CN111471056B - Macrocyclic immunomodulator - Google Patents

Macrocyclic immunomodulator Download PDF

Info

Publication number
CN111471056B
CN111471056B CN202010066537.3A CN202010066537A CN111471056B CN 111471056 B CN111471056 B CN 111471056B CN 202010066537 A CN202010066537 A CN 202010066537A CN 111471056 B CN111471056 B CN 111471056B
Authority
CN
China
Prior art keywords
alkyl
substituted
hydrogen
halogen
compound
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
CN202010066537.3A
Other languages
Chinese (zh)
Other versions
CN111471056A (en
Inventor
李进
张登友
潘飞
马荣
朱文吉
吕开智
陈欣
张毅
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.)
Hitgen Inc
Original Assignee
Hitgen Inc
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 Hitgen Inc filed Critical Hitgen Inc
Publication of CN111471056A publication Critical patent/CN111471056A/en
Application granted granted Critical
Publication of CN111471056B publication Critical patent/CN111471056B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/06—Peri-condensed systems
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D515/06—Peri-condensed systems

Abstract

The invention provides a macrocyclic immunomodulator, and discloses a compound shown in a formula I, a tautomer, an enantiomer, or a pharmaceutically acceptable salt, a crystal form, a hydrate or a solvate thereof. Experimental results show that the compound can be effectively combined with STING and has a good STING protein agonistic function. Thus, the compounds of the present invention are useful as STING agonists and for the treatment of various related disorders. The compound provided by the invention has a very good application prospect in preparing medicines for treating diseases related to STING activity, particularly medicines for treating inflammatory diseases, autoimmune diseases, infectious diseases, cancers or precancerous syndromes.

Description

Macrocyclic immunomodulator
Technical Field
The invention belongs to the field of medicines, and relates to a macrocyclic immunomodulator.
Background
The immune system of the human body can be generally divided into the "innate" and "adaptive" systems. The natural immune system plays an important role in resisting infection, inhibiting tumor growth and the pathogenesis of autoimmune diseases, mainly recognizes pathogenic microorganisms and cancer cell components through a pattern recognition receptor, starts a downstream signal path, finally kills the pathogenic microorganisms and the cancer cell components by inducing cytokine expression, adapts to the immune system and promotes the generation of antibodies and specific T lymphocytes.
STING (interferon gene stimulating factor, TMEM173, MITA, etc.) is a key node molecule in response to DNA invasion in the cell, and under the stimulation of cytoplasmic DNA, it recognizes signals of cytoplasmic DNA receptors, playing a key role in inducing the process of interferon production. After recognition of foreign or endogenous "non-self" DNA by the host cell's DNA recognition receptor, a signal is transmitted to the node molecule STING, which then rapidly dimerizes and translocates from the endoplasmic reticulum to the nucleosome pericytes. Activation of STING results in upregulation of IRF3 and NK κ B pathways, leading to induction of interferon- β and other cytokines.
Compounds that induce human interferon may be useful in the treatment of a variety of conditions including allergic and other inflammatory conditions, allergic rhinitis and asthma, infectious diseases, neurodegenerative diseases, pre-cancerous syndromes and cancer, and may also be useful as immunological compositions or vaccine adjuvants. Therefore, activation of STING is a potential method for treating diseases associated with the type 1 IFN pathway, including inflammatory, allergic and autoimmune diseases, infectious diseases, cancer, pre-cancerous syndromes.
Disclosure of Invention
The invention provides a compound shown as a formula I or a tautomer, an enantiomer, or a pharmaceutically acceptable salt, a crystal form, a hydrate or a solvate thereof:
Figure BDA0002376124010000011
wherein the content of the first and second substances,
R1、R2are respectively and independently selected from hydrogen and C1～C6Alkyl groups of (a);
R3selected from hydrogen, C1～C6Alkyl, halogen of (a);
R4selected from hydrogen, C1～C6Alkyl, halogen or none of (a);
R5selected from hydrogen, C1～C6Alkyl groups of (a);
X2selected from C or N;
ring B is selected from the group consisting of 0 to 4RaSubstituted benzene ring, substituted by 0-4RaA substituted 5-to 6-membered aromatic heterocycle;
Raselected from halogen, hydroxyl, amino, and a group consisting of 0 to 4RbOptionally substituted C1～C6An alkyl group;
Rbselected from halogen, hydroxy, amino, C1～C6An alkoxy group;
x is selected from-O-, -S (O)n-or none; n is 1 or 2;
L1、L2are respectively and independently selected from 0 to 4RiSubstituted C1～C10Alkylene of (a) with 0 to 4RiSubstituted C2～C10Wherein when R isiAt least 2 times, L1、L2R in (1)iCan be connected to form a 3-10 membered ring;
Riis selected from-ORjHalogen, -CN, C1～C6An alkyl group;
Rjselected from hydrogen, C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
z is selected from-O-, -C (O) -,
Figure BDA0002376124010000021
Rc、Rdare respectively and independently selected from hydrogen and C1～C6Alkyl, halogen substituted C1～C6Alkyl, -C (O) RkOr none, or RcAnd RdAre linked to the nitrogen atom to which they are attached to form a group consisting of 0 to 4ReOptionally substituted 3-to 8-membered heterocycloalkane substituted with 0 to 4ReAn optionally substituted 3-to 10-membered heteroaromatic ring;
Rkselected from the group consisting of 0 to 4RmSubstituted 5-to 6-membered cycloalkyl, substituted with 0 to 4RmA substituted 5-to 6-membered heterocycloalkyl group; rmIs selected from C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
Rg、Rhindependently selected from-C (O) -, -C (O) O-, or none;
Reis selected from-ORf-、C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
Rfselected from hydrogen, C1～C6Alkyl, halogen substituted C1～C6An alkyl group.
Further, the compounds are represented by formula I:
Figure BDA0002376124010000022
wherein the content of the first and second substances,
R1、R2are respectively and independently selected from hydrogen and C1～C6Alkyl groups of (a);
R3selected from hydrogen, C1～C6Alkyl, halogen of (a);
R4selected from hydrogen, C1～C6Alkyl, halogen or none of (a);
R5selected from hydrogen, C1～C6Alkyl groups of (a);
X2selected from C or N;
ring B is selected from the group consisting of 0 to 4RaSubstituted benzene ring, substituted by 0-4RaA substituted 5-to 6-membered aromatic heterocycle;
Raselected from the group consisting of 0 to 4RbOptionally substituted C1～C6An alkyl group;
Rbselected from halogen, hydroxy, amino, C1～C6An alkoxy group;
x is selected from-O-, -S-or none;
L1、L2are respectively and independently selected from 0 to 4RiSubstituted C1～C10Wherein when R isiAt least 2 times, L1、L2R in (1)iCan be connected to form a 3-10 membered ring;
Riis selected from-ORjHalogen, -CN, C1～C6An alkyl group;
Rjselected from hydrogen, C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
z is selected from-O-, -C (O) -,
Figure BDA0002376124010000031
Rc、Rdare respectively and independently selected from hydrogen and C1～C6Alkyl, halogen substituted C1～C6Alkyl or not, or RcAnd RdAre linked to the nitrogen atom to which they are attached to form a group consisting of 0 to 4ReOptionally substituted 3-to 8-membered heterocycloalkane substituted with 0 to 4ReAn optionally substituted 3-to 10-membered heteroaromatic ring;
Rg、Rhindependently selected from-C (O) -, -C (O) O-, or none;
Reis selected from-ORf-、C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
Rfselected from hydrogen, C1～C6Alkyl, halogen substituted C1～C6An alkyl group.
Further, the compound is represented by formula II:
Figure BDA0002376124010000032
ring B is selected from
Figure BDA0002376124010000033
R6、R7、R8Are independently selected from hydrogen and 0-4RbOptionally substituted C1～C6An alkyl group;
Rbselected from halogen, hydroxy, amino, C1～C6An alkoxy group;
R1、R2are respectively and independently selected from hydrogen and C1～C6Alkyl groups of (a);
R3、R4are respectively and independently selected from hydrogen and C1～C6Alkyl, halogen of (a);
R5selected from hydrogen, C1～6Alkyl groups of (a);
L1、L2are respectively and independently selected from 0 to 4RiSubstituted C1～C10Wherein when R isiAt least 2 times, L1、L2R in (1)iCan be connected to form a 3-10 membered ring;
Riis selected from-ORjHalogen, -CN, C1～C6An alkyl group;
Rjselected from hydrogen, C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
z is selected from the group consisting of-O-, -C (O) NR-, -NR-, (I),
Figure BDA0002376124010000034
R is selected from hydrogen and C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
Rc、Rdare respectively and independently selected from hydrogen and C1～C6Alkyl or not, or RcAnd RdAre linked to the nitrogen atom to which they are attached to form a group consisting of 0 to 4ReOptionally substituted 3-to 8-membered heterocycloalkane substituted with 0 to 4ReAn optionally substituted 3-to 10-membered heteroaromatic ring;
Reis selected from-ORf-、C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
Rfselected from hydrogen, C1～C6Alkyl, halogen substituted C1～C6An alkyl group.
Further, Z is-O-.
Further, the compound represented by the formula II is:
Figure BDA0002376124010000041
further, the compound is represented by formula III:
Figure BDA0002376124010000051
R1、R2are respectively and independently selected from hydrogen and C1～C6Alkyl groups of (a);
R3、R4are respectively and independently selected from hydrogen and C1～C6Alkyl, halogen of (a);
R5selected from hydrogen, C1～6Alkyl groups of (a);
ring B is selected from
Figure BDA0002376124010000052
R6、R7、R8Are independently selected from hydrogen and 0-4RbOptionally substituted C1～C6An alkyl group;
Rbselected from halogen, hydroxy, amino, C1～C6An alkoxy group;
Rc、Rdare respectively and independently selected from hydrogen and C1～C6Alkyl or not, or RcAnd RdAre linked to the nitrogen atom to which they are attached to form a group consisting of 0 to 4ReOptionally substituted
Figure BDA0002376124010000053
Is coated with 0 to 4ReOptionally substituted
Figure BDA0002376124010000054
Is coated with 0 to 4ReOptionally substituted
Figure BDA0002376124010000055
Rg、RhIndependently selected from-C (O) -, -C (O) O-, or none;
L1、L2are respectively and independently selected from 0 to 4RiSubstituted C1～C10Wherein when R isiAt least 2 times, L1、L2R in (1)iCan be connected to form a 3-10 membered ring;
Riis selected from-ORjHalogen, -CN, C1～C6An alkyl group;
Rjselected from hydrogen, C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
Reis selected from-ORf-、C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
Rfselected from hydrogen, C1～C6Alkyl, halogen substituted C1～C6An alkyl group.
Further, the compound represented by the formula III is:
Figure BDA0002376124010000056
further, the compound is represented by formula IV:
Figure BDA0002376124010000061
ring B is selected from
Figure BDA0002376124010000062
R6、R7、R8Are independently selected from hydrogen and 0-4RbOptionally substituted C1～C6An alkyl group;
Rbselected from halogen, hydroxy, amino, C1～C6An alkoxy group;
R1、R2are respectively and independently selected from hydrogen and C1～C6Alkyl groups of (a);
R3、R4are respectively and independently selected from hydrogen and C1～C6Alkyl, halogen of (a);
R5selected from hydrogen, C1～C6Alkyl groups of (a);
L1、L2are respectively and independently selected from 0 to 4RiSubstituted C1～C10Wherein when R isiAt least 2 times, L1、L2R in (1)iCan be connected to form a 3-10 membered ring;
Riis selected from-ORjHalogen, -CN, C1～C6An alkyl group;
Rjselected from hydrogen, C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
z is selected from the group consisting of-O-, -C (O) NR-, -NR-, (I),
Figure BDA0002376124010000063
R is selected from hydrogen and C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
Rc、Rdare respectively and independently selected from hydrogen and C1～C6Alkyl or not, or RcAnd RdAre linked to the nitrogen atom to which they are attached to form a group consisting of 0 to 4ReOptionally substituted 3-to 8-membered heterocycloalkane substituted with 0 to 4ReAn optionally substituted 3-to 10-membered heteroaromatic ring;
Reis selected from-ORf-、C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
Rfselected from hydrogen, C1～C6Alkyl, halogen substituted C1～C6An alkyl group.
Further, the compound is represented by formula V:
Figure BDA0002376124010000064
ring B is selected from
Figure BDA0002376124010000065
R6、R7、R8Are independently selected from hydrogen and 0-4RbOptionally substituted C1～C6An alkyl group;
Rbselected from halogen, hydroxy, amino, C1～C6An alkoxy group;
R1、R2are respectively and independently selected from hydrogen and C1～C6Alkyl groups of (a);
R3、R4are respectively and independently selected from hydrogen and C1～C6Alkyl, halogen of (a);
R5selected from hydrogen, C1～C6Alkyl groups of (a);
L1、L2are respectively and independently selected from 0 to 4RiSubstituted C1～C10Wherein when R isiAt least 2 times, L1、L2R in (1)iCan be connected to form a 3-10 membered ring;
Riis selected from-ORjHalogen, -CN, C1～C6An alkyl group;
Rjselected from hydrogen, C1～C6Alkyl, halogen substituted C1～C6An alkyl group.
Further, the compound represented by the formula V is:
Figure BDA0002376124010000071
further, the compound is represented by formula VI:
Figure BDA0002376124010000072
wherein the content of the first and second substances,
ring B is selected from the group consisting of 0 to 3RaA substituted 5-membered nitrogen-containing aromatic heterocycle;
Raselected from halogen, hydroxyl, amino, and 0-3RbOptionally substituted C1～C6An alkyl group;
Rbselected from halogen, hydroxyl;
R1、R2are respectively and independently selected from hydrogen and C1～C6Alkyl groups of (a);
R3、R4are respectively and independently selected from hydrogen and C1～C6Alkyl, halogen of (a);
R5selected from hydrogen, C1～C6Alkyl groups of (a);
L1、L2are respectively and independently selected from 0 to 4RiSubstituted C1～C6Alkylene of (a) with 0 to 4RiSubstituted C2～C6The alkenylene group of (a) is,
Riselected from halogen, -CN, C1～C6An alkyl group;
x is selected from-O-, -S (O)n-or none, n is 1 or 2;
z is selected from-O-, -C (O) -,
Figure BDA0002376124010000073
Rc、Rdare respectively and independently selected from hydrogen and C1～C6Alkyl, halogen substituted C1～C6Alkyl, -C (O) RkOr none; rkSelected from the group consisting of 0 to 4RmSubstituted 5-to 6-membered cycloalkyl, substituted with 0 to 4RmA substituted 5-to 6-membered heterocycloalkyl group; rmIs selected from C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
Rg、Rhindependently selected from-C (O) -, -C (O) O-, or none.
Further, it is characterized in that:
ring B is selected from
Figure BDA0002376124010000081
R6、R7、R8Are respectively and independently selected from hydrogen, halogen, hydroxyl, amino and 0-3RbOptionally substituted C1～C2An alkyl group;
Rbselected from halogen, hydroxyl;
R1、R2are respectively and independently selected from hydrogen and C1～C3Alkyl groups of (a);
R3、R4are respectively and independently selected from hydrogen and C1～C3Alkyl, halogen of (a);
R5selected from hydrogen, C1～C3Alkyl groups of (a);
L1、L2are respectively and independently selected from 0 to 2RiSubstituted C1～C3Alkylene of (a) with 0 to 2RiSubstituted C2～C3The alkenylene group of (a) is,
Riselected from halogen, -CN, C1～C3An alkyl group;
x is selected from-O-, -S (O)n-or none, n is 1 or 2;
z is selected from-O-, -C (O) -,
Figure BDA0002376124010000082
preferably, Z is-O-;
Rc、Rdare respectively and independently selected from hydrogen and C1～C3Alkyl, halogen substituted C1～C3Alkyl, -C (O) RkOr none; rkSelected from the group consisting of 0 to 2RmA substituted 5-to 6-membered cycloalkyl group substituted with 0 to 2RmA substituted piperidine ring; rmIs selected from C1～C3Alkyl, halogen substituted C1～C3An alkyl group;
Rg、Rhindependently selected from-C (O) -, -C (O) O-, or none.
Further, the compound is:
Figure BDA0002376124010000083
Figure BDA0002376124010000091
in some embodiments of the inventionIn embodiments, for compounds of formula I, ring B is preferably substituted with 0-4RaSubstituted 5-membered nitrogen-containing aromatic heterocycles, RaSelected from halogen, C substituted by 0-4 halogen1～C6Alkyl radical, L1Is selected from C2～C6Alkylene of (C)2～C6Alkenylene of (A), L2Is selected from C2～C6Z is selected from-O-, -C (O) -, -NHC (O) O-, -NRc-、-C(O)NH-，RcSelected from hydrogen, C1～C6Alkyl, halogen substituted C1～C6Alkyl, -C (O) Rk，RkSelected from the group consisting of 0 to 2RmA substituted 5-to 6-membered cycloalkyl group substituted with 0 to 2RmSubstituted 5-to 6-membered heterocycloalkyl, RmIs selected from C1～C6Alkyl, halogen substituted C1～C6An alkyl group.
In some embodiments of the invention, for compounds of formula I, ring B is more preferably substituted with 0-3RaSubstituted pyrrole, substituted by 0-3RaSubstituted pyrazoles, substituted pyrazoles with 0 to 3RaSubstituted imidazole, substituted with 0-3RaSubstituted thiazoles, substituted with 0-3RaSubstituted isothiazole, substituted isothiazolaSubstituted oxazole substituted with 0 to 3RaSubstituted isoxazoles, RaSelected from halogen, C substituted by 0-3 halogen1～C6An alkyl group.
The invention also provides application of the compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof in preparing a drug for activating STING.
The invention also provides the application of the compound, or the stereoisomer thereof, or the pharmaceutically acceptable salt thereof, or the solvate thereof, or the prodrug thereof, or the metabolite thereof in preparing a medicament for treating diseases related to the STING activity.
Further, the disease related to STING activity is one or more of diseases related to inflammatory diseases, autoimmune diseases, infectious diseases, cancer, and precancerous syndrome.
The invention also provides application of the compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof in preparing a medicament for treating inflammatory diseases, autoimmune diseases, infectious diseases, cancers or precancerous syndromes.
The invention also provides the application of the compound, or the stereoisomer thereof, or the pharmaceutically acceptable salt thereof, or the solvate thereof, or the prodrug thereof, or the metabolite thereof in preparing an immunologic adjuvant.
The invention also provides a medicament which is a preparation prepared from the compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof and pharmaceutically acceptable auxiliary materials.
Experimental results show that the compound can be effectively combined with STING and has a good STING protein agonistic function. Thus, the compounds of the present invention are useful as STING agonists and for the treatment of various related disorders. The compound provided by the invention has a very good application prospect in preparing medicines for treating diseases related to STING activity, particularly medicines for treating inflammatory diseases, autoimmune diseases, infectious diseases, cancers or precancerous syndromes.
A disease associated with STING activity as defined herein is a disease in which STING plays an important role in the pathogenesis of the disease.
Diseases associated with STING activity include inflammatory, allergic and autoimmune diseases, infectious diseases, cancer, precancerous syndromes.
"cancer" or "malignancy" refers to any of a variety of diseases characterized by uncontrolled abnormal proliferation of cells, the body's ability of affected cells to spread to other sites either locally or through the bloodstream and lymphatic system (i.e., metastasis), and any of a number of characteristic structural and/or molecular features. "cancer cells" refers to cells that undergo multiple stages of early, intermediate or late stage tumor progression. The cancer includes sarcoma, breast cancer, lung cancer, brain cancer, bone cancer, liver cancer, kidney cancer, colon cancer and prostate cancer. In some embodiments, the compound of formula I is used to treat a cancer selected from the group consisting of colon cancer, brain cancer, breast cancer, fibrosarcoma, and squamous cell carcinoma. In some embodiments, the cancer is selected from melanoma, breast cancer, colon cancer, lung cancer, and ovarian cancer. In some embodiments, the cancer treated is a metastatic cancer.
Inflammatory diseases include a variety of conditions characterized by pathological inflammation of tissue. Examples of inflammatory diseases include acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, vasculitis, house dust mite-induced airway inflammation, and interstitial cystitis. There is a significant overlap between inflammatory and autoimmune diseases. Some embodiments of the invention relate to the treatment of the inflammatory disease asthma. The immune system is usually involved in inflammatory diseases, manifested in allergic reactions and in some myopathies, many of which cause abnormal inflammation.
The compounds and derivatives provided in the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, OH) naming system.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
The minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, e.g. prefix Ca～CbAlkyl of (a) indicates any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C1～C6The alkyl group of (A) is an alkyl group having 1to 6 carbon atoms.
"alkyl" in the context of the present invention means having the indicated numberA saturated hydrocarbon chain of the member atom(s). E.g. C1～C6Alkyl refers to alkyl groups having 1to 6 carbon atoms. The alkyl group may be linear or branched. Representative branched alkyl groups have one, two, or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. The alkyl group may also be part of another group, such as C1～C6An alkoxy group.
In the invention Ca～CbThe alkoxy group means a group in which an alkyl group having "a" to "b" carbon atoms is bonded to a corresponding oxygen atom.
"C" in the invention1～C10The "alkylene group" of (a) means a divalent saturated aliphatic hydrocarbon group having 1to 10 carbon atoms. Alkylene groups include branched and straight chain hydrocarbyl groups. For example, "(C)1～C6) Alkylene "is intended to include methylene, ethylene, propylene, 2-methylpropylene, dimethylethylene, pentylene, and the like. Thus, the term "propylene" can be exemplified by the following structure:
Figure BDA0002376124010000111
likewise, the term "dimethylbutylene" can be exemplified, for example, by any of the following structures:
Figure BDA0002376124010000112
furthermore, the term "(C)1～C6) Alkylene "is intended to include such branched alkyl groups such as cyclopropylmethylene, which may be exemplified by the following structures:
Figure BDA0002376124010000113
likewise, "C2～C10The "alkenylene group" of (a) means an aliphatic hydrocarbon group having 2 to 10 carbon atoms and containing one or more carbon-carbon double bonds. Alkenylene radical packageIncluding branched and straight chain groups. The carbon-carbon double bonds in the alkenylene group include cis-double bonds and trans-double bonds.
"halogen" in the present invention means a halogen group: fluorine, chlorine, bromine or iodine.
The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and physiologically compatible with the recipient.
The terms "salt" and "pharmaceutically acceptable salt" refer to acid and/or base salts of the above compounds or stereoisomers thereof, with inorganic and/or organic acids and bases, as well as zwitterionic (inner) salts, and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound or a stereoisomer thereof may be obtained by appropriately (e.g., equivalently) mixing the above compound or a stereoisomer thereof with a predetermined amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization. The salt in the invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.
In certain embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compounds of the present invention may be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition for modulating cellular function or treating a disease. If a group of compounds is used, the compounds may be administered to the subject simultaneously, separately or sequentially.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the invention are known products, and can be obtained by purchasing commercial products.
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using (Bruker AvanceIII 400 and Bruker Avance 300) nuclear magnetic instrument in deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS).
LC-MS was measured using Shimadzu LC-MS 2020 (ESI).
HPLC was performed using Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A).
Reversed phase preparative chromatography Gilson GX-281 reversed phase preparative chromatography was used.
The thin layer chromatography silica gel plate is a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Known starting materials for the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Enduragi chemistry, Chengdulong chemistry, Shaoshi chemistry technology, and Bailingwei technology.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.
In the examples, the reaction was carried out under a nitrogen atmosphere without specific mention.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is room temperature, unless otherwise specified.
In the examples, M is mole per liter, unless otherwise specified.
The room temperature is the most suitable reaction temperature and is 20-30 ℃.
DCM: refers to methylene chloride.
DMF: refers to N, N-dimethylformamide.
DMSO, DMSO: refers to dimethyl sulfoxide.
DIPEA: refers to diisopropylethylamine.
HATU: is 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate.
Pd(dppf)Cl2: refers to [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride.
TFA: refers to trifluoroacetic acid.
NBS: refers to N-bromosuccinimide.
1. Synthesis of intermediate 4-chloro-3-hydroxy-5-nitrobenzamide:
Figure BDA0002376124010000121
step 1: synthesis of 4-chloro-3-methoxy-5-nitrobenzamide
Add a (18.5g, 75.3mmol) to a single neck flask containing aqueous ammonia (200mL) and stir at 60 ℃ for 3 h. The reaction was concentrated to 100mL, cooled and filtered, and the solid was washed with ice water and dried to give 4-chloro-3-methoxy-5-nitrobenzamide (12.5g, 54.1mmol) as a brown solid.
1H NMR(400MHz,DMSO-d6):δ(ppm)δ8.29(s,1H),8.04(d,1H),7.87(d,1H),7.78(s,1H),4.01(s,3H)。
MS(ESI)m/z＝231[M+H]+。
Step 2: synthesis of 4-chloro-3-hydroxy-5-nitrobenzamide
B (12.5g, 54.1mmol) was dispersed in dry DCM (150mL) under ice bath, and boron tribromide (200mL, 1M) was slowly added dropwise thereto. After the dropwise addition, the ice bath was removed, and the reaction was carried out overnight at room temperature under nitrogen protection. After the reaction was completed, the reaction solution was poured into ice water, vigorously stirred for 30min, filtered, and the filter cake was washed with water and dried to give 4-chloro-3-hydroxy-5-nitrobenzamide (10g, 46.2mmol, 85.3% yield) as a pale yellow solid.
1H NMR(400MHz,DMSO-d6):δ(ppm)11.73(s,1H),δ8.21(s,1H),7.92(s,1H),7.80(s,1H),7.66(s,1H)。
MS(ESI)m/z＝217[M+H]+。
2. Synthesizing an intermediate 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate:
Figure BDA0002376124010000131
step 1: synthesis of 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl chloride
1-Ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (4g, 25.9mmol) was dispersed in dry DCM (80mL) and oxalyl chloride (3.9g, 31.1mmol) and catalytic amount of DMF were added dropwise thereto under ice bath. After 1h at room temperature, the volatiles were removed by rotary evaporation under reduced pressure. DCM (20mL) was added to the crude product and the solvent removed by rotary evaporation to give 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl chloride (4.46g, 100% yield) which was used directly in the next reaction.
Step 2: synthesis of 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate
G (4.46g, 25.9mmol) was dissolved in dry acetone (20mL) at 0 ℃ and added dropwise to a solution of potassium thiocyanate (5g, 51.5mmol) in acetone (100mL), stirred at room temperature for 3H, the reaction was filtered to remove inorganic salts, and the crude filtrate after concentration was purified by silica gel column (eluent ethyl acetate/petroleum ether, v/v. 1/15) to give 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate H (4g, 20.4mmol, 78.7%) as a clear tan liquid.
MS(ESI)m/z＝196[M+H]+。
3. And (3) synthesizing an intermediate 4-ethyl-2-methylthiazole-5-carbonyl isothiocyanate:
Figure BDA0002376124010000132
step 1: synthesis of 4-ethyl-2-methylthiazole-5-formyl chloride
4-Ethyl-2-methylthiazole-5-carboxylic acid (2g, 11.7mmol) was dispersed in dry DCM (40ml) and oxalyl chloride (1.9g, 15.1mmol) and a catalytic amount of DMF were added dropwise thereto under ice bath. After 1h at room temperature, the volatiles were removed by rotary evaporation under reduced pressure. DCM (20ml) was added to the crude product and the solvent removed by rotary evaporation to give 4-ethyl-2-methylthiazole-5-carbonyl chloride (2.2g, 100% yield) which was used directly in the next reaction.
Step 2: synthesis of 4-ethyl-2-methylthiazole-5-carbonyl isothiocyanate
4-Ethyl-2-methylthiazole-5-carbonyl isothiocyanate (2.15g, 10.2mmol, 87% yield) was obtained by dissolving 4-ethyl-2-methylthiazole-5-carbonyl chloride (2.2g, 11.7mmol) in dry acetone (10mL) and adding dropwise to a solution of potassium thiocyanate (2.3g, 23.4mmol) in acetone (50mL) at 0 deg.C, stirring at room temperature for 3h, filtering the reaction system to remove inorganic salts, and purifying the crude filtrate after concentration by silica gel column (eluent ethyl acetate/petroleum ether, v/v ═ 1/15) to obtain 4-ethyl-2-methylthiazole-5-carbonyl isothiocyanate (2.15g, 10.2 mmol) as a clear brown-yellow liquid.
MS(ESI)m/z＝213[M+H]+。
4. Synthesis of intermediate 4-ethyl-2-methyloxazole-5-carbonyl isothiocyanate
Figure BDA0002376124010000141
Step 1: synthesis of methyl 2-chloro-3-oxopentanoate
Adding SO2Cl2(7.2g, 58mmol) was added dropwise to a solution of methyl 3-oxopentanoate (5g, 38mmol) in dichloromethane (100mL) while cooling on ice, the temperature was raised to room temperature and the mixture was stirred for 4 hours, the reaction mixture was washed with a saturated sodium carbonate solution, the separated organic phase was washed with a saturated sodium chloride solution, followed by drying over anhydrous sodium sulfate, and the filtrate obtained by filtration was dried by spin-drying to give the compound 2-chloro-3-oxoMethyl valerate (6g, 36.5mmol), colorless oil, was used directly in the next reaction.
MS(ESI)m/z＝166.0[M+H]+。
Step 2: synthesis of methyl 2-acetoxy-3-oxopentanoate
TEA (12.5mL) was added dropwise to a DMF (63mL) solution of acetic acid (12.5mL) while cooling on ice, and after warming to room temperature, methyl 2-chloro-3-oxopentanoate (6g, 36.5mmol) was added to the reaction mixture and stirred at room temperature overnight. TLC to monitor the reaction was complete, the reaction was poured into water, extracted with dichloromethane, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and the filtrate obtained by filtration was dried to give the compound methyl 2-acetoxy-3-oxopentanoate (3.0g, 15.9mmol) as a yellow oil which was used directly in the next reaction.
And step 3: synthesis of 4-ethyl-2-methyloxazole-5-carboxylic acid methyl ester
Methyl 2-acetoxy-3-oxopentanoate (3.0g, 15.9mmol) was dissolved in acetic acid (50mL), followed by addition of ammonium acetate (9.8g, 127.6 mmol). The mixture was warmed to 120 ℃ and stirred at this temperature for 4 hours. After the reaction solution was concentrated, it was diluted with water and extracted with ethyl acetate, and the separated organic phase was washed with water and saturated brine in this order, then dried over anhydrous sodium sulfate, the filtrate obtained by filtration was dried, and the crude product was purified by silica gel column separation (eluent: petroleum ether/ethyl acetate, 9/1) to obtain methyl 4-ethyl-2-methyloxazole-5-carboxylate (0.52g, 3.1 mmol).
MS(ESI)m/z＝170.1[M+H]+
1H NMR(400MHz,CDCl3):δ(ppm)3.89(s,3H),2.84(q,J＝7.6Hz,2H),2.50(s,3H),1.23(t,J＝7.6Hz,3H).
And 4, step 4: synthesis of 4-ethyl-2-methyloxazole-5-carboxylic acid
Methyl 4-ethyl-2-methyloxazole-5-carboxylate (323mg, 1.9mmol) was dissolved in THF/MeOH (10mL/5mL), and lithium hydroxide hydrate (160mg, 3.8mmol) was added and stirred at room temperature overnight. The reaction was diluted with water, extracted with ethyl acetate and the separated aqueous phase was adjusted to pH 2.0 with HCl (2M) and re-extracted with ethyl acetate. The organic phase obtained again was dried over anhydrous sodium sulfate, filtered and dried to give 4-ethyl-2-methyloxazole-5-carboxylic acid (220mg, 1.42mmol) as a white solid.
MS(ESI)m/z＝156.1[M+H]+。
And 5: synthesis of 4-ethyl-2-methyloxazole-5-carbonyl isothiocyanate
4-Ethyl-2-methyloxazole-5-carboxylic acid (220mg, 1.42mmol) was dispersed in dry THF (10mL) and oxalyl chloride (270mL, 2.13mmol) and a catalytic amount of DMF were added dropwise thereto under ice bath. After 30min of reaction at room temperature, the volatile matter was removed by rotary evaporation under reduced pressure. DCM (20mL) was added to the crude product, and the solvent was removed by rotary evaporation to give the crude yellow oil which was used directly in the next reaction.
The above yellow oil was dissolved in dry acetone (10mL) at 0 ℃ and added dropwise to a clear solution of potassium thiocyanate (276mg, 2.84mmol) in acetone (15mL) and stirred at room temperature for 3h, the reaction system was filtered to remove inorganic salts, washed with n-hexane, and the crude product after concentration of the filtrate was purified by silica gel column (eluent ethyl acetate/petroleum ether, v/v. RTM. 1/7) to give 4-ethyl-2-methyloxazole-5-carbonyl isothiocyanate (176mg, 63%) as a clear pale yellow liquid.
MS(ESI)m/z＝197.0[M+H]+
5. Synthesis of intermediate compound methyl 3-bromo-4-fluoro-5-nitrobenzoate
Figure BDA0002376124010000151
Step 1: synthesis of 3-bromo-4-fluoro-5-nitrobenzoic acid
4-fluoro-3-nitrobenzoic acid (50g, 270mmol) was dispersed in concentrated sulfuric acid (200ml) and NBS (47.5g, 270mmol) was added. The temperature was raised to 75 ℃ and stirred overnight. After cooling to room temperature, it was slowly poured into ice water and stirred, a pale yellow solid precipitated, and the solid was filtered off and dried to obtain the objective compound (66 g).
Step 2: synthesis of methyl 3-bromo-4-fluoro-5-nitrobenzoate
Thionyl chloride (44.5g, 373.5mmol) was added dropwise to a solution of 3-bromo-4-fluoro-5-nitrobenzoic acid (66g, 249mmol) in methanol (400ml) while cooling on ice. The temperature was raised to 75 ℃ and stirred overnight. Concentration to about 100ml of residual solvent continued precipitation of solid after cooling, filtration and drying of the solid to give methyl 3-bromo-4-fluoro-5-nitrobenzoate (56 g).
6. Synthesis of intermediate compound methyl 4-chloro-3-hydroxy-5-nitrobenzoate
Figure BDA0002376124010000152
Methyl 4-chloro-3-methoxy-5-nitrobenzoate (10g, 40.7mmol) was dispersed in anhydrous dichloromethane (100mL), boron tribromide (40.8g,162.8mmol) was slowly added dropwise in an ice bath, and after the addition was completed, the temperature was slowly raised to room temperature and the reaction was stirred overnight. After the reaction was complete, methanol was slowly added dropwise in an ice bath to quench, and then it was spin-dried. Methanol (100mL) and concentrated sulfuric acid (0.2mL) were added thereto, and the reaction mixture was heated to 75 ℃ and stirred overnight. After cooling, the mixture was concentrated under reduced pressure to remove the solvent, 150mL of water was added, the mixture was ultrasonically dispersed, filtered, the solid was washed with water again, and the solid was dried to give methyl 4-chloro-3-hydroxy-5-nitrobenzoate (8.89g, 38.4mmol, yield 94%).
Example 1
Figure BDA0002376124010000161
Step 1: synthesis of 3-bromo-4-fluoro-5-nitrobenzoic acid
4-fluoro-3-nitrobenzoic acid (18.7g, 101.02mmol) and NBS (17.98g, 101.02mmol) were added to concentrated sulfuric acid (40mL) at room temperature and the reaction stirred at 65 ℃ for 16 h. After completion of the reaction, water was added to precipitate a solid, which was filtered, and the filter cake was washed with water and dried to give 3-bromo-4-fluoro-5-nitrobenzoic acid (compound 1a) (19g, 71.97mmol) as a pale yellow solid in yield: 71 percent.
MS(ESI)m/z＝265[M+H]+。
Step 2 Synthesis of methyl 3-bromo-4-fluoro-5-nitrobenzoate
Thionyl chloride (8mL, 110mmol) was added dropwise to a solution of 3-bromo-4-fluoro-5-nitrobenzoic acid (19g, 71.97mmol) in methanol (150mL) while cooling on ice, and after addition, the reaction was allowed to warm to 70 ℃ and stirred for 16 h. After completion of the reaction, methanol was dried by spinning, the crude product was dissolved in ethyl acetate, washed with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered and then spun to give methyl 3-bromo-4-fluoro-5-nitrobenzoate (compound 1b) (18g, 64.74mmol) as a pale yellow solid, yield: 89 percent.
MS(ESI)m/z＝279[M+H]+。
And step 3: synthesis of methyl 3-bromo-4- ((3- ((tert-butoxycarbonyl) amino) propyl) amino) -5-nitrobenzoate
Methyl 3-bromo-4-fluoro-5-nitrobenzoate (1.25g, 7.19mmol) and tert-butyl- (3-aminopropyl) carbamate (2g, 7.19mmol) were added to DMF (20mL) at room temperature, followed by the addition of DIPEA (2.8g, 21.57mmol), and the mixture was stirred at room temperature for 0.5 h. After completion of the reaction, ethyl acetate was added for extraction (50mL × 3), the organic phases were combined and washed with water and saturated brine, respectively, and the solvent was dried by spinning to give methyl 3-bromo-4- ((3- ((tert-butoxycarbonyl) amino) propyl) amino) -5-nitrobenzoate (compound 1c) (2.55g, 5.92mmol) as a yellow solid in 82% yield.
MS(ESI)m/z＝433[M+H]+。
And 4, step 4: (E) synthesis of (E) -3- (3- (tert-butoxy) -3-oxoprop-1-en-1-yl) -4- ((3- ((tert-butoxycarbonyl) amino) propyl) amino) -5-methylester nitrobenzene
Compound 1c (500mg, 1.16mmol), tert-butyl acrylate (180mg, 1.4mmol) and potassium carbonate (320mg, 2.31mmol) were added to toluene (5mL) at room temperature, the air was replaced with nitrogen, and Pd (dppf) Cl was added2(85mg, 0.116mmol), purged with nitrogen, warmed to 100 ℃ and stirred for reaction for 16 h. After completion of the reaction, it was cooled to room temperature, extracted with ethyl acetate (20mL × 3) by adding water, the organic phases were combined and washed with water and saturated brine, respectively, the solvent was dried by spinning, and purified by silica gel column (eluent: ethyl acetate/petroleum ether, v/v ═ 1/15) to give (E) -3- (3- (tert-butoxy) -3-oxoprop-1-en-1-yl) -4- ((3- ((tert-butoxycarbonyl) amino) propyl) amino) -5-methylester nitrobenzene (compound 1d) (400mg, 0.834mmol), light yellow solid, yield: 72 percent.
MS(ESI)m/z＝480[M+H]+。
And 5: synthesis of methyl 3-amino-5- (3- (tert-butoxy) -3-oxopropyl) -4- ((3- ((tert-butoxycarbonyl) amino) propyl) amino) benzoate
To a solution of compound 1d (200mg, 0.417mmol) in methanol and ethyl acetate was added 10% palladium on carbon (20mg), which was reduced by hydrogenation for 3h, the palladium on carbon was removed by filtration, and the filtrate was concentrated to give methyl 3-amino-5- (3- (tert-butoxy) -3-oxopropyl) -4- ((3- ((tert-butoxycarbonyl) amino) propyl) amino) benzoate (compound 1e) (184mg, 0.407mmol), which was used directly in the next reaction.
MS(ESI)m/z＝452[M+H]+。
Step 6: synthesis of methyl 7- (3- (tert-butoxy) -3-oxopropyl) -1- (3- ((tert-butoxycarbonyl) amino) propyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-methyl) carboxamido) -1H-benzo [ d ] imidazole-5-carboxylate
Compound 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (80mg, 0.41mmol) was added dropwise to a solution of compound 1e (180mg, 0.399mmol) in DMF (3mL) while cooling on ice, and reacted for 0.5H. HATU (160mg, 0.421mmol) and N, N-diisopropylethylamine (110mg,0.851mmol) were then added to the reaction mixture and stirred at room temperature for an additional 3H, and the reaction mixture was separated by reverse phase MPLC (eluent acetonitrile/water-1/2, v/v) to give methyl 7- (3- (tert-butoxy) -3-oxopropyl) -1- (3- ((tert-butoxycarbonyl) amino) propyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-methyl) carboxamido) -1H-benzo [ d ] imidazole-5-carboxylate (compound 1f) (240mg, 0.391mmol) as a white solid in 96% yield.
MS(ESI)m/z＝613[M+H]+。
And 7: synthesis of 3- (1- (3-aminopropyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -5- (methoxycarbonyl) -1H-benzo [ d ] imidazol-7-yl) propionic acid
TFA (1mL) was added to 1f (230mg, 0.375mmol) of DCM (2mL) while cooling on ice and reacted at rt for 1H, after completion of the reaction and spin-dried to give crude 3- (1- (3-aminopropyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -5- (methoxycarbonyl) -1H-benzo [ d ] imidazol-7-yl) propionic acid (compound 1g) (300mg) which was used directly in the next step.
MS(ESI)m/z＝457[M+H]+。
And 8: synthesis of methyl 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -8-oxo-7, 8,9,10,11, 12-hexahydro-6H-2, 9,12 a-triazacycloheptane [ cd ] ] indene-4-carboxylate
HATU (170mg,0.372mmol) and DIPEA (145mg, 1.12mmol) were added to a solution of 1g (170mg,0.372mmol) of DMF (2mL) and DCM (4mL) under ice-bath and stirred for 0.5H, after completion of the reaction, water was added and extracted with ethyl acetate (10mLx3), the combined organic phases were washed with water and saturated brine respectively, and the solvent was dried by spinning to give methyl 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -8-oxo-7, 8,9,10,11, 12-hexahydro-6H-2, 9,12 a-triazacycloheptane [ cd ] indene-4-carboxylate (Compound 1H) (110mg, 0.25mmol), a white solid in 67% yield.
MS(ESI)m/z＝439[M+H]+。
And step 9: synthesis of 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -8-oxo-7, 8,9,10,11, 12-hexahydro-6H-2, 9,12 a-triazacyclodecane benzo [ cd ] indene-4-carboxylic acid
Compound 1h (100mg, 0.228mmol) was dissolved in a mixed solvent of tetrahydrofuran (2mL) and methanol (1mL), and a solution of lithium hydroxide (50mg, 1.14mmol) in water (2mL) was added. The reaction solution was stirred at room temperature for 2 h. The spin-dried organic solvent was diluted with water, extracted once with ethyl acetate, the aqueous phase acidified to pH ≈ 4 with dilute hydrochloric acid (1M), extracted with ethyl acetate (10mL × 3), the combined organic phases washed with water and saturated brine, respectively, and the spin-dried solvent gave 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -8-oxo-7, 8,9,10,11, 12-hexahydro-6H-2, 9,12 a-triazacyclodecane benzo [ cd ] indene-4-carboxylic acid (compound 1i) (74mg,0.174mmol), white solid, yield 76.3%.
MS(ESI)m/z＝425[M+H]+。
Step 10: synthesis of 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -8-oxo-7, 8,9,10,11, 12-hexahydro-6H-2, 9,12 a-triazacyclodecane benzo [ cd ] indene-4-carboxamide
HATU (73mg,0.192mmol) was added to a solution of compound 1i (70mg,0.165mmol) in DMF (2mL) while cooling on ice. After 15min, DIPEA (65mg,0.5mmol) and ammonium chloride (30mg, 0.56mmol) were added. The reaction was carried out for 1h and the reaction was separated using reverse phase MPLC (eluent acetonitrile/water 1/1, v/v) to give compound 1(10.69mg) as a white solid in 14% yield.
MS(ESI)m/z＝424[M+H]+。
1H NMR(400MHz，DMSO-d6):δ(ppm)1.35(t,J＝7.2Hz,3H)1.91～2.09(m,2H)2.18(s,3H)2.76～2.87(m,2H)2.98～3.11(m,2H)4.56～4.65(m,4H)6.63(s,1H)7.31(s,1H)7.60(s,1H)7.87(s,2H)7.91(s,1H)
Example 2
Figure BDA0002376124010000191
Step 1: synthesis of tert-butyl (3- (3- (benzyloxy) propoxy) propyl) carbamate
Sodium hydride (550mg, 13.7mmol) was added to a mixed solvent of tert-butyl (3-hydroxypropyl) carbamate (2g, 11.42mmol) in DMF (8mL) and tetrahydrofuran (16mL) under ice bath. After stirring for 30 minutes, 3-benzyloxybromopropane (3.66g, 15.989mmol) was added and the reaction was allowed to warm to room temperature for 10 h. After completion of the reaction, water was added, ethyl acetate was extracted (50mL × 3), the organic phases were combined and the solvent was dried by evaporation, and the crude product was separated by column chromatography (eluent: ethyl acetate/petroleum ether 1/10, v/v) to give tert-butyl (3- (3- (benzyloxy) propoxy) propyl) carbamate (compound 2a) (1.23g, 3.8mmol) as a colorless oil in 33% yield.
MS(ESI)m/z＝324[M+H]+。
Step 2: synthesis of tert-butyl (3- (3-hydroxypropoxy) propyl) carbamate
Palladium on carbon (10%, 80mg) was added to a solution of compound 2a (800mg, 2.47mmol) in methanol and ethyl acetate, and the mixture was reduced by hydrogenation for 3 hours, and then the palladium on carbon was removed by filtration, and the filtrate was concentrated to give tert-butyl (3- (3-hydroxypropoxy) propyl) carbamate (compound 2b) (519mg, 2.227mmol) in 90% yield. Directly used for the next reaction.
MS(ESI)m/z＝234[M+H]+。
And step 3: synthesis of tert-butyl (3- (3- (5-carbamoyl-2-chloro-3-nitrophenoxy) propoxy) propyl) carbamate
Compound 2b (510mg, 2.19mmol) and 4-chloro-3-hydroxy-5-nitrobenzamide (500mg, 2.3mmol) were dissolved in dry tetrahydrofuran (20mL) at room temperature, air was replaced with nitrogen and triphenylphosphine (907mg, 3.45mmol) and diisopropyl azodicarboxylate (700mg, 3.45mmol) were added, and the reaction was stirred for 10 h. After completion of the reaction, ethyl acetate was added to extract (20mL x3), the organic phases were combined and the solvent was dried and the crude product was separated by column chromatography (eluent ethyl acetate/petroleum ether 1/2, v/v) to give 3- (3- (5-carbamoyl-2-chloro-3-nitrophenoxy) propoxy) propyl) carbamic acid tert-butyl ester (compound 2c) (750mg, 1.736mmol) in 75% yield.
MS(ESI)m/z＝432[M+H]+。
And 4, step 4: synthesis of 3- (3- (3-aminopropoxy) propoxy) -4-chloro-5-nitrobenzamide
TFA (3mL) was added to Compound 2c (740mg, 1.716mmol) in DCM (6mL) and reacted at room temperature for 1h, after completion the reaction was spin-dried, the crude product was adjusted to pH ≈ 8 with a saturated solution of sodium bicarbonate, extracted with ethyl acetate (20mLx3), the combined organic phases washed with saturated brine, and after drying, spin-dried to give 3- (3- (3-aminopropoxy) propoxy) -4-chloro-5-nitrobenzamide (Compound 2d) (555mg, 1.68mmol) which was used directly in the next step.
MS(ESI)m/z＝332[M+H]+。
And 5: synthesis of 10-nitro-3, 4,6,7,8, 9-hexahydro-2H-benzo [ b ] [1,8,4] dioxoazacycloundecane-12-carboxamide
3- (3- (3-Aminopropoxy) propoxy) -4-chloro-5-nitrobenzamide (200mg, 0.604mmol) and potassium carbonate (100mg, 0.725mmol) were dissolved in DMF (120mL) at room temperature and the reaction was stirred at 90 ℃ for 20 h. After the reaction was completed, the solvent was spin-dried, and ethyl acetate (50mL) was dissolved, and then washed with water and saturated brine, respectively, and spin-dried to obtain 10-nitro-3, 4,6,7,8, 9-hexahydro-2H-benzo [ b ] [1,8,4] dioxocycloundecane-12-carboxamide (compound 2e) (177mg, 0.597mmol) in 99% yield, which was used directly in the next step.
MS(ESI)m/z＝296[M+H]+。
Step 6: synthesis of 10-amino-3, 4,6,7,8, 9-hexahydro-2H-benzo [ b ] [1,8,4] dioxoundecane-12-carboxamide
Palladium on carbon (10%, 20mg) was added to a solution of 2e (170mg, 0.574mmol) in methanol and ethyl acetate, and the mixture was reduced by hydrogenation for 3 hours, followed by filtration of the palladium on carbon, and concentration of the filtrate to give 10-amino-3, 4,6,7,8, 9-hexahydro-2H-benzo [ b ] [1,8,4] dioxoundecane-12-carboxamide (Compound 2f) (150mg, 0.566mmol) with a yield of 98%. Directly used for the next reaction.
MS(ESI)m/z＝266[M+H]+。
And 7: synthesis of 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7,8,9,11,12, 13-hexahydro-6, 10-dioxa 2,13 a-diazacycloundecane benzo [ cd ] indene-4-carboxamide
The compound 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (80mg, 0.41mmol) was added dropwise to a solution of the compound 2f (108mg, 0.407mmol) in DMF (3mL) while cooling on ice, and reacted for 0.5H. HATU (160mg, 0.421mmol) and N, N-diisopropylethylamine (105mg,0.814mmol) were then added to the reaction mixture, which was stirred at room temperature for 3h, and after completion of the reaction, was purified by reverse phase HPLC to give compound 2(8.7mg, yield 5%) as a white solid.
MS(ESI)m/z＝427[M+H]+。
1H NMR(400MHz，DMSO-d6):δ(ppm)1.35(t,J＝7.2Hz,3H)1.86～1.96(m,4H)2.17(s,3H)3.33～3.35(m,2H)3.61～3.75(m,2H)4.38～4.47(m,2H)4.47～4.55(m,2H)4.61(q,J1＝14Hz,J2＝7.2Hz,2H)6.64(s,1H)7.35(s,1H)7.45(s,1H)7.67(s,1H)7.98(s,1H)12.85(s,1H).
Example 3
Figure BDA0002376124010000211
The compound 1- (2-fluoroethyl) -3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (64mg, 0.3mmol) was added dropwise to a solution of compound 2f (80mg, 0.3mmol) in DMF (3mL) while cooling on ice, and reacted for 0.5H. HATU (114mg, 0.3mmol) and N, N-diisopropylethylamine (77mg,0.6mmol) were then added to the reaction mixture, which was stirred at room temperature for 3h, and after completion of the reaction, was purified by reverse phase HPLC to give compound 3(19.2mg, 14.4% yield).
MS(ESI)m/z＝445[M+H]+
1H NMR(400MHz,MeOD):δ(ppm)7.64-7.65(m,1H)，7.46(m,1H)，6.78(s,1H)，5.03-5.06(t,J＝5.2Hz,1H)，4.97-5.00(t,J＝5.2Hz,1H)，4.84-4.85(t,J＝5.2Hz,1H)，4.72-4.75(t,J＝5.2Hz,1H)，4.66(s,2H)，4.48(s,2H)，3.80(s,2H)，3.50-3.52(t,J＝3.6Hz,2H)，2.28(s,3H)，2.02-2.05(m,4H).
Example 4
Figure BDA0002376124010000212
The compound 1- (2-fluoroethyl) -3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (44mg, 0.226mmol) was added dropwise to a solution of compound 2f (60mg, 0.226mmol) in DMF (3mL) while cooling on ice, and reacted for 0.5H. HATU (86mg, 0.226mmol) and N, N-diisopropylethylamine (58mg,0.452mmol) were then added to the reaction mixture, which was stirred at room temperature for 3h, and after completion of the reaction, was purified by reverse phase HPLC to give compound 4(9.9mg, yield 10.3%).
MS(ESI)m/z＝428[M+H]+
1H NMR(400MHz,MeOD):δ(ppm)7.65(s,1H),7.47(s,1H),4.59-4.75(m,2H),4.42-4.55(m,2H),3.71-3.90(m,2H),3.50-3.51(m,2H),3.08-3.15(m,2H),2.52(s,3H),2.00-2.08(m,4H),1.28-1.32(m,3H).
Example 5
Figure BDA0002376124010000221
The compound 1- (2-fluoroethyl) -3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (64mg, 0.3mmol) was added dropwise to a solution of compound 2f (80mg, 0.3mmol) in DMF (3mL) while cooling on ice, and reacted for 0.5H. HATU (114mg, 0.3mmol) and N, N-diisopropylethylamine (77mg,0.6mmol) were then added to the reaction mixture, which was stirred at room temperature for 3h, and after completion of the reaction, was purified by reverse phase HPLC to give compound 5(55mg, yield 41.4%).
MS(ESI)m/z＝444[M+H]+
1H NMR(400MHz,DMSO-d6):δppm12.80(s,1H),7.98(s,1H),7.65(s,1H),7.35-7.45(m,2H),4.41-4.47(m,4H),3.67(s,2H),3.34-3.35(m,2H),3.17-3.23(m,2H),2.61(s,3H),1.90(m,4H),1.21-1.25(t,J＝7.6Hz,3H).
Example 6
Figure BDA0002376124010000222
The compound 3- (difluoromethyl) -1-ethyl-1H-pyrazole-5-carbonyl isothiocyanate (52mg, 0.226mmol) was added dropwise to a solution of compound 2f (60mg, 0.226mmol) in DMF (3mL) while cooling on ice, and reacted for 0.5H. HATU (86mg, 0.226mmol) and N, N-diisopropylethylamine (58mg,0.452mmol) were then added to the reaction mixture, which was stirred at room temperature for 3h, and after completion of the reaction, was purified by reverse phase HPLC to give compound 6(41mg, 39.4% yield).
MS(ESI)m/z＝463[M+H]+
1H NMR(400MHz,DMSO-d6):δ(ppm)12.93(s,1H),7.64-7.65(m,1H),7.46(m,1H),6.78(s,1H),5.76(s,1H),4.72-4.75(m,2H),4.42-4.45(m,4H),3.60-3.77(m,2H),3.34-3.38(m,2H),1.87-1.99(m,4H),1.39-1.43(t,J＝7.2Hz,3H).
Example 7
Figure BDA0002376124010000231
Step 1: synthesis of tert-butyl (3- (2- (benzyloxy) ethoxy) propyl) carbamate
Sodium hydride (550mg, 13.7mmol) was added to a mixed solvent of tert-butyl (3-hydroxypropyl) carbamate (2g, 11.42mmol) in DMF (8mL) and tetrahydrofuran (16mL) under ice bath. After stirring for 30 minutes, 3-benzyloxybromoethane (3.42g, 15.99mmol) was added and the reaction was allowed to warm to room temperature for 10 hours. After completion of the reaction, water was added, ethyl acetate was extracted (50mLx3), the organic phases were combined and the solvent was dried and the crude product was isolated by column chromatography (eluent: ethyl acetate/petroleum ether 1/10, v/v) to give tert-butyl 3- (2- (benzyloxy) ethoxy) propyl) carbamate 7a (1.23g, 3.98mmol) as a colourless oil in 34.9% yield.
MS(ESI)m/z＝310[M+H]+。
Step 2: synthesis of tert-butyl (3- (2-hydroxyethoxy) propyl) carbamate
To a solution of compound 7a (1.2g, 3.88mmol) in methanol and ethyl acetate was added 10% palladium on carbon (120mg), which was reduced by hydrogenation for 3 hours, the palladium on carbon was removed by filtration, and the filtrate was concentrated to give tert-butyl (3- (2-hydroxyethoxy) propyl) carbamate 7b (760mg, 3.49mmol) in 90% yield. Directly used for the next reaction.
MS(ESI)m/z＝220[M+H]+。
And step 3: synthesis of (tert-butyl (3- (2- (5-carbamoyl-2-chloro-3-nitrophenoxy) ethoxy) propyl) carbamate
Compound 7b (510mg, 2.19mmol) and 4-chloro-3-hydroxy-5-nitrobenzamide (500mg, 2.3mmol) were dissolved in dry tetrahydrofuran (20mL) at room temperature, air was replaced with nitrogen and triphenylphosphine (907mg, 3.45mmol) and diisopropyl azodicarboxylate (700mg, 3.45mmol) were added, and the reaction was stirred for 10 h. After completion of the reaction, extraction with ethyl acetate was added (20mL x3), the organic phases were combined and the solvent was dried and the crude product was separated by column chromatography (eluent ethyl acetate/petroleum ether 1/2, v/v) to give (tert-butyl (3- (2- (5-carbamoyl-2-chloro-3-nitrophenoxy) ethoxy) propyl) carbamate 7c (750mg, 1.736mmol) in 75% yield.
MS(ESI)m/z＝418[M+H]+。
And 4, step 4: synthesis of 3- (2- (3-aminopropoxy) ethoxy) -4-chloro-5-nitrobenzamide
TFA (3mL) was added to Compound 2c (740mg, 1.716mmol) in DCM (6mL) and reacted at room temperature for 1h, after completion the reaction was spin-dried, the crude product was adjusted to pH ≈ 8 with a saturated solution of sodium bicarbonate, extracted with ethyl acetate (20mLx3), the combined organic phases washed with saturated brine and after drying spin-dried to give 3- (2- (3-aminopropoxy) ethoxy) -4-chloro-5-nitrobenzamide 7d (555mg, 1.68mmol) which was used directly in the next step.
MS(ESI)m/z＝318[M+H]+。
And 5: synthesis of 9-nitro-2, 3,5,6,7, 8-hexahydrobenzo [ E ] [1,4,7] dioxozetane-11-carboxamide
3- (3- (3-Aminopropoxy) propoxy) -4-chloro-5-nitrobenzamide (200mg, 0.604mmol) and potassium carbonate (100mg, 0.725mmol) were dissolved in DMF (120mL) at room temperature and the reaction was stirred at 90 ℃ for 20 h. After the reaction was completed, the solvent was spin-dried, and ethyl acetate (50mL) was dissolved, and then washed with water and saturated brine, respectively, and spin-dried to obtain 9-nitro-2, 3,5,6,7, 8-hexahydrobenzo [ E ] [1,4,7] dioxozetane-11-carboxamide 7E (177mg, 0.597mmol) in 99% yield, which was used directly in the next step.
MS(ESI)m/z＝282[M+H]+。
Step 6: synthesis of 9-amino-2, 3,5,6,7, 8-hexahydrobenzo [ E ] [1,4,7] dioxozetane-11-carboxamide
Palladium on carbon (10%, 20mg) was added to a solution of 2E (170mg, 0.574mmol) in methanol and ethyl acetate, and the solution was reduced by hydrogenation for 3 hours, followed by filtration of the palladium on carbon, and concentration of the filtrate to give 9-amino-2, 3,5,6,7, 8-hexahydrobenzo [ E ] [1,4,7] dioxoazadecane-11-carboxamide 7f (150mg, 0.566mmol) with a yield of 98%. Directly used for the next reaction.
MS(ESI)m/z＝252[M+H]+。
And 7: synthesis of 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -8,10,11,12 tetrahydro-7H-6, 9-dioxa-2, 12 a-diazacyclo-benzo [ cd ] indene-4-carboxamide
The compound 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (80mg, 0.41mmol) was added dropwise to a solution of compound 7f (108mg, 0.407mmol) in DMF (3mL) while cooling on ice, and reacted for 0.5H. HATU (160mg, 0.421mmol) and N, N-diisopropylethylamine (105mg,0.814mmol) were then added to the reaction mixture, which was stirred at room temperature for 3h, and after completion of the reaction, was purified by reverse phase HPLC to give compound 7(8.7mg, yield 5%) as a white solid.
MS(ESI)m/z＝413[M+H]+。
Example 8
Figure BDA0002376124010000241
Figure BDA0002376124010000251
Step 1: synthesis of 2- (3- ((tert-butoxycarbonyl) amino) propoxy) ethyl methanesulfonate
Tert-butyl (3- (2-hydroxyethoxy) propyl) carbamate (1.15g,5.25mmol) was dissolved in DCM (30mL), TEA (2.2mL,15.8mmol) was added, methanesulfonyl chloride (0.49mL,6.30mmol) was added dropwise with cooling in an ice bath, and the reaction was completed by stirring for 2 hours in an ice bath. Water was added to separate the DCM phase, the aqueous layer was extracted 2 times with DCM, and the combined organic phases were dried and spun dry to give compound 8a (1.6g) in yield: 103 percent. Used directly in the next step.
MS(ESI)m/z＝298[M+H]+。
Step 2: synthesis of S- (2- (3- ((tert-butoxycarbonyl) amino) propoxy) ethyl) ethanethiol ester
Compound 8a (1.6g,5.39mmol) was dissolved in DMF (20mL), potassium thioacetate (1.23g,10.77mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, water was added, extraction was performed with ethyl acetate (20mL × 3), the organic phases were combined, dried, and the crude product obtained after concentration was purified by column chromatography (PE: EA ═ 5:1) to obtain compound 8b (1.31g) as a pale yellow oil, yield: 87.8 percent.
MS(ESI)m/z＝278[M+H]+。
And step 3: synthesis of S- (2- (3-aminopropoxy) ethyl) ethanethiol ester
Compound 8b (1.31g,4.73mmol) was dissolved in DCM (30mL), TFA (5mL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain a compound S- (2- (3-aminopropoxy) ethyl) ethanethiol ester 8c, which was used directly in the next reaction.
MS(ESI)m/z＝178[M+H]+。
And 4, step 4: synthesis of methyl 4- ((3- (2- (acetylthio) ethoxy) propyl) amino) -3-bromo-5-nitrobenzoate
Compound 8c (837mg,4.73mmol) was dissolved in DMF (20mL), and methyl 3-bromo-4-fluoro-5-nitrobenzoate (850mg,3.09mmol) and TEA (1.96mL,14.2mmol) were added and stirred at room temperature overnight. Water dilution, ethyl acetate extraction (20mL × 3), organic phases combined, dried and concentrated to give the crude product which was purified by column chromatography (PE: EA ═ 5:1) to give methyl 4- ((3- (2- (acetylthio) ethoxy) propyl) amino) -3-bromo-5-nitrobenzoate 8d (1.183g) yield: 84.9 percent.
MS(ESI)m/z＝435[M+H]+。
And 5: synthesis of methyl 3-bromo-4- ((3- (2-mercaptoethoxy) propyl) amino) -5-nitrobenzoate
Compound 8d (1.1g,2.53mmol) was dissolved in MeOH (20mL), MeONa (410mg,7.6mmol) was added with ice cooling and stirring for 1h to complete the reaction. Diluted hydrochloric acid (3M) was added to pH ≈ 4, spin-dried, the residue was dissolved in water, extracted with ethyl acetate (15mL × 3), the combined organic phases were dried and spin-dried to give methyl 3-bromo-4- ((3- (2-mercaptoethoxy) propyl) amino) -5-nitrobenzoate 8e (980mg) as a yellow solid, which was used directly in the next step, yield: 98.7 percent.
MS(ESI)m/z＝393[M+H]+。
Step 6: synthesis of methyl 9-nitro-2, 3,5,6,7, 8-hexahydrobenzo [ e ] [1,4,7] oxathiaacridine-11-carboxylate
Compound 8e (980mg,2.49mmol) was dissolved in 1, 4-dioxane (30mL) and Xantphos (288mg,0.498mmol), DIPEA (1.23mL,7.47mmol) and Pd were added sequentially under nitrogen2(dba)3(228mg,0.249mmol), and reacted at 100 ℃ overnight. Filtering to remove insoluble substances, concentrating, and purifying by column chromatography to obtain 9-nitro-2, 3,5,6,7, 8-hexahydrobenzo [ e ]][1,4,7]Methylthioacridine-11-carboxylate 8f (180mg) as a yellow solid, yield: 23.2 percent.
MS(ESI)m/z＝313[M+H]+。
And 7: synthesis of methyl 9-amino-2, 3,5,6,7, 8-hexahydrobenzo [ e ] [1,4,7] oxathiazine-11-carboxylate
Compound 8f (50mg,0.16mmol) was suspended in MeOH (8mL), and Na was added dropwise under cooling in an ice bath2S2O4(139mg,0.80mmol) of the reaction solution was stirred at room temperature for 2 hours, and the reaction was completed. Filtering to remove insoluble substances, drying the filtrate, dissolving the residue in water, extracting with ethyl acetate (10 mL. multidot.3), mixing the organic phases, drying, and concentratingDrying to obtain 9-amino-2, 3,5,6,7, 8-hexahydrobenzo [ e][1,4,7]Oxothiazine-11-carboxylic acid methyl ester 8g (45mg) was used directly in the next step.
MS(ESI)m/z＝283[M+H]+。
And 8: synthesis of ethyl 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -8,10,11, 12-tetrahydro-7H-9-oxa-6-thia-2, 12 a-diazacyclodecene [ cd ] indene-4-carboxylate
Compound 8g (45mg,0.16mmol) was dissolved in 5mL DMF and isothiocyanato-1-ethyl-3-methyl-5-pyrazolecarboxylic acid (32mg,0.16mmol) was added under ice-bath, stirred for 10min and then sent to LCMS, indicating completion of the reaction. HATU (67mg,0.176mmol) and DIPEA (0.85mL,0.48mmol) were added and stirred at room temperature overnight. Diluted with water, extracted with ethyl acetate (10mL x2), the combined organic phases dried and spin dried to give ethyl 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -8,10,11, 12-tetrahydro-7H-9-oxa-6-thia-2, 12 a-diazacyclodecene [ cd ] indene-4-carboxylate 8H (62mg) as a yellow solid which was used directly in the next step.
MS(ESI)m/z＝444[M+H]+。
And step 9: synthesis of 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -8,10,11, 12-tetrahydro-7H-9-oxa-6-thia-2, 12 a-diazacyclodecene [ cd ] indene-4-carboxylic acid
Compound 8H (62mg,0.14mmol) was dissolved in 5mL of a mixed solvent of MeOH/H2O (10:1), and lithium hydroxide hydrate (59mg,1.4mmol) was added and the reaction was heated to 40 ℃ for overnight. After cooling to room temperature, adding diluted hydrochloric acid (1M) to adjust the pH to 4, and spin-drying. The residue was dissolved in water, extracted with ethyl acetate (10mL x2), the combined organic phases dried and spin-dried to give 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -8,10,11, 12-tetrahydro-7H-9-oxa-6-thia-2, 12 a-diazacyclodecene [ cd ] indene-4-carboxylic acid 8i (42mg) which was used directly in the next reaction.
MS(ESI)m/z＝430[M+H]+。
Step 10: synthesis of 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -8,10,11, 12-tetrahydro-7H-9-oxa-6-thia-2, 12 a-diazacyclodecene [ cd ] indene-4-carboxamide
Compound 8i (42mg,0.1mmol) was dissolved in DMF (3mL), followed by addition of TEA (0.55mL,0.4mmol), HATU (57mg,0.15mmol), stirring at room temperature for 30min, addition of ammonium chloride (18mg,0.3mmol), and stirring at room temperature overnight. The reaction was purified by reverse phase prep-HPLC to give compound 8(10 mg).
MS(ESI)m/z＝429[M+H]+。
1H NMR(400MHz,DMSO-d6)δ13.00(s,1H),8.05–7.98(m,3H),7.41(s,1H),6.15–6.12(m,1H),4.61–4.58(m,2H),4.21–4.18(m,1H),3.87-3.84(m,1H),3.75-3.73(m,1H),3.14-3.05(m,2H),2.86-2.75(m,2H),2.34-2.31(m,1H),2.07(s,3H),2.05-1.95(m,1H),1.35(t,J＝7.5Hz,3H).
Example 9
Figure BDA0002376124010000271
Step 1: synthesis of 4- ((tert-butyldimethylsilyl) oxy) butan-2-ol
To a solution of butane-1, 3-diol (5g, 55.48mmol) in dichloromethane (100mL) was added tert-butyldimethylsilyl chloride (8.36g, 55.48mmol) and imidazole (4.53g, 66.58mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the separated organic phase was washed with water and saturated brine, respectively, and concentrated after drying to give 4- ((tert-butyldimethylsilyl) oxy) butan-2-ol 9a (13.89 g). The reaction mixture was used in the next reaction without further purification.
MS(ESI)m/z＝205[M+H]+。
Step 2: synthesis of tert-butyl (3- ((4- ((tert-butyldimethylsilyl) oxy) but-2-yl) oxy) propyl) carbamate
To a solution of compound 9a (6g, 29.36mmol) in DMF (100mL) under ice bath was added sodium hydride (1.4g, 35.23mmol) and stirred for 0.5 h. Then, tert-butyl 3-bromopropyl) carbamate (9.09g, 38.2mmol) was warmed to room temperature and stirred overnight. After quenching with saturated ammonium chloride, the reaction was poured into water, extracted with ethyl acetate (100mL x3), the combined organic phases were washed with water and saturated brine, respectively, dried and concentrated to give tert-butyl (3- ((4- ((tert-butyldimethylsilyl) oxy) but-2-yl) oxy) propyl) carbamate 9b (8.28g) which was used directly in the next reaction.
MS(ESI)m/z＝362[M+H]+。
And step 3: synthesis of tert-butyl (3- ((4-hydroxybut-2-yl) oxy) propyl) carbamate
To a solution of compound 9b (8.28g, 22.9mmol) in tetrahydrofuran (80mL) was added TBAF (34.35mmol, 1M in tetrahydrofuran) at room temperature. The reaction was warmed to 55 ℃ and stirred overnight. The reaction was poured into water, extracted with ethyl acetate (100mL × 3), and the organic phase was washed with saturated brine, dried and then spin-dried. The crude product was purified by silica gel column (elution machine: petroleum ether/ethyl acetate 1/1, v/v) to give tert-butyl (3- ((4-hydroxybut-2-yl) oxy) propyl) carbamate 9c (1.86 g).
MS(ESI)m/z＝248[M+H]+。
And 4, step 4: synthesis of tert-butyl (3- ((4- (5-carbamoyl-2-chloro-3-nitrophenoxy) but-2-yl) oxy) propyl) carbamate
Compound 9c (600mg, 2.42mmol) and 4-chloro-3-hydroxy-5-nitrobenzamide (420mg, 1.94mmol) were dissolved in dry tetrahydrofuran (20mL) at room temperature, air was replaced with nitrogen and triphenylphosphine (1.14g, 4.36mmol) and diisopropyl azodicarboxylate (880mg, 4.36mmol) were added. The reaction was then allowed to warm to 60 ℃ and stirred overnight. After completion of the reaction, ethyl acetate was added for extraction (20mL × 3), the organic phases were combined and the solvent was dried by evaporation, and the crude product was separated by column chromatography (eluent dichloromethane/methanol 50/1, v/v) to give tert-butyl (3- ((4- (5-carbamoyl-2-chloro-3-nitrophenoxy) but-2-yl) oxy) propyl) carbamate 9d (320mg, yield 29.6%).
MS(ESI)m/z＝446[M+H]+。
And 5: synthesis of 3- (3- (3-aminopropoxy) butoxy) -4-chloro-5-nitrobenzamide
TFA (3mL) was added to Compound 9d (320mg, 0.72mmol) in DCM (10mL) and reacted at RT for 1h, after completion of the reaction and spin-dried under reduced pressure to give 3- (3- (3-aminopropoxy) butoxy) -4-chloro-5-nitrobenzamide 9e (350mg, trifluoroacetate salt) which was used directly in the next step.
MS(ESI)m/z＝346[M+H]+。
Step 6: synthesis of 4-methyl-10-nitro-3, 4,6,7,8, 9-hexahydro-2H-benzo [ b ] [1,8,4] dioxoazaundecane-12-carboxamide
Compound 9e (350mg (70% purity), 0.72mmol) and potassium carbonate (76mg, 1.1mmol) were dissolved in DMF (150mL) at room temperature and the reaction was stirred at 90 ℃ for 3 h. After completion of the reaction, the solvent was dried by spin-drying, and the solvent was dissolved in ethyl acetate (50mL), washed with water and saturated brine, respectively, and then spin-dried, followed by purification on a normal-phase silica gel column (eluent: dichloromethane/methanol ═ 100/3, v/v) to give 4-methyl-10-nitro-3, 4,6,7,8, 9-hexahydro-2H-benzo [ b ] [1,8,4] dioxoundecane-12-carboxamide 9f (200mg, 90% yield).
MS(ESI)m/z＝310[M+H]+。
And 7: synthesis of 10-amino-4-methyl-3, 4,6,7,8, 9-hexahydro-2H-benzo [ b ] [1,8,4] dioxoazaundecane-12-carboxamide
Palladium on carbon (10%, 20mg) was added to a 9f (127mg, 0.41mmol) solution in methanol, and the mixture was reduced by hydrogenation for 3 hours, and palladium on carbon was filtered off, and the filtrate was concentrated to give 9g (90mg, 78.7% yield) of 10-amino-4-methyl-3, 4,6,7,8, 9-hexahydro-2H-benzo [ b ] [1,8,4] dioxoundecane-12-carboxamide. Directly used for the next reaction.
MS(ESI)m/z＝280[M+H]+。
And 8: synthesis of 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -9-methyl 7,8,9,11,12,13 hexahydro-6, 10-dioxa 2,13 a-diazacycloundecane [ CD ] indene-4-carboxamide
The compound 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (62mg, 0.0.32mmol) was added dropwise to a solution of the compound 9g (90mg, 0.32mmol) in DMF (3mL) while cooling on ice, and reacted for 0.5H. HATU (147mg, 0.38mmol) and N, N-diisopropylethylamine (82mg,0.64mmol) were then added to the reaction mixture, which was stirred at room temperature for 3h, and after completion of the reaction, was purified by reverse phase HPLC to give compound 9(33mg, yield 23%) as a white solid.
MS(ESI)m/z＝441[M+H]+。
Example 9-1
Figure BDA0002376124010000291
Step 1: synthesis of 4- ((triphenylmethyl) oxy) butan-2-ol
To a solution of butane-1, 3-diol (50g, 554.8mmol) in dichloromethane (750mL) was added trimethylchloromethane (8.36g, 154.8mmol), triethylamine (140mL, 665.8mmol) and 4-dimethylaminopyridine (1.3g, 10.6mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the separated organic phase was washed with water and saturated brine, respectively, dried, concentrated, and separated by column chromatography (petroleum ether/ethyl acetate: 20/1,10/1, v/v) to give 4- ((triphenylmethyl) oxy) butan-2-ol 9-1a (110g, 59.6%) as a colorless transparent oil.
MS(ESI)m/z＝333.0[M+H]+。
Step 2: synthesis of 1-tert-butyldimethylsilyl-3- ((4- (triphenylmethoxy) butan-2-yl) oxy) propan-1-ol
To a solution of compound 9-1a (50g, 150.0mmol) in DMF (500mL) under ice bath was added sodium hydride (9g, 225mmol) and stirred for 0.5 h. 3-Bromopropoxy (tert-butyl) dimethylsilane (45.5g, 180mmol) and tetrabutylammonium iodide (5.5g, 15mmol) were then added in that order. The reaction was warmed to room temperature, heated to 80 ℃ and stirred overnight. After quenching with saturated ammonium chloride, the reaction solution was poured into water, extracted with ethyl acetate (600mL × 3), the combined organic phases were washed with water and saturated brine, respectively, dried and concentrated to give a crude product, which was purified by silica gel column separation (petroleum ether/ethyl acetate 20/1-10/1, v/v) to give 9-1b (14g, 18.5%) as a colorless oil.
MS(ESI)m/z＝505.0[M+H]+。
And step 3: synthesis of 3- ((4- (triphenylmethoxy) butan-2-yl) oxy) propan-1-ol
To a solution of compound 9-1b (14g, 27.78mmol) in tetrahydrofuran (50mL) was added TBAF (33mmol, 1M in tetrahydrofuran) at room temperature. Stir overnight. The reaction was poured into water, extracted with ethyl acetate (100mL × 3), and the organic phase was washed with saturated brine, dried and then spin-dried. The crude product was purified by silica gel column (eluent: petroleum ether/ethyl acetate 70/30, v/v) to give 9-1c (7.7g, 74%) as a colourless oil.
MS(ESI)m/z＝391.0[M+H]+。
And 4, step 4: synthesis of 3- ((4- (triphenylmethoxy) butan-2-yl) oxy) propan-1-ol p-toluenesulfonate
Compound 9-1c (7.5g, 19.23mmol) was dissolved in a mixture of dichloromethane (20mL) and pyridine (20mL) at room temperature, and p-toluenesulfonyl chloride (4.03g, 21.15mmol) was added. The reaction solution is stirred at room temperature overnight, after the reaction is finished, the reaction solution is concentrated, dichloromethane and pyridine are removed by rotation, then water is added for dilution, ethyl acetate is used for extraction, the combined organic phase is concentrated, insoluble substances are filtered out, the filtrate is concentrated and dried to obtain 9-1d (8.75g), and the mixture is directly used for the next reaction without purification. .
MS(ESI)m/z＝545.0[M+H]+。
And 5: synthesis of tert-butyl (3- (((4- (trityloxy) butan-2-yl) oxy) propyl) carbamate
Compound 9-1d (8.75g, 16.7mmol) was dissolved in DMF (80mL) and K2CO3(4.6g, 33.5mmol), bis (tert-butoxycarbonyl) amine (4.0g, 18.5mmol) and iodomethane (20mg) were added in that order. The reaction was heated to 80 ℃ overnight, after completion of the reaction diluted with water and extracted with ethyl acetate, the combined organic phases were dried by spin drying to give the crude product which was purified by silica gel column (elution machine: petroleum ether/ethyl acetate 100/5, v/v) to give 9-1e (2.9g, 34%) as a colourless oil.
MS(ESI)m/z＝590.0[M+H]+。
Step 6: synthesis of tert-butyl (3- ((4-hydroxybut-2-yloxy) propyl) carbamate
Formic acid (2mL) was added dropwise to a solution of 9-1e (2.9g, 5.0mmol) in dichloromethane (30mL) at room temperature and the reaction stirred at room temperature for 3 h. After completion of the reaction, water was added for dilution, dichloromethane was extracted, the combined organic phases were washed with water and saturated brine, respectively, spin-dried and purified by normal phase silica gel column (eluent: petroleum ether/ethyl acetate 70/30, v/v) to give 9-1f (1.2g, 57% yield) as a colorless oil.
MS(ESI)m/z＝348.0[M+H]+。
And 7: synthesis of methyl 3- (3- (3- (((tert-butoxycarbonyl) amino) propoxy) butoxy) -4-chloro-5-nitrobenzoate
Compound 9-1f (600mg, 2.42mmol) and methyl 4-chloro-3-hydroxy-5-nitrobenzoate (562mg, 2.43mmol) were dissolved in dry tetrahydrofuran (10mL) at room temperature, and triphenylphosphine (1.15g, 4.37mmol) and diisopropyl azodicarboxylate (4mg, 4.37mmol) were added after displacing air with nitrogen. The reaction was then allowed to warm to 60 ℃ and stirred overnight. After completion of the reaction, extraction with ethyl acetate was performed (20mL × 3), the organic phases were combined and the solvent was dried by spinning, and the crude product was separated by column chromatography (eluent petroleum ether/ethyl acetate 85/15, v/v) to give 9-1g (1.91g, crude product containing triphenylphosphine oxide) as a yellow oil.
MS(ESI)m/z＝462.0[M+H]+。
And 8: synthesis of methyl 3- (3- (3-aminopropoxy) butoxy) -4-chloro-5-nitrobenzoate
TFA (2mL) was added dropwise to a solution of compound 9-1g (1.9g crude, 2.38mmol) in dichloromethane (10mL) while cooling on ice, and the reaction was carried out at room temperature for 2 h. After completion of the reaction, the solvent was dried by rotary evaporation to give the compound methyl 3- (3- (3-aminopropoxy) butoxy) -4-chloro-5-nitrobenzoate as a yellow oil for 9-1h (1.39g, crude). Directly used for the next reaction.
MS(ESI)m/z＝362.0[M+H]+。
And step 9: synthesis of methyl (S) -4-methyl-10-nitro-3, 4,6,7,8, 9-hexahydro-2H-benzo [ b ] [1,8,4] dioxazacycloundecene-12-carboxylate
Compound 9-1h (1.39g (70% purity), 3.85mmol) and potassium carbonate (797mg, 5.77mmol) were dissolved in DMF (400mL) at room temperature and the reaction was stirred at 60 ℃ overnight. After completion of the reaction, the solvent was dried by spin-drying, and the residue was dissolved in ethyl acetate (50mL), washed with water and saturated brine, respectively, and then purified with a normal-phase silica gel column (eluent: dichloromethane/methanol 100/3, v/v) to give 802mg of a racemate, which was further separated by SFC purification to give 9-1i (300mg) as an orange solid.
MS(ESI)m/z＝325.0[M+H]+。
1H NMR(400MHz,DMSO)δ8.50(t,J＝6.2Hz,1H),8.21(d,J＝1.9Hz,1H),7.48(d,J＝1.8Hz,1H),4.55–4.45(m,1H),4.22–4.09(m,1H),3.94(td,J＝10.3,2.4Hz,1H),3.82(s,3H),3.68–3.51(m,2H),3.44–3.34(m,1H),3.19–3.07(m,1H),1.96–1.62(m,4H),1.13(d,J＝6.3Hz,3H).
Step 10: synthesis of methyl (S) -4-methyl-10-amino-3, 4,6,7,8, 9-hexahydro-2H-benzo [ b ] [1,8,4] dioxazacycloundecene-12-carboxylate
To a 9-1i (300mg, 0.93mmol) mixed solution of methanol (15mL) and tetrahydrofuran (15mL) was added palladium on carbon (10%, 113mg), reduced by hydrogenation for 3h, the palladium on carbon was filtered off, and the filtrate was concentrated to give 9-1l (300mg, crude). Directly used for the next reaction.
MS(ESI)m/z＝295.0[M+H]+。
Step 11: synthesis of (S) -1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -9-methyl-7, 8,9,11,12, 13-hexahydro-6, 10-dioxa-2, 13 a-diazacyclobenzo [ cd ] indan-4-carboxylic acid methyl ester
The compound 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (33mg, 0.17mmol) was added dropwise to a solution of the compound 9-1l (50mg, 0.17mmol) in DMF (2mL) while cooling on ice, and reacted for 0.5H. HATU (77mg, 0.20mmol) and N, N-diisopropylethylamine (43mg,0.34mmol) were then added to the reaction mixture, stirring was continued at room temperature for 3h, and after completion of the reaction, filtration washing was carried out to give compound 9-1m (77mg, crude) as a white solid.
MS(ESI)m/z＝456.0[M+H]+。
Step 12: synthesis of (S) -1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -9-methyl-7, 8,9,11,12, 13-hexahydro-6, 10-dioxa-2, 13 a-diazacyclobenzo [ cd ] indan-4-carboxylic acid
Compound 9-1m (77mg,0.17mmol) was dissolved in 5mL of a mixed solvent of MeOH/H2O (10:1), and lithium hydroxide hydrate (70mg,1.7mmol) was added and heated to 65 ℃ for reaction for 5H. After cooling to room temperature, dilution with water, extraction with ethyl acetate, adjustment of the separated aqueous phase to pH with dilute hydrochloric acid (3M): 3-2, filtering and drying the precipitated white solid to obtain 9-1n (55mg, 73% yield) white solid.
MS(ESI)m/z＝442.0[M+H]+。
Step 13: synthesis of (S) -1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -9-methyl-7, 8,9,11,12, 13-hexahydro-6, 10-dioxa-2, 13 a-diazacyclobenzo [ cd ] indan-4-carboxamide
Compound 9-1n (55mg,0.12mmol) was dissolved in DMF (2mL), DIPEA (31mg,0.24mmol) and HATU (55mg,0.14mmol) were added in this order, and the mixture was stirred at room temperature for 30min, then ammonium hydrogencarbonate (19.7mg,0.25mmol) was added and the mixture was stirred at room temperature overnight. The reaction was diluted with water to precipitate a white solid, which was collected by filtration and washed three times with water to give 9-1(47.79mg, 86% yield).
MS(ESI)m/z＝443.0[M+H]+。
1H NMR(400MHz,DMSO)δ12.81(s,1H),7.96(s,1H),7.65(s,1H),7.43(s,1H),7.33(s,1H),6.62(s,1H),4.71–4.53(m,4H),4.39–4.29(m,1H),4.18(t,J＝10.1Hz,1H),3.65–3.53(m,1H),3.48(s,1H),3.30–3.23(m,1H),2.17(s,3H),1.99–1.84(m,3H),1.79(d,J＝14.6Hz,1H),1.35(t,J＝7.1Hz,3H),1.17(d,J＝6.3Hz,3H).
Example 9-2
Figure BDA0002376124010000321
Step 1: synthesis of methyl (R) -4-methyl-10-nitro-3, 4,6,7,8, 9-hexahydro-2H-benzo [ b ] [1,8,4] dioxazacycloundecene-12-carboxylate
Compound 9-1h (1.39g (70% purity), 3.85mmol) and potassium carbonate (797mg, 5.77mmol) were dissolved in DMF (400mL) at room temperature and the reaction was stirred at 60 ℃ overnight. After completion of the reaction, the solvent was dried by spin-drying, and the solvent was dissolved in ethyl acetate (50mL), washed with water and saturated brine, respectively, and then spin-dried, purified with a normal-phase silica gel column (eluent: dichloromethane/methanol 100/3, v/v), and the obtained racemate was separated by SFC purification to give 9-2a (300mg) as an orange solid.
MS(ESI)m/z＝325.0[M+H]+。
1H NMR(400MHz,DMSO)δ8.50(t,J＝6.2Hz,1H),8.21(d,J＝1.9Hz,1H),7.48(d,J＝1.8Hz,1H),4.55–4.46(m,1H),4.21–4.09(m,1H),3.99–3.89(m,1H),3.82(s,3H),3.65–3.52(m,2H),3.42–3.34(m,1H),3.20–3.06(m,1H),1.96–1.62(m,4H),1.13(d,J＝6.3Hz,3H).
Step 2: synthesis of methyl (R) -4-methyl-10-amino-3, 4,6,7,8, 9-hexahydro-2H-benzo [ b ] [1,8,4] dioxazacycloundecene-12-carboxylate
To a mixed solution of 9-2a (300mg, 0.93mmol) in methanol (15mL) and tetrahydrofuran (15mL) was added palladium on carbon (10%, 113mg), which was reduced by hydrogenation for 3h, the palladium on carbon was filtered off, and the filtrate was concentrated to give 9-2b (307mg, crude). Directly used for the next reaction.
MS(ESI)m/z＝295.0[M+H]+。
And step 3: synthesis of (R) -1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -9-methyl-7, 8,9,11,12, 13-hexahydro-6, 10-dioxa-2, 13 a-diazacyclobenzo [ cd ] indan-4-carboxylic acid methyl ester
The compound 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (33mg, 0.17mmol) was added dropwise to a solution of the compound 9-2b (50mg, 0.17mmol) in DMF (2mL) while cooling on ice, and reacted for 0.5H. HATU (77mg, 0.20mmol) and N, N-diisopropylethylamine (43mg,0.34mmol) were then added to the reaction mixture, stirring was continued at room temperature for 3h, and after completion of the reaction, filtration washing was carried out to give compound 9-2c (74mg, crude) as a white solid.
MS(ESI)m/z＝456.0[M+H]+。
And 4, step 4: synthesis of (R) -1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -9-methyl-7, 8,9,11,12, 13-hexahydro-6, 10-dioxa-2, 13 a-diazacyclobenzo [ cd ] indan-4-carboxylic acid
Compound 9-2c (74mg,0.16mmol) was dissolved in 5mL of a mixed solvent of MeOH/H2O (10:1), and lithium hydroxide hydrate (70mg,1.7mmol) was added and heated to 65 ℃ for reaction for 5H. After cooling to room temperature, dilution with water, extraction with ethyl acetate, adjustment of the separated aqueous phase to pH with dilute hydrochloric acid (3M): 3-2, filtering and drying the precipitated white solid to obtain 9-2d (64mg, 85% yield) white solid.
MS(ESI)m/z＝442.0[M+H]+。
And 5: synthesis of (R) -1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -9-methyl-7, 8,9,11,12, 13-hexahydro-6, 10-dioxa-2, 13 a-diazacyclobenzo [ cd ] indan-4-carboxamide
Compound 9-2d (64mg,0.14mmol) was dissolved in DMF (2mL), DIPEA (36mg,0.28mmol) and HATU (66mg,0.17mmol) were added sequentially, and the mixture was stirred at room temperature for 30min, then ammonium hydrogencarbonate (22mg,0.28mmol) was added, and the mixture was stirred at room temperature overnight. The reaction was diluted with water to precipitate a white solid which was collected by filtration and washed three times with water to give 9-2(58mg, 90% yield).
MS(ESI)m/z＝441.0[M+H]+。
1H NMR(400MHz,DMSO)δ12.81(s,1H),7.96(s,1H),7.66(s,1H),7.43(s,1H),7.33(s,1H),6.62(s,1H),4.71–4.53(m,4H),4.35(dt,J＝5.2,4.1Hz,1H),4.18(t,J＝9.8Hz,1H),3.65–3.53(m,1H),3.53–3.42(m,1H),3.29–3.22(m,1H),2.17(s,3H),1.98–1.83(m,3H),1.83–1.72(m,1H),1.35(t,J＝7.1Hz,3H),1.17(d,J＝6.3Hz,3H).
Example 10
Figure BDA0002376124010000341
Step 1: synthesis of methyl 3-amino-5-bromo-4- ((3- ((tert-butoxycarbonyl) amino) propyl) amino) benzoate
Compound 1c (600mg, 1.39mmol) was dissolved in methanol (10mL), the solution was cooled to 0 ℃ and then aqueous ammonia (2.5mL) and aqueous sodium dithionite (1.2g, 6.9mmol) were added in that order (5 mL). The reaction mixture was stirred at 0 ℃ for 1h, and the color of the reaction changed from orange-red to white. The reaction mixture was evaporated to remove methanol by rotary evaporation, diluted with water, extracted with ethyl acetate (20 mL. times.4), and the separated organic phase was washed with saturated brine (20 mL. times.2), dried over anhydrous sodium sulfate, filtered, and then dried by rotary evaporation to give compound 10a (440mg, yield 79%).
MS(ESI)m/z＝402.1[M+H]+
Step 2: synthesis of methyl 7-bromo-1- (3- ((tert-butoxycarbonyl) amino) propyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -1H-benzo [ d ] imidazole-5-carboxylate
Compound 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (214mg, 1.1mmol) was added dropwise to a solution of compound 10a (440mg, 1.1mmol) in DMF (5mL) while cooling on ice, and reacted for 0.5H. HATU (493mg, 1.3mmol) and N, N-diisopropylethylamine (284mg,2.2mmol) were then added to the reaction mixture, which was stirred at room temperature for 3h and separated by reverse phase MPLC (eluent acetonitrile/water 1/2, v/v) to give compound 10b (560mg, 90% yield).
MS(ESI)m/z＝563.1[M+H]+。
And step 3: synthesis of methyl 7-bromo-1- (3- ((tert-butoxycarbonyl) amino) propyl) -2- (1-ethyl-3-methyl-N- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxamido) -1H-benzo [ d ] imidazole-5-carboxylate
DIPEA (503mg, 3.9mmol) was added to 10b (550mg, 0.98mmol) in DMF (5mL) at room temperature and the temperature was raised to 40 ℃ for reaction overnight. The reaction was poured into water, extracted with ethyl acetate (5mL × 3), and the combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 10c (640mg, yield 94%) which was used directly in the next step.
MS(ESI)m/z＝693.2[M+H]+。
And 4, step 4: (E) synthesis of methyl (E) -7- (4- (tert-butoxy) -4-oxobut-1-en-1-yl) -1- (3- ((tert-butoxycarbonyl) amino) propyl) -2- (1-3-methyl-1H-pyrazole-5-carboxamido) -1H-benzo [ d ] imidazole-5-carboxylate
To 10c (640mg, 0.92mmol) of N, N-dimethylacetamide was added palladium acetate (1.03g, 4.6mmol), 2-dicyclohexylphosphonium-2, 4, 6-triisopropylbiphenyl (86mg, 0.18mmol) and DIPEA (356mg, 2.76mmol) at room temperature. After nitrogen replacement, the temperature is raised to 110 ℃ under the inert atmosphere, and the reaction is carried out for 18 h. The reaction mixture was poured into water, extracted with ethyl acetate (10mL × 3), and the combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by a silica gel column (petroleum ether/ethyl acetate 1/1) to give compound 10c (400mg, yield 70%).
MS(ESI)m/z＝625.3[M+H]+。
And 5: (E) synthesis of (E) -4- (1- (3-aminopropyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -5- (methoxycarbonyl) -1H-benzo [ d ] imidazol-7-yl) but-3-enoic acid
TFA (5mL) was added to a solution of 10c (254mg, 0.4mmol) in dichloromethane (5mL) while cooling on ice. After warming to room temperature and stirring overnight, the solvent was spun off and excess trifluoroacetic acid was removed under reduced pressure using an oil pump, yielding compound 10d (235mg, 100% yield) which was used directly in the next step.
MS(ESI)m/z＝469.2[M+H]+
Step 6: synthesis of methyl 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -9-oxo-8, 9,10,11,12, 13-hexahydro-2, 10,13 a-triazacyclopentene [ cd ] indene-4-carboxylate
Compound 10d (235mg, 0.4mmol) was dissolved in DMF (10mL) and DIPEA (258mg, 2.0mmol) and HBTU (167mg, 0.44mmol) were added. After 2 hours of reaction at room temperature, the reaction mixture was poured into water, extracted with ethyl acetate (10mL × 3), the combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by a silica gel column (petroleum ether/ethyl acetate: 1/2) to give compound 10e (84mg, yield 45%).
MS(ESI)m/z＝451.2[M+H]+
And 7: synthesis of 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -9-oxo-8, 9,10,11,12, 13-hexahydro-2, 10,13 a-triazacyclopentene [ cd ] indene-4-carboxylic acid
Compound 10e (84mg, 0.18mmol) was dissolved in a mixed solvent of tetrahydrofuran (2mL) and methanol (1mL), and a solution of lithium hydroxide (76mg, 1.8mmol) in water (2mL) was added. The reaction solution was stirred at room temperature for 16 h. The spin-dried organic solvent was diluted with water, the aqueous phase was acidified with dilute hydrochloric acid (1M) to pH 4, extracted with ethyl acetate (10mL x3), the combined organic phases were washed with water and saturated brine, respectively, and the solvent was spin-dried to give compound 10f (65mg, 83% yield)
MS(ESI)m/z＝437.2[M+H]+。
And 8: synthesis of 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -9-oxo-8, 9,10,11,12, 13-hexahydro-2, 10,13 a-triazacyclopentene [ cd ] indene-4-carboxamide
HATU (68mg, 0.18mmol) was added to a solution of compound 10f (65mg, 0.15mmol) in DMF (2mL) while cooling on ice. After 15min, DIPEA (58mg,0.45mmol) and ammonium chloride (29mg, 0.54mmol) were added. The reaction was carried out for 1h and the reaction was separated using reverse phase MPLC (eluent acetonitrile/water 1/1, v/v) to give 10g of compound (26mg, yield 33%).
MS(ESI)m/z＝436.2[M+H]+。
And step 9: synthesis of 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -9-oxo-6, 7,8,9,10,11,12, 13-octahydro-2, 10,13 a-triazacycloaryl [ cd ] indene-4-carboxamide
To a solution of 10g (24mg, 0.055mmol) in methanol (5mL) was added palladium on carbon (10%, 10mg) at room temperature, and the reaction was hydrogenated for 1 h. The palladium on carbon was removed by filtration, and the solvent was dried by evaporation to give compound 10(10mg, yield 42%).
MS(ESI)m/z＝438.2[M+H]+
1H NMR(400MHz,MeOD):δppm7.96(s,1H),7.87(s,1H),7.75(s,1H),6.82(s,1H),4.73(q,J＝6.8,14Hz,2H),4.44(s,2H),3.14(s,2H),2.32(s,3H),2.26(m,2H),1.47(t,J＝7.2Hz,3H),1.30-1.35(m,2H)
Example 11
Figure BDA0002376124010000361
Step 1: synthesis of methyl (S) -1- (1-ethyl-4-fluoro-3-methyl-1H-pyrazole-5-carboxamide) -9-methyl-7, 8,9,11,12, 13-hexahydro-6, 10-dioxa-2, 13 a-diazacyclobenzo [ cd ] indan-4-carboxylate
The compound 1-ethyl-3-methyl 4-fluoro-1H-pyrazole-5-carbonyl isothiocyanate (215mg, 1.01mmol) was added dropwise to a solution of the compound (S) -10-amino-4-methyl-3, 4,6,7,8, 9-hexahydro-2H-benzo [ b ] [1,8,4] dioxazacycloundecene-12-carboxylic acid methyl ester (277mg, 0.92mmol) in DMF (4mL) while cooling on ice for 0.5H. HATU (420mg, 1.1mmol) and N, N-diisopropylethylamine (237mg,1.84mmol) were then added to the reaction mixture, stirring was continued at room temperature for 3h, and after completion of the reaction, filtration washing was carried out to give compound 11a (380mg, crude) as a white solid.
MS(ESI)m/z＝474.0[M+H]+。
Step 2: synthesis of (S) -1- (1-ethyl-4-fluoro-3-methyl-1H-pyrazole-5-carboxamide) -9-methyl-7, 8,9,11,12, 13-hexahydro-6, 10-dioxa-2, 13 a-diazacyclobenzo [ cd ] indan-4-carboxylic acid
Compound 11a (374mg,0.79mmol) was dissolved in 30mL of a mixed solvent of MeOH/H2O (10:1), and lithium hydroxide hydrate (329mg,7.9mmol) was added and the mixture was heated to 65 ℃ for reaction for 5 hours. After cooling to room temperature, dilution with water, extraction with ethyl acetate, adjustment of the separated aqueous phase to pH with dilute hydrochloric acid (3M): 3-2, filtering and drying the precipitated white solid to obtain 11b (247mg, 68% yield) as a white solid.
MS(ESI)m/z＝460.0[M+H]+。
And step 3: synthesis of (S) -1- (1-ethyl-4-fluoro-3-methyl-1H-pyrazole-5-carboxamide) -9-methyl-7, 8,9,11,12, 13-hexahydro-6, 10-dioxa-2, 13 a-diazacyclobenzo [ cd ] indan-4-carboxamide
Compound 11b (247mg,0.53mmol) was dissolved in DMF (4mL), and DIPEA (130mg,1.0mmol), HATU (241mg,0.63mmol) were added in that order, and stirred at room temperature for 30min, followed by addition of ammonium bicarbonate (85mg,1.0mmol), and stirred at room temperature overnight. The reaction was diluted with water to precipitate a white solid which was collected by filtration and washed three times with water to give 11(195mg, 80% yield).
MS(ESI)m/z＝459.0[M+H]+。
1H NMR(400MHz,DMSO)δ12.83(s,1H),7.97(s,1H),7.66(s,1H),7.44(s,1H),7.34(s,1H),4.77–4.58(m,2H),4.58–4.44(m,2H),4.34(d,J＝12.6Hz,1H),4.18(t,J＝10.1Hz,1H),3.65–3.52(m,1H),3.47(s,1H),3.30–3.19(m,1H),2.15(s,3H),1.99–1.69(m,4H),1.33(t,J＝7.1Hz,3H),1.16(d,J＝6.2Hz,3H).
Example 12
Figure BDA0002376124010000371
Step 1: synthesis of methyl (R) -1- (1-ethyl-4-fluoro-3-methyl-1H-pyrazole-5-carboxamide) -9-methyl-7, 8,9,11,12, 13-hexahydro-6, 10-dioxa-2, 13 a-diazacyclobenzo [ cd ] indan-4-carboxylate
The compound 1-ethyl-3-methyl 4-fluoro-1H-pyrazole-5-carbonyl isothiocyanate (215mg, 1.01mmol) was added dropwise to a solution of the compound (R) -10-amino-4-methyl-3, 4,6,7,8, 9-hexahydro-2H-benzo [ b ] [1,8,4] dioxazacycloundecene-12-carboxylic acid methyl ester (306mg, 0.92mmol) in DMF (4mL) while cooling on ice for 0.5H. HATU (420mg, 1.1mmol) and N, N-diisopropylethylamine (237mg,1.84mmol) were then added to the reaction mixture, stirring was continued at room temperature for 3h, and after completion of the reaction, filtration washing was carried out to give compound 12a (370mg, crude) as a white solid.
MS(ESI)m/z＝474.0[M+H]+。
Step 2: synthesis of (R) -1- (1-ethyl-4-fluoro-3-methyl-1H-pyrazole-5-carboxamide) -9-methyl-7, 8,9,11,12, 13-hexahydro-6, 10-dioxa-2, 13 a-diazacyclobenzo [ cd ] indan-4-carboxylic acid
Compound 12a (363mg,0.77mmol) was dissolved in 30mL of a mixed solvent of MeOH/H2O (10:1), and lithium hydroxide hydrate (352mg,7.8mmol) was added and heated to 65 ℃ for reaction for 5H. After cooling to room temperature, dilution with water, extraction with ethyl acetate, adjustment of the separated aqueous phase to pH with dilute hydrochloric acid (3M): 3-2, filtering and drying the precipitated white solid to obtain 12b (250mg, 77% yield) as a white solid.
MS(ESI)m/z＝460.0[M+H]+。
And step 3: synthesis of (R) -1- (1-ethyl-4-fluoro-3-methyl-1H-pyrazole-5-carboxamide) -9-methyl-7, 8,9,11,12, 13-hexahydro-6, 10-dioxa-2, 13 a-diazacyclobenzo [ cd ] indan-4-carboxamide
Compound 12b (250mg,0.54mmol) was dissolved in DMF (4mL), and DIPEA (139mg,1.0mmol), HATU (246mg,0.65mmol) were added in that order, and stirred at room temperature for 30min, followed by addition of ammonium bicarbonate (86mg,1.0mmol), and stirred at room temperature overnight. The reaction was diluted with water to precipitate a white solid which was collected by filtration and washed three times with water to give 12(196mg, 80% yield).
1H NMR(400MHz,DMSO)δ12.86(s,1H),7.97(s,1H),7.66(s,1H),7.44(s,1H),7.34(s,1H),4.74–4.58(m,2H),4.58–4.47(m,2H),4.41–4.28(m,1H),4.18(t,J＝10.1Hz,1H),3.65–3.53(m,1H),3.53–3.42(m,1H),3.30–3.22(m,1H),2.01–1.86(m,2H),1.85–1.66(m,2H),1.33(t,J＝7.1Hz,3H),1.16(d,J＝6.3Hz,3H).
Example 13
Figure BDA0002376124010000381
Step 1: synthesis of (S) -1- (4-ethyl-2-methylthiazole-5-carboxamido) -9-methyl-7, 8,9,11,12, 13-hexahydro-6, 10-bisoxazole-2, 13 a-diazacyclopentene [ cd ] indene 4-carboxylic acid methyl ester
The compound 4-ethyl-2-methylthiazole-5-carbonyl isothiocyanate (107mg, 0.50mmol) was added dropwise to a solution of the compound (S) -10-amino-4-methyl-3, 4,6,7,8, 9-hexahydro-2H-benzo [ b ] [1,8,4] dioxazacycloundecene-12-carboxylic acid methyl ester (153mg, 0.46mmol) in DMF (4mL) under ice bath for 0.5H. HATU (210mg, 0.55mmol) and N, N-diisopropylethylamine (118mg,0.90mmol) were then added to the reaction mixture, stirring was continued at room temperature for 3h, and after completion of the reaction the mixture was washed with water to give compound 13a (185mg, crude) as a white solid.
MS(ESI)m/z＝473.0[M+H]+。
Step 2: synthesis of (S) -1- (4-ethyl-2-methylthiazole-5-carboxamido) -9-methyl-7, 8,9,11,12, 13-hexahydro-6, 10-bisoxazole-2, 13 a-diazacyclopentene [ cd ] indene 4-carboxylic acid
Compound 13a (181mg,0.39mmol) was dissolved in 15mL of a mixed solvent of MeOH/H2O (10:1), and lithium hydroxide hydrate (176mg,3.9mmol) was added and heated to 65 ℃ for reaction for 5H. After cooling to room temperature, dilution with water, extraction with ethyl acetate, adjustment of the separated aqueous phase to pH with dilute hydrochloric acid (3M): 3-2, filtering and drying the precipitated white solid to obtain 13b (125mg, 77% yield) as a white solid.
MS(ESI)m/z＝459.0[M+H]+。
And step 3: synthesis of (S) -1- (4-ethyl-2-methylthiazole-5-carboxamido) -9-methyl-7, 8,9,11,12, 13-hexahydro-6, 10-bisoxazole-2, 13 a-diazacyclopentene [ cd ] indene 4-carboxamide
Compound 13b (125mg,0.27mmol) was dissolved in DMF (3mL) and DIPEA (70mg,0.5mmol), HATU (123mg,0.33mmol) were added sequentially and stirred at room temperature for 30min, followed by addition of ammonium bicarbonate (43mg,0.33mmol) and stirring at room temperature overnight. The reaction was diluted with water to precipitate a white solid which was collected by filtration and washed three times with water to give 13(98mg, 80% yield).
MS(ESI)m/z＝458.0[M+H]+。
Example 14
Figure BDA0002376124010000391
Step 1: synthesis of (R) -1- (4-ethyl-2-methylthiazole-5-carboxamido) -9-methyl-7, 8,9,11,12, 13-hexahydro-6, 10-bisoxazole-2, 13 a-diazacyclopentene [ cd ] indene 4-carboxylic acid methyl ester
The compound 4-ethyl-2-methylthiazole-5-carbonyl isothiocyanate (110mg, 0.52mmol) was added dropwise to a solution of the compound (R) -10-amino-4-methyl-3, 4,6,7,8, 9-hexahydro-2H-benzo [ b ] [1,8,4] dioxazacycloundecene-12-carboxylic acid methyl ester (139mg, 0.47mmol) in DMF (4mL) under ice bath for 0.5H. HATU (214mg, 0.56mmol) and N, N-diisopropylethylamine (121mg,0.94mmol) were then added to the reaction mixture, stirring was continued at room temperature for 3h, and after completion of the reaction the mixture was washed with water to give compound 13a (175mg, crude) as a white solid.
MS(ESI)m/z＝473.0[M+H]+。
Step 2: synthesis of (R) -1- (4-ethyl-2-methylthiazole-5-carboxamido) -9-methyl-7, 8,9,11,12, 13-hexahydro-6, 10-bisoxazole-2, 13 a-diazacyclopentene [ cd ] indene 4-carboxylic acid
Compound 14a (90mg,0.19mmol) is dissolved in 10mL MeOH/H2To a mixed solvent of O (10:1), hydrated lithium hydroxide (88mg,1.95mmol) was added, and the mixture was heated to 65 ℃ to react for 5 hours. After cooling to room temperature, dilution with water, extraction with ethyl acetate, adjustment of the separated aqueous phase to pH with dilute hydrochloric acid (3M): 3-2, filtering and drying the precipitated white solid to obtain 14b (63mg, 76% yield) as a white solid.
MS(ESI)m/z＝459.0[M+H]+。
And step 3: synthesis of (R) -1- (4-ethyl-2-methylthiazole-5-carboxamido) -9-methyl-7, 8,9,11,12, 13-hexahydro-6, 10-bisoxazole-2, 13 a-diazacyclopentene [ cd ] indene 4-carboxamide
Compound 14b (63mg,0.14mmol) was dissolved in DMF (3mL) and DIPEA (40mg,0.3mmol), HATU (62mg,0.16mmol) were added sequentially and stirred at room temperature for 30min, followed by addition of ammonium bicarbonate (13mg,0.165mmol) and stirring at room temperature overnight. The reaction was diluted with water to precipitate a white solid, which was collected by filtration and washed three times with water to give 14(49mg, 80% yield).
MS(ESI)m/z＝458.0[M+H]+
Example 15
Figure BDA0002376124010000401
Step 1: synthesis of methyl 3-bromo-4- ((3-hydroxypropyl) amino) -5-nitrobenzoate
The compound 3-hydroxypropylamine (622mg,8.29mmol) and DIPEA (1.78g,13.8mmol) were added dropwise to a solution of the compound methyl 3-bromo-4-fluoro-5-nitrobenzoate (1.92g,6.9mmol) in DMF (10mL) at room temperature for 3 h. After completion of the reaction, water was added for dilution, dichloromethane was extracted, the combined organic phases were washed with water, with saturated brine, dried and concentrated to give compound 15a (2.1g, crude) as a yellow oil. Directly used for the next reaction.
MS(ESI)m/z＝334.0[M+H]+。
Step 2: synthesis of methyl 3-amino-5-bromo-4- ((3-hydroxypropyl) amino) benzoate
Aqueous ammonia (5mL, 33mmol) was added to compound 15a (1.1g,3.3mmol) in MeOH (20mL) solvent for 5min, after which sodium hydrosulfite (2.87g,16.5mmol) was added in water (6mL), gradually warmed to room temperature and stirred for 2h to complete the reaction, diluted with water, extracted with dichloromethane, the separated organic phase was added with water, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give 15b (772mg, 77% yield) as a yellow oil. Used in the next reaction without purification.
MS(ESI)m/z＝304.0[M+H]+。
And step 3: synthesis of methyl 7-bromo-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1- (3-hydroxypropyl) -1H-benzo [ d ] imidazole-5-carboxylate
The compound 1-ethyl-3-methyl 4-fluoro-1H-pyrazole-5-carbonyl isothiocyanate (545mg, 2.79mmol) was added dropwise to a solution of compound 15b (770mg, 2.54mmol) in DMF (10mL) while cooling on ice, and reacted for 0.5H. HATU (1.16mg, 1.1mmol) and N, N-diisopropylethylamine (655mg,5.08mmol) were then added to the reaction mixture, stirring was continued at room temperature for 3h, and after completion of the reaction the mixture was washed with water to give compound 15c (765mg, crude) as a pale pink solid.
MS(ESI)m/z＝465.0[M+H]+。
And 4, step 4: synthesis of methyl 7-bromo-2- (1-ethyl-3-methyl-N- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxamide) -1- (3-hydroxypropyl) -1H-benzo [ d ] imidazole 5-carboxylate
To a solution of compound 15c (765mg, 1.65mmol) in tetrahydrofuran (15mL) was added cesium carbonate (1.6g, 4.97mmol), (2- (chloromethoxy) ethyl) trimethylsilane (550mg, 3.3mmol) at room temperature. Stir overnight. After completion of the reaction, the reaction solution was concentrated, and the crude product obtained was purified by silica gel column (eluent: dichloromethane/methanol 95/5, v/v) to give 15d (570mg, 58% yield) as an off-white solid.
MS(ESI)m/z＝594.0[M+H]+。
And 5: synthesis of methyl 7- (3- ((tert-butoxycarbonyl) amino) prop-1-yn-1-yl) -2- (1-ethyl-3-methyl-N- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxamido) -1- (3-hydroxypropyl) -1H-benzo [ d ] imidazole-5-carboxylate
Compound 15d (270mg, 0.45mmol) was dissolved in N, N-dimethylformamide (5mL) at room temperature, and N-t-butoxycarbonylpropynylamine (106mg, 0.68mmol), Pd (PPh) and the like were added3)2Cl2(16mg,0.02mmol), tri-tert-butylphosphine (10% in toluene, 37mg, 0.04mmol), cuprous iodide (8.7mg, 0.04mmol) and DIPEA (117mg, 0.91 mmol). The mixture was replaced with nitrogen 5 times, heated to 85 ℃ under nitrogen and stirred at this temperature overnight, concentrated after completion of the reaction, dried to give the crude product, which was purified by silica gel column (eluent: dichloromethane/methanol 92/8, v/v) to give 15e (76mg, 25% yield) as a white solid.
MS(ESI)m/z＝669.0[M+H]+。
Step 6: synthesis of methyl 7- (3- ((tert-butoxycarbonyl) amino) propyl) -2- (1-ethyl-3-methyl-N- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxamide-1- (3-hydroxypropyl) -1H-benzo [ d ] imidazole-5-carboxylate
Compound 15e (76mg, 0.11mmol) was dissolved in methanol (8mL), Pd/C (20mg, N) was added, hydrogen replaced, and the mixture was stirred at room temperature for 48h under hydrogen balloon protection. After completion of the reaction, Pd/C was removed by filtration, and the filtrate was spin-dried to give 15f (68mg, yield 89%) as a colorless oil.
MS(ESI)m/z＝673.0[M+H]+。
And 7: synthesis of methyl 7- (3- ((tert-butoxycarbonyl) amino) propyl) -2- (1-ethyl-3-methyl-N- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxamido-1- (3- (((((4-nitrophenoxy) carbonyl) oxy) propyl) -1H-benzo [ d ] imidazole-5-carboxylate
Phenyl p-nitrochloroformate (18mg, 0.09mmol) and pyridine (13mg,0.16 mmol) were added to a solution of 15f (68mg, 0.08mmol) in dichloromethane (10mL) under ice-cooling. Then the reaction was stirred for 3 h. After completion of the reaction, the organic phase was distilled off under reduced pressure, and the resulting crude product was purified by TLC (developing solvent: dichloromethane/methanol-15/1, v/v) silica gel plate to give 15g (32mg, 49% yield) as a colorless oil.
MS(ESI)m/z＝838.0[M+H]+。
And 8: synthesis of methyl 7- (3-aminopropyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1- (3- ((((4-nitrophenoxy) carbonyl) oxy) propyl) -1H-benzo [ d ] imidazole-5-carboxylate
Trifluoroacetic acid (1mL) was added dropwise to a solution of compound 15g (32mg, 0.02mmol) in dichloromethane (3mL) at room temperature, stirred at room temperature for 2h, after completion of the reaction, the organic phase was removed by swirling and dried to give 15h (35mg, crude) as a yellow oil.
MS(ESI)m/z＝608.0[M+H]+。
And step 9: synthesis of methyl 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -10-oxo-6, 7,8,9,10,12,13, 14-octahydro-11-oxa-2, 9, 14 a-triazacyclododecyl [ cd ] indene-4-carboxylate
DIPEA (13mg,0.1 mmol) was added dropwise to a solution of compound 15h (35mg crude, 0.02mmol) in acetonitrile (5mL) at room temperature and reacted for 5h at room temperature. After completion of the reaction, the organic phase was distilled off under reduced pressure to give a crude product, which was purified by TLC (developing solvent: dichloromethane/methanol-15/1, v/v) silica gel plate to give 15i (10mg, crude product) as a yellow oil.
MS(ESI)m/z＝469.0[M+H]+。
Step 10: synthesis of 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -10-oxo-6, 7,8,9,10,12,13, 14-octahydro-11-oxa-2, 9, 14 a-triazacyclododecyl [ cd ] indan-4-carboxylic acid
Compound 15i (10mg (70% purity), 0.01mmol) was dissolved in ammonia water (5mL) at room temperature, warmed to 90 ℃ and stirred for reaction overnight. After completion of the reaction, the solvent was spin-dried to give 15j (15mg, cupin) as a yellow oil. Used in the next reaction without purification.
MS(ESI)m/z＝455.0[M+H]+。
Step 11: synthesis of 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -10-oxo-6, 7,8,9,10,12,13, 14-octahydro-11-oxa-2, 9, 14 a-triazacyclododecyl [ cd ] indan-4-carboxamide
To a 15h (15mg, crude, 0.01mmol) solution of dioxane (3mL) was added (Boc)2O (3mg,0.015mmol), pyridine (one drop) and NH4HCO3(2mg, 0.02 mmol). After completion of the reaction, the solvent was dried by spinning, and the crude product was chromatographed on preparative thin layer chromatography (developing solvent: dichloromethane/methanol-15/1, v/v) followed by MPLC (eluent: water/acetonitrile) to give compound 15(3.5mg, 77% yield) as a white solid.
MS(ESI)m/z＝454.0[M+H]+。
Example 16
Figure BDA0002376124010000431
Step 1: synthesis of 4-methyl-2-phenyl-1, 3-dioxane
1, 3-butanediol (15g, 167mmol), benzaldehyde (17.7g, 167mmol), anhydrous sodium sulfate (40g, 333mmol) and p-toluenesulfonic acid (2.9g, 17mmol) were dissolved in DCM (200mL) under nitrogen protection and reacted at room temperature for 10 h. After completion of the reaction the inorganic salt was filtered and the organic phase dried the solvent to give 16a (29g, 163mmol) in 97% yield.
MS(ESI)m/z＝179[M+H]+。
Step 2: synthesis of 3- (benzyloxy) butan-1-ol
Under nitrogen protection, a DCM (200mL) solution of 16a (17.8g, 100mmol) was cooled to-78 deg.C, DIBAL-H (100mL,1M dichloromethane solution, 100mmol) was slowly added dropwise, and the reaction was allowed to warm to room temperature for 10H. After completion of the reaction, the reaction was quenched with sodium sulfate decahydrate, the inorganic salts were filtered, the organic phase was spin dried and the crude product was separated by column chromatography (eluent: ethyl acetate/petroleum ether-1/4, v/v) to give 16b (14.7g, 81mmol) in 82% yield.
MS(ESI)m/z＝181[M+H]+。
And step 3: synthesis of tert-butyl (3- (3- (benzyloxy) butoxy) propyl) carbamate sodium hydride (107mg, 2.66mmol) was added to a mixed solvent of 16b (400mg, 2.22mmol) of DMF (8mL) and tetrahydrofuran (16mL) under ice bath. After stirring for 30 minutes, N-t-butoxycarbonylbromopropylamine 16c (635mg, 2.66mmol) was added, and the reaction was allowed to warm to room temperature for 10 hours. After completion of the reaction water was added, extracted with ethyl acetate (50mL x3), the organic phases combined and the solvent was dried and the crude product was separated by column chromatography (eluent: ethyl acetate/petroleum ether 1/10, v/v) to give 16d (847g, 2.51mmol) in 57% yield.
MS(ESI)m/z＝338[M+H]+。
And 4, step 4: synthesis of tert-butyl (3- (3-hydroxybutoxy) propyl) carbamate
To a solution of compound 16d (847mg, 2.51mmol) in methanol and ethyl acetate was added palladium on carbon (10%, 80mg), which was reduced by hydrogenation for 3 hours, filtered to remove the palladium on carbon, and the filtrate was concentrated to give 16e (562mg, 2.27mmol) in 99% yield. Directly used for the next reaction.
MS(ESI)m/z＝248[M+H]+。
And 5: synthesis of tert-butyl (3- (3- (5-carbamoyl-2-chloro-3-nitrophenoxy) propoxy) propyl) carbamate
Compound 16e (562mg, 2.27mmol) and 4-chloro-3-hydroxy-5-nitrobenzamide (491mg, 2.27mmol) were dissolved in dry tetrahydrofuran (20mL) at room temperature, air was replaced with nitrogen, triphenylphosphine (894mg, 3.41mmol) and diisopropyl azodicarboxylate (689mg, 3.41mmol) were added, and the reaction was stirred for 10 h. After completion of the reaction, extraction was performed with ethyl acetate (20mL × 3), the organic phases were combined and the solvent was dried and the crude product was isolated by column chromatography (eluent ethyl acetate/petroleum ether 1/2, v/v) to give 16f (900mg, 2.01mmol) in 92% yield.
MS(ESI)m/z＝446[M+H]+。
Step 6: synthesis of 3- ((4- (3-aminopropoxy) but-2-yl) oxy) -4-chloro-5-nitrobenzamide
TFA (20mL) was added to Compound 16f (900mg, 2.01mmol) in DCM (20mL) and reacted at room temperature for 1h, after completion of the reaction was spin-dried, the crude product was adjusted to pH ≈ 8 with a saturated solution of sodium bicarbonate, extracted with ethyl acetate (20mLx3), the combined organic phases were washed with saturated brine, and after drying, spin-dried to give 16g (377mg, 1.09mmol) in 54% yield, which was used directly in the next step.
MS(ESI)m/z＝346[M+H]+。
And 7: synthesis of 2-methyl-10-nitro-3, 4,6,7,8, 9-hexahydro-2H-benzo [ b ] [1,8,4] diazacycloundecane-12-carboxamide
16g (377mg, 1.09mmol) and potassium carbonate (301mg, 2.18mmol) were dissolved in DMF (120mL) at room temperature and the reaction was stirred at 90 ℃ for 20 h. After completion of the reaction, the solvent was dried by rotary drying, and ethyl acetate (50mL) was dissolved and washed with water and saturated brine, respectively, to give a yield of 99% over 16h (366mg, 1.09mmol), which was used directly in the next step.
MS(ESI)m/z＝310[M+H]+。
And 8: synthesis of 2-methyl-10-amino-3, 4,6,7,8, 9-hexahydro-2H-benzo [ b ] [1,8,4] diazacycloundecane-12-carboxamide
Palladium on carbon (10%, 20mg) was added to a solution of 16h (336mg, 1.09mmol) in methanol and ethyl acetate, and the solution was reduced by hydrogenation for 3h, after which palladium on carbon was filtered off and the filtrate was concentrated to give 16i (272mg, 0.975mmol) in 89% yield. Directly used for the next reaction.
MS(ESI)m/z＝280[M+H]+。
And step 9: synthesis of 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7-methyl-7, 8,9,11,12, 13-hexahydro-6, 10-dioxa-2, 13 a-diazacycloundecano-benzo [ cd ] indene-4-carboxamide
Compound 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (35mg, 0.18mmol) was added dropwise to a solution of compound 16i (50mg, 0.18mmol) in DMF (3mL) while cooling on ice, and reacted for 0.5H. HATU (75mg, 0.20mmol) and N, N-diisopropylethylamine (46mg,0.36mmol) were then added to the reaction mixture, which was stirred at room temperature for 3h, and after completion of the reaction, was purified by reverse phase HPLC to give compound 16(5.5mg, yield 7.1%).
MS(ESI)m/z＝441[M+H]+
1H NMR(400M,DMSO-d6)δ12.84(s,1H),7.97-8.04(m,1H),7.62-7.67(m,1H),7.42-7.48(m,1H),7.31-7.38(m,1H),6.63(s,1H),4.92-4.98(m,1H),4.76-4.84(m,1H),4.56-4.66(m,2H),4.24-4.30(m,1H),3.94-4.01(m,1H),3.07-3.21(m,2H),2.17(s,3H),1.85-2.11(m,4H),1.61-1.69(m,1H),1.52(d,J＝6.08Hz,3H),1.35(t,J＝7.08Hz,3H).
Example 17
Figure BDA0002376124010000451
Step 1: synthesis of 1- (4-ethyl-2- (fluoromethyl) thiazole-5-carboxamido) -7,8,9,11,12, 13-hexahydro-6, 10-bisoxazole-2, 13 a-diazacyclohexyl [ cd ] indene 4-carboxamide
Compound 4-Ethyl-2- (fluoromethyl) thiazole-5-carbonyl isothiocyanate (23mg, 0.1mmol) was added dropwise to a solution of compound 2f (27mg, 0.1mmol) in DMF (3mL) while cooling on ice, and reacted for 0.5 h. HATU (46mg, 0.12mmol) and N, N-diisopropylethylamine (26mg,0.2mmol) were then added to the reaction mixture and stirred at room temperature for 3h, after completion of the reaction, it was purified by reverse phase MPLC to give compound 17(20mg, 43% yield).
MS(ESI)m/z＝462[M+H]+
1H NMR(400M,DMSO-d6)δ12.86(s,1H),7.85-8.11(m,1H),7.60-7.72(m,1H),7.43-7.55(m,1H),7.31-7.41(m,1H),5.65-5.78(m,1H),5.53-5.64(m,1H),4.33-4.64(m,4H),3.63-3.74(m,1H),3.21-3.29(m,2H),1.82-2.00(m,2H),1.20-1.32(m,3H).
Example 18
Figure BDA0002376124010000452
The compound 2- (difluoromethyl) -4-ethylthiazole-5-carbonyl isothiocyanate (25mg, 0.1mmol) was added dropwise to a solution of compound 2f (27mg, 0.1mmol) in DMF (3mL) while cooling on ice, and reacted for 0.5 h. HATU (46mg, 0.12mmol) and N, N-diisopropylethylamine (26mg,0.2mmol) were then added to the reaction mixture, which was stirred at room temperature for 3h, and after completion of the reaction, was purified by reverse phase HPLC to give compound 18(8.5mg, yield 17.7%).
MS(ESI)m/z＝480[M+H]+
1H NMR(400M,DMSO-d6)δ12.91(s,1H),7.95-8.03(m,1H),7.65-7.70(m,1H),7.44-7.50(m,1H),7.14-7.44(m,2H),4.40-4.58(m,4H),3.64-3.76(m,2H),3.25-3.31(m,2H),1.86-1.99(m,2H),1.27(t,J＝7.48Hz,3H).
Example 19
Figure BDA0002376124010000461
The compound 1-ethyl-4-fluoro-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (21mg, 0.1mmol) was added dropwise to a DMF (3mL) solution of the compound 2f (27mg, 0.1mmol) while cooling on ice, and reacted for 0.5H. HATU (46mg, 0.12mmol) and N, N-diisopropylethylamine (26mg,0.2mmol) were then added to the reaction mixture, which was stirred at room temperature for 3h, and after completion of the reaction, was purified by reverse phase HPLC to give compound 19(6.6mg, 14.9% yield).
MS(ESI)m/z＝445[M+H]+
1H NMR(400MHz,DMSO-d6)12.85(s,1H),7.98(s,1H),7.67(s,1H),7.45(s,1H),7.35(s,1H),4.55～4.40(m,6H),3.75～3.70(m,2H),2.16(s,3H),1.92～1.90(m,4H),1.34(t,J＝7.2Hz,3H)
Example 20
Figure BDA0002376124010000462
The compound 1-ethyl-4-chloro-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (23mg, 0.1mmol) was added dropwise to a DMF (3mL) solution of the compound 2f (27mg, 0.1mmol) while cooling on ice, and reacted for 0.5H. HATU (46mg, 0.12mmol) and N, N-diisopropylethylamine (26mg,0.2mmol) were then added to the reaction mixture, which was stirred at room temperature for 3h, and after completion of the reaction, was purified by reverse phase HPLC to give compound 20(5.8mg, 12.6% yield).
MS(ESI)m/z＝461[M+H]+
1H NMR(400MHz,DMSO-d6)12.96(s,1H),7.99(s,1H),7.69(s,1H),7.47(s,1H),7.36(s,1H),4.55～4.45(m,6H),3.79～3.74(m,2H),2.17(s,3H),1.94～1.90(m,4H),1.36(t,J＝7.2Hz,3H)
Example 21
Figure BDA0002376124010000471
Step 1: synthesis of benzyl (3- ((tert-butoxycarbonyl) amino) propylbenzyl (3- ((tert-butyldimethylsilyl) oxy) propyl) carbamate
To a solution of N-BOC propanediamine (2.1g, 12mmol) in acetonitrile was added DIPEA (3.1g, 24mmol) and O-TBS bromopropane (2.0g, 7.9mmol) at room temperature. The reaction solution is heated to 80 ℃ and reacted for 4 h. After cooling to room temperature, benzyloxycarboyl succinimide (2.98g, 12mmol) was reacted further for 3 h. The solvent was dried by evaporation and purified by silica gel column (petroleum ether/ethyl acetate: 5/1) to give compound 21a (2.4g, 62%)
MS(ESI)m/z＝481.3[M+H]+
Step 2: synthesis of benzyl (3- ((tert-butoxycarbonyl) amino) propyl) (3-hydroxypropyl) carbamate
Compound 21a (2.4g, 5mmol) was dissolved in tetrahydrofuran (5mL), tetrabutylammonium fluoride (10mL, 1M) was added, the reaction was carried out for 2 hours, tetrahydrofuran was removed by rotary evaporation, the crude product was dissolved in ethyl acetate, washed with water and saturated brine, respectively, and after concentration, purification by silica gel column (petroleum ether/ethyl acetate 2/3) was carried out to give compound 21b (1.3g, yield 70%)
MS(ESI)m/z＝367.2[M+H]+
And step 3: synthesis of methyl 3- (3- (((benzyloxy) carbonyl) (3- ((tert-butoxycarbonyl) amino) propyl) amino) propoxy) -4-chloro-5-nitrobenzoate
21b (400mg, 1.09mmol) and methyl 4-chloro-3-hydroxy-5-nitrobenzoate (252mg, 1.09mmol) were dissolved in dry tetrahydrofuran (10mL) and triphenylphosphine (428mg, 1.63mmol) was added. When the ice bath was cooled to 0 ℃, diisopropyl azodicarboxylate (440mg, 2.18mmol) was added under nitrogen. Then, the temperature is raised to room temperature, and the reaction is carried out for 18 h. After rotary drying, purification by column (petroleum ether/ethyl acetate: 3/2) gave compound 21c (600mg, yield 94%).
MS(ESI)m/z＝580.2[M+H]+
And 4, step 4: synthesis of methyl 3- (3- ((3-aminopropyl) ((benzyloxy) carbonyl) amino) propoxy) -4-chloro-5-nitrobenzoate
Trifluoroacetic acid (5mL) was added to a solution of 21c (600mg, 1.03mmol) in dichloromethane (10mL) while cooling on ice, warmed to room temperature for 1h, the solvent was dried by spinning, and excess trifluoroacetic acid was removed by an oil pump to give compound 21d (700mg, yield 100%).
MS(ESI)m/z＝480.2[M+H]+
And 5: synthesis of 5-benzyl 12-methyl 10-nitro-3, 4,6,7,8, 9-hexahydrobenzo [ b ] [1,4,8] diazacycloundecane-5, 12(2H) -dicarboxylate
21d (700mg, 1.03mmol) was dissolved in DMF (100mL), potassium carbonate (569mg, 4.12mmol) was added, the mixture was raised to 90 ℃ to react for 16h, the solvent was dried, ethyl acetate was added to dissolve the solvent, the inorganic salt was removed by washing with water, and the organic phase was dried to give crude product, which was purified by silica gel column (petroleum ether/ethyl acetate: 2/1) to give compound 21e (230mg, 50% yield)
MS(ESI)m/z＝444.1[M+H]+
Step 6: synthesis of 5-benzyl 12-methyl 10-amino-3, 4,6,7,8, 9-hexahydrobenzo [ b ] [1,4,8] diazacycloundecane-5, 12(2H) -dicarboxylate
21e (230mg, 0.52mmol) was dissolved in methanol (5mL) and tetrahydrofuran (5mL) and aqueous ammonia (1mL) was added under ice bath. After 10min, an aqueous solution (2mL) of sodium dithionite (452mg, 2.6mmol) was added to the reaction. Half an hour later, the reaction was completed, ethyl acetate was extracted, and the organic phase was dried with water, saturated brine and anhydrous sodium sulfate, respectively, filtered and concentrated to obtain compound 21f (190mg, yield 88%)
MS(ESI)m/z＝414.2[M+H]+
And 7: synthesis of methyl 10- ((benzyloxy) carbonyl) -1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -8,9,10,11,12, 13-hexahydro-7H-6-oxa-2, 10,13 a-triazacyclo [ cd ] indene-4-carboxylate
1-Ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (85mg, 0.46mmol) was added to a solution of 21f (190mg, 0.46mmol) in DMF (10mL) while cooling on ice. After ten minutes, DIPEA (148mg, 1.15mmol) and HATU (194mg, 0.51mmol) were added. After 2 hours of reaction, DMF was dried by evaporation, and ethyl acetate was added to precipitate a solid, which was collected by filtration to obtain 21g (200mg, yield 74%) of the compound.
MS(ESI)m/z＝575.2[M+H]+
And 8: synthesis of 10- ((benzyloxy) carbonyl) -1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -8,9,10,11,12, 13-hexahydro-7H-6-oxa-2, 10,13 a-triazacyclo [ cd ] indene-4-carboxylic acid 21g (200mg, 0.34mmol) was dissolved in methanol (3mL) and tetrahydrofuran (3mL), and lithium hydroxide hydrate (74mg, 1.7mmol) was added. Raising the temperature to 75 ℃ and reacting for 2 h. After cooling, the pH was adjusted to about 3 with dilute hydrochloric acid (1M), a solid precipitated, which was filtered and dried to give compound 21h (160mg, yield 84%).
MS(ESI)m/z＝561.2[M+H]+
And step 9: synthesis of 10- ((benzyloxy) carbonyl) -1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -8,9,10,11,12, 13-hexahydro-7H-6-oxa-2, 10,13 a-triazacyclo [ cd ] indene-4-carboxamide
To a solution of 21h (160mg, 0.28mmol) in DMF (5mL) under ice bath were added HATU (106mg, 0.28mmol), DIPEA (108mg, 0.84mmol) and ammonium chloride (74mg, 1.4 mmol). After 2 hours of reaction, DMF was spin-dried, the mixture was dissolved in ethyl acetate, washed with water and saturated brine, and the organic phase was spin-dried to give compound 21i (130mg, yield 82%).
MS(ESI)m/z＝560.2[M+H]+
Step 10: synthesis of 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -8,9,10,11,12, 13-hexahydro-7H-6-oxa-2, 10,13 a-triazaheterocyclyl [ cd ] indene-4-carboxamide
21i (130mg, 0.23mmol) was dispersed in dichloromethane (5mL), and hydrobromic acid/acetic acid (33%, 5mL) was added and reacted at room temperature for 1 h. The solvent was dried by evaporation to give crude product (140mg, hydrobromide and acetic acid), 50mg of which was separated and purified by preparative HPLC to give compound 21(22 mg).
MS(ESI)m/z＝426.2[M+H]+
1H NMR(400MHz,DMSO):δppm8.06(s,1H)，7.73(s,1H)，7.54(s,1H)，7.40(s,1H)，6.72(s,1H)，4.62-4.55(m,6H)，3.20(s,br,2H)，2.94(s,br,2H)，2.19-2.13(m,5H)，2.08(s,br,2H)，1.36(t,J＝7.4,3H).
Example 22
Figure BDA0002376124010000491
Figure BDA0002376124010000501
Step 1: synthesis of tert-butyl (3- (3- (benzyloxy) propoxy) propyl) carbamate sodium hydride (550mg, 13.7mmol) was added to a mixed solvent of tert-butyl (3-hydroxypropyl) carbamate (2g, 11.42mmol) in DMF (8mL) and tetrahydrofuran (16mL) under ice bath. After stirring for 30 minutes, 3-benzyloxybromopropane (3.66g, 15.989mmol) was added and the reaction was allowed to warm to room temperature for 10 h. After completion of the reaction, water was added, ethyl acetate was extracted (50mL × 3), the organic phases were combined and the solvent was dried and the crude product was separated by column chromatography (eluent: ethyl acetate/petroleum ether 1/10, v/v) to give tert-butyl (3- (3- (benzyloxy) propoxy) propyl) carbamate (compound 22a) (1.23g, 3.8mmol) as a colorless oil in 33% yield.
MS(ESI)m/z＝324[M+H]+。
Step 2: synthesis of tert-butyl (3- (3-hydroxypropoxy) propyl) carbamate
Palladium on carbon (10%, 80mg) was added to a solution of compound 22a (800mg, 2.47mmol) in methanol and ethyl acetate, and the mixture was reduced by hydrogenation for 3 hours, followed by filtration to remove the palladium on carbon, and the filtrate was concentrated to give tert-butyl (3- (3-hydroxypropoxy) propyl) carbamate (compound 22b) (519mg, 2.227mmol) in 90% yield. Directly used for the next reaction.
MS(ESI)m/z＝234[M+H]+。
And step 3: synthesis of 3- (3-tert-butoxycarbonylamino) propoxy) propyl methanesulfonate
Compound 22b (800mg,3.43mmol) and triethylamine (1.43mL,10.3mmol) were dissolved in DCM (20mL) under ice-bath, methanesulfonyl chloride (0.3mL,4.12mmol) was added slowly dropwise, and after dropping, the reaction was allowed to warm to room temperature overnight. LCMS showed the reaction was complete and the reaction was washed with water, dried and spun dry to give methanesulfonic acid 3- (3-tert-butoxycarbonylamino) propoxy) propyl ester (compound 22c) (1.35g,4.34mmol) in 126% yield for the next reaction.
MS(ESI)m/z＝312[M+H]+。
And 4, step 4: synthesis of 3- (3-tert-butoxycarbonylamino) propoxy) propylthioester acetate
Compound 22c (1.35g,4.34mmol) was dissolved in DMF (20mL), potassium thioacetate (0.94g,8.68mmol) was added and stirred at room temperature overnight. LCMS showed reaction completion. The reaction mixture was poured into water, extracted with ethyl acetate (3 × 40mL), the ethyl acetate layers were combined, dried, spin-dried, and purified by column chromatography (eluent: ethyl acetate/petroleum ether 1/5, v/v) (ninhydrin color development) to give acetic acid-3- (3-tert-butoxycarbonylamino) propoxy) propylthioester (compound 22d) (1.062g,3.65mmol) as a yellow oil in 84% yield.
MS(ESI)m/z＝292[M+H]+。
And 5: synthesis of acetic acid-3- (3-aminopropoxy) propylthioester
Compound 22d (1.062g,3.65mmol) was added to a mixed solvent of dichloromethane (20mL) and trifluoroacetic acid (4mL) at room temperature and stirred overnight. LCMS showed the reaction was complete and the reaction was directly spin dried to give the trifluoroacetate salt of acetic acid-3- (3-aminopropoxy) propylthioester (compound 22e) (1.11g,3.65mmol) in 100% yield.
MS(ESI)m/z＝192[M+H]+。
Step 6: synthesis of methyl 4- (3- (3-ethylthiopropoxy) propylamino) -3-bromo-5-nitrobenzoate
The trifluoroacetate salt of compound 22e (1.11g,3.65mmol) was dissolved in DMF (15mL), and methyl 3-bromo-4-fluoro-5-nitrobenzoate (1.00g,3.65mmol) and triethylamine (1.51mL,10.95mmol) were added successively at room temperature, and the mixture was stirred at room temperature overnight. LCMS showed the reaction was complete and the reaction was poured into water, extracted with ethyl acetate (3 × 40mL), the ethyl acetate layers combined and dried, spin dried and purified by column chromatography (eluent: ethyl acetate/petroleum ether 1/6, v/v) to give methyl 4- (3- (3-ethylthiopropoxy) propylamino) -3-bromo-5-nitrobenzoate (compound 22f) (1.52g,3.39mmol) in 92.8% yield.
MS(ESI)m/z＝448[M+H]+。
And 7: synthesis of methyl 4- (3- (3-mercaptopropoxy) propylamino) -3-bromo-5-nitrobenzoate
Compound 22f (1.52g,3.39mmol) was dissolved in methanol (40mL), sodium methoxide (366mg,6.79mmol) was added under ice bath, and the reaction was stirred for 30min under ice bath, LCMS showed completion. Adding 1M HCl to adjust the pH to acidity, and spin-drying. The residue was dissolved in water and ethyl acetate (50mL), and the ethyl acetate layer was separated, dried and then spin-dried to give methyl 4- (3- (3-mercaptopropoxy) propylamino) -3-bromo-5-nitrobenzoate (compound 22g) (1.30g,3.19mmol) in 94.3% yield.
MS(ESI)m/z＝406[M+H]+。
And 8: synthesis of methyl 10-nitro-3, 4,6,7,8, 9-hexahydro-2H-benzo [ f ] [1,5,8] oxathiolane-undecane-12-carboxylate
At room temperature, 22g (1.30g,3.19mmol) of compound was dissolved in dioxane (80mL), N-diisopropylethylamine (1.58mL,9.57mmol), Xantphos (369mg,0.638mmol), Pd2(dba)3(292mg,0.319mmol) were added sequentially under nitrogen, and the mixture was heated to 100 ℃ for reaction overnight. LCMS showed reaction completion. Insoluble matter was removed excessively, and the filtrate was spin-dried and purified by column chromatography (eluent: ethyl acetate/petroleum ether: 1/5to 1/3, v/v) to give methyl 10-nitro-3, 4,6,7,8, 9-hexahydro-2H-benzo [ f ] [1,5,8] oxathiazetidine-12-carboxylate (compound 22H) (570mg,1.74mmol), yield 54.7%.
MS(ESI)m/z＝327[M+H]+。
And step 9: synthesis of methyl 10-amino-3, 4,6,7,8, 9-hexahydro-2H-benzo [ f ] [1,5,8] oxathiolane-undecane-12-carboxylate
Compound 22h (400mg,1.23mmol) was suspended in methanol (30mL), aqueous ammonia (1mL) was added in an ice bath, an aqueous solution (5mL) of sodium dithionite (1.07g,6.14mmol) was added dropwise, after dropping, the mixture was warmed to room temperature and stirred for 2 hours, and LCMS indicated completion of the reaction. Insoluble matter was removed by filtration, the filtrate was dried by spinning, the residue was redissolved with water and ethyl acetate (50mL), and the ethyl acetate layer was separated and dried by spinning to obtain methyl 10-amino-3, 4,6,7,8, 9-hexahydro-2H-benzo [ f ] [1,5,8] oxathiazetidine-12-carboxylate (compound 22i) (320mg,1.08mmol) with a yield of 88.1%.
MS(ESI)m/z＝297[M+H]+。
Step 10: synthesis of methyl 1- (4-ethyl-2-methylthiazole-5-carboxamide) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundec [ cd ] indene-4-carboxylate
Compound 22i (160mg,0.54mmol) was dissolved in DMF (5mL), and 4-ethyl-2-methylthiazole-5-carbonyl isothiocyanate (126mg,0.594mmol) was added with cooling on an ice bath, reacted for 30 minutes on an ice bath, and after completion of addition by LCMS, HATU (226mg,0.594mmol) and N, N-diisopropylethylamine (0.28mL,1.62mmol) were added, warmed to room temperature and stirred overnight. LCMS showed the reaction was complete, the precipitated solid was filtered, and the filter cake was washed once with DMF (1mL) and petroleum ether (20mL) each, and dried to give methyl 1- (4-ethyl-2-methylthiazole-5-carboxamido) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundec [ cd ] indene-4-carboxylate (compound 22j) (140mg,0.295mmol) in 54.6% yield.
MS(ESI)m/z＝475[M+H]+。
Step 11: synthesis of 1- (4-ethyl-2-methylthiazole-5-carboxamido) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundec [ cd ] indene-4-carboxylic acid
Compound 22j (70mg,0.148mmol) was suspended in methanol (5mL), water (1mL) and lithium hydroxide monohydrate (62mg,1.48mmol) were added, the temperature was raised to 40 ℃ and stirred overnight, LCMS indicated reaction completion. The mixture was acidified by addition of 1M HCl and the solvent was dried. The residue was redissolved with water and dichloromethane (30mL) to separate the dichloromethane layer, dried and then spin-dried to give 1- (4-ethyl-2-methylthiazole-5-carboxamido) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundec [ cd ] indene-4-carboxylic acid (compound 22k) (61mg,0.133mmol) in 81.8% yield.
MS(ESI)m/z＝461[M+H]+。
Step 12: synthesis of 1- (4-ethyl-2-methylthiazole-5-carboxamide) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundec [ cd ] indene-4-carboxamide
Compound 22k (61mg,0.133mmol) was dissolved in DMF (5mL), N-diisopropylethylamine (0.09mL,0.532mmol) and HATU (76mg,0.20mmol) were added, and after stirring at room temperature for 30 minutes, ammonium chloride (21mg,0.398mmol) was added and the mixture was stirred at room temperature overnight. LCMS showed the reaction was complete, the reaction was poured into water, extracted with ethyl acetate (3 × 30mL), the ethyl acetate layers were combined, dried and spun dry, purified by prep-HPLC to give 1- (4-ethyl-2-methylthiazole-5-carboxamido) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundec [ cd ] indene-4-carboxamide (compound 22) (23.5mg,0.051mmol) in 28% yield.
MS(ESI)m/z＝460[M+H]+。
1H NMR(400MHz,DMSO-d6)δ12.93(s,1H),8.07(s,1H),7.97(d,J＝16.7Hz,2H),7.40(s,1H),5.53(s,1H),4.19(s,1H),3.21(s,4H),3.22–3.15(m,1H),2.99(s,1H),2.61(s,3H),2.29(s,1H),1.96(s,1H),1.62(s,2H),1.53(s,1H),1.24(t,J＝7.3Hz,4H).
Example 23
Figure BDA0002376124010000531
Step 1: synthesis of methyl 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundec [ cd ] indene-4-carboxylate
Compound 22i (160mg,0.54mmol) was dissolved in DMF (5mL), and 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (116mg,0.594mmol) was added under cooling in ice bath, and after completion of addition by LCMS for 30 minutes, HATU (226mg,0.594mmol) and N, N-diisopropylethylamine (0.28mL,1.62mmol) were added, and the mixture was warmed to room temperature and stirred overnight. LCMS showed the reaction was complete, the reaction was poured into water, ethyl acetate extracted (3 × 30mL), the ethyl acetate layers were combined, dried and spun dry to give methyl 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundec [ cd ] indene-4-carboxylate (compound 23a) (335mg,0.733mmol), yield 136%.
MS(ESI)m/z＝458[M+H]+。
Step 2: synthesis of 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundec [ cd ] indene-4-carboxylic acid
Compound 23a (190mg,0.416mmol) was suspended in methanol (5mL), water (1mL) and lithium hydroxide monohydrate (175mg,4.16mmol) were added, the temperature was raised to 50 ℃ and stirred overnight, LCMS indicated reaction completion. The mixture was acidified by addition of 1M HCl and the solvent was dried. The residue was redissolved with water and ethyl acetate (30mL), the ethyl acetate layer was separated, dried and then spin-dried to give 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundec [ cd ] indene-4-carboxylic acid (compound 23b) (148mg,0.334mmol), yield 80.4%.
MS(ESI)m/z＝444[M+H]+。
And step 3: synthesis of 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundec [ cd ] indene-4-carboxamide
Compound 23b (148mg,0.334mmol) was dissolved in DMF (5mL), N-diisopropylethylamine (0.22mL,1.336mmol), HATU (190mg,0.501mmol) were added, and after stirring at room temperature for 30 minutes, ammonium chloride (53mg,1.00mmol) was added and the mixture was stirred at room temperature overnight. LCMS showed the reaction was complete, the reaction was poured into water, extracted with ethyl acetate (3 × 30mL), the ethyl acetate layers were combined, dried and spun dry, purified by prep-HPLC to give 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundecane [ cd ] indene-4-carboxamide (compound 23) (17.5mg,0.040mmol) in 11.4% yield.
MS(ESI)m/z＝443[M+H]+。
1H NMR(400MHz,DMSO-d6)δ12.96(s,1H),8.08(s,1H),7.99(d,J＝10.0Hz,2H),7.40(s,1H),6.65(s,1H),5.52(s,1H),4.62(q,J＝7.2Hz,2H),4.25(s,1H),3.73(s,1H),3.57(s,1H),3.26(s,1H),3.17(s,1H),2.98(s,1H),2.25(s,1H),2.18(s,3H),1.97(s,1H),1.63(s,1H),1.53(s,1H),1.36(t,J＝7.1Hz,3H).
Example 24
Figure BDA0002376124010000541
Step 1: synthesis of methyl 1- (4-ethyl-2-methylthiazole-5-carboxamide) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundec [ cd ] indene-4-carboxylate-6, 6-dioxide
Compound 22j (70mg,0.147mmol) was dissolved in dichloromethane (10mL), and m-chloroperoxybenzoic acid (51mg,0.295mmol) was added and stirred at room temperature overnight. LCMS shows that the reaction is finished, the reaction solution is washed by water, an organic layer is separated, and after drying, spin drying is carried out, so that 1- (4-ethyl-2-methylthiazole-5-formamido) -7,8,9,11,12, 13-hexahydro-10-oxo-6-sulfur-2, 13 a-diazacycloundec [ cd ] indene-4-methyl formate-6, 6-dioxide (compound 24a) (76mg,0.15mmol) is obtained, and the yield is 101.7%.
MS(ESI)m/z＝507[M+H]+。
Step 2: synthesis of 1- (4-ethyl-2-methylthiazole-5-carboxamide) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundec [ cd ] indene-4-carboxylic acid-6, 6-dioxide
Compound 24a (76mg,0.15mmol) was suspended in methanol (5mL), water (1mL) and lithium hydroxide monohydrate (63mg,1.5mmol) were added, the temperature was raised to 50 ℃ and stirred overnight, LCMS indicated reaction completion. The mixture was acidified by addition of 1M HCl and the solvent was dried. The residue was redissolved with water and ethyl acetate (30mL), the ethyl acetate layer was separated, dried and spin-dried to give 1- (4-ethyl-2-methylthiazole-5-carboxamido) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundec [ cd ] indene-4-carboxylic acid-6, 6-dioxide (compound 24b) (25mg,0.051mmol), yield 34%.
MS(ESI)m/z＝493[M+H]+。
And step 3: synthesis of 1- (4-ethyl-2-methylthiazole-5-carboxamide) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundec [ cd ] indene-4-carboxamide-6, 6-dioxide
Compound 24b (25mg,0.051mmol) was dissolved in DMF (5mL), N-diisopropylethylamine (0.033mL,0.204mmol) and HATU (29mg,0.077mmol) were added, and after stirring at room temperature for 30 minutes, ammonium chloride (8mg,0.152mmol) was added and stirring at room temperature overnight. LCMS showed the reaction was complete, the reaction was poured into water, extracted with ethyl acetate (3 × 30mL), the ethyl acetate layers were combined, dried and spun dry, purified by prep-HPLC to give 1- (4-ethyl-2-methylthiazole-5-carboxamido) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundec [ cd ] indene-4-carboxamide-6, 6-dioxide (compound 24) (0.9mg,0.0018mmol), 3.6% yield.
MS(ESI)m/z＝492[M+H]+。
1H NMR(400MHz,Methanol-d4)δ8.42(d,J＝1.6Hz,1H),8.22(d,J＝1.7Hz,1H),5.60(s,1H),5.36(t,J＝4.8Hz,1H),,3.37(s,3H),2.72(s,3H),2.34(s,3H),2.21(s,2H),1.79(s,1H),1.62(s,1H),1.43(s,1H),1.37–1.28(m,1H),0.92(t,J＝6.7Hz,3H)
Example 25
Figure BDA0002376124010000551
Step 1: synthesis of 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundec [ cd ] indene-4-carboxylic acid methyl ester-6-oxide
Compound 23a (136mg,0.298mmol) was dissolved in dichloromethane (5mL), m-chloroperoxybenzoic acid (61mg,0.357mmol) was added under ice-cooling, and the mixture was stirred for 3 hours under ice-cooling. LCMS shows that the reaction is finished, the reaction liquid is washed by saturated solution of sodium bicarbonate, an organic layer is separated, and after drying, spin drying is carried out, so as to obtain 1- (1-ethyl-3-methyl-1H-pyrazole-5-formamido) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundec [ cd ] indene-4-methyl formate-6-oxide (compound 25a) (50mg,0.106mmol) with the yield of 35.5 percent.
MS(ESI)m/z＝474[M+H]+。
Step 2: synthesis of 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundec [ cd ] indene-4-carboxylic acid-6-oxide
Compound 25a (50mg,0.106mmol) was suspended in methanol (5mL), water (1mL) and lithium hydroxide monohydrate (45mg,1.06mmol) were added, and the reaction was stirred overnight with LCMS indicating completion at 50 ℃. The mixture was acidified by addition of 1M HCl and the solvent was dried. The residue was redissolved with water and ethyl acetate (30mL), the ethyl acetate layer was separated, dried and spin-dried to give 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundec [ cd ] indene-4-carboxylic acid-6-oxide (compound 25b) (50mg,0.11mmol), 103% yield.
MS(ESI)m/z＝460[M+H]+。
And step 3: synthesis of 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundec [ cd ] indene-4-carboxamide-6-oxide
Compound 25b (50mg,0.11mmol) was dissolved in DMF (5mL), N-diisopropylethylamine (0.07mL,0.44mmol), HATU (63mg,0.165mmol) were added, and after stirring at room temperature for 30 minutes, ammonium chloride (18mg,0.33mmol) was added and the mixture was stirred at room temperature overnight. LCMS showed the reaction was complete, the reaction was poured into water, ethyl acetate extracted (3 × 30mL), the ethyl acetate layers were combined, dried and spun dry, and purified by prep-HPLC to give 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundecane [ cd ] indene-4-carboxamide-6-oxide (compound 25) (0.9mg,0.002mmol), 1.8% yield.
MS(ESI)m/z＝459[M+H]+。
1H NMR(400MHz,DMSO-d6)δ13.08(s,1H),8.30(d,J＝15.1Hz,2H),8.15(s,1H),7.56–7.46(m,1H),6.67(s,1H),4.74(t,J＝12.6Hz,1H),4.61(p,J＝7.0,6.6Hz,2H),4.42–4.33(m,1H),4.04(s,1H),3.54(t,J＝10.6Hz,1H),3.48(t,J＝5.3Hz,2H),3.18(d,J＝6.6Hz,1H),2.27(s,1H),2.19(s,3H),2.00(dt,J＝13.2,6.3Hz,1H),1.75(d,J＝15.2Hz,1H),1.36(t,J＝7.1Hz,3H),1.24(s,2H)
Example 26
Figure BDA0002376124010000561
Step 1: synthesis of methyl 1- (4-ethyl-2-methylthiazole-5-carboxamido) -8,10,11, 12-tetrahydro-7H-9-oxo-6-thio-2, 12 a-diazacyclo-deca [ cd ] indene-4-carboxylate
Compound 8g (120mg,0.425mmol) was dissolved in DMF (5mL), and 4-ethyl-2-methylthiazole-5-carbonyl isothiocyanate (90mg,0.425mmol) was added with cooling in ice bath, reacted for 30 minutes in ice bath, and after completion of addition by LCMS, HATU (178mg,0.468mmol) and N, N-diisopropylethylamine (0.23mL,1.28mmol) were added, warmed to room temperature and stirred overnight. LCMS showed the reaction was complete, the reaction was poured into water, extracted with ethyl acetate (3 × 30mL), the ethyl acetate layers were combined, dried and spun dry to give methyl 1- (4-ethyl-2-methylthiazole-5-carboxamido) -8,10,11, 12-tetrahydro-7H-9-oxo-6-thio-2, 12 a-diazacyclodecan [ cd ] indene-4-carboxylate (compound 26a) (220mg,0.478mmol) in 112% yield.
MS(ESI)m/z＝461[M+H]+。
Step 2: synthesis of 1- (4-ethyl-2-methylthiazole-5-carboxamido) -8,10,11, 12-tetrahydro-7H-9-oxo-6-thio-2, 12 a-diazacyclo-deca [ cd ] indene-4-carboxylic acid
Compound 26a (220mg,0.478mmol) was suspended in methanol (10mL), water (2mL) and lithium hydroxide monohydrate (201mg,4.78mmol) were added, the temperature was raised to 40 ℃ and stirring was continued overnight with LCMS to show completion of the reaction. The mixture was acidified by addition of 1M HCl and the solvent was dried. The residue was redissolved with water and dichloromethane (30mL) to separate the dichloromethane layer, dried and then spin-dried to give 1- (4-ethyl-2-methylthiazole-5-carboxamido) -8,10,11, 12-tetrahydro-7H-9-oxo-6-thio-2, 12 a-diazacyclodecan [ cd ] indene-4-carboxylic acid (compound 26b) (80mg,0.179mmol) in 37.5% yield.
MS(ESI)m/z＝447[M+H]+。
And step 3: synthesis of 1- (4-ethyl-2-methylthiazole-5-carboxamido) -8,10,11, 12-tetrahydro-7H-9-oxo-6-thio-2, 12 a-diazacyclo-deca [ cd ] indene-4-carboxamide
Compound 26b (80mg,0.179mmol) was dissolved in DMF (5mL), triethylamine (0.1mL,0.716mmol) and HATU (102mg,0.0.269mmol) were added, and after stirring at room temperature for 30 minutes, ammonium chloride (29mg,0.538mmol) was added and the mixture was stirred at room temperature overnight. LCMS showed the reaction was complete, the reaction was poured into water, extracted with ethyl acetate (3 × 30mL), the ethyl acetate layers were combined, dried and spun dry, purified by prep-HPLC to give 1- (4-ethyl-2-methylthiazole-5-carboxamido) -8,10,11, 12-tetrahydro-7H-9-oxo-6-thio-2, 12 a-diazacyclodecan [ cd ] indene-4-carboxamide (compound 26) (6mg,0.013mmol) in 7.5% yield.
MS(ESI)m/z＝446[M+H]+。
1H NMR(400MHz,DMSO-d6)δ12.98(s,1H),8.08–7.93(m,3H),7.41(s,1H),6.18–6.07(m,1H),4.16–4.07(m,1H),3.86(dt,J＝10.5,3.9Hz,1H),3.74(d,J＝9.5Hz,1H),3.19(q,J＝7.7Hz,2H),3.10(dt,J＝13.9,4.1Hz,2H),2.89(s,1H),2.73(s,1H),2.60(s,3H),2.34(s,1H),2.04(s,1H),1.23(t,J＝7.5Hz,3H).
Example 27
Figure BDA0002376124010000571
To a solution of 21(20mg, 0.047mmol) in methanol (2mL) was added acetic acid to a pH of about 4, followed by addition of a solution of formalin (1 mL). After 0.5h reaction at room temperature, sodium cyanoborohydride (15mg, 0.24mmol), when reacted to completion, was purified by preparative HPLC to give compound 27(8mg, 38% yield)
MS(ESI)m/z＝440.2[M+H]+。
1H NMR(400MHz,DMSO):δppm12.79(s,1H)，7.96(s,1H)，7.67(s,1H)，7.46(s,1H)，7.33(s,1H)，6.65(s,1H)，4.73(t,J＝6.52，1H)，4.63(q,J＝6.57，2H)，4.54(m,2H)，2.28-2.22(m,5H)，2.18(s,3H)，1.87-1.83(m,2H)，1.80-1.76(m,2H)，1.36(t,J＝6.87,3H).
Example 28
Figure BDA0002376124010000581
1-methylpiperidine-4-carboxylic acid (8mg, 0.056mmol) was dissolved in DMF (2mL), HATU (21mg, 0.056mmol) and DIPEA (12mg, 0.094mmol) were added thereto at room temperature, and after stirring for 1 hour, 21(20mg, 0.047mmol) was added to the reaction mixture. After two hours the reaction was complete and the reaction solution was purified by preparative HPLC to give compound 28(4.8mg, 15% yield)
MS(ESI)m/z＝551.3[M+H]+。
1H NMR(400MHz,DMSO):δppm7.99(s,1H)，7.69(s,1H)，7.55(s,0.3H)，7.51(s,0.8H)，7.35(s,1H)，6.75(s,0.7H)，6.75(s,0.3H)，4.62(q,J＝7.28,4H)，4.46-4.36(m,3H)，4.29-4.24(m,2H)，4.20-4.15(m,1H)，3.72-3.67(m,0.6H)，3.56-3.50(m,2H)，3.49-3.39(m,3H)，3.35-3.29(m,0.4H)，3.09-2.94(m,3H)，2.79-2.75(m,3H)，2.21-2.18(m,3H)，2.16-2.10(m,2H)，2.05-1.95(m,2H)，1.94-1.80(m,4H)，1.36(t,J＝7.28,3H).
The advantageous effects of the present invention are described below by way of test examples.
Test example 1 binding affinity test of the Compound of the present invention to Sting protein
(1) Experimental methods
Binding affinity of Compounds to Sting proteins was determined using the protein Heat transfer assay (TSA) at 20mM Hepes,150mM NaCl,1mM MgCl2Mixing 100ug/ml Sting Protein with different concentrations of compound and 5 XSYPRO Orange dye in 1mM DTT pH 7.5 buffer, measuring the Protein dissolution curve on a qPCR instrument, fitting the Tm with Protein Thermal Shift Software 1.3 Software, calculating the difference in Tm for proteins with and without compound addition, based on the difference in Tm for proteins with and without compound additionΔThe Tm is fitted to the change of compound concentration to obtain a dissociation constant Kd, and the lower the Kd, the stronger the binding affinity of the compound to Sting protein.
(2) Results of the experiment
TABLE 1 binding affinities of Compounds to Sting proteins
Compound (I) Kd
2 +++
3 +++
4 ++
5 +++
6 +++
7 ++
9 +++
13 +++
16 +++
17 +++
19 +++
20 +++
21 +
22 ++
23 ++
27 +
28 ++
Wherein the Kd values determined for each compound are classified according to the following instructions:
"+" indicates a Kd value of greater than 100. mu.M and less than 500. mu.M;
"+ +" indicates a Kd value of less than 100. mu.M and greater than 50. mu.M;
"+ + + +" indicates a Kd value of less than 50 μ M;
the experimental results show that the compound of the invention has good ability of binding with Sting protein, especially the compounds 2-6, 9, 13, 16, 17, 19, 20, 23 and 28. Therefore, the compound of the present invention can be used as an effective STING protein regulator.
Test example 2 testing of Sting protein agonistic function by the Compound of the present invention
(1) Experimental methods
This experiment evaluates the function of sting agonists by measuring changes in CXCL10(IP10) cytokines produced by compounds stimulating the human peripheral blood mononuclear cell line, THP1 cells (shanghai cell bank). The first day of the experiment the ELISA plates were coated according to the instructions of the IP10 ELISA detection kit (BD, # 550926). Dissolving a compound DMSO into a stock solution, diluting the stock solution into 2X working concentration by using a culture medium, and adding the stock solution into a 96-well plate, wherein each well is 100 mu L; taking logarithmTHP1 cells in growth phase were counted and diluted 2x 106At a concentration of 100. mu.L/well in a 96-well plate containing the above-mentioned compound, and mixing at 37 ℃ with 5% CO2The culture was carried out in an incubator for 18 hours. The following day, 100. mu.L of the cell culture supernatant was collected per well, assayed according to the protocol of the IP10 ELISA kit (BD, #550926), and OD450 values were read, converted to IP10 concentrations according to the standard curve, and EC was calculated using a GraphPad 5.0 binding-effect curve50The value is obtained. EC (EC)50A concentration at half maximal effect (EC 50) refers to the concentration of drug that causes 50% of the individuals to be effective.
(2) Results of the experiment
TABLE 2 Effect of Compounds on CXCL10(IP10) cytokines
Compound (I) EC50
2 ++
4 ++
9-1 +++
9-2 ++
11 +++
12 ++
19 ++
20 ++
22 +
23 ++
27 +
Wherein the EC of each compound is determined50The values are classified as follows:
"+" indicates EC50Values greater than 10 μ M and less than 50 μ M;
"+ +" indicates EC50Values less than 10. mu.M greater than 1. mu.M;
"+ + + +" denotes EC50A value of less than 1 μ M;
the experimental results show that the compound of the invention has good activity of stimulating CXCL10(IP10) cytokine production of THP1 cells and good STING protein agonistic function, and particularly the compound 2,4, 9-1, 9-2, 11,12, 19, 20, 23.
In conclusion, the invention provides the compound with a novel structure shown in the formula I, and experimental results show that the compound can be effectively combined with STING and has a good STING protein agonistic function. Thus, the compounds of the present invention are useful as STING agonists and for the treatment of various related disorders. The compound provided by the invention has a very good application prospect in preparing medicines for treating diseases related to STING activity, particularly medicines for treating inflammatory diseases, autoimmune diseases, infectious diseases, cancers or precancerous syndromes.

Claims (20)

1. A compound represented by formula I or a pharmaceutically acceptable salt thereof:
Figure FDA0003010068650000011
wherein the content of the first and second substances,
R1、R2are respectively and independently selected from hydrogen and C1～C6Alkyl, cyano, nitro, hydroxy, amino, C1～C6Alkoxy radical, C1～C6Alkylamino, halogen substituted C1～C6An alkyl group;
R3selected from hydrogen, C1～C6Alkyl, halogen of (a);
R4selected from hydrogen, C1～C6Alkyl, halogen, cyano, nitro, hydroxy, amino, C1～C6Alkoxy radical, C1～C6Alkylamino, halogen substituted C1～C6Alkyl or none;
R5selected from hydrogen, C1～C6Alkyl groups of (a);
X2selected from C or N;
ring B is selected from the group consisting of 0 to 4RaSubstituted benzene ring, substituted by 0-4RaA substituted 5-to 6-membered aromatic heterocycle;
Raselected from halogen, hydroxyl, amino, and a group consisting of 0 to 4RbOptionally substituted C1～C6An alkyl group;
Rbselected from halogen, hydroxy, amino, C1～C6An alkoxy group;
x is selected from-O-, -S (O)n-or none; n is 1 or 2;
L1、L2are respectively and independently selected from 0 to 4RiSubstituted C1～C10Alkylene of (a) with 0 to 4RiSubstituted C2～C10Wherein when R isiAt least 2 times, L1、L2R in (1)iCan be connected to form a 3-10 membered ring;
Riis selected from-ORjHalogen, -CN, C1～C6An alkyl group;
Rjselected from hydrogen, C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
z is selected from-O-, -C (O) -,
Figure FDA0003010068650000012
Rc、Rdare respectively and independently selected from hydrogen and C1～C6Alkyl, halogen substituted C1～C6Alkyl, -C (O) RkOr none, or RcAnd RdAre linked to the nitrogen atom to which they are attached to form a group consisting of 0 to 4ReOptionally substituted 3-to 8-membered heterocycloalkane substituted with 0 to 4ReAn optionally substituted 3-to 10-membered heteroaromatic ring;
Rkselected from the group consisting of 0 to 4RmSubstituted 5-to 6-membered cycloalkyl, substituted with 0 to 4RmA substituted 5-to 6-membered heterocycloalkyl group; rmIs selected from C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
Rg、Rhindependently selected from-C (O) -, -C (O) O-, or none;
Reis selected from-ORf-、C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
Rfselected from hydrogen, C1～C6Alkyl, halogen substituted C1～C6An alkyl group.
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: the compound is represented by formula I:
Figure FDA0003010068650000021
wherein the content of the first and second substances,
R1、R2are respectively and independently selected from hydrogen and C1～C6Alkyl groups of (a);
R3selected from hydrogen, C1～C6Alkyl, halogen of (a);
R4selected from hydrogen, C1～C6Alkyl, halogen or none of (a);
R5selected from hydrogen, C1～C6Alkyl groups of (a);
X2selected from C or N;
ring B is selected from the group consisting of 0 to 4RaSubstituted benzene ring, substituted by 0-4RaA substituted 5-to 6-membered aromatic heterocycle;
Raselected from the group consisting of 0 to 4RbOptionally substituted C1～C6An alkyl group;
Rbselected from halogen, hydroxy, amino, C1～C6An alkoxy group;
x is selected from-O-, -S-or none;
L1、L2are respectively and independently selected from 0 to 4RiSubstituted C1～C10Wherein when R isiAt least 2 times, L1、L2R in (1)iCan be connected to form a 3-10 membered ring;
Riis selected from-ORjHalogen, -CN, C1～C6An alkyl group;
Rjselected from hydrogen, C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
z is selected from-O-, -C (O) -,
Figure FDA0003010068650000022
Rc、Rdare respectively and independently selected from hydrogen and C1～C6Alkyl, halogen substituted C1～C6Alkyl or not, or RcAnd RdAre linked to the nitrogen atom to which they are attached to form a group consisting of 0 to 4ReOptionally substituted 3-to 8-memberedHeterocyclic alkane, with 0-4ReAn optionally substituted 3-to 10-membered heteroaromatic ring;
Rg、Rhindependently selected from-C (O) -, -C (O) O-, or none;
Reis selected from-ORf-、C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
Rfselected from hydrogen, C1～C6Alkyl, halogen substituted C1～C6An alkyl group.
3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein: the compound is represented by formula II:
Figure FDA0003010068650000023
ring B is selected from
Figure FDA0003010068650000031
R6、R7、R8Are independently selected from hydrogen and 0-4RbOptionally substituted C1～C6An alkyl group;
Rbselected from halogen, hydroxy, amino, C1～C6An alkoxy group;
R1、R2are respectively and independently selected from hydrogen and C1～C6Alkyl groups of (a);
R3、R4are respectively and independently selected from hydrogen and C1～C6Alkyl, halogen of (a);
R5selected from hydrogen, C1～6Alkyl groups of (a);
L1、L2are respectively and independently selected from 0 to 4RiSubstituted C1～C10Wherein when R isiAt least 2 times, L1、L2R in (1)iCan be connected to form a 3-10 membered ring;
Riis selected from-ORjHalogen, -CN, C1～C6An alkyl group;
Rjselected from hydrogen, C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
z is selected from the group consisting of-O-, -C (O) NR-, -NR-, (I),
Figure FDA0003010068650000032
R is selected from hydrogen and C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
Rc、Rdare respectively and independently selected from hydrogen and C1～C6Alkyl or not, or RcAnd RdAre linked to the nitrogen atom to which they are attached to form a group consisting of 0 to 4ReOptionally substituted 3-to 8-membered heterocycloalkane substituted with 0 to 4ReAn optionally substituted 3-to 10-membered heteroaromatic ring;
Reis selected from-ORf-、C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
Rfselected from hydrogen, C1～C6Alkyl, halogen substituted C1～C6An alkyl group.
4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein: z is-O-.
5. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein: the compound shown in the formula II is:
Figure FDA0003010068650000033
Figure FDA0003010068650000041
6. the compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein: the compound is shown as formula III:
Figure FDA0003010068650000042
R1、R2are respectively and independently selected from hydrogen and C1～C6Alkyl groups of (a);
R3、R4are respectively and independently selected from hydrogen and C1～C6Alkyl, halogen of (a);
R5selected from hydrogen, C1～6Alkyl groups of (a);
ring B is selected from
Figure FDA0003010068650000051
R6、R7、R8Are independently selected from hydrogen and 0-4RbOptionally substituted C1～C6An alkyl group;
Rbselected from halogen, hydroxy, amino, C1～C6An alkoxy group;
Rc、Rdare respectively and independently selected from hydrogen and C1～C6Alkyl or not, or RcAnd RdAre linked to the nitrogen atom to which they are attached to form a group consisting of 0 to 4ReOptionally substituted
Figure FDA0003010068650000052
Is coated with 0 to 4ReOptionally substituted
Figure FDA0003010068650000053
Is coated with 0 to 4ReOptionally substituted
Figure FDA0003010068650000054
Rg、RhIndependently selected from-C (O) -, -C (O) O-, or none;
L1、L2are respectively and independently selected from 0 to 4RiSubstituted C1～C10Wherein when R isiAt least 2 times, L1、L2R in (1)iCan be connected to form a 3-10 membered ring;
Riis selected from-ORjHalogen, -CN, C1～C6An alkyl group;
Rjselected from hydrogen, C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
Reis selected from-ORf-、C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
Rfselected from hydrogen, C1～C6Alkyl, halogen substituted C1～C6An alkyl group.
7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein: the compound shown in the formula III is:
Figure FDA0003010068650000055
8. the compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein: the compound is shown as formula IV:
Figure FDA0003010068650000056
ring B is selected from
Figure FDA0003010068650000061
R6、R7、R8Are independently selected from hydrogen and 0-4RbOptionally substituted C1～C6An alkyl group;
Rbselected from halogen, hydroxy, amino, C1～C6An alkoxy group;
R1、R2are respectively and independently selected from hydrogen and C1～C6Alkyl groups of (a);
R3、R4are respectively and independently selected from hydrogen and C1～C6Alkyl, halogen of (a);
R5selected from hydrogen, C1～C6Alkyl groups of (a);
L1、L2are respectively and independently selected from 0 to 4RiSubstituted C1～C10Wherein when R isiAt least 2 times, L1、L2R in (1)iCan be connected to form a 3-10 membered ring;
Riis selected from-ORjHalogen, -CN, C1～C6An alkyl group;
Rjselected from hydrogen, C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
z is selected from the group consisting of-O-, -C (O) NR-, -NR-, (I),
Figure FDA0003010068650000062
R is selected from hydrogen and C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
Rc、Rdare respectively and independently selected from hydrogen and C1～C6Alkyl or not, or RcAnd RdAre linked to the nitrogen atom to which they are attached to form a group consisting of 0 to 4ReOptionally substituted 3-to 8-membered heterocycloalkane substituted with 0 to 4ReAn optionally substituted 3-to 10-membered heteroaromatic ring;
Reis selected from-ORf-、C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
Rfselected from hydrogen, C1～C6Alkyl, halogen substituted C1～C6An alkyl group.
9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein: the compound is shown as a formula V:
Figure FDA0003010068650000063
ring B is selected from
Figure FDA0003010068650000064
R6、R7、R8Are independently selected from hydrogen and 0-4RbOptionally substituted C1～C6An alkyl group;
Rbselected from halogen, hydroxy, amino, C1～C6An alkoxy group;
R1、R2are respectively and independently selected from hydrogen and C1～C6Alkyl groups of (a);
R3、R4are respectively and independently selected from hydrogen and C1～C6Alkyl, halogen of (a);
R5selected from hydrogen, C1～C6Alkyl groups of (a);
L1、L2are respectively and independently selected from 0 to 4RiSubstituted C1～C10Wherein when R isiAt least 2 times, L1、L2R in (1)iCan be connected to form a 3-10 membered ring;
Riis selected from-ORjHalogen, -CN, C1～C6An alkyl group;
Rjselected from hydrogen, C1～C6Alkyl, halogen substituted C1～C6An alkyl group.
10. The compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein: the compound shown in the formula V is:
Figure FDA0003010068650000071
11. the compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: the compound is represented by formula VI:
Figure FDA0003010068650000072
wherein the content of the first and second substances,
ring B is selected from the group consisting of 0 to 3RaA substituted 5-membered nitrogen-containing aromatic heterocycle;
Raselected from halogen, hydroxyl, amino, and 0-3RbOptionally substituted C1～C6An alkyl group;
Rbselected from halogen, hydroxyl;
R1、R2are respectively and independently selected from hydrogen and C1～C6Alkyl groups of (a);
R3、R4are respectively and independently selected from hydrogen and C1～C6Alkyl, halogen of (a);
R5selected from hydrogen, C1～C6Alkyl groups of (a);
L1、L2are respectively and independently selected from 0 to 4RiSubstituted C1～C6Alkylene of (a) with 0 to 4RiSubstituted C2～C6The alkenylene group of (a) is,
Riselected from halogen, -CN, C1～C6An alkyl group;
x is selected from-O-, -S (O)n-or none, n is 1 or 2;
z is selected from-O-, -C (O) -,
Figure FDA0003010068650000073
Rc、Rdare respectively and independently selected from hydrogen and C1～C6Alkyl, halogen substituted C1～C6Alkyl, -C (O) RkOr none; rkSelected from the group consisting of 0 to 4RmSubstituted 5-to 6-membered cycloalkyl, substituted with 0 to 4RmA substituted 5-to 6-membered heterocycloalkyl group; rmIs selected from C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
Rg、Rhindependently selected from-C (O) -, -C (O) O-, or none.
12. The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein:
ring B is selected from
Figure FDA0003010068650000081
R6、R7、R8Are respectively and independently selected from hydrogen, halogen, hydroxyl, amino and 0-3RbOptionally substituted C1～C2An alkyl group;
Rbselected from halogen, hydroxyl;
R1、R2are respectively and independently selected from hydrogen and C1～C3Alkyl groups of (a);
R3、R4are respectively and independently selected from hydrogen and C1～C3Alkyl, halogen of (a);
R5selected from hydrogen, C1～C3Alkyl groups of (a);
L1、L2are respectively and independently selected from 0 to 2RiSubstituted C1～C3Alkylene of (a) with 0 to 2RiSubstituted C2～C3The alkenylene group of (a) is,
Riselected from halogen, -CN, C1～C3An alkyl group;
x is selected from-O-, -S (O)n-or none, n is 1 or 2;
z is selected from-O-, -C (O) -,
Figure FDA0003010068650000082
Rc、Rdare respectively and independently selected from hydrogen and C1～C3Alkyl, halogen substituted C1～C3Alkyl, -C (O) RkOr none; rkSelected from the group consisting of 0 to 2RmA substituted 5-to 6-membered cycloalkyl group substituted with 0 to 2RmA substituted piperidine ring; rmIs selected from C1～C3Alkyl, halogen substituted C1～C3An alkyl group;
Rg、Rhindependently selected from-C (O) -, -C (O) O-, or none.
13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein: z is-O-.
14. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein: the compound is:
Figure FDA0003010068650000083
Figure FDA0003010068650000091
15. use of a compound according to any one of claims 1to 14, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for activating STING species.
16. Use of a compound according to any one of claims 1to 14, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease associated with STING activity.
17. Use according to claim 16, characterized in that: the diseases related to STING activity are one or more of diseases related to inflammatory diseases, autoimmune diseases, infectious diseases, cancer and precancerous syndrome.
18. Use of a compound according to any one of claims 1to 14, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an inflammatory, autoimmune, infectious, cancer or pre-cancerous syndrome.
19. Use of a compound according to any one of claims 1to 14, or a pharmaceutically acceptable salt thereof, in the preparation of an immunoadjuvant.
20. A medicament, characterized by: the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1to 14, and pharmaceutically acceptable auxiliary materials.
CN202010066537.3A 2019-01-23 2020-01-20 Macrocyclic immunomodulator Active CN111471056B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910052988 2019-01-23
CN2019100529889 2019-01-23

Publications (2)

Publication Number Publication Date
CN111471056A CN111471056A (en) 2020-07-31
CN111471056B true CN111471056B (en) 2021-07-02

Family

ID=71736070

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010066537.3A Active CN111471056B (en) 2019-01-23 2020-01-20 Macrocyclic immunomodulator

Country Status (2)

Country Link
CN (1) CN111471056B (en)
WO (1) WO2020151682A1 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021026009A1 (en) 2019-08-02 2021-02-11 Mersana Therapeutics, Inc. Bis-[n-((5-carbamoyl)-1h-benzo[d]imidazol-2-yl)-pyrazol-5-carboxamide] derivatives and related compounds as sting (stimulator of interferon genes) agonists for the treatment of cancer
KR20220167275A (en) 2020-04-10 2022-12-20 오노 야꾸힝 고교 가부시키가이샤 cancer treatment methods

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101268077A (en) * 2005-08-05 2008-09-17 阿斯利康(瑞典)有限公司 Tricyclic benzimidazoles and their use as metabotropic glutamate receptor modulators
US20090270372A1 (en) * 2003-02-26 2009-10-29 Societe De Conseils De Recherches Et Novel derivatives of benzimidazole and imidazo-pyridine and their use as medicaments
CN101583372A (en) * 2006-10-24 2009-11-18 默克公司 HCV NS3 protease inhibitors
CN101765602A (en) * 2007-06-28 2010-06-30 赛诺菲-安万特 Derivative, its preparation and its therapeutics purposes of 6-ring amino-3-(pyridin-4-yl) imidazo [1,2-b] pyridazine
CN102802731A (en) * 2009-06-10 2012-11-28 詹森药业有限公司 Benzimidazole derivatives useful as TRPM8 channel modulators
CN102834513A (en) * 2008-03-05 2012-12-19 拜奥克里斯特制药公司 Antiviral therapeutic agents
WO2017175156A1 (en) * 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides useful as protein modulators
CN109071514A (en) * 2016-04-07 2018-12-21 葛兰素史密斯克莱知识产权发展有限公司 Heterocycleamide as protein modulator

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW201206946A (en) * 2010-07-15 2012-02-16 Bristol Myers Squibb Co Compounds for the reduction of beta-amyloid production
CN104039799B (en) * 2012-01-11 2016-04-13 霍夫曼-拉罗奇有限公司 As the macrocyclic amide of proteinase inhibitor
US10214542B2 (en) * 2015-10-08 2019-02-26 Bayer Pharma Aktiengesellschaft Modified macrocyclic compounds

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090270372A1 (en) * 2003-02-26 2009-10-29 Societe De Conseils De Recherches Et Novel derivatives of benzimidazole and imidazo-pyridine and their use as medicaments
CN101268077A (en) * 2005-08-05 2008-09-17 阿斯利康(瑞典)有限公司 Tricyclic benzimidazoles and their use as metabotropic glutamate receptor modulators
CN101583372A (en) * 2006-10-24 2009-11-18 默克公司 HCV NS3 protease inhibitors
CN101765602A (en) * 2007-06-28 2010-06-30 赛诺菲-安万特 Derivative, its preparation and its therapeutics purposes of 6-ring amino-3-(pyridin-4-yl) imidazo [1,2-b] pyridazine
CN102834513A (en) * 2008-03-05 2012-12-19 拜奥克里斯特制药公司 Antiviral therapeutic agents
CN102802731A (en) * 2009-06-10 2012-11-28 詹森药业有限公司 Benzimidazole derivatives useful as TRPM8 channel modulators
WO2017175156A1 (en) * 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides useful as protein modulators
CN109071514A (en) * 2016-04-07 2018-12-21 葛兰素史密斯克莱知识产权发展有限公司 Heterocycleamide as protein modulator

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
大环二芳基庚烷类化合物的波普特征;张毅 等;《波谱学杂志》;20101231;第27卷(第4期);第669-677页 *

Also Published As

Publication number Publication date
WO2020151682A1 (en) 2020-07-30
CN111471056A (en) 2020-07-31

Similar Documents

Publication Publication Date Title
CN110016025B (en) Immunomodulator
WO2021218110A1 (en) Benzothiazolyl biaryl compound, and preparation method and use
CN101754966B (en) Hepatitis c virus inhibitors
CN102227407B (en) Hepatitis c virus inhibitors
CN111499617B (en) Immunomodulator
WO2021169990A1 (en) Kras inhibitors for treating cancers
WO2018223909A1 (en) Chimeric molecule and preparation therefor and use thereof
CN110016021B (en) Immunomodulator
CN106458982A (en) Indazole compounds as irak4 inhibitors
KR20100016431A (en) Pharmaceutical compounds
CN113950481A (en) Macrocyclic compounds
KR20100016433A (en) Pyrimidine derivatives as inhibitors of phosphatidylinositol-3-kinase
CN103476768A (en) 6,5-heterocyclic propargylic alcohol compounds and uses therefor
WO2022166974A1 (en) Pyridopyrimidinone derivative, preparation method therefor, and use thereof
CN111032644B (en) Diarylthiohydantoin compounds useful as androgen receptor antagonists
CN111471056B (en) Macrocyclic immunomodulator
WO2020168927A1 (en) Nitrogen-containing fused cyclic compound, preparation method therefor and use thereof
WO2022268230A1 (en) Compound as kif18a inhibitor
WO2023284651A1 (en) N-(2-aminophenyl)benzamide compound and application thereof
CN115536656A (en) Heterocyclic compounds as HPK1 inhibitors
CN115768765A (en) Methods and compounds for treating genetic diseases
WO2023066371A1 (en) Nitrogen-containing tetracyclic compound, preparation method therefor, and medical use thereof
WO2021197467A1 (en) Multi-target anti-tumor compound, preparation method therefor and use thereof
WO2021114691A1 (en) Nitrogen-containing ring-fused compound, preparation method therefor and use thereof
WO2020233645A1 (en) Macrolide derivatives, preparation method 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