd,J＝4.9,3.8Hz,1H),7.13–7.00(m,2H),6.11(s,1H),6.09–5.79(m,2H),5.12(d,J＝76.7Hz,2H),4.83–4.70(m,1H),3.32(dd,J＝14.2,4.3Hz,1H),3.11(s,3H),3.05(dd,J＝13.9,11.2Hz,1H).
Example 12
Figure BDA0001453142600000163
(S) -2- (8-chloro-2- (naphthalene-2-formyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid
The title compound was prepared according to the method of example 1 steps M and N, using naphthalene-2-carboxylic acid instead of the compound benzofuran-6-carboxylic acid to give a white solid. LCMS ESI (+) M/z:616(M + 1).1H NMR(600MHz,DMSO)δ12.90(s,1H),8.79(d,J＝8.3Hz,1H),8.07–7.98(m,4H),7.89(s,1H),7.79(d,J＝7.8Hz,1H),7.70(d,J＝7.7Hz,1H),7.67–7.56(m,3H),7.48(d,J＝8.1Hz,1H),7.51–7.27(m,1H),7.23–6.77(m,1H),6.12(s,1H),6.05–5.69(m,2H),5.31–4.85(m,2H),4.84–4.71(m,1H),3.33(dd,J＝14.0,4.1Hz,1H),3.12(s,3H),3.07(dd,J＝13.8,11.2Hz,1H).
Example 13
Figure BDA0001453142600000171
(S) -2- (8-chloro-2- (benzofuran-2-formyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid
The title compound was prepared according to the method of example 1 steps M and N, using benzofuran-2-carboxylic acid instead of the compound benzofuran-6-carboxylic acid to give a white solid. LCMS ESI (+) M/z:606(M + 1).
1H NMR(600MHz,DMSO)δ12.90(brs,1H),8.77(d,J＝8.3Hz,1H),7.88(s,1H),7.79(d,J＝7.8Hz,2H),7.71(d,J＝8.4Hz,1H),7.69(d,J＝7.7Hz,1H),7.58(t,J＝7.7Hz,1H),7.56(brs,1H),7.54(s,1H),7.51(t,J＝7.8Hz,1H),7.38(t,J＝7.5Hz,1H),7.09(s,1H),6.13(s,1H),6.11–5.94(m,2H),5.34–5.03(m,2H),4.84–4.74(m,1H),3.30(dd,J＝14.0,4.0Hz,1H),3.12(s,3H),3.05(dd,J＝13.9,11.1Hz,1H).
Example 14
Figure BDA0001453142600000172
(S) -2- (5-chloro-7- ((3-hydroxybenzyl) carbamoyl) -1H-indole-4-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid
The synthesis method is as follows:
Figure BDA0001453142600000173
step O: 5-chloro-7- ((3-methoxybenzyl) carbamoyl) -1H-indole-4-carboxylic acid methyl ester (Compound 2-1)
HATU (418mg,1.1mmol) and DIPEA (390mg,3mmol) were added to a vigorously stirred solution of compounds 1-5(279mg,1.1mmol) in DMF (5mL) under nitrogen, the reaction mixture was reacted at room temperature for 1 hour, m-methoxybenzylamine (137mg,1mmol) was added, the mixture was stirred at room temperature for 2 hours, ethyl acetate (100mL) was added, washed with water (20mL), saturated brine (20mL), the organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated, the residue was purified by flash chromatography, eluted with 50% ethyl acetate of petroleum ether to give the desired product as a white solid (335mg,0.90mmol 90%).LCMS ESI(+)m/z:373(M+1)。1H NMR(600MHz,DMSO)δ11.60(s,1H),9.36(t,J＝5.7Hz,1H),7.86(s,1H),7.50(s,1H),7.26(t,J＝7.8Hz,1H),6.94(d,J＝7.4Hz,1H),6.94(s,1H),6.83(dd,J＝2.1，7.0Hz,1H),6.56(d,J＝2.0Hz,1H)，4.52(d,J＝5.8Hz,2H),3.96(s,3H),3.74(s,3H).
Compound 2-3 was prepared according to the procedures of example 1, steps J and K, using compound 2-1 instead of compound 1-9 to give a pale yellow solid. LCMS ESI (+) M/z:674(M + 1).
Step P: (S) -2- (5-chloro-7- ((3-hydroxybenzyl) carbamoyl) -1H-indole-4-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid (Compound 2-4)
Under the protection of nitrogen at 0 ℃, BBr is put3(1M dichloromethane solution, 0.3mL,0.3mmol) was added dropwise to a vigorously stirred solution of compounds 2-3(67mg,0.1mmol) in DCM (2mL), the reaction mixture was reacted at room temperature for 2 hours and then diluted with DCM (20mL), the reaction was quenched with water (5mL), the organic phase was dried over anhydrous sodium sulfate, after filtration, the filtrate was concentrated and the residue was purified by preparative reverse phase HPLC to afford the desired product as a white solid (20mg,0.35mmol 35%). LCMS ESI (+) M/z 570(M + 1).1H NMR(600MHz,MeOD)δ7.96(s,1H),7.88(d,J＝7.8Hz,1H),7.75(d,J＝7.6Hz,1H),7.67(s,1H),7.62(t,J＝7.7Hz,1H),7.40(d,J＝3.1Hz,1H),7.16(t,J＝7.8Hz,1H),6.84(d,J＝7.6Hz,1H),6.82(s,1H),6.69(dd,J＝7.9,1.2Hz,1H),6.34(d,J＝3.1Hz,1H),5.15(dd,J＝10.6,4.6Hz,1H),3.56(dd,J＝14.2,4.6Hz,1H),3.19(dd,J＝14.2,10.6Hz,1H),3.07(s,3H).
Example 15
Figure BDA0001453142600000181
(S) -2- (5-chloro-7- ((benzofuran-6-carboxamido) methyl) -1H-indole-4-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid
The synthesis method is as follows:
Figure BDA0001453142600000182
compounds 3-4 were prepared according to the procedure for example 1, steps M, J, K and N to give light yellow solids. LCMS ESI (+) M/z:594(M + 1).1H NMR(600MHz,MeOD)δ8.06(s,1H),7.94(s,1H),7.93(d,J＝1.9Hz,1H),7.86(d,J＝7.9Hz,1H),7.79(d,J＝8.2Hz,1H),7.75–7.70(m,2H),7.61(t,J＝7.7Hz,1H),7.35(d,J＝3.1Hz,1H),7.10(s,1H),6.94(d,J＝0.9Hz,1H),6.32(d,J＝3.1Hz,1H),5.12(dd,J＝10.4,4.7Hz,1H),4.83(s,2H),3.54(dd,J＝14.2,4.6Hz,1H),3.19(dd,J＝14.1,10.5Hz,1H).
Example 16
Figure BDA0001453142600000191
(S) -2- (8-chloro-2- (benzofuran-6-carbonyl) -2,3,5, 6-tetrahydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid;
the synthesis method is as follows:
Figure BDA0001453142600000192
step Q: (S) -2- (8-chloro-2- (tert-butoxycarbonyl) -2,3,5, 6-tetrahydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid benzyl ester (4-1)
Sodium cyanoborohydride (126mg,2mmol) was added dropwise to a vigorously stirred solution of compounds 1-11(326mg,0.5mmol) in acetic acid (5mL), the reaction mixture was reacted at room temperature for 16 hours and then diluted with DCM (50mL), the reaction was quenched with water (5mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and the residue was purified by flash chromatography eluting with petroleum ether 50% ethyl acetate to give the desired product as a white solid (262mg,0.4mmol 80%). LCMS ESI (+) M/z:654(M + 1).
The title compound was prepared according to the method of example 1, steps L, M and N, using compound 4-1 instead of compound 1-11 to give a white solid. LCMS ESI (+) M/z 608(M + 1).1H NMR(600MHz,MeOD)δ7.93(s,1H),7.92(d,J＝2.1Hz,1H),7.85(d,J＝7.6Hz,1H),7.79–7.67(m,3H),7.60(t,J＝7.7Hz,1H),7.52–7.38(m,1H),7.10–6.99(m,1H),6.96(d,J＝1.4Hz,1H),5.02(dd,J＝10.3,4.5Hz,1H),4.49–4.34(m,1H),3.51(dd,J＝14.2,4.5Hz,1H),3.16(dd,J＝14.0,10.5Hz,2H),3.11(s,3H),2.94–2.85(m,1H),2.81-2.73(m,1H).
Example 17
Figure BDA0001453142600000201
(S) -2- (8-chloro-2- (1H-indole-6-carbonyl) -2,3,5, 6-tetrahydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid
The title compound was prepared according to the synthesis of example 16 using 1H-indole-6-carboxylic acid instead of the compound benzofuran-6-carboxylic acid to give a white solid. LCMS ESI (+) M/z 607(M + 1).1H NMR(600MHz,DMSO)δ12.85(brs,1H),11.37(s,1H),8.75(d,J＝8.1Hz,1H),7.87(s,1H),7.78(d,J＝7.8Hz,1H),7.67(d,J＝7.4Hz,1H),7.62(d,J＝8.1Hz,1H),7.61–7.47(m,3H),7.13(d,J＝5.9Hz,1H),7.09–6.91(m,1H),6.51(s,1H),4.77–4.34(m,4H),3.31(dd,J＝14.1,4.1Hz,2H),3.16(s,3H),3.15–3.08(m,2H),3.03(dd,J＝13.9,11.3Hz,1H),2.72–2.56(m,2H).
Example 18
Figure BDA0001453142600000202
(S) -2- (8-chloro-2- (3-hydroxybenzyl) -1-oxo-2, 3,5, 6-tetrahydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid
The synthesis method is as follows:
Figure BDA0001453142600000203
compound 5-1 was prepared according to the procedure for example 16, step Q, using compound 3-1 instead of compound 1-11 to give a white solid. LCMS ESI (+) M/z 375(M + 1). Step R: 8-chloro-2- (3-hydroxybenzyl) -1-oxo-2, 3,5, 6-tetrahydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxylic acid methylester (5-2)
Paraformaldehyde (4mg,0.128mmol) and BEMP (0.4mL,1M in THF) were added to a vigorously stirred solution of compound 5-1(24mg,0.064mmol) in DMA (1mL), the reaction mixture was reacted at 40 ℃ for 16 h, TosCl (37mg,0.194mmol) was added, and after 2h at room temperature the reaction was continued, the reaction was quenched with water (5mL), extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, the residue was purified by flash chromatography, eluting with 30% ethyl acetate in petroleum ether to give the desired product as a white solid (20mg,0.0518mmol 81%). LCMS ESI (+) M/z:387(M + 1).
Compound 5-4 was prepared according to the procedures of example 1, steps J and K, using compound 5-2 instead of compound 1-9 to give a pale yellow solid. LCMS ESI (+) M/z:688(M + 1).
The title compound was prepared according to the method of example 14 step P using compound 5-4 instead of compound 2-3 to give a white solid. LCMS ESI (+) M/z 584(M + 1).1H NMR(600MHz,MeOD)δ7.93(s,1H),7.86(d,J＝8.0Hz,1H),7.72(d,J＝7.6Hz,1H),7.61(t,J＝7.8Hz,1H),7.46(s,1H),7.17(t,J＝7.8Hz,1H),6.81(d,J＝7.9Hz,1H),6.78(s,1H),6.73(dd,J＝8.1,2.1Hz,1H),5.03(dd,J＝10.6,4.6Hz,1H),4.66(s,2H),4.42(q,J＝8.1Hz,2H),3.65–3.60(m,1H),3.52(dd,J＝14.3,4.4Hz,1H),3.17-3.12(m,2H),3.12(s,3H),3.00–2.93(m,1H),2.87–2.79(m,1H).
Example 19
Figure BDA0001453142600000211
(S) -2- (8-chloro-2- (3-hydroxybenzyl) -3-oxo-2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid
Figure BDA0001453142600000212
Step S: 5-chloro-7- (((3-methoxybenzyl) amino) methyl) -1H-indole-4-carboxylic acid methyl ester (6-1)
Under nitrogen, PPh3(26mg,0.99mmol) in THF (0.5mL) was added dropwise to a vigorously stirred solution of 5-chloro-7- (azidomethyl) -1-hydro-indole-4-carboxylic acid methyl ester (24mg,0.09mmol) in THF (0.5mL), the reaction mixture was reacted at room temperature for 16 hours, m-methoxybenzaldehyde (25mg,0.18mmol) was added, the mixture was stirred at room temperature for 2 hours, the reaction solution was concentrated and methanol (1mL) was added, sodium cyanoborohydride (23mg,0.36mmol) was added to the reaction system with stirring, after 1 hour of reaction was continued, water quenching was added, extraction was performed with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, after filtration, the filtrate was concentrated, the residue was purified by flash chromatography, eluted with 30% ethyl acetate of petroleum ether to give the desired product as a white solid (30mg,0.0819mmol 91%). LCMS ESI (+) M/z:359(M + 1).
And T: 8-chloro-2- (3-hydroxybenzyl) -3-oxo-2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxylic acid methyl ester (6-2)
Triphosgene (30mg,0.1mmol) and DBU (30mg,0.2mmol) were added sequentially to a vigorously stirred solution of methyl 5-chloro-7- (((3-methoxybenzyl) amino) methyl) -1H-indole-4-carboxylate (30mg,0.0819mmol) in methylene chloride (5mL) under a blanket of nitrogen. After the reaction system was reacted at room temperature for 3 hours, the reaction was quenched by addition of saturated NaCl (1mL), extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by flash chromatography, eluting with 30% ethyl acetate with petroleum ether, to give the desired product as a white solid (25mg,0.0651mmol 79%). LCMS ESI (+) M/z:385(M + 1).
Compound 6-4 was prepared according to the procedures of example 1, steps J and K, using compound 6-2 instead of compound 1-9 to give a pale yellow solid. LCMS ESI (+) M/z:688(M + 1).
The title compound was prepared according to the method of example 14 step P using compound 6-4 instead of compound 2-3 to give a white solid. LCMS ESI (+) M/z:582(M + 1).1H NMR(600MHz,DMSO)δ9.45(s,1H),7.88(s,1H),7.82–7.78(m,2H),7.69(d,J＝7.8Hz,1H),7.59(t,J＝7.6Hz,1H),7.16(t,J＝7.8Hz,2H),6.76(d,J＝7.4Hz,1H),6.73(s,1H),6.68(dd,J＝7.8,2.6Hz,1H),6.54(s,1H),6.34(s,1H),4.80(s,2H),4.79–4.74(m,1H),4.64(s,2H),3.19–3.16(m,1H),3.13(s,3H),3.10–3.05(m,1H).
Example 20
Figure BDA0001453142600000221
(S) -2- (9-chloro-2- (1H-indole-6-carbonyl) -1,2,3, 4-tetrahydro- [1,4] diazepine [6,7,1-hi ] indole-8-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid
Figure BDA0001453142600000222
Step U: 9-chloro-1, 2,3, 4-tetrahydro- [1,4] diazepine [6,7,1-hi ] indole-8-carboxylic acid methyl ester (7-1)
A solution of compounds 1-8(80mg,0.336mmol) in DMF (1.5mL) was added dropwise to a vigorously stirred zero-degree suspension of NaH (27mg,0.675mmol) in DCM (1.5mL) under nitrogen. After the reaction mixture was stirred at zero for 10 minutes, a solution of 2-bromoethyl) diphenylsulfonium trifluoromethanesulfonate (200mg,0.451mmol) in DCM (1.5mL) was added dropwise to the reaction system, the mixture was stirred at room temperature for 4 hours, quenched with saturated ammonium chloride solution, extracted with DCM, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, the residue was purified by flash chromatography, eluting with 10% methanol of DCM, to give the desired product as a white solid (78mg,0.295mmol 88%). LCMS ESI (+) M/z 265(M + 1).
Compound 7-5 was prepared according to the procedure for example 1 using steps M, J, K and N in sequence, using compound 7-1 instead of compound 1-12, 1H-indole-6-carboxylic acid instead of compound benzofuran-6-carboxylic acid to give a white solid. LCMS ESI (+) M/z 619(M + 1).1H NMR(600MHz,DMSO)δ12.83(brs,1H),11.28(s,1H),8.81(d,J＝8.2Hz,1H),7.90(s,1H),7.80(d,J＝7.8Hz,1H),7.71(d,J＝7.6Hz,1H),7.59(t,J＝7.7Hz,1H),7.55(d,J＝8.1Hz,1H),7.46(t,J＝2.5Hz,1H),7.43–7.38(m,1H),7.36(s,1H),6.88(brs,1H),6.78–6.58(m,1H),6.49(s,1H),6.22(brs,1H),4.90(brs,2H),4.84–4.75(m,1H),4.41(brs,2H),4.13(brs,2H),3.34(dd,J＝14.1,4.1Hz,1H),3.13(s,3H),3.07(dd,J＝13.9,11.2Hz,1H).
Example 21
Figure BDA0001453142600000231
(S) -2- (9-chloro-2- (3-hydroxybenzyl) -1-oxo-1, 2,3, 4-tetrahydro- [1,4] diaza [6,7,1-hi ] indole-8-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid (8-7)
Figure BDA0001453142600000241
Step V: 1- (2- ((tert-butoxycarbonyl) amino) ethyl) -5-chloro-1H-indole-4, 7-dicarboxylic acid methyl ester (8-1)
At room temperature, adding Cs2CO3(1.95g,6mmol) and the compound 2- (tert-butoxycarbonylamino) ethyl bromide (896mg,4mmol) were added to a solution of the compounds 1-4(534mg,2mmol) in acetonitrile (10mL), the reaction mixture was stirred at 80 deg.C for 16 h, filtered, the cake was washed with ethyl acetate, the filtrate was concentrated and the residue was purified by flash chromatography eluting with 30% ethyl acetate in petroleum ether to give the desired product as a white solid (421mg,1.02mmol 51%). LCMS ESI (+) M/z:411(M + 1).1H NMR(400MHz,CDCl3)δ7.71(s,1H),7.20(d,J＝2.9Hz,1H),6.69(d,J＝3.1Hz,1H),4.48(t,J＝6.0Hz,2H),4.03(s,3H),3.99(s,3H),3.41(q,J＝6.0Hz,2H),2.05(s,1H),1.40(s,9H).
Compound 8-2 was prepared according to the procedure of example 1, step L, using compound 8-1 instead of compound 1-11 to give the desired product as a yellow oil (200mg,0.645mmol 100%). LCMS ESI (+) M/z 311(M + 1).
Step W: 9-chloro-1-oxo-1, 2,3, 4-tetrahydro- [1,4] diaza [6,7,1-hi ] indole-8-carboxylic acid methyl ester (8-3)
A solution of compound 8-2(40mg,0.129mmol) in acetic acid was stirred at 100 deg.C for 16 h, cooled to room temperature, the solution was concentrated and the residue was purified by preparative thin layer chromatography using 70% ethyl acetate in petroleum ether to afford the desired product as a white solid (35mg,0.125mmol 95%). LCMS ESI (+) M/z:279(M + 1).
Step X: 9-chloro-2- (3-methoxybenzyl) -1-1-oxo-1, 2,3, 4-tetrahydro- [1,4] diaza [6,7,1-hi ] indole-8-carboxylic acid methyl ester (8-4)
A solution of compound 8-3(35mg,0.125mmol) in DMF (0.5mL) was added dropwise to a vigorously stirred zero-degree suspension of NaH (10mg,0.26mmol) in DMF (0.5mL) under nitrogen. After the reaction mixture was stirred at zero for 10 minutes, 3-methoxybenzyl bromide (59mg,0.336mmol) was added dropwise to the reaction and the mixture was stirred for an additional 2 hours at room temperature, quenched with saturated ammonium chloride solution, extracted with DCM, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and the residue was purified by flash chromatography eluting with 50% ethyl acetate in petroleum ether to give the desired product as a white solid (45mg,0.113mmol 90%). LCMS ESI (+) M/z 399(M + 1).
Compounds 8-6 were prepared according to the procedures of example 1, steps J and K, using compound 8-3 instead of compound 1-9 to give the desired product as a pale yellow solid (34mg,0.048 mmol). LCMS ESI (+) M/z:700(M + 1).
Compound 8-7 was prepared according to the procedure of example 2, step P, using compound 8-6 instead of compound 2-3 to give the desired product 8-7 as a white solid (10mg,0.0167 mmol). LCMS ESI (+) M/z:596(M + 1).1H NMR (600MHz, DMSO) δ 9.41(s,1H),8.84(s,1H),7.89(s,1H),7.80(d, J ═ 7.9Hz,1H),7.78(s,1H),7.71(d, J ═ 7.7Hz,1H),7.59(t, J ═ 7.7Hz,1H),7.46(d, J ═ 3.1Hz,1H),7.15(t, J ═ 7.8Hz,1H),6.77(d, J ═ 7.6Hz,1H),6.75(s,1H),6.68(dd, J ═ 8.0,1.7Hz,1H),6.29(d, J ═ 2.9, 1H), 4.84-4.63 (m,3H),4.30 (m, 3.30, 3H), 3.76 (dd, 3H ═ 8.0,1.7Hz,1H), 1H, 6.29(d, 3.9, 3H), 3.9, 3H, 13H, 3mg ═ 3H, 13H, 3H, 13H, 3H, 13H, 3H, 13H, 5, 3H, 3,5, 13, 3,5, 3,5, 1,5, 1, 3, 1, 3, 1, 3, 1,5, 1, 3, 1, and white by-7, 3, 7, 3, 7, 3, 7, 3: 674(M + 1).1H NMR(600MHz,DMSO)δ9.41(s,1H),9.18–8.36(m,1H),7.89(s,1H),7.85(s,1H),7.77(d,J＝7.7Hz,1H),7.73–7.62(m,2H),7.56(t,J＝7.7Hz,1H),7.15(t,J＝7.8Hz,1H),6.77(d,J＝7.6Hz,1H),6.75(s,1H),6.68(dd,J＝8.0,1.4Hz,1H),4.75(brs,3H),4.43–4.08(m,2H),3.77(brs,2H),3.32–3.00(m,5H).
Example 22
Figure BDA0001453142600000251
(S) -2- (8-chloro-6-fluoro-2- (1H-indole-6-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid
Figure BDA0001453142600000261
Step Y: 2-tert-butyl 7-methyl 8-chloro-6-fluoro-1H-pyrrolo [3,2,1-ij ] quinazoline-2, 7(3H) -dicarboxylate (compound 9-1)
1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt (380mg,1.1mmol) and acetic acid (120mg,2mmol) were added to a solution of compound 9-1(350mg,1mmol) in acetonitrile (2mL) under nitrogen. After stirring the reaction mixture at room temperature for 1 hour, it was diluted with ethyl acetate, the reaction was washed successively with water and saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated, and the residue was purified by flash chromatography eluting with 30% ethyl acetate in petroleum ether to give the desired product 9-1 as a white solid (300mg,0.815mmol 82%). LCMS ESI (+) M/z 369(M + 1).
Compound 9-6 was prepared according to the procedure for example 1 using steps J, K, L, M and N in sequence, using compound 9-1 instead of compound 1-9, 1H-indole-6-carboxylic acid instead of compound benzofuran-6-carboxylic acid to give compound 9-6 as a white solid. LCMS ESI (+) M/z:623(M + 1).1H NMR(600MHz,DMSO)δ12.77(brs,1H),11.40(s,1H),8.92(d,J＝8.1Hz,1H),7.87(s,1H),7.78(d,J＝7.9Hz,1H),7.67(d,J＝7.7Hz,1H),7.64(d,J＝8.1Hz,1H),7.57(t,J＝7.7Hz,1H),7.54–7.44(m,3H),7.11–6.95(m,2H),6.53(s,1H),5.79(s,2H),5.20–4.96(m,2H),4.89–4.69(m,1H),3.27(dd,J＝14.1,4.9Hz,1H),3.13(s,3H),3.06(dd,J＝14.0,9.9Hz,1H).
Example 23
Figure BDA0001453142600000271
(S) -2- (8-chloro-2- (1H-indole-5-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid
The title compound was prepared according to the method of example 1 steps M and N, using 1H-indole-5-carboxylic acid instead of the compound benzofuran-6-carboxylic acid to give a white solid. LCMS ESI (+) M/z 605(M + 1).1H NMR(600MHz,DMSO)δ12.90(s,1H),11.41(s,1H),8.78(d,J＝8.2Hz,1H),7.89(s,1H),7.79(d,J＝7.7Hz,1H),7.70(d,J＝7.6Hz,1H),7.67(s,1H),7.59(t,J＝7.7Hz,1H),7.51–7.38(m,3H),7.14(d,J＝8.2Hz,1H),7.06–6.86(m,1H),6.53(s,1H),6.12(s,1H),5.96–5.79(m,2H),5.14–4.95(m,2H),4.85–4.74(m,1H),3.34(dd,J＝14.1,4.1Hz,1H),3.12(s,3H),3.06(dd,J＝13.8,11.3Hz,1H).
Cell adhesion and inhibition experiments:
t-cell adhesion assays were performed using the human T-lymphocyte cell line Jurkat (ATCC TIB-152): goat Anti-Human IgG (Fc specific) (Sigma I8885) was diluted to 10. mu.g/ml in PBS, incubated at 4 ℃ for 12 hours in 100uL/96 well plates, the wells were decanted, blocked with 200uL of 1% BSA at 37 ℃ for 90 minutes, and the plates were washed 3 times with PBS. 50uL of 1ug/mL ICAM-1 (containing 0.1% BSA, 0.01% Tween20) was added to each well and incubated at 37 ℃ for 3 hours. Using assay buffer (20mM HEPES pH 7.6,140mM NaCl,1mM MgCl)2,1mM MnCl20.2% glucose) wash the plate 3 times.
Jurkat cell machine 100-G centrifugation process re-suspended the cells in 37 ℃ assay buffer (20mM HEPES pH 7.6,140mM NaCl,1mM MgCl)21mM MnCl2, 0.2% glucose), 2. mu.l of 1mM of BCECF-AM was added per mL of the cell suspension. Incubate at 37 ℃ for 30 minutes with stirring every 10 minutes during incubation. After incubation, the cells were washed with assay buffer at 37 ℃. Suspend cells to 6X106Concentration in/mL.
The inhibitor was diluted to 2X final concentration in assay buffer and 50uL was taken at room temperatureThe compound solution was mixed with 60uL of Jurkat cells and incubated at 37 ℃ for 30 minutes. 100 μ L/well of cells and inhibitor were added to the plate and incubated at room temperature for 1 hour. Measuring the total fluorescence ex:485 by using a fluorometer; em is 530; cutoff 530 to measure total fluorescence. Washing the plate once with the assay buffer, and measuring the fluorescence value ex:485 by using a fluorimeter; em is 530; cutoff is as follows. Drawing the result into an inhibition-concentration relation graph, and calculating the EC by using a standard method50. Table I shows the partial EC determined in this way50The value is obtained.
Table one: cell adhesion and inhibited EC50
Figure BDA0001453142600000272
Figure BDA0001453142600000281
Application example one: eye drop preparation
5.0g (the amount of addition may be 3.5g, 4.5g, 6g, or 8g depending on the inhibitor) of the compound obtained in example 2 was added to 90mL of sterile physiological saline, 0.7g (the amount of addition may be 0.5g, 1.0g, or 1.5g depending on the inhibitor) of NaOH was added, and the mixture was stirred to obtain a transparent solution; to the solution obtained above, NaH was added2PO4The aqueous solution is saturated until the pH of the solution is between 6.75 and 7.25. To the resulting aqueous solution, sterile physiological saline was added until the total volume reached 100.0 mL. The above solution was bubbled with nitrogen for 1 hour, and the resulting solution was sealed and stored at 5 ℃ in the dark. And subpackaging into disposable eye drop bags, wherein each bag contains 60microL of preparation solution. The method and specific proportions of the formulation may also be adjusted as desired, depending on the nature of the particular compound and the requirements of use.
Application experiment example two: ointment formulations
Mixing the following materials to prepare ointment # 1: the compound obtained in example 2, 1.0 g; PEG400,15 g; butylated hydroxytoluene: 0.02 g; span 80 surfactant, 2 g; white wax, 10 g; 71.98g of white petrolatum.
Mixing the following materials to prepare ointment # 2: the compound obtained in example 10, 1.5 g; PEG900,25 g; span 80 surfactant, 0.9 g; white wax, 9.1 g; 78.3g of white petrolatum.
Mixing the following materials to prepare ointment # 3: the compound obtained in example 15, 1.0 g; PEG200,20 g; butylated hydroxytoluene: 0.01 g; span 60 surfactant, 2 g; white wax, 7 g; white petrolatum 65 g.
Mixing the following materials to prepare ointment # 4: the compound obtained in example 17, 1.2 g; PEG400,15 g; butylated hydroxytoluene: 0.01 g; span 60 surfactant, 1 g; white wax, 10 g; white petrolatum 75 g.
Mixing the following materials to prepare ointment # 5: the compound obtained in example 19, 2.0 g; PEG100,24 g; butylated hydroxytoluene: 0.02 g; span 80 surfactant, 6 g; white wax, 15 g; white petrolatum 60 g.

Claims (10)

1. An inhibitor of immune cell migration, characterized by the structure shown in the following equation:
Figure FDA0003456404580000011
R1selected from aryl, heteroaryl, substituted alkenyl;
the substituted alkenyl is selected from the group consisting of aryl and heteroaryl substituted by one or more hydrogen atoms in an olefin chain with a carbon chain length of not more than 6;
the aryl is selected from an aromatic system consisting of one or more five-membered and six-membered rings, and one or more hydrogen on the aromatic ring can be substituted by alkyl and hydroxyl groups with the carbon atom number not more than 6;
the heteroaryl is selected from an aromatic system consisting of five-membered and six-membered rings, and one or more carbon atoms on the aromatic ring are substituted by nitrogen, oxygen and sulfur;
R2is halogen substituted on any or several of aromatic rings;
R3is selected from
Figure FDA0003456404580000012
X is selected from CR4R5、C0；
Y is selected from N;
z is selected from CR8R9、(CR8R9)2、C0；
U is selected from N;
w is selected from CR10；
V is selected from CR12；
I is selected from CR14R15、CO；
Wherein n is selected from 0,1 and 2;
R4，R5，R8，R9，R14，R15selected from hydrogen;
R10，R12selected from hydrogen;
X-Y, Z-U, U-W, W-V are connected through a single bond or a double bond;
Y-Z are connected through single bonds or double bonds.
2. The inhibitor of immune cell migration according to claim 1, wherein: a compound selected from G1, G2, G3, G4, G5;
wherein the G1 compound has a structure represented by the following chemical formula:
Figure FDA0003456404580000021
the G2 compound has a structure represented by the following chemical formula:
Figure FDA0003456404580000022
the G3 compound has a structure represented by the following chemical formula:
Figure FDA0003456404580000023
the G4 compound has a structure represented by the following chemical formula:
Figure FDA0003456404580000024
the G5 compound has a structure represented by the following chemical formula:
Figure FDA0003456404580000031
3. the inhibitor of immune cell migration according to claim 1, wherein:
(S) -2- (8-chloro-2- (benzofuran-6-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazoline-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid;
(S) -2- (8-chloro-2- (pyrazolo [1,5-a ] pyridine-2-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid;
(S) -2- (8-chloro-2- (1H-indole-6-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid;
(S) -2- (8-chloro-2- (1H-indole-2-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid;
(S) -2- (8-chloro-2- (1H-indole-4-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid;
(S) -2- (8-chloro-2- (3-hydroxyphenyl-1-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid;
(S) -2- (8-chloro-2- (3-methyl-1H-indene-2-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid;
(S, E) -2- (8-chloro-2- (3- (2-hydroxyphenyl) acryloyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid;
(S, E) -2- (8-chloro-2- (3- (furan-3-yl) acryloyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid;
(S, E) -2- (8-chloro-2- (3- (furan-2-yl) acryloyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid;
(S, E) -2- (8-chloro-2- (3- (thiophen-2-yl) acryloyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid;
(S) -2- (8-chloro-2- (naphthalene-2-formyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid;
(S) -2- (8-chloro-2- (benzofuran-2-formyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid;
(S) -2- (5-chloro-7- ((benzofuran-6-carboxamido) methyl) -1H-indole-4-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid;
(S) -2- (8-chloro-2- (benzofuran-6-carbonyl) -2,3,5, 6-tetrahydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid;
(S) -2- (8-chloro-2- (1H-indole-6-carbonyl) -2,3,5, 6-tetrahydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid;
(S) -2- (8-chloro-2- (3-hydroxybenzyl) -1-oxo-2, 3,5, 6-tetrahydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid;
(S) -2- (8-chloro-2- (3-hydroxybenzyl) -3-oxo-2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid;
(S) -2- (9-chloro-2- (1H-indole-6-carbonyl) -1,2,3, 4-tetrahydro- [1,4] diazepine [6,7,1-hi ] indole-8-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid;
(S) -2- (9-chloro-2- (3-hydroxybenzyl) -1-oxo-1, 2,3, 4-tetrahydro- [1,4] diazepine [6,7,1-hi ] indole-8-carboxamido) -3- (3- (methylsulfonyl) phenyl) propanoic acid;
(S) -2- (8-chloro-6-fluoro-2- (1H-indole-6-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid;
(S) -2- (8-chloro-2- (1H-indole-5-carbonyl) -2, 3-dihydro-1H-pyrrolo [3,2,1-ij ] quinazolin-7-carboxamido) -3- (3- (methylsulfonyl) phenyl) propionic acid.
4. The inhibitor of migration of immune cells of claim 2, wherein said G1 compound is prepared by a process comprising:
carrying out halogenation reaction on the 2-amido terephthalic acid dialkyl ester to obtain an intermediate product I;
obtaining an intermediate product II through bromination or iodination and alkynylation reaction of the intermediate product;
carrying out double ring-combination reaction on the intermediate product to form a third intermediate product;
the intermediate product III is subjected to hydrolysis, reduction and amination reactions in sequence to obtain an intermediate product IV;
performing cyclization reaction on the intermediate product IV to obtain an intermediate product V;
the intermediate product is hydrolyzed and amidated to obtain intermediate product VI;
carrying out deprotection, amidation and hydrolysis reactions on the intermediate product six to obtain a target product G1;
wherein, the intermediate product I is-2-amino terephthalic acid dialkyl ester halogenated at 5-position and/or 6-position, and the structure is shown as follows:
Figure FDA0003456404580000051
alkyl is alkyl;
the intermediate product II is a compound shown in the following structure:
Figure FDA0003456404580000052
LG1is a leaving group;
the intermediate product III is a five-membered benzo nitrogen-containing heterocycle, and the structure of the intermediate product III is shown as follows:
Figure FDA0003456404580000061
the intermediate product IV is a compound shown in the following structure:
Figure FDA0003456404580000062
the intermediate product V is a compound shown in the following structure:
Figure FDA0003456404580000063
pro is an amino protecting group;
the intermediate product six is a compound shown in the following structure:
Figure FDA0003456404580000064
LG2is a leaving group.
5. The inhibitor of migration of immune cells according to claim 2, wherein said G2 compound is prepared by the following steps:
carrying out reduction, deprotection, amidation and hydrolysis reactions on the compound A to obtain a target product;
wherein the compound A is a compound shown in the following structure:
Figure FDA0003456404580000065
pro is an amino protecting group, LG2Is a leaving group.
6. The inhibitor of migration of immune cells according to claim 2, wherein said G3 compound is prepared by the following steps:
carrying out amidation, hydrolysis, amidation and hydrolysis reactions on the compound B-1 to obtain a target product;
wherein the compound B-1 is a compound shown in the following structure:
Figure FDA0003456404580000071
alkyl is alkyl.
7. The inhibitor of migration of immune cells according to claim 2, wherein said G4 compound is prepared by the following steps:
carrying out amidation, hydrolysis, amidation and hydrolysis reactions on the compound B-2 to obtain a target product;
the preparation method of the G5 compound is as follows:
carrying out amidation, reduction, cyclization, hydrolysis, amidation and hydrolysis reactions on the compound B-2 to obtain a target product;
wherein the compound B-2 is a compound shown in the following structure:
Figure FDA0003456404580000072
alkyl is alkyl.
8. The inhibitor of migration of immune cells of any one of claims 1 to 7, wherein:
the immunocyte migration inhibitor is used for relieving and treating dry eye disease, eczematous dermatitis and psoriasis.
9. The agent for inhibiting migration of immune cells according to any one of claims 1 to 7, which is prepared by the steps of:
step one, uniformly mixing an immune cell migration inhibitor, sterile physiological saline and alkali;
step two, adding a buffer solution until the pH value of the system is 6.75-7.25;
step three, continuously adding sterile normal saline, bubbling nitrogen into the system for 0.5-3 hours, and then packaging;
wherein in the first step, the mass ratio of the immune cell migration inhibitor, the sterile physiological saline to the alkali is 1:10-25: 0.01-0.5;
the mass ratio of the sterile normal saline in the first step and the third step is 1: 0.01-0.5.
10. The preparation prepared by using the immune cell migration inhibitor according to any one of claims 1 to 7, which is prepared by mixing the following components in parts by mass:
Figure FDA0003456404580000081
CN201711050899.8A 2017-10-31 2017-10-31 Immune cell migration inhibitor Active CN109721605B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201711050899.8A CN109721605B (en) 2017-10-31 2017-10-31 Immune cell migration inhibitor
PCT/CN2018/087630 WO2019085441A1 (en) 2017-10-31 2018-05-21 Immune cell migration inhibitor

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201711050899.8A CN109721605B (en) 2017-10-31 2017-10-31 Immune cell migration inhibitor

Publications (2)

Publication Number Publication Date
CN109721605A CN109721605A (en) 2019-05-07
CN109721605B true CN109721605B (en) 2022-03-11

Family

ID=66293712

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201711050899.8A Active CN109721605B (en) 2017-10-31 2017-10-31 Immune cell migration inhibitor

Country Status (2)

Country Link
CN (1) CN109721605B (en)
WO (1) WO2019085441A1 (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3114240C (en) 2018-10-30 2023-09-05 Gilead Sciences, Inc. Imidazopyridine derivatives as alpha4beta7 integrin inhibitors
CA3115830C (en) 2018-10-30 2023-09-12 Gilead Sciences, Inc. Compounds for inhibition of .alpha.4.beta.7 integrin
AU2019373240B2 (en) 2018-10-30 2023-04-20 Gilead Sciences, Inc. Quinoline derivatives as alpha4beta7 integrin inhibitors
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
WO2021030438A1 (en) 2019-08-14 2021-02-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001012186A1 (en) * 1999-08-13 2001-02-22 Biogen, Inc. Cell adhesion inhibitors
WO2002068421A2 (en) * 2000-11-29 2002-09-06 Cell Therapeutics, Inc. Tricyclic compounds and their analogs as inhibitors of cytokine signaling
WO2013184757A1 (en) * 2012-06-06 2013-12-12 Irm Llc Compounds and compositions for modulating egfr activity

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001012186A1 (en) * 1999-08-13 2001-02-22 Biogen, Inc. Cell adhesion inhibitors
WO2002068421A2 (en) * 2000-11-29 2002-09-06 Cell Therapeutics, Inc. Tricyclic compounds and their analogs as inhibitors of cytokine signaling
WO2013184757A1 (en) * 2012-06-06 2013-12-12 Irm Llc Compounds and compositions for modulating egfr activity

Also Published As

Publication number Publication date
CN109721605A (en) 2019-05-07
WO2019085441A1 (en) 2019-05-09

Similar Documents

Publication Publication Date Title
CN109721605B (en) Immune cell migration inhibitor
CN110016025B (en) Immunomodulator
EP3256468B1 (en) Tricyclic compounds and uses thereof in medicine
CN110582491B (en) Rho-related protein kinase inhibitor, pharmaceutical composition containing Rho-related protein kinase inhibitor, and preparation method and application of Rho-related protein kinase inhibitor
EP2485731B1 (en) Heterocyclic compounds useful as pdk1 inhibitors
CN111936475A (en) Immunomodulator, composition and preparation method thereof
WO2021218110A1 (en) Benzothiazolyl biaryl compound, and preparation method and use
CN110573501A (en) Rho-related protein kinase inhibitor, pharmaceutical composition containing same, and preparation method and application thereof
TW200817411A (en) Pyrimidine derivative as PI3 inhibitor and use thereof
EP0649425B1 (en) Pyridino-, pyrrolidino- and azepino-substituted oximes useful as anti-atherosclerosis and anti-hypercholesterolemic agents
WO2020156363A1 (en) Immunomodulator
JPH05504969A (en) Angiotensin 2 antagonists containing substituted benzyl elements
TW201014855A (en) Compounds for the treatment of hepatitis C
WO2020011246A1 (en) Benzene ring-containing compound, preparation method therefor and application thereof
WO2023274383A1 (en) Kras g12d inhibitor and use thereof
CN107207504B (en) Phthalazinone derivatives, preparation method and use thereof
WO2023061294A1 (en) Nitrogen-containing heterocyclic derivative regulator, preparation method therefor and application thereof
IL311024A (en) Substituted tricyclic compounds as parp inhibitors and use thereof
WO2022213975A1 (en) Compounds targeting y220c mutant of p53
CN111440161B (en) Bicyclic heteroaryl compound with PAR4 antagonistic activity and application thereof
CN106478634A (en) Condensed imidazole compound, its preparation method, pharmaceutical composition and purposes
CN102844318B (en) Be used for the treatment of the compound of respiratory syncytial virus infection
JP2022551299A (en) COMPOUND HAVING BRD4 INHIBITORY ACTIVITY, PREPARATION AND USE THEREOF
JP3537446B2 (en) Tricyclic benzazepine compounds
CN112969694A (en) Rho-related protein kinase inhibitor, pharmaceutical composition containing same and application thereof

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
GR01 Patent grant
GR01 Patent grant
CP03 Change of name, title or address
CP03 Change of name, title or address

Address after: 325006, Room 4020, Building B, Gene Medicine Valley North District, Ouhai District, Wenzhou City, Zhejiang Province

Patentee after: Weimu Biotechnology (Zhejiang) Co.,Ltd.

Address before: 201203 rooms 207 and 209, building 5, No. 334 Edison Road, China (Shanghai) pilot Free Trade Zone, Pudong New Area, Shanghai

Patentee before: VIVAVISION BIOPHARMA (SHANGHAI) Co.,Ltd.