CN111471056A - Macrocyclic immunomodulator - Google Patents

Macrocyclic immunomodulator Download PDF

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CN111471056A
CN111471056A CN202010066537.3A CN202010066537A CN111471056A CN 111471056 A CN111471056 A CN 111471056A CN 202010066537 A CN202010066537 A CN 202010066537A CN 111471056 A CN111471056 A CN 111471056A
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CN111471056B (en
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李进
张登友
潘飞
马荣
朱文吉
吕开智
陈欣
张毅
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Hitgen Inc
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    • 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
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    • 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
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    • 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
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • 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
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    • 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
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    • 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
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    • C07—ORGANIC CHEMISTRY
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    • 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
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    • 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 (stimulator of interferon genes, TMEM173, MITA, etc.) is a key node molecule in the intracellular response to DNA invasion, recognises signals from cytoplasmic DNA receptors under cytoplasmic DNA stimulation and plays a key role in the induction of interferon-producing processes after the host cell's DNA recognition receptors recognise foreign or endogenous "non-self" DNA, signals are transmitted to the node molecule STING which then rapidly dimerises and translocates from the endoplasmic reticulum to the perinuclear periplasm activation of STING leads to up-regulation of the 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 isiWhen there are at least 2, 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 isiWhen there are at least 2, 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 isiWhen there are at least 2, 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 isiWhen there are at least 2, 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 isiWhen there are at least 2, 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 isiWhen there are at least 2, 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 invention, 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 group of (5), 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 present invention refers to a saturated hydrocarbon chain having the indicated number of member atoms. 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 group "It is intended to include such branched hydrocarbon 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 groups include both 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 () at 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).
L C-MS was measured using Shimadzu Mass spectrometer (Shimadzu L C-MS 2020 (ESI)).
HP L C was measured using Shimadzu high pressure liquid chromatograph (Shimadzu L C-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 with a hydrogen balloon attached to it of about 1L volume.
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
Adding a (18.5g, 75.3mmol) into a single-neck flask containing ammonia water (200m L), stirring at 60 ℃ for 3h, concentrating the reaction solution to 100m L, cooling, filtering, washing the solid with ice water, and drying to obtain 4-chloro-3-methoxy-5-nitrobenzamide (12.5g, 54.1mmol) as a brown solid.
1H NMR(400MHz,DMSO-d6):(ppm)8.29(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) is dispersed in dry DCM (150M L) under ice bath, boron tribromide (200M L, 1M) is slowly added dropwise, the ice bath is removed after the dropwise addition is finished, nitrogen protection is carried out, the reaction is carried out overnight at room temperature, after the reaction is completed, the reaction liquid is poured into ice water, after vigorous stirring for 30min, filtration is carried out, the filter cake is washed by water, and the filter cake is dried to obtain 4-chloro-3-hydroxy-5-nitrobenzamide (10g, 46.2mmol, 85.3% yield) as a light yellow solid.
1H NMR(400MHz,DMSO-d6):(ppm)11.73(s,1H),8.21(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 (80m L) and oxalyl chloride (3.9g, 31.1mmol) and a catalytic amount of DMF were added dropwise thereto under ice bath after reaction at room temperature for 1H, the volatiles were removed by rotary evaporation under reduced pressure, DCM (20m L) was added to the crude product and the solvent was 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 (20m L) and added dropwise to a solution of potassium thiocyanate (5g, 51.5mmol) in acetone (100m L) at 0 ℃ and stirred at room temperature for 3H, the reaction was filtered to remove inorganic salts, and the crude filtrate was concentrated and 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 (2.2g, 11.7mmol) was dissolved in dry acetone (10m L) at 0 ℃ and added dropwise to a solution of potassium thiocyanate (2.3g, 23.4mmol) in acetone (50m L) and stirred at room temperature for 3h, the reaction system 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 4-ethyl-2-methylthiazole-5-carbonyl isothiocyanate (2.15g, 10.2mmol, yield 87%) 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 (100m L) on an ice bath, 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 brine, and then dried over anhydrous sodium sulfate, and the filtrate obtained by filtration was dried by spinning to give the compound methyl 2-chloro-3-oxopentanoate (6g, 36.5mmol) as a colorless oil which was used in the next reaction.
MS(ESI)m/z＝166.0[M+H]+。
Step 2: synthesis of methyl 2-acetoxy-3-oxopentanoate
TEA (12.5m L) was added dropwise to a DMF (63m L) solution of acetic acid (12.5m L) while cooling on ice, after warming to room temperature, methyl 2-chloro-3-oxopentanoate (6g, 36.5mmol) was added to the reaction mixture, and the mixture was stirred at room temperature overnight, T L C monitored for completion of the reaction, the reaction mixture 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 by spinning 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 (50m L), ammonium acetate (9.8g, 127.6mmol) was added, the mixture was warmed to 120 ℃ and stirred at this temperature for 4 hours, the reaction mixture was concentrated, diluted with water, extracted with ethyl acetate, 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 by spinning, and the crude product was purified by silica gel column separation (eluent: petroleum ether/ethyl acetate, 9/1) to give methyl 4-ethyl-2-methyloxazole-5-carboxylate (0.52g, 3.1 mmol).
MS(ESI)m/z＝170.1[M+H]+
1H NMR(400MHz,CDCl3):(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
4-Ethyl-2-methyloxazole-5-carboxylic acid methyl ester (323mg, 1.9mmol) was dissolved in THF/MeOH (10M L/5M L), lithium hydroxide hydrate (160mg, 3.8mmol) was added and stirred at room temperature overnight the reaction was diluted with water, extracted with ethyl acetate, the separated aqueous phase was adjusted to pH 2.0 with HCl (2M) and then re-extracted with ethyl acetate the resulting organic phase was dried over anhydrous sodium sulfate and filtered 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 (10m L), oxalyl chloride (270m L, 2.13mmol) and a catalytic amount of DMF were added dropwise thereto under ice bath, after reaction at room temperature for 30min, volatile matter was removed by rotary evaporation under reduced pressure, DCM (20m L) was added to the crude product, and the crude product was obtained as a yellow oil after removal of the solvent by rotary evaporation and used directly in the next reaction.
The above yellow oil was dissolved in dry acetone (10m L) and added dropwise to a clear solution of potassium thiocyanate (276mg, 2.84mmol) in acetone (15m L) at 0 ℃ 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 ═ 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
Dispersing 4-chloro-3-methoxy-5-nitrobenzoic acid methyl ester (10g, 40.7mmol) in anhydrous dichloromethane (100m L), slowly dropwise adding boron tribromide (40.8g,162.8mmol) in an ice bath, slowly heating to room temperature after dropwise adding, stirring, reacting overnight, after reaction, slowly dropwise adding methanol in an ice bath, quenching, spin-drying, adding methanol (100m L) and concentrated sulfuric acid (0.2m L), heating the reaction liquid to 75 ℃, stirring overnight, cooling, concentrating under reduced pressure, removing the solvent, adding 150m L water, ultrasonically dispersing, filtering, washing the solid with water, and drying the solid to obtain 4-chloro-3-hydroxy-5-nitrobenzoic acid methyl ester (8.89g, 38.4mmol, the yield is 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 (40m L) at room temperature, the temperature was raised to 65 ℃ and the reaction was stirred for 16h, 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 71% yield.
MS(ESI)m/z＝265[M+H]+。
Step 2 Synthesis of methyl 3-bromo-4-fluoro-5-nitrobenzoate
Under the ice bath, thionyl chloride (8m L, 110mmol) is added dropwise into a methanol (150m L) solution of 3-bromo-4-fluoro-5-nitrobenzoic acid (19g, 71.97mmol), after the addition, the temperature is raised to 70 ℃, the reaction is stirred for 16 hours, after the reaction is completed, methanol is dried in a rotary mode, a crude product is dissolved by ethyl acetate, water and saturated salt water are respectively used for washing, after anhydrous sodium sulfate is dried and filtered, methyl 3-bromo-4-fluoro-5-nitrobenzoate (compound 1b) (18g, 64.74mmol) is obtained through rotary drying, and a light yellow solid is obtained with the yield of 89%.
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 (20m L) at room temperature, DIPEA (2.8g, 21.57mmol) was added, the mixture was stirred at room temperature for 0.5h after completion of the reaction, ethyl acetate was added and extracted (50m L x3) and 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 (5m L) at room temperature, the air was replaced with nitrogen, and Pd (dppf) Cl was added2(85mg, 0.116mmol), purging with nitrogen, heating to 100 deg.C, stirring for 16h, cooling to room temperature, adding water, extracting with ethyl acetate (20m L X3), combining the organic phases, washing with water and saturated brine, spin-drying the solvent, and purifying with silica gel column (eluent: ethyl acetate)Petroleum ether, v/v ═ 1/15) gave (E) -3- (3- (tert-butoxy) -3-oxoprop-1-en-1-yl) -4- ((3- ((tert-butoxycarbonyl) amino) propyl) amino) -5-methyl ester 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 (3m L) while cooling on ice for 0.5H, HATU (160mg, 0.421mmol) and N, N-diisopropylethylamine (110mg,0.851mmol) were then added to the reaction mixture, stirring was continued at room temperature for 3H, and the reaction mixture was separated by reverse phase MP L C (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, 0.391) 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 (1m L) was added to 1f (230mg, 0.375mmol) of DCM (2m L) on an ice bath and reacted at room temperature 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 (2m L) and DCM (4m L) under ice-bath and stirred for 0.5H, after completion of the reaction, water was added and extracted with ethyl acetate (10m L x3), 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-carboxamido) -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 the mixed solvents tetrahydrofuran (2M L) and methanol (1M L), lithium hydroxide (50mg, 1.14mmol) was added in water (2M L) solution after stirring the reaction solution at room temperature for 2H, water was added to dilute the spin-dried organic solvent, extraction was performed once with ethyl acetate, the aqueous phase was acidified to pH ≈ 4 with dilute hydrochloric acid (1M), ethyl acetate was extracted (10M L x3), the combined organic phases were washed with water and saturated brine, respectively, and the solvent was spin-dried to give 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), a 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 (2m L) while cooling on ice for 15min, DIPEA (65mg,0.5mmol) and ammonium chloride (30mg, 0.56mmol) were added, the reaction was reacted for 1h, and the reaction was separated with reverse phase MP L C (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):(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 (8m L) and tetrahydrofuran (16m L) under ice-bath stirring for 30min, 3-benzyloxy bromopropane (3.66g, 15.989mmol) was added, the temperature was raised to room temperature and reaction was carried out for 10h, after completion of the reaction, water was added, ethyl acetate was extracted (50m L × 3), the organic phases were combined with spin-dried solvent, and the crude product was separated by column chromatography (eluent: ethyl acetate/petroleum ether ═ 1/10, v/v) to give tert-butyl 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 (20m L) at room temperature, triphenylphosphine (907mg, 3.45mmol) and diisopropyl azodicarboxylate (700mg, 3.45mmol) were added after displacement of air with nitrogen, the reaction was stirred for 10h, after completion of the reaction, ethyl acetate was added to extract (20m L x3), the organic phases were combined with spin-dried solvent, and the crude product was separated by column chromatography (eluent ethyl acetate/petroleum ether ═ 1/2, v/v) to give tert-butyl 3- (3- (5-carbamoyl-2-chloro-3-nitrophenoxy) propoxy) propyl) carbamate (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 (3m L) was added to Compound 2c (740mg, 1.716mmol) in DCM (6m L) and reacted at RT for 1h, after completion of the reaction was spin-dried, the crude product was adjusted to pH 8 with saturated solution of sodium bicarbonate, extracted with ethyl acetate (20m L X3), the combined organic phases were washed with saturated brine, dried and 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
At room temperature, 3- (3- (3-aminopropoxy) propoxy) -4-chloro-5-nitrobenzamide (200mg, 0.604mmol) and potassium carbonate (100mg, 0.725mmol) are dissolved in DMF (120m L), the temperature is increased to 90 ℃, the mixture is stirred and reacted for 20H, after the reaction is completed, the solvent is dried in a rotary manner, ethyl acetate (50m L) is dissolved, the mixture is respectively washed by water and saturated saline, and the solvent is dried in a rotary manner to obtain 10-nitro-3, 4,6,7,8, 9-hexahydro-2H-benzo [ b ] [1,8,4] dioxoazacycloundecane-12-carboxamide (compound 2e) (177mg, 0.597mmol) with the yield of 99 percent and the compound is directly used 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 compound 2f (108mg, 0.407mmol) in DMF (3m L) while cooling on ice, reacted for 0.5H, then HATU (160mg, 0.421mmol) and N, N-diisopropylethylamine (105mg,0.814mmol) were added to the reaction mixture, stirring was continued at room temperature for 3H, and after completion of the reaction, compound 2(8.7mg, yield 5%) was purified by reverse-phase HP L C to give a white solid.
MS(ESI)m/z＝427[M+H]+。
1H NMR(400MHz，DMSO-d6):(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
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 (3m L) while cooling on ice for 0.5H, HATU (114mg, 0.3mmol) and N, N-diisopropylethylamine (77mg,0.6mmol) were added to the reaction mixture, stirring was continued at room temperature for 3H, and after completion of the reaction, compound 3 was purified by reverse-phase HP L C (19.2mg, 14.4% yield).
MS(ESI)m/z＝445[M+H]+
1H NMR(400MHz,MeOD):(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
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 (3m L) while cooling on ice, and reacted for 0.5H, then HATU (86mg, 0.226mmol) and N, N-diisopropylethylamine (58mg,0.452mmol) were added to the reaction mixture, and stirring was continued at room temperature for 3H, after completion of the reaction, compound 4 was purified by reverse-phase HP L C (9.9mg, yield 10.3%).
MS(ESI)m/z＝428[M+H]+
1H NMR(400MHz,MeOD):(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 (3m L) while cooling on ice for 0.5H, HATU (114mg, 0.3mmol) and N, N-diisopropylethylamine (77mg,0.6mmol) were added to the reaction mixture, stirring was continued at room temperature for 3H, and after completion of the reaction, compound 5(55mg, yield 41.4%) was purified by reverse-phase HP L C.
MS(ESI)m/z＝444[M+H]+
1H NMR(400MHz,DMSO-d6):ppm12.80(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 (3m L) while cooling on ice for 0.5H, HATU (86mg, 0.226mmol) and N, N-diisopropylethylamine (58mg,0.452mmol) were added to the reaction mixture, stirring was continued at room temperature for 3H, and after completion of the reaction, compound 6(41mg, yield 39.4%) was purified by reverse-phase HP L C.
MS(ESI)m/z＝463[M+H]+
1H NMR(400MHz,DMSO-d6):(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 (8m L) and tetrahydrofuran (16m L) under ice-bath stirring for 30min, 3-benzyloxy bromoethane (3.42g, 15.99mmol) was added, the temperature was raised to room temperature and reaction was carried out for 10h, after completion of the reaction, water was added, ethyl acetate was extracted (50m L x3), the organic phases were combined with spin-dried solvent, and the crude product was separated 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 colorless 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 (20m L) at room temperature, triphenylphosphine (907mg, 3.45mmol) and diisopropyl azodicarboxylate (700mg, 3.45mmol) were added after displacement of air with nitrogen, the reaction was stirred for 10h, after completion of the reaction, ethyl acetate was added for extraction (20m L x3), the organic phases were combined with spin-dried solvents and the crude product was isolated 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 (3m L) was added to Compound 2c (740mg, 1.716mmol) in DCM (6m L) and reacted at RT for 1h, after completion of the reaction was spin-dried, the crude product was adjusted to pH 8 with saturated solution of sodium bicarbonate, extracted with ethyl acetate (20m L X3), the combined organic phases were 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
At room temperature, 3- (3- (3-aminopropoxy) propoxy) -4-chloro-5-nitrobenzamide (200mg, 0.604mmol) and potassium carbonate (100mg, 0.725mmol) are dissolved in DMF (120m L), the temperature is increased to 90 ℃, the reaction is stirred for 20h, after the reaction is completed, the solvent is dried in a rotary manner, ethyl acetate (50m L) is dissolved, the ethyl acetate is respectively washed by water and saturated saline, and the ethyl acetate is dried in a rotary manner to obtain 9-nitro-2, 3,5,6,7, 8-hexahydrobenzo [ E ] [1,4,7] dioxodecane-11-carboxamide 7E (177mg, 0.597mmol), the yield is 99%, and the product is directly used 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 (3m L) while cooling on ice, and reacted for 0.5H, then HATU (160mg, 0.421mmol) and N, N-diisopropylethylamine (105mg,0.814mmol) were added to the reaction mixture, and stirring was continued at room temperature for 3H, after completion of the reaction, and then compound 7(8.7mg, yield 5%) was purified by reverse-phase HP L C to obtain 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
(3- (2-Hydroxyethoxy) propyl) carbamic acid tert-butyl ester (1.15g,5.25mmol) is dissolved in DCM (30m L), TEA (2.2m L, 15.8mmol) is added, methanesulfonyl chloride (0.49m L, 6.30mmol) is added dropwise under ice-bath cooling, stirring is carried out for 2 hours under ice-bath, reaction is completed, water is added, DCM phase is separated, aqueous layer is extracted for 2 times with DCM, organic phases are combined and dried by spin drying, compound 8a (1.6g) yield is 103%, and the product is directly used in 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 (20m L), potassium thioacetate (1.23g,10.77mmol) was added, stirred at room temperature overnight, water was added after the reaction was complete, ethyl acetate was extracted (20m L x3), the organic phases were combined and dried, and the crude product obtained after concentration was purified by column chromatography (PE: EA ═ 5:1) to give compound 8b (1.31g) as a pale yellow oil with a yield of 87.8%.
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 (30m L), TFA (5m L) was added and stirred at RT overnight the reaction was concentrated under reduced pressure to give compound S- (2- (3-aminopropoxy) ethyl) ethanethiol ester, Synthesis 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 (20m L), methyl 3-bromo-4-fluoro-5-nitrobenzoate (850mg,3.09mmol) and TEA (1.96m L, 14.2mmol) were added, stirred at rt overnight, diluted with water, extracted with ethyl acetate (20m L × 3), the 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) in 84.9% yield.
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 (20M L), MeONa (410mg,7.6mmol) was added with ice-bath cooling and stirred for 1h, completion of the reaction was achieved, dilute hydrochloric acid (3M) was added to adjust pH 4, spin dried, the residue was dissolved in water, ethyl acetate was extracted (15M L. multidot.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 in 98.7% yield.
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 (30m L) and Xantphos (288mg,0.498mmol), DIPEA (1.23m L, 7.47mmol) and Pd were added in that order under nitrogen protection2(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 (8m L), and Na was added dropwise thereto under cooling in an ice bath2S2O4(139mg,0.80mmol) of the aqueous solution, stirring at room temperature for 2h, allowing the reaction to complete, filtering to remove insoluble materials, draining the filtrate, dissolving the residue in water, extracting with ethyl acetate (10m L x3), drying the combined organic phases, draining,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 5m L DMF and added isothiocyanato 1-ethyl-3-methyl-5-pyrazolecarboxylic acid (32mg,0.16mmol) under ice-bath and after stirring for 10min L CMS was sent to show completion of the reaction HATU (67mg,0.176mmol) and DIPEA (0.85m L, 0.48mmol) were added and stirred overnight at room temperature, diluted with water, extracted with ethyl acetate (10m L X2), the combined organic phases were dried and spun dry 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 5M L MeOH/H2O (10:1) solvent mixture, lithium hydroxide hydrate (59mg,1.4mmol) was added, heated to 40 ℃ for overnight reaction, cooled to room temperature, diluted hydrochloric acid (1M) was added to adjust to Ph-4, dried, the residue was dissolved in water, extracted with ethyl acetate (10M L X2), the combined organic phases were dried and 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 (3m L), TEA (0.55m L, 0.4mmol), HATU (57mg,0.15mmol) were added sequentially and stirred at room temperature for 30min, ammonium chloride (18mg,0.3mmol) was added and stirred at room temperature overnight, the reaction was purified by reverse phase prep-HP L C to give compound 8(10 mg).
MS(ESI)m/z＝429[M+H]+。
1H NMR(400MHz,DMSO-d6)13.00(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 (100m L) was added tert-butyldimethylsilyl chloride (8.36g, 55.48mmol) and imidazole (4.53g, 66.58mmol), stirred at room temperature overnight, the reaction was poured into water, the separated organic phase was washed with water and saturated brine, respectively, dried and concentrated to give 4- ((tert-butyldimethylsilyl) oxy) butan-2-ol 9a (13.89g), which 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
Sodium hydride (1.4g, 35.23mmol) was added to a solution of compound 9a (6g, 29.36mmol) in DMF (100m L) while cooling on ice, stirring for 0.5h, 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 (100m L 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
TBAF (34.35mmol, 1M tetrahydrofuran solution) was added to a solution of compound 9b (8.28g, 22.9mmol) in tetrahydrofuran (80M L) at room temperature, the reaction was raised to 55 ℃, stirred overnight, the reaction was poured into water, ethyl acetate was extracted (100M L x3), the organic phase was washed with saturated brine, dried and spun dry, and 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 (20m L) at room temperature, triphenylphosphine (1.14g, 4.36mmol) and diisopropyl azodicarboxylate (880mg, 4.36mmol) were added after displacement of air with nitrogen then raised to 60 ℃ and stirred overnight the reaction was completed, ethyl acetate was added to extract (20m L x3) after completion of the reaction, the organic phases were combined and the solvent was dried by rotation to give crude product which was isolated 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, 29.6% yield).
MS(ESI)m/z＝446[M+H]+。
And 5: synthesis of 3- (3- (3-aminopropoxy) butoxy) -4-chloro-5-nitrobenzamide
TFA (3m L) was added to Compound 9d (320mg, 0.72mmol) in DCM (10m L) 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) 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 (150m L) at room temperature, the reaction was stirred at 90 ℃ for 3H after completion of the reaction, the solvent was dried after the reaction, ethyl acetate (50m L) was dissolved, washed with water and saturated brine, respectively, and purified by 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] dioxoazaundecane-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 (3m L) while cooling on ice, reacted for 0.5H, then HATU (147mg, 0.38mmol) and N, N-diisopropylethylamine (82mg,0.64mmol) were added to the reaction mixture, stirred at room temperature for 3H, and after completion of the reaction, purified by reverse-phase HP L C 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 (750m L) was added trimethylchloromethane (8.36g, 154.8mmol), triethylamine (140m L, 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, the separated organic phase was washed with water and saturated brine, respectively, dried and concentrated, and column chromatography (petroleum ether/ethyl acetate ═ 20/1,10/1, v/v) gave 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
Sodium hydride (9g, 225mmol) was added to a solution of compound 9-1a (50g, 150.0mmol) in DMF (500m L) while cooling on ice, followed by stirring for 0.5h, then 3-bromopropoxy (tert-butyl) dimethylsilane (45.5g, 180mmol) and tetrabutylammonium iodide (5.5g, 15mmol) were added sequentially, the reaction was warmed to room temperature, and stirred overnight, the reaction was quenched with saturated ammonium chloride, poured into water, extracted with ethyl acetate (600m L x3), the combined organic phases were washed with water and saturated brine, 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
TBAF (33mmol, 1M tetrahydrofuran solution) was added to a solution of compound 9-1b (14g, 27.78mmol) in tetrahydrofuran (50M L) at room temperature under stirring overnight, the reaction was poured into water, extracted with ethyl acetate (100M L × 3), the organic phase was washed with saturated brine, dried and spun dry, 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 colorless 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
Dissolving a compound 9-1c (7.5g, 19.23mmol) in a mixed solution of dichloromethane (20m L) and pyridine (20m L) at room temperature, adding p-toluenesulfonyl chloride (4.03g, 21.15mmol), stirring the reaction solution at room temperature overnight, concentrating after the reaction is finished, removing dichloromethane and pyridine by rotation, then adding water for dilution, extracting by ethyl acetate, concentrating the combined organic phase, filtering out insoluble substances, concentrating and drying the filtrate to obtain 9-1d (8.75g), and directly using the filtrate in 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 (80m L), K2CO3(4.6g, 33.5mmol), bis (tert-butoxycarbonyl) amine (4.0g, 18.5mmol) and iodomethane (20mg) were added in that order, heated to 80 ℃ overnight, diluted with water after completion of the reaction and extracted with ethyl acetate, and the combined organic phases were spin-dried to give 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 colorless oil.
MS(ESI)m/z＝590.0[M+H]+。
Step 6: synthesis of tert-butyl (3- ((4-hydroxybut-2-yloxy) propyl) carbamate
Formic acid (2m L) was added dropwise to a solution of 9-1e (2.9g, 5.0mmol) in dichloromethane (30m L) at room temperature, the reaction was stirred at room temperature for 3h, 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, and after spin-drying, purification was carried out on a 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 (10m L) at room temperature, triphenylphosphine (1.15g, 4.37mmol) and diisopropyl azodicarboxylate (4mg, 4.37mmol) were added after displacing air with nitrogen, the reaction was stirred at 60 ℃ overnight, after completion of the reaction ethyl acetate was added and extracted (20m L x3), the organic phases were combined and the crude product was isolated 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 (2m L) was added dropwise to a solution of compound 9-1g (1.9g crude, 2.38mmol) in dichloromethane (10m L) while cooling on ice, and after completion of the reaction at room temperature for 2h, the solvent was dried by spinning and dried to give the compound methyl 3- (3- (3-aminopropoxy) butoxy) -4-chloro-5-nitrobenzoate (1.39g crude) as a yellow oil, which was used directly in 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
At room temperature, compound 9-1h (1.39g (70% purity), 3.85mmol) and potassium carbonate (797mg, 5.77mmol) were dissolved in DMF (400m L), heated to 60 ℃ and stirred to react overnight, after the reaction was completed, the solvent was spin-dried, ethyl acetate (50m L) was dissolved, washed with water and saturated brine, respectively, after spin-drying, purified by normal phase silica gel column (eluent: dichloromethane/methanol ═ 100/3, v/v), the resulting racemate 802mg was obtained, and separated by SFC purification to give 9-1i (300mg), an orange solid.
MS(ESI)m/z＝325.0[M+H]+。
1H NMR(400MHz,DMSO)8.50(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
Palladium on carbon (10%, 113mg) was added to a 9-1i (300mg, 0.93mmol) mixed solution of methanol (15m L) and tetrahydrofuran (15m L), and the mixture was reduced by hydrogenation for 3 hours, followed by filtration of the palladium on carbon, and the filtrate was concentrated to give 9-1l (300mg, crude product) which was used directly in 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
Under ice bath, the compound 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (33mg, 0.17mmol) is added dropwise to a DMF (2m L) solution of the compound 9-1l (50mg, 0.17mmol) for reaction for 0.5H, then HATU (77mg, 0.20mmol) and N, N-diisopropylethylamine (43mg,0.34mmol) are added into the reaction solution, stirring is continued for 3H at room temperature, and after the reaction is completed, water filtration and washing are carried out to obtain the compound 9-1m (77mg, crude product) 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
Dissolving a compound 9-1M (77mg,0.17mmol) in a mixed solvent of 5M L MeOH/H2O (10:1), adding hydrated lithium hydroxide (70mg,1.7mmol), heating to 65 ℃, reacting for 5H, cooling to room temperature, adding water for dilution, extracting with ethyl acetate, adjusting the pH of the separated water phase to 3-2 with diluted hydrochloric acid (3M), and filtering and drying the separated 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 (2m L), DIPEA (31mg,0.24mmol) and HATU (55mg,0.14mmol) were added sequentially, stirred at room temperature for 30min, ammonium bicarbonate (19.7mg,0.25mmol) was added, stirred at room temperature overnight, the reaction was diluted with water to precipitate a white solid, 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)12.81(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
At room temperature, compound 9-1h (1.39g (70% purity), 3.85mmol) and potassium carbonate (797mg, 5.77mmol) were dissolved in DMF (400m L), heated to 60 ℃ and stirred to react overnight, after completion of the reaction, the solvent was spin-dried, ethyl acetate (50m L) was dissolved, washed with water and saturated brine, respectively, after spin-drying, purified by normal phase silica gel column (eluent: dichloromethane/methanol ═ 100/3, v/v), and the resulting 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)8.50(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
Palladium on carbon (10%, 113mg) was added to a mixed solution of 9-2a (300mg, 0.93mmol) in methanol (15m L) and tetrahydrofuran (15m L), and the mixture was reduced by hydrogenation for 3 hours, followed by filtration of the palladium on carbon, and the filtrate was concentrated to give 9-2b (307mg, crude product) which was used directly in 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
Under ice bath, the compound 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (33mg, 0.17mmol) is added dropwise to a DMF (2m L) solution of the compound 9-2b (50mg, 0.17mmol) for reaction for 0.5H, then HATU (77mg, 0.20mmol) and N, N-diisopropylethylamine (43mg,0.34mmol) are added to the reaction solution, stirring is continued for 3H at room temperature, and after the reaction is completed, water filtration and washing are carried out to obtain the compound 9-2c (74mg, crude product) 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
Dissolving a compound 9-2c (74mg,0.16mmol) in a mixed solvent of 5M L MeOH/H2O (10:1), adding hydrated lithium hydroxide (70mg,1.7mmol), heating to 65 ℃, reacting for 5H, cooling to room temperature, adding water for dilution, extracting with ethyl acetate, adjusting the pH of the separated water phase to 3-2 with diluted hydrochloric acid (3M), and filtering and drying the separated white solid to obtain 9-2d (64mg, 85% yield) as a 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 (2m L), DIPEA (36mg,0.28mmol), HATU (66mg,0.17mmol) were added sequentially, stirred at room temperature for 30min, ammonium bicarbonate (22mg,0.28mmol) was added, stirred at room temperature overnight, the reaction was diluted with water to precipitate a white solid, 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)12.81(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 (10m L), the solution was cooled to 0 ℃, then aqueous ammonia (2.5m L) and aqueous solution (5m L) of sodium dithionite (1.2g, 6.9mmol) were added in sequence, the reaction mixture was stirred at 0 ℃ for 1h, the color of the reaction solution changed from orange red to white, the reaction solution was rotary evaporated to remove methanol, then diluted with water, extracted with ethyl acetate (20m L× 4), the resulting organic phase was separated, washed with saturated brine (20m L× 2), dried over anhydrous sodium sulfate, filtered, and then rotary dried 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 (5m L) while cooling on ice for 0.5H, then HATU (493mg, 1.3mmol) and N, N-diisopropylethylamine (284mg,2.2mmol) were added to the reaction mixture, stirring was continued at room temperature for 3H, and the reaction mixture was separated by reverse phase MP L C (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) of DMF (5m L) at room temperature, warmed to 40 ℃ for reaction overnight, the reaction was poured into water, extracted with ethyl acetate (5m L × 3), 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 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
Palladium acetate (1.03g, 4.6mmol), 2-dicyclohexyl-phosphorus-2, 4, 6-triisopropylbiphenyl (86mg, 0.18mmol) and DIPEA (356mg, 2.76mmol) were added to N, N-dimethylacetamide (10 c) (640mg, 0.92mmol) at room temperature, the temperature was raised to 110 ℃ under an inert atmosphere after nitrogen substitution, the reaction mixture was poured into water, extracted with ethyl acetate (10m L ═ 3), the combined organic phases were washed with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by 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 (5m L) was added to a solution of 10c (254mg, 0.4mmol) in dichloromethane (5m L) while cooling on ice, warmed to room temperature and stirred overnight, the solvent was spun off and excess trifluoroacetic acid was removed under reduced pressure using an oil pump to give 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 (10m L), DIPEA (258mg, 2.0mmol) and HBTU (167mg, 0.44mmol) were added, the reaction was reacted at room temperature for 2h, the reaction solution was poured into water, ethyl acetate was extracted (10m L × 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 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
Dissolving the compound 10e (84mg, 0.18mmol) in mixed solvents of tetrahydrofuran (2M L) and methanol (1M L), adding a solution of lithium hydroxide (76mg, 1.8mmol) in water (2M L), stirring the reaction solution at room temperature for 16h, adding water to dilute the rotary drying organic solvent, acidifying the aqueous phase to pH 4 with dilute hydrochloric acid (1M), extracting with ethyl acetate (10M L × 3), combining the organic phases, washing with water and saturated brine respectively, and rotary drying the solvent to obtain the 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 (2m L) while cooling on ice for 15min, DIPEA (58mg,0.45mmol) and ammonium chloride (29mg, 0.54mmol) were added, the reaction was reacted for 1h, and the reaction was separated with reverse phase MP L C (eluent acetonitrile/water 1/1, v/v) to give compound 10g (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
Palladium on carbon (10%, 10mg) was added to a solution of 10g (24mg, 0.055mmol) in methanol (5m L) at room temperature, followed by hydrogenation for 1h, 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):ppm7.96(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 (4m L) while cooling on ice, reacted for 0.5H, then HATU (420mg, 1.1mmol) and N, N-diisopropylethylamine (237mg,1.84mmol) were added to the reaction solution, and stirring was continued at room temperature for 3H, and after completion of the reaction, filtration washing was carried out to obtain the 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
Dissolving a compound 11a (374mg,0.79mmol) in a mixed solvent of 30M L MeOH/H2O (10:1), adding hydrated lithium hydroxide (329mg,7.9mmol), heating to 65 ℃, reacting for 5H, cooling to room temperature, adding water for dilution, extracting with ethyl acetate, adding diluted hydrochloric acid (3M) to a separated water phase to adjust the pH to 3-2, and filtering and drying precipitated white solid to obtain 11b (247mg, 68% yield) as 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 (4m L), DIPEA (130mg,1.0mmol) and HATU (241mg,0.63mmol) were added sequentially and stirred at room temperature for 30min, ammonium bicarbonate (85mg,1.0mmol) was added 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)12.83(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 (4m L) while cooling on ice, reacted for 0.5H, then HATU (420mg, 1.1mmol) and N, N-diisopropylethylamine (237mg,1.84mmol) were added to the reaction solution, and stirring was continued at room temperature for 3H, and after completion of the reaction, filtration washing was carried out to obtain the 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
Dissolving a compound 12a (363mg,0.77mmol) in a mixed solvent of 30M L MeOH/H2O (10:1), adding hydrated lithium hydroxide (352mg,7.8mmol), heating to 65 ℃, reacting for 5H, cooling to room temperature, adding water for dilution, extracting with ethyl acetate, adding diluted hydrochloric acid (3M) to a separated water phase to adjust the pH to 3-2, and filtering and drying precipitated white solid to obtain 12b (250mg, 77% yield) as 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 (4m L), DIPEA (139mg,1.0mmol) and HATU (246mg,0.65mmol) were added sequentially and stirred at room temperature for 30min, ammonium bicarbonate (86mg,1.0mmol) was added 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)12.86(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 (4m L) while cooling on ice, reacted for 0.5H, HATU (210mg, 0.55mmol) and N, N-diisopropylethylamine (118mg,0.90mmol) were added to the reaction solution, and stirring was continued at room temperature for 3H, and after completion of the reaction, filtered and washed to give the 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
Dissolving the compound 13a (181mg,0.39mmol) in a mixed solvent of 15M L MeOH/H2O (10:1), adding hydrated lithium hydroxide (176mg,3.9mmol), heating to 65 ℃, reacting for 5H, cooling to room temperature, adding water for dilution, extracting with ethyl acetate, adding diluted hydrochloric acid (3M) to the separated water phase to adjust the pH to 3-2, and 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 (3m L), DIPEA (70mg,0.5mmol) and HATU (123mg,0.33mmol) were added sequentially and stirred at room temperature for 30min, ammonium bicarbonate (43mg,0.33mmol) was added 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 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] diazacycloundecene-12-carboxylic acid methyl ester (139mg, 0.47mmol) in DMF (4m L) while cooling on ice, reacted for 0.5H, HATU (214mg, 0.56mmol) and N, N-diisopropylethylamine (121mg,0.94mmol) were added to the reaction solution, and stirring was continued at room temperature for 3H, and after completion of the reaction, filtered and washed to give the 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 10m L 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 (3m L), DIPEA (40mg,0.3mmol) and HATU (62mg,0.16mmol) were added sequentially and stirred at room temperature for 30min, ammonium bicarbonate (13mg,0.165mmol) was added 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 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
At room temperature, the compound 3-hydroxy propylamine (622mg,8.29mmol) and DIPEA (1.78g,13.8mmol) were added dropwise to a DMF (10m L) solution of the compound 3-bromo-4-fluoro-5-nitrobenzoic acid methyl ester (1.92g,6.9mmol), reacted for 3h, after completion of the reaction, diluted with water, extracted with dichloromethane, the combined organic phases were washed with water, washed with saturated brine, dried and concentrated to give the compound 15a (2.1g, crude product) as a yellow oil, which was used directly in 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
Ammonia (5m L, 33mmol) was added to compound 15a (1.1g,3.3mmol) in MeOH (20m L) in an ice bath and after 5min sodium hydrosulfite (2.87g,16.5mmol) in water (6m L) was added and the reaction was completed after stirring for 2h, diluted with water, extracted with dichloromethane, the separated organic phase was washed with water, washed with saturated brine and dried over anhydrous sodium sulfate to concentrate to give 15b (772mg, 77% yield) as a yellow oil which was 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
Under ice bath, the compound 1-ethyl-3-methyl 4-fluoro-1H-pyrazole-5-carbonyl isothiocyanate (545mg, 2.79mmol) is added dropwise to a DMF (10m L) solution of the compound 15b (770mg, 2.54mmol) for reaction for 0.5H, then HATU (1.16mg, 1.1mmol) and N, N-diisopropylethylamine (655mg,5.08mmol) are added to the reaction solution, stirring is continued for 3H at room temperature, and after the reaction is completed, water filtration washing is carried out to obtain the compound 15c (765mg, crude product) as a light 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
Cesium carbonate (1.6g, 4.97mmol), (2- (chloromethoxy) ethyl) trimethylsilane (550mg, 3.3mmol) was added to a solution of compound 15c (765mg, 1.65mmol) in tetrahydrofuran (15m L) at room temperature, stirred overnight, the reaction was concentrated after completion of the reaction, and the resulting crude product 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 (5m L) 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 (8m L), Pd/C (20mg, N) was added, hydrogen was substituted, and the mixture was stirred at room temperature for 48h under the protection of a hydrogen balloon, 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 15f (68mg, 0.08mmol) solution of dichloromethane (10m L) under ice-bath, the mixture was allowed to warm to room temperature, and then the reaction was stirred for 3 hours, after completion of the reaction, the organic phase was distilled off under reduced pressure to give a crude product, which was purified on a T L C (developing solvent: dichloromethane/methanol ═ 15/1, v/v) silica gel plate to give 15g (32mg, 49% yield) of 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 (1m L) was added dropwise to a solution of compound 15g (32mg, 0.02mmol) in dichloromethane (3m L) 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 (5m L) 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 on a T L C (developing solvent: dichloromethane/methanol 15/1, v/v) silica gel plate to give 15i (10mg, crude) 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% pure), 0.01mmol) was dissolved in ammonia (5m L) at room temperature and warmed to 90 ℃ and stirred overnight after completion of the reaction the solvent was spun dry and dried to give 15j (15mg, cupin) as a yellow oil which was 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 solution of 15h (15mg, crude, 0.01mmol) in dioxane (3m L) was added (Boc)2O (3mg,0.015mmol), pyridine (one drop) and NH4HCO3(2mg, 0.02 mmol.) stirring overnight at room temperature, after completion of the reaction, the solvent was dried by spinning, and the crude product was subjected to preparative thin layer chromatography (developing solvent: dichloromethane/methanol-15/1, v/v) followed by MP L C (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
Under the protection of nitrogen, 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 (200m L) and reacted at room temperature for 10h, after completion of the reaction, the inorganic salt was filtered and the organic phase was dried to give 16a (29g, 163mmol) with 97% yield.
MS(ESI)m/z＝179[M+H]+。
Step 2: synthesis of 3- (benzyloxy) butan-1-ol
Under the protection of nitrogen, a DCM (200M L) solution of 16a (17.8g, 100mmol) is cooled to-78 ℃, DIBA L-H (100M L,1M dichloromethane solution, 100mmol) is slowly dropped, the temperature is raised to room temperature for reaction for 10H, after the reaction is finished, sodium sulfate decahydrate is added for quenching the reaction, inorganic salts are filtered, organic phase is dried by rotation, and crude products are separated by column chromatography (eluent: ethyl acetate/petroleum ether 1/4, v/v) to obtain 16b (14.7g, 81mmol), and the yield is 82%.
MS(ESI)m/z＝181[M+H]+。
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 (8m L) and tetrahydrofuran (16m L) under ice-bath, after stirring for 30 minutes, N-tert-butoxycarbonylbromopropylamine 16c (635mg, 2.66mmol) was added, the temperature was raised to room temperature and reaction was carried out for 10 hours, after completion of the reaction, water was added, ethyl acetate was extracted (50m L x3), the organic phases were combined and the solvent was dried by spin-drying, and the crude product was isolated by column chromatography (eluent: ethyl acetate/petroleum ether ═ 1/10, v/v) to give 16d (847g, 2.51mmol) with a yield of 57%.
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 (20m L) at room temperature, triphenylphosphine (894mg, 3.41mmol) and diisopropyl azodicarboxylate (689mg, 3.41mmol) were added after displacement of air with nitrogen, the reaction was stirred for 10h, after completion of the reaction, ethyl acetate was added for extraction (20m L x3), the organic phases were combined and the crude product was isolated by column chromatography (eluent ethyl acetate/petroleum ether 1/2, v/v) to give a yield of 92% 16f (900mg, 2.01 mmol).
MS(ESI)m/z＝446[M+H]+。
Step 6: synthesis of 3- ((4- (3-aminopropoxy) but-2-yl) oxy) -4-chloro-5-nitrobenzamide
TFA (20m L) was added to Compound 16f (900mg, 2.01mmol) in DCM (20m L) and reacted at RT for 1h, after completion of the reaction was spin-dried, the crude product was adjusted to pH 8 with saturated solution of sodium bicarbonate, extracted with ethyl acetate (20m L X3), the combined organic phases were washed with saturated brine, dried and spin-dried to give 16g (377mg, 1.09mmol) in 54% yield for 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 (120m L) at room temperature, the temperature was raised to 90 ℃ and the reaction was stirred for 20h after completion of the reaction, the solvent was dried by spinning, ethyl acetate (50m L) was dissolved and washed with water and saturated brine respectively, and dried by spinning to give a yield of 99% for 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
The 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 (3m L) while cooling on ice for 0.5H, HATU (75mg, 0.20mmol) and N, N-diisopropylethylamine (46mg,0.36mmol) were added to the reaction mixture, stirring was continued at room temperature for 3H, and after completion of the reaction, compound 16(5.5mg, yield 7.1%) was purified by reverse-phase HP L C.
MS(ESI)m/z＝441[M+H]+
1H NMR(400M,DMSO-d6)12.84(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
The compound 4-ethyl-2- (fluoromethyl) thiazole-5-carbonyl isothiocyanate (23mg, 0.1mmol) was added dropwise to a solution of the compound 2f (27mg, 0.1mmol) in DMF (3m L) while cooling on ice, and reacted for 0.5h, then HATU (46mg, 0.12mmol) and N, N-diisopropylethylamine (26mg,0.2mmol) were added to the reaction mixture, and stirring was continued at room temperature for 3h, after completion of the reaction, and the compound 17 was purified by reverse phase MP L C (20mg, yield 43%).
MS(ESI)m/z＝462[M+H]+
1H NMR(400M,DMSO-d6)12.86(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 (3m L) while cooling on ice for 0.5h, HATU (46mg, 0.12mmol) and N, N-diisopropylethylamine (26mg,0.2mmol) were added to the reaction mixture, stirring was continued at room temperature for 3h, and after completion of the reaction, compound 18(8.5mg, yield 17.7%) was purified by reverse-phase HP L C.
MS(ESI)m/z＝480[M+H]+
1H NMR(400M,DMSO-d6)12.91(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 solution of compound 2f (27mg, 0.1mmol) in DMF (3m L) while cooling on ice, reacted for 0.5H, then HATU (46mg, 0.12mmol) and N, N-diisopropylethylamine (26mg,0.2mmol) were added to the reaction mixture, stirred at room temperature for 3H, and after completion of the reaction, purified by reverse-phase HP L C to give compound 19(6.6mg, yield 14.9%).
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 solution of compound 2f (27mg, 0.1mmol) in DMF (3m L) while cooling on ice, reacted for 0.5H, then HATU (46mg, 0.12mmol) and N, N-diisopropylethylamine (26mg,0.2mmol) were added to the reaction mixture, stirred at room temperature for 3H, and after completion of the reaction, purified by reverse-phase HP L C to give compound 20(5.8mg, yield 12.6%).
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 (5M L), tetrabutylammonium fluoride (10M L, 1M) was added, the tetrahydrofuran was removed by rotary evaporation after 2h of reaction, the crude product was dissolved in ethyl acetate, washed with water and saturated brine, respectively, and purified by silica gel column (petroleum ether/ethyl acetate ═ 2/3) after concentration 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 (10m L), triphenylphosphine (428mg, 1.63mmol) was added, the ice bath was cooled to 0 ℃, diisopropyl azodicarboxylate (440mg, 2.18mmol) was added under nitrogen protection, then warmed to room temperature, the reaction was allowed to react for 18h, and after spin-drying, column purification (petroleum ether/ethyl acetate 3/2) afforded compound 21c (600mg, 94% yield).
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 (5m L) was added to a solution of 21c (600mg, 1.03mmol) in dichloromethane (10m L) while cooling on ice, allowed to warm 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
Dissolving 21d (700mg, 1.03mmol) in DMF (100m L), adding potassium carbonate (569mg, 4.12mmol), heating to 90 ℃ for reaction for 16h, spin-drying the solvent, adding ethyl acetate for dissolution, washing with water to remove inorganic salts, and spin-drying the organic phase to obtain a crude product, which is purified by silica gel column (petroleum ether/ethyl acetate 2/1) to obtain 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 (5m L) and tetrahydrofuran (5m L), ammonia (1m L) was added under ice-bath for 10min, then aqueous solution (2m L) of sodium dithionite (452mg, 2.6mmol) was added to the reaction solution after half an hour, the reaction was completed, ethyl acetate was extracted, the organic phase was dried with water, saturated brine and anhydrous sodium sulfate, filtered and concentrated to give compound 21f (190mg, 88% yield)
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 (10m L) while cooling on ice for ten minutes, DIPEA (148mg, 1.15mmol) and HATU (194mg, 0.51mmol) were added and reacted for 2 hours, DMF was dried by spin drying, ethyl acetate was added to precipitate a solid, and the solid was collected by filtration to obtain 21g of the compound (200mg, yield 74%).
MS(ESI)m/z＝575.2[M+H]+
Step 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 (3M L) and tetrahydrofuran (3M L), lithium hydroxide hydrate (74mg, 1.7mmol) was added, the temperature was raised to 75 ℃ and after 2H cooling, the pH was adjusted to around 3 with dilute hydrochloric acid (1M), a solid was precipitated, filtered and dried to give the compound 21H (160mg, 84% yield).
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
HATU (106mg, 0.28mmol), DIPEA (108mg, 0.84mmol) and ammonium chloride (74mg, 1.4mmol) were added to a 21h (160mg, 0.28mmol) DMF (5m L) solution on ice bath, after 2h reaction, DMF was dried by spinning, ethyl acetate was dissolved, and then washed with water and saturated brine, respectively, and the organic phase was dried to obtain 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 (5m L), hydrobromic acid/acetic acid (33%, 5m L) was added and the reaction was run for 1h at room temperature to give crude (140mg, hydrobromide and containing acetic acid) which was purified by preparative HP L C to give compound 21(22 mg).
MS(ESI)m/z＝426.2[M+H]+
1H NMR(400MHz,DMSO):ppm8.06(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 (8m L) and tetrahydrofuran (16m L) under ice-bath stirring for 30min, 3-benzyloxy bromopropane (3.66g, 15.989mmol) was added, the temperature was raised to room temperature for 10h, water was added after the reaction was complete, ethyl acetate was added for extraction (50m L x3), 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- (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
Under ice bath, compound 22b (800mg,3.43mmol) and triethylamine (1.43m L, 10.3mmol) were dissolved in DCM (20m L), methanesulfonyl chloride (0.3m L, 4.12mmol) was slowly added dropwise, after the addition, the reaction was allowed to warm to room temperature overnight. L CMS showed completion of the reaction, and the reaction was washed with water, dried and spun to obtain methanesulfonic acid-3- (3-tert-butoxycarbonylamino) propoxy) propyl ester (compound 22c) (1.35g,4.34mmol), yield 126%, which was used directly in 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 (20m L), potassium thioacetate (0.94g,8.68mmol) was added and stirred at rt overnight. L CMS showed the reaction was complete. the reaction was poured into water, ethyl acetate extracted (3x40m L), the ethyl acetate layers were combined, dried and spun dry, and purified by column chromatography (eluent: ethyl acetate/petroleum ether 1/5, v/v) (ninhydrin color development) to give 3- (3-tert-butoxycarbonylamino) propoxy) propylthioester acetate-3- (3-tert-butoxycarbonylamino) propylthioester as a yellow oil (compound 22d) (1.062g,3.65mmol), 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 (20m L) and trifluoroacetic acid (4m L) at room temperature, and stirred overnight L CMS showed that the reaction was completed, and the reaction solution was directly spin-dried to obtain the trifluoroacetate salt of acetic acid-3- (3-aminopropoxy) propylthioester (compound 22e) (1.11g,3.65mmol) with a yield of 100%.
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 (15m L) and then methyl 3-bromo-4-fluoro-5-nitrobenzoate (1.00g,3.65mmol) and triethylamine (1.51m L, 10.95mmol) were added sequentially at room temperature and stirred overnight at room temperature L CMS showed completion, the reaction was poured into water, extracted with ethyl acetate (3 × 40m L), the ethyl acetate layers were combined and dried, spun dry 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 (40M L), sodium methoxide (366mg,6.79mmol) was added under ice bath and stirred for 30min under ice bath, L CMS showed completion of the reaction 1M HCl was added to make acidic, spin dried the residue was dissolved with water and ethyl acetate (50M L) and the ethyl acetate layer was separated and dried and spin dried to give methyl 4- (3- (3-mercaptopropoxy) propylamino) -3-bromo-5-nitrobenzoate (compound 22g) (1.30g,3.19mmol) with 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, compound 22g (1.30g,3.19mmol) was dissolved in dioxane (80m L) and N, N-diisopropylethylamine (1.58m L, 9.57mmol), xanthphos (369mg,0.638mmol), Pd2(dba)3(292mg,0.319mmol) were added sequentially under nitrogen protection and allowed to react overnight at 100 ℃. L CMS showed the reaction to be complete. insoluble material was removed by transition, the filtrate was dried by spinning, and purified by column chromatography (eluent: ethyl acetate/petroleum ether to 1/5 1/3, v/v) to give 10-nitro-3, 4,6,7,8, 9-hexahydro-2H-benzo [ f ] [1,5,8] oxathiolane-12-carboxylic acid methyl ester (compound 22H) (570mg,1.74mmol), 54.7% yield.
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 (30m L), aqueous ammonia (1m L) was added under ice-bath, aqueous sodium dithionite (1.07g,6.14mmol) solution (5m L) was added dropwise, after dropping, the mixture was warmed to room temperature and stirred for 2 hours, L CMS showed completion of the reaction, insoluble matter was removed by filtration, the filtrate was dried, the residue was redissolved with water and ethyl acetate (50m L), the ethyl acetate layer was separated and dried, and dried to give methyl 10-amino-3, 4,6,7,8, 9-hexahydro-2H-benzo [ f ] [1,5,8] oxathiazetidine-12-carboxylate (Compound 22i) (320mg,1.08mmol), yield 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 (5m L), 4-ethyl-2-methylthiazole-5-carbonyl isothiocyanate (126mg,0.594mmol) was added with ice bath cooling, the reaction was carried out for 30 minutes in ice bath, after L CMS showed the completion of addition, HATU (226mg,0.594mmol) and N, N-diisopropylethylamine (0.28m L, 1.62mmol) were added, the mixture was warmed to room temperature and stirred overnight. L CMS showed the completion of reaction, the precipitated solid was filtered, and the cake was washed once with each of DMF (1m L) and petroleum ether (20m L) 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-diazacycloundecane [ cd ] indene-4-carboxylate (compound 22j) (140mg, 0.295) 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 (5M L), water (1M L) and lithium hydroxide monohydrate (62mg,1.48mmol) were added, the mixture was stirred overnight at 40 ℃ with L CMS showing completion, 1M HCl was added to adjust to acidity, the solvent was dried, the residue was redissolved with water and dichloromethane (30M L), the dichloromethane layer was separated, dried and then dried to give 1- (4-ethyl-2-methylthiazole-5-carboxamide) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundecane [ cd ] indene-4-carboxylic acid (compound 22k) (61mg,0.133mmol), 81.8%.
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 (5m L), N-diisopropylethylamine (0.09m L, 0.532mmol), HATU (76mg,0.20mmol) were added, stirring at room temperature for 30min then ammonium chloride (21mg,0.398mmol) was added, stirring at room temperature overnight L CMS showed the reaction was complete, the reaction was poured into water, ethyl acetate was extracted (3X30m L), the ethyl acetate layers were combined, dried and spun dry, and prep-HP L C was purified to give 1- (4-ethyl-2-methylthiazole-5-carboxamido) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundecan [ cd ] indene-4-carboxamide (Compound 22) (23.5mg,0.051mmol), 28% yield.
MS(ESI)m/z＝460[M+H]+。
1H NMR(400MHz,DMSO-d6)12.93(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 (5m L), 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (116mg,0.594mmol) was added under ice-bath cooling, reaction was performed for 30 minutes under ice-bath cooling, after L CMS showed addition, HATU (226mg,0.594mmol) and N, N-diisopropylethylamine (0.28m L, 1.62mmol) were added, warmed to room temperature and stirred overnight, L CMS showed completion, the reaction solution was poured into water, ethyl acetate was extracted (3x30m L), ethyl acetate layers were combined, dried and dried 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-diazacyclo [ 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 (5M L), water (1M L) and lithium hydroxide monohydrate (175mg,4.16mmol) were added, the mixture was stirred overnight at 50 ℃ with L CMS showing completion of the reaction 1M HCl was added to adjust to acidity, the solvent was dried, the residue was redissolved with water and ethyl acetate (30M L), the ethyl acetate layer was separated, dried and dried to give 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-carboxylic acid (compound 23b) (148mg,0.334mmol) in 80.4% yield.
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 (5m L), N-diisopropylethylamine (0.22m L, 1.336mmol), HATU (190mg,0.501mmol) were added, ammonium chloride (53mg,1.00mmol) was added after stirring at room temperature for 30min, and stirring at room temperature overnight L CMS showed the reaction was complete, the reaction was poured into water, ethyl acetate was extracted (3 × 30m L), the ethyl acetate layers were combined, dried and spun dry, and prep-HP L C was purified to give 1- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -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), yield 11.4%.
MS(ESI)m/z＝443[M+H]+。
1H NMR(400MHz,DMSO-d6)12.96(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 (10m L), m-chloroperoxybenzoic acid (51mg,0.295mmol) was added and stirred at room temperature overnight. L CMS showed completion of the reaction, the reaction solution was washed with water, the organic layer was separated and dried and then spin-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-6, 6-dioxide (compound 24a) (76mg,0.15mmol), yield 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 (5M L), water (1M L) and lithium hydroxide monohydrate (63mg,1.5mmol) were added, the mixture was stirred overnight at 50 ℃ with L CMS showing completion of the reaction 1M HCl was added to adjust to acidity, the solvent was dried, the residue was redissolved with water and ethyl acetate (30M L), the ethyl acetate layer was separated, dried and dried to give 1- (4-ethyl-2-methylthiazole-5-carboxamido) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundecane [ cd ] indene-4-carboxylic acid-6, 6-dioxide (compound 24b) (25mg,0.051mmol) in 34% yield.
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 (5m L), N-diisopropylethylamine (0.033m L, 0.204mmol), HATU (29mg,0.077mmol) were added, stirred at room temperature for 30min, ammonium chloride (8mg,0.152mmol) was added, stirred at room temperature overnight. L CMS showed the reaction was complete, the reaction was poured into water, ethyl acetate extracted (3 × 30m L), the ethyl acetate layers were combined, dried and spun dry to purify prep-HP L C to obtain 1- (4-ethyl-2-methylthiazole-5-carboxamido) -7,8,9,11,12, 13-hexahydro-10-oxo-6-thio-2, 13 a-diazacycloundecane [ 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)8.42(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 (5m L), m-chloroperoxybenzoic acid (61mg,0.357mmol) was added under ice-bath cooling, and the reaction was stirred for 3 hours under ice-bath L CMS showed completion, and the reaction solution was washed with saturated solution of sodium bicarbonate to separate an organic layer, which was dried and then 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 methyl ester-6-oxide (compound 25a) (50mg,0.106mmol) with a yield of 35.5%.
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 (5M L), water (1M L) and lithium hydroxide monohydrate (45mg,1.06mmol) were added, the mixture was allowed to warm to 50 ℃ and stirred overnight, L CMS showed the reaction was complete, 1M HCl was added to adjust to acidity, the solvent was dried, the residue was redissolved with water and ethyl acetate (30M L), the ethyl acetate layer was separated, dried and dried to give 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-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 (5m L), N-diisopropylethylamine (0.07m L, 0.44mmol), HATU (63mg,0.165mmol) were added, ammonium chloride (18mg,0.33mmol) was added after stirring at room temperature for 30min, and stirring at room temperature overnight L CMS showed the reaction was complete, the reaction was poured into water, ethyl acetate was extracted (3x30m L), the ethyl acetate layers were combined, dried and spun dry, and prep-HP L C was purified 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) in 1.8% yield.
MS(ESI)m/z＝459[M+H]+。
1H NMR(400MHz,DMSO-d6)13.08(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
The compound 8g (120mg,0.425mmol) was dissolved in DMF (5m L), 4-ethyl-2-methylthiazole-5-carbonyl isothiocyanate (90mg,0.425mmol) was added with ice-bath cooling, reacted for 30 minutes with ice-bath cooling, after L CMS showed the addition was completed, HATU (178mg,0.468mmol) and N, N-diisopropylethylamine (0.23m L, 1.28mmol) were added, warmed to room temperature and stirred overnight. L CMS showed the reaction was completed, the reaction solution was poured into water, ethyl acetate was extracted (3X30m L), ethyl acetate layers were combined, dried and spun to obtain methyl 1- (4-ethyl-2-methylthiazole-5-carboxamide) -8,10,11, 12-tetrahydro-7H-9-oxo-6-thio-2, 12 a-diazacyclodecan [ cd ] indene-4-carboxylate (compound 26a) (220mg,0.478mmol), yield 112%.
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 (10M L), water (2M L) and lithium hydroxide monohydrate (201mg,4.78mmol) were added, the mixture was stirred overnight at 40 ℃ with L CMS showing completion of the reaction, 1M HCl was added to adjust to acidity, the solvent was dried, the residue was redissolved with water and dichloromethane (30M L), the dichloromethane layer was separated, dried and then dried to give 1- (4-ethyl-2-methylthiazole-5-carboxamide) -8,10,11, 12-tetrahydro-7H-9-oxo-6-thioxo-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 (5m L), triethylamine (0.1m L, 0.716mmol), HATU (102mg,0.0.269mmol) were added, ammonium chloride (29mg,0.538mmol) was added after stirring at room temperature for 30min, stirring at room temperature overnight L CMS showed the reaction was complete, the reaction was poured into water, ethyl acetate was extracted (3 × 30m L), the ethyl acetate layers were combined, dried and spun dry, and purified with prep-HP L C 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), yield 7.5%.
MS(ESI)m/z＝446[M+H]+。
1H NMR(400MHz,DMSO-d6)12.98(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 (2m L) was added acetic acid to a pH of about 4, then a solution of formaldehyde in alcohol (1m L) was added, after 0.5h reaction at room temperature, sodium cyanoborohydride (15mg, 0.24mmol) was added and, after completion of the reaction, compound 27(8mg, 38% yield) was purified by preparative HP L C
MS(ESI)m/z＝440.2[M+H]+。
1H NMR(400MHz,DMSO):ppm12.79(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
Dissolving 1-methylpiperidine-4-carboxylic acid (8mg, 0.056mmol) in DMF (2m L), adding HATU (21mg, 0.056mmol) and DIPEA (12mg, 0.094mmol) at room temperature, stirring for 1h, adding 21(20mg, 0.047mmol) to the reaction solution, reacting completely after two hours, purifying the reaction solution by preparative HP L C to obtain compound 28(4.8mg, 15% yield)
MS(ESI)m/z＝551.3[M+H]+。
1H NMR(400MHz,DMSO):ppm7.99(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 protein heat transfer assay (TSA) at 20mM hepes,150mM NaCl,1mM MgCl21mM DTT, pH 7.5 buffer 100ug/ml Sting protein was mixed with different concentrations of compound and 5X SYPRO Orange dye, the protein dissolution curve was measured on a qPCR instrument, the Tm was fitted with the Software protein thermal Shift Software 1.3, the difference in Tm for proteins with and without compound added was calculated based on the difference in Tm for the protein with and without compound added based on the pHΔThe 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
The function of sting agonist was evaluated by measuring the change in CXC L10 (IP10) cytokine production by compound-stimulated human peripheral blood mononuclear cell line THP1 cells (Shanghai cell bank). The first day of experiment E L ISA plate was coated according to the instructions of the IP 10E L ISA detection kit (BD, # 550926). The compound DMSO was dissolved in stock solution and diluted to 2 working concentration with culture medium, 96 well plates were added at 100. mu. L per well, and THP1 cells in logarithmic growth phase were counted and diluted to 2 10. mu.106At a concentration of/m L, adding to the above compound-containing 96-well plate at a concentration of 100. mu. L per well, mixing well at 37 ℃ with 5% CO2Culturing in incubator for 18 hr, collecting the cell culture supernatant on the next day, detecting with 100 μ L per well according to the instruction of IP 10E L ISA detection kit (BD, #550926), reading OD450 value, converting into IP10 concentration according to standard curve, and calculating EC 10 concentration by GraphPad 5.0 simulation mixture 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 CXC L10 (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 CXC L10 (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 (19)

1. A compound of formula I or a tautomer, enantiomer, or pharmaceutically acceptable salt, crystal form, hydrate, or solvate thereof:
Figure FDA0002376122000000011
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 isiWhen there are at least 2, 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 FDA0002376122000000012
Rc、Rdare respectively and independently selected from hydrogen and C1～C6Alkyl, halogen substituted C1～C6Alkyl, -C (O) RkOr none, or RcAnd RdTo which they are connectedThe nitrogen atoms are linked to form a group 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. A compound according to claim 1, or a tautomer, enantiomer, or pharmaceutically acceptable salt, crystal, hydrate, or solvate thereof, wherein: the compound is represented by formula I:
Figure FDA0002376122000000021
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 isiWhen there are at least 2, 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 FDA0002376122000000022
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.
3. A compound according to claim 2, or a tautomer, enantiomer, or pharmaceutically acceptable salt, crystal, hydrate, or solvate thereof, wherein: the compound is represented by formula II:
Figure FDA0002376122000000023
ring B is selected from
Figure FDA0002376122000000031
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 isiWhen there are at least 2, L1、L2R in (1)iCan be connected to form a 3-10 membered ring;
Riselected from-ORj, halogen, -CN, C1～C6An alkyl group;
rj is selected from hydrogen and C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
z is selected from the group consisting of-O-, -C (O) NR-, -NR-, (I),
Figure FDA0002376122000000032
R is selected from hydrogen and C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
Rc、Rdare respectively independentSelected from hydrogen, 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. A compound according to claim 3, or a tautomer, enantiomer, or pharmaceutically acceptable salt, crystal, hydrate, or solvate thereof, wherein: z is-O-.
5. A compound according to claim 3, or a tautomer, enantiomer, or pharmaceutically acceptable salt, crystal, hydrate, or solvate thereof, wherein: the compound shown in the formula II is:
Figure FDA0002376122000000033
Figure FDA0002376122000000041
6. a compound according to claim 2, or a tautomer, enantiomer, or pharmaceutically acceptable salt, crystal, hydrate, or solvate thereof, wherein: the compound is shown as formula III:
Figure FDA0002376122000000042
Figure FDA0002376122000000051
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 FDA0002376122000000052
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 FDA0002376122000000053
Is coated with 0 to 4ReOptionally substituted
Figure FDA0002376122000000054
Is coated with 0 to 4ReOptionally substituted
Figure FDA0002376122000000055
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 isiWhen there are at least 2, L1、L2R in (1)iCan be combined withConnecting 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 of claim 6, or a tautomer, enantiomer, or pharmaceutically acceptable salt, crystal, hydrate, or solvate thereof, wherein: the compound shown in the formula III is:
Figure FDA0002376122000000056
8. a compound according to claim 2, or a tautomer, enantiomer, or pharmaceutically acceptable salt, crystal, hydrate, or solvate thereof, wherein: the compound is shown as formula IV:
Figure FDA0002376122000000057
Figure FDA0002376122000000061
ring B is selected from
Figure FDA0002376122000000062
R6、R7、R8Are independently selected from hydrogen and 0-4RbOptionally substitutedC of (A)1～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 isiWhen there are at least 2, L1、L2R in (1)iCan be connected to form a 3-10 membered ring;
Riselected from-ORj, halogen, -CN, C1～C6An alkyl group;
rj is selected from hydrogen and C1～C6Alkyl, halogen substituted C1～C6An alkyl group;
z is selected from the group consisting of-O-, -C (O) NR-, -NR-, (I),
Figure FDA0002376122000000063
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. A compound according to claim 8, or a tautomer, enantiomer, or pharmaceutically acceptable salt, crystal, hydrate, or solvate thereof, wherein: the compound is shown as a formula V:
Figure FDA0002376122000000064
ring B is selected from
Figure FDA0002376122000000065
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 isiWhen there are at least 2, 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. A compound according to claim 9, or a tautomer, enantiomer, or pharmaceutically acceptable salt, crystal, hydrate, or solvate thereof, wherein: the compound shown in the formula V is:
Figure FDA0002376122000000071
11. a compound according to claim 1, or a tautomer, enantiomer, or pharmaceutically acceptable salt, crystal, hydrate, or solvate thereof, wherein: the compound is represented by formula VI:
Figure FDA0002376122000000072
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 FDA0002376122000000073
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. A compound according to claim 11, or a tautomer, enantiomer, or pharmaceutically acceptable salt, crystal, hydrate, or solvate thereof, wherein:
ring B is selected from
Figure FDA0002376122000000081
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 FDA0002376122000000082
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.
13. A compound according to claim 12, or a tautomer, enantiomer, or pharmaceutically acceptable salt, crystal, hydrate, or solvate thereof, wherein: the compound is:
Figure FDA0002376122000000083
Figure FDA0002376122000000091
14. use of a compound of any one of claims 1to 13, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, in the preparation of a medicament for activating STING.
15. Use of a compound of any one of claims 1to 13, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a prodrug thereof, or a metabolite thereof, in the manufacture of a medicament for the treatment of a disease associated with STING activity.
16. Use according to claim 15, 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.
17. Use of a compound according to any one of claims 1to 13, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a prodrug thereof, or a metabolite thereof, in the manufacture of a medicament for the treatment of an inflammatory, autoimmune, infectious, cancer or pre-cancerous syndrome.
18. Use of a compound of any one of claims 1to 13, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, in the preparation of an immunoadjuvant.
19. A medicament, characterized by: a preparation comprising the compound of any one of claims 1to 13, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable excipient.
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