CN120965663A - sEH inhibitor compounds, pharmaceutical compositions, their preparation methods and applications - Google Patents

sEH inhibitor compounds, pharmaceutical compositions, their preparation methods and applications

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Publication number
CN120965663A
CN120965663A CN202410620234.XA CN202410620234A CN120965663A CN 120965663 A CN120965663 A CN 120965663A CN 202410620234 A CN202410620234 A CN 202410620234A CN 120965663 A CN120965663 A CN 120965663A
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China
Prior art keywords
alkyl
compound
alkoxy
different
same
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CN202410620234.XA
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Chinese (zh)
Inventor
梁建华
丁静
朱心红
朱旻帧
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Beijing Institute of Technology BIT
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Beijing Institute of Technology BIT
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Priority to CN202410620234.XA priority Critical patent/CN120965663A/en
Priority to PCT/CN2025/083855 priority patent/WO2025236852A1/en
Publication of CN120965663A publication Critical patent/CN120965663A/en
Pending legal-status Critical Current

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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • 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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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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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Abstract

The compound shown in the formula (I), the tautomer, the stereoisomer, the hydrate, the solvate, the pharmaceutically acceptable salt or the prodrug thereof have excellent sEH inhibition effect, and can be used for preventing and/or treating diseases related to sEH inhibition, such as inflammation.

Description

SEH inhibitor compound, pharmaceutical composition, preparation method and application thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to sEH inhibitor compounds, a pharmaceutical composition, a preparation method and application thereof.
Background
Inflammation is the first warning signal of human body to deal with invasion of microorganisms and pathogens, and long-term, chronic inflammation can lead to the occurrence of various diseases such as cardiovascular diseases, cancers, alzheimer's disease, senile dementia, asthma, rheumatoid arthritis, etc. Arachidonic acid (Arachidonic acid, AA) is a polyunsaturated fatty acid and prior studies have shown that the arachidonic acid pathway produces active mediators that regulate a range of different inflammatory processes. Arachidonic acid is metabolized by the Cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP) pathways, which are primarily responsible for the production of pro-inflammatory mediators such as prostaglandins and leukotrienes. COX inhibitors, which are non-steroidal anti-inflammatory drugs (NSAIDs), are widely used clinically in the treatment of inflammatory diseases. Representative drugs of this class include celecoxib, rofecoxib, etoricoxib and the like. Celecoxib is the first FDA approved selective COX-2 inhibitor known to have gastrointestinal and cardiovascular side effects. Rofecoxib and etoricoxib have been withdrawn from the market due to the possibility of causing serious cardiovascular side effects, such as heart attacks and strokes. Thus, there is an urgent need for an effective and safe method of treating inflammatory diseases. In contrast, CYP2C and CYP2J enzymes in the CYP pathway can convert arachidonic acid to the anti-inflammatory mediators epoxyeicosatrienoic acid (EETs), which are important signaling molecules in organisms, with the effects of mediating vasodilation, reducing inflammatory responses, and analgesia. However, EETs are metabolized by soluble epoxide hydrolase (sEH) to the corresponding pro-inflammatory factor dihydroxyeicosatrienoic acids (DHETs). Previous studies have shown that inhibition of sEH can significantly reduce the conversion of EETs to the corresponding DHETs, thereby reducing inflammation and pain states. This suggests that sEH may be a pharmacological target for the treatment of inflammatory diseases and pain.
A large number of compounds in natural products showed inhibitory effects on sEH, but IC 50 values were all at the micromolar level and were not of value for further preclinical studies. To date, synthetic compounds AR9281, GSK2256294 and EC5026 have entered the clinical trial phase, but no sEH inhibitor class of drugs is currently marketed.
Thus, there is a need for new backbone soluble epoxide hydrolase inhibiting compounds with IC 50 values at nanomolar levels for anti-inflammatory target soluble epoxide hydrolases.
Disclosure of Invention
The present invention provides a compound, tautomer, stereoisomer, isotopic label, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, represented by the following formula (I):
Wherein ring B is selected from 5-6 membered heterocycle, 5-6 membered heteroaryl ring;
R 1 is selected from the group consisting of C 1-10 alkyl, 3-14 membered heterocyclyl, C 6-14 aryl, optionally substituted with one, two or more R 11, 5-14 membered heteroaryl, each R 11 being identical or different and independently of the others selected from H, C 1-10 alkoxy, C 3-10 cycloalkyl, optionally substituted by one, two or more R 12, C 1-10 alkyl-C (=O) -, 3-14 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, each R 12 being identical or different and being selected independently of one another from H, CN, halogen, C 1-10 alkyl, optionally substituted by one, two or more R 13, C 1-10 alkoxy, C 1-10 alkyl-C (=o) -, C 1-10 alkoxy-C (=o) -, C 3-10 cycloalkyl-C (=o) -, C 1-10 alkyl-S (=O) 2-、H2N-S(＝O)2 -, each R 13 being identical or different and being selected independently of one another from H, halogen, C 1-10 alkyl, C 1-10 alkoxy, C 6-14 aryl;
Each R 2, which is the same or different, is independently selected from H, C 1-10 alkyl, C 1-10 alkoxy;
Each R 3 is the same or different and is independently selected from H, CN, unsubstituted or optionally substituted by one, two or more R 31 amino, C 1-10 alkyl, C 1-10 alkoxy, 3-14 membered heterocyclyl, C 1-10 alkyl-S (=O) 2-、H2N-S(＝O)2-、C1-10 alkyl-C (O) NH-, each R 31 is the same or different and is independently selected from H, halogen, oxo (=O), C 1-10 alkyl, C 1-10 alkoxy, -NH (C 1-10 alkyl), N (C 1-10 alkyl) (C 1-10 alkyl), 5-14 membered heteroaryl, halogenated 5-14 membered heteroaryl;
Or two adjacent R 3 together with the atoms to which they are each attached form a 3-to 14-membered heterocyclyl which is unsubstituted or optionally substituted by one, two or more R 32, each R 32 being the same or different and independently of the others selected from H, C 1-10 alkyl, C 1-10 alkoxy;
Each R b, which is the same or different, is independently selected from H, C 1-10 alkyl, C 1-10 alkoxy;
m is selected from 0,1, 2 or 3;
n is selected from 0,1, 2, 3, 4 or 5;
p is selected from 0, 1 or 2.
According to an embodiment of the invention, ring B is selected from the group consisting of a 5 membered nitrogen containing heterocycle, a 5 membered nitrogen containing heteroaryl ring, a 6 membered nitrogen containing heterocycle, a 6 membered nitrogen containing heteroaryl ring;
According to an embodiment of the present invention, ring B is selected from an imidazole ring, a pyrrole ring, a pyridine ring or a piperidine ring.
In accordance with an embodiment of the present invention,Selected from the group consisting of
In accordance with an embodiment of the present invention,Selected from the group consisting of
According to an embodiment of the invention, R 1 is selected from the group consisting of C 1-6 alkyl, 3-8 membered heterocyclyl, C 6-10 aryl, optionally substituted with one, two or more R 11, 5-10 membered heteroaryl, each R 11 being identical or different and independently of the others selected from H, C 1-6 alkoxy, C 3-8 cycloalkyl, optionally substituted by one, two or more R 12, C 1-6 alkyl-C (=O) -, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, each R 12 being identical or different and being selected independently of one another from H, CN, halogen, C 1-6 alkyl, optionally substituted by one, two or more R 13, C 1-6 alkoxy, C 1-6 alkyl-C (=o) -, C 1-6 alkoxy-C (=o) -, C 3-8 cycloalkyl-C (=o) -, C 1-6 alkyl-S (=O) 2-、H2N-S(＝O)2 -, each R 13 being identical or different and being selected independently of one another from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl;
According to an embodiment of the invention, R 1 is selected from the group consisting of C 1-6 alkyl, 3-8 membered heterocyclyl, C 6-10 aryl, each R 11 being identical or different and independently selected from H, R 11, optionally substituted with one, two or more, C 1-6 alkyl-C (=O) -, halogenated C 1-6 alkoxy, a group which is unsubstituted or optionally substituted by one, two or more R 12, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, each R 12 being identical or different and independently of the other selected from H, CN, halogen, C 1-6 alkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 1-6 alkyl-C (=O) -, halogenated C 1-6 alkyl-C (=O) -, C 1-6 alkoxy-C (=O) -, and, C 6-10 aryl-C 1-6 alkoxy-C (=o) -, C 3-8 cycloalkyl-C (=o) -, C 1-6 alkyl-S (=o) 2-、H2N-S(＝O)2 -;
According to an embodiment of the invention, R 1 is selected from-CH 2-R11.
According to an embodiment of the invention, each R 11 is identical or different and is selected independently of the others from trifluoromethoxy,And optionally substituted with one, two or more R 12, tetrahydrofuranyl, tetrahydropyranyl, cyclohexyl, piperidinyl, phenyl.
According to an embodiment of the invention, each R 11 is identical or different and is selected independently of the others from
According to an embodiment of the invention, each R 12, which is the same or different, is independently selected from H, CN, methoxy, -C (O) OCH 3, benzyloxycarbonyl, trifluoromethoxy, difluoromethoxy, trifluoromethyl, methylsulfonyl, aminosulfonyl,
According to an embodiment of the invention, R 1 is selected from C 1-6 alkyl, 5-6 membered heterocyclyl-C 1-3 alkyl, C 1-6 alkyl-C (=o) -piperidinyl, Halogenated C 1-3 Alkoxyphenyl, C 1-3 alkoxy-C (=O) -cyclohexyl-C 1-3 alkyl, C 1-3 alkyl-C (=O) -piperidinyl-C 1-3 alkyl, Halogenated C 1-3 alkyl-C (=O) -piperidinyl-C 1-3 alkyl, C 3-6 cycloalkyl-C (=O) -piperidinyl-C 1-3 alkyl, Phenyl C 1-3 alkyl-C (=O) -piperidinyl-C 1-3 alkyl, C 1-3 alkoxyphenyl C 1-3 alkyl, Halogenated C 1-3 alkoxyphenyl C 1-3 alkyl, halogenated C 1-3 alkylphenyl C 1-3 alkyl, cyanophenyl C 1-3 alkyl, H 2N-S(O)2 -phenylC 1-3 alkyl, C 1-3 alkyl-S (O) 2 -phenylC 1-3 alkyl, pyridinyl C 1-3 alkyl;
According to an embodiment of the invention, R 1 is selected from
According to an embodiment of the invention, each R 2 is the same or different and is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy.
According to an embodiment of the invention, each R 3 is the same or different and is independently selected from H, CN, unsubstituted or optionally substituted by one, two or more R 31, amino, C 1-6 alkyl, C 1-6 alkoxy, 3-8 membered heterocyclyl, C 1-6 alkyl-S (=O) 2-、H2N-S(＝O)2-、C1-6 alkyl-C (O) NH-; each R 31 is the same or different and is independently selected from H, halogen, oxo (=O), C 1-6 alkyl, C 1-6 alkoxy, -NH (C 1-6 alkyl), N (C 1-6 alkyl) (C 1-6 alkyl), 5-10 membered heteroaryl, halogenated 5-10 membered heteroaryl;
Or two adjacent R 3 together with the atoms to which they are each attached form a 3-8 membered heterocyclyl which is unsubstituted or optionally substituted by one, two or more R 32, each R 32 being identical or different and independently of the others selected from H, C 1-6 alkyl, C 1-6 alkoxy.
According to an embodiment of the invention, each R 31 is the same or different and is independently selected from H, halogen, oxo (=o), C 1-3 alkyl, C 1-3 alkoxy, -NH (C 1-3 alkyl), N (C 1-3 alkyl) (C 1-3 alkyl), pyridinyl, halopyridinyl.
According to an embodiment of the invention, each R 3 is the same or different and is independently selected from H, CN, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, Halogenated C 1-6 alkoxy, C 1-6 alkyl-C (O) -, -NH (C 1-6 alkyl), -N (C 1-6 alkyl) (C 1-6 alkyl), -C 1-6 alkyl-NH (C 1-6 alkyl), -C 1-6 alkyl-N (C 1-6 alkyl) (C 1-6 alkyl), C 1-6 alkyl-3-8 membered heterocyclyl, C 1-6 alkyl-S (=O) 2-、H2N-S(＝O)2 -, 5-10 membered heteroaryl-C 1-6 alkyl-C (O) NH-, Halo 5-10 membered heteroaryl-C 1-6 alkyl-C (O) NH-;
or two adjacent R 3 groups form a 3-8 membered heterocyclic group with the atom to which each is attached.
According to an embodiment of the invention, R 3 is selected from H, CN, amino, methyl, methoxy, trifluoromethoxy, acetyl, dimethylamino,
Or two adjacent R 3's form with the atom to which they are each attached
In accordance with an embodiment of the present invention,Selected from the group consisting of
According to an embodiment of the invention, each R b is the same or different and is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy.
According to an embodiment of the present invention, the compound represented by formula (I) has the structure shown below:
Wherein R 1、R2、R3、Rb, m, n, p independently of one another have the above-described definition.
According to an embodiment of the present invention, the compound represented by formula (I) has the structure shown below:
Wherein rings B, R 1、R2、R31、Rb, m, p have the above-described definition independently of each other.
According to an embodiment of the present invention, the compound represented by formula (I) has the structure shown below:
wherein rings B, R 2、R3、R12、Rb, m, p have the above-described definition independently of each other.
According to an embodiment of the present invention, the compound represented by formula (I) has the structure shown below:
Wherein the rings B, R 2、R3、R11、Rb, m, n, p have the above-described definitions independently of each other. According to an embodiment of the present invention, the compound represented by formula (I) has the structure shown below:
wherein R 3、R12, independently of one another, have the abovementioned definition.
According to an exemplary embodiment of the present invention, the compound of formula (I) may have one of the following structures:
The invention also provides a preparation method of the compound shown in the formula (I), a tautomer, a stereoisomer, an isotope label, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, which comprises the following steps of reacting the following compound a with the compound b in the presence of carbonyl diimidazole to obtain the compound shown in the formula (I);
Wherein the rings B, R 1、R2、R3、Rb, m, n, p have the above-described definitions independently of each other.
According to an embodiment of the present invention, the preparation method may be performed in the presence of a solvent such as an organic solvent. For example, the organic solvent may be selected from at least one of alcohols such as methanol, ethanol, isopropanol, n-butanol, ethers such as ethyl propyl ether, n-butyl ether, anisole, phenetole, cyclohexylmethyl ether, dimethyl ether, diethyl ether, dimethylethylene glycol, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, diethyl ether, and polyethers of ethylene oxide and/or propylene oxide, aliphatic, cycloaliphatic or aromatic hydrocarbons such as pentane, hexane, heptane, octane, nonane, and classes which may be substituted with fluorine and chlorine atoms such as methylene chloride, chloroform, carbon tetrachloride, fluorobenzene, chlorobenzene or dichlorobenzene, cyclohexane, methylcyclohexane, petroleum ether, octane, benzene, toluene, chlorobenzene, bromobenzene, xylene, ethyl acetate, butyl acetate, ethylene carbonate and dibutyl carbonate or diethyl carbonate.
The invention also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises the compound shown in the formula (I), a tautomer, a stereoisomer, an isotope label, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof.
According to an embodiment of the invention, the pharmaceutical composition further comprises pharmaceutically acceptable excipients.
The invention also provides a compound shown in the formula (I), a tautomer, a stereoisomer, an isotope label, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, or application of the pharmaceutical composition in preparing medicines.
According to an embodiment of the invention, the pharmaceutical composition or the medicament is for the treatment of diseases associated with sEH inhibition, such as for the treatment of inflammation (e.g. foot swelling inflammation, pancreatitis, neuroinflammation), analgesia, myocardial ischemia, fibrosis, renal failure, diabetes, hypertension and cardiovascular diseases.
The invention also provides a compound shown in a formula (I), a tautomer, a stereoisomer, an isotope label, a hydrate, a solvate, a pharmaceutically acceptable salt or prodrug thereof or the pharmaceutical composition for preventing and/or treating sEH inhibition related diseases.
According to an embodiment of the invention, the disease associated with sEH inhibition is selected from the group consisting of inflammation (e.g. foot swelling inflammation, pancreatitis, neuroinflammation), analgesia, myocardial ischemia, fibrosis, renal failure, diabetes, hypertension, and cardiovascular disease.
The present invention also provides a method for preventing and/or treating diseases associated with sEH inhibition, comprising administering to a patient a therapeutically effective amount of at least one compound of formula (I), a tautomer, stereoisomer, isotopic label, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or said pharmaceutical composition.
According to an embodiment of the invention, the disease associated with sEH inhibition is selected from the group consisting of inflammation (e.g. foot swelling inflammation, pancreatitis, neuroinflammation), analgesia, myocardial ischemia, fibrosis, renal failure, diabetes, hypertension, and cardiovascular disease.
The therapeutically effective amount or dosage of the present invention will vary depending on several factors, including the route of administration selected, the formulation of the composition, the patient's response, the severity of the condition, the weight of the subject and the discretion of the prescribing physician, for example 1-200mg/kg,40-150mg/kg, such as 50mg/kg. The dosage may be increased or decreased over time, as required by the individual patient. In some cases, the patient is initially given a low dose and then increased to an effective dose that the patient can tolerate. In addition, the patient may administer multiple doses, particularly in time increments (e.g., daily, weekly, biweekly, monthly, quarterly, bi-yearly, or the like), over a defined period of time.
Advantageous effects
The compound shown in the formula (I), tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof have excellent sEH inhibition effect and can be used for preventing and/or treating diseases related to sEH inhibition.
Drawings
Fig. 1 is a graph showing pancreatic cut-out and pancreatic inflammatory infiltration scores for compound C17 for use in treating pancreatitis.
Figure 2 is the inflammatory factor levels in plasma after compound C17 is used to treat pancreatitis.
Fig. 3 shows analgesic effects of compounds C5, C9, C17 and C30 in a mouse acetic acid torsion experiment.
Definition and description of terms
Unless otherwise indicated, the radical and term definitions recited in the specification and claims of the present application, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. Such combinations and combinations of radical definitions and structures should be understood to be within the scope of the present description and/or claims.
The numerical ranges recited in the specification and claims are equivalent to at least each specific integer number recited therein unless otherwise stated. For example, a numerical range "1-10" corresponds to each of the integer numbers recited in the numerical range "1-10," i.e., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.
It should be understood that in describing one, two or more herein, "more" shall mean an integer greater than 2, such as greater than or equal to 3, such as 3, 4,5, 6,7, 8, 9 or 10.
The term "C 1-10 alkyl" denotes a straight or branched saturated hydrocarbon group having 1,2, 3,4, 5, 6, 7, 8, 9 or 10 carbon atoms. The C 1-10 alkyl group includes C 1-3 alkyl, C 1-6 alkyl, C 3-6 alkyl, and the like. "C 1-10 alkyl" means straight and branched chain alkyl having 1,2, 3,4, 5, 6, 7, 8, 9, or 10 carbon atoms, "C 1-8 alkyl" means straight and branched chain alkyl having 1,2, 3,4, 5, 6, 7, or 8 carbon atoms, "C 1-6 alkyl" means straight and branched chain alkyl having 1,2, 3,4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, or the like, or an isomer thereof.
The term "C 3-10 cycloalkyl" denotes a saturated monovalent monocyclic, bicyclic (e.g., fused, bridged, spiro) hydrocarbon ring or tricyclic hydrocarbon ring having 3,4, 5, 6, 7, 8, 9, or 10 carbon atoms. The C 3-10 cycloalkyl group includes C 3-8 cycloalkyl, C 3-5 cycloalkyl, C 6-8 cycloalkyl, C 3-4 cycloalkyl, C 5-6 cycloalkyl, C 6 cycloalkyl, and the like. The C 3-10 cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as campholyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, 6-dimethylbicyclo [3.1.1] heptyl, 2, 6-trimethylbicyclo [3.1.1] heptyl, bicyclo [2.2.2] octyl, 2, 7-diazaspiro [3,5] nonyl, 2, 6-diazaspiro [3,4] octyl, or a tricyclic hydrocarbon group such as adamantyl.
The term "3-14 membered heterocyclyl" means a saturated or unsaturated, non-aromatic ring or ring system and contains at least one heteroatom selected from O, S and N. The heterocyclic group may be attached to the remainder of the molecule through any of the carbon atoms or a nitrogen atom, if present. The heterocyclic group may include fused or bridged rings as well as spiro rings. In particular, the heterocyclic groups may include, but are not limited to, 3-membered rings such as aziridine, oxetane, 4-membered rings such as azetidinyl, oxetane, 5-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, or 6-membered rings such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl, or 7-membered rings such as diazepinyl. Optionally, the heterocyclyl may be benzo-fused. The heterocyclyl may be bicyclic, such as, but not limited to, a 5,5 membered ring, such as hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl ring, or a 5,6 membered bicyclic ring, such as hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl ring. The heterocyclic group may be partially unsaturated, i.e. it may contain one or more double bonds, such as but not limited to dihydrofuranyl, dihydropyranyl, 2, 5-dihydro-1H-pyrrolyl, 4H- [1,3,4] thiadiazinyl, 1,2,3, 5-tetrahydrooxazolyl or 4H- [1,4] thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolinyl. When the 3-14 membered heterocyclic group is linked to other groups to form the compound of the present invention, the carbon atom on the 3-14 membered heterocyclic group may be linked to other groups, or the heterocyclic atom (e.g., N atom) on the 3-14 membered heterocyclic ring may be linked to other groups. For example, when the 3-14 membered heterocyclic group is selected from piperazinyl and tetrahydropyrrolyl, it may be that a nitrogen atom or a carbon atom on the piperazinyl group is bonded to other groups. Or when the 3-14 membered heterocyclic group is selected from piperidyl, it may be a nitrogen atom on the piperidyl ring or a carbon atom in the ortho, meta or para position thereof, to other groups.
The term "C 6-14 aryl" is understood to mean preferably a monovalent aromatic or partially aromatic mono-, bi-or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms ("C 6-14 aryl"), in particular a ring having 6 carbon atoms ("C 6 aryl"), for example phenyl, or biphenyl, or a ring having 9 carbon atoms ("C 9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl"), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl"), for example fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl"), for example anthracenyl. When the C 6-20 aryl group is substituted, it may be mono-substituted or poly-substituted. The substitution site is not limited, and may be, for example, ortho, para or meta substitution.
The term "5-14 membered heteroaryl" means a mono-or polyvalent, mono-, bi-or tricyclic aromatic ring system having 5,6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms and the ring atoms of which contain 1 to 5 heteroatoms independently selected from N, O and S, which may be fused, spiro or bridged. The number of heteroatoms in the 5-14 membered heteroaryl is 1-5, preferably 1-3. Further, the 5-14 membered heteroaryl groups in each case may be benzo-fused. The 5-14 membered heteroaryl group includes a 5-8 membered heteroaryl group, a 5-9 membered heteroaryl group, a 5-10 membered heteroaryl group, a 5-6 membered heteroaryl group, an 8-10 membered heteroaryl group, a 6 membered heteroaryl group, and the like. Examples of heteroaryl groups include, but are not limited to, 5-membered rings such as oxazolyl, pyrazolyl, thienyl, thiazolyl, triazolyl, imidazolyl, and the like, and 6-membered rings such as pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and the like. The heterocyclic groups may be bicyclic including, but not limited to, 5 membered rings such as tetrahydrocyclopentapyrazole, 5,6 membered rings such as tetrahydroindole, tetrahydropyrazolopyridine, tetrahydroimidazopyridine, tetrahydrobenzisoxazole, tetrahydrobenzoxazole, tetrahydrobenzothiazole, tetrahydrobenzisothiazole, dihydrofuropyrazole, tetrahydrobenzofuran, dihydrobenzofuran, tetrahydrobenzothiophene, 6 membered rings such as tetrahydroquinoline, 5,7 membered rings such as tetrahydrocycloheptothiazole, tetrahydrocycloheptafuran. The heterocyclyl may be tricyclic including, but not limited to, 6, 7-dihydrospiro [ cyclopropane-1, 5-pyrrolo [1,2-c ] imidazole ]. When the 5-14 membered heteroaryl is substituted, it may be mono-substituted or poly-substituted. And, the substitution site thereof is not limited, and for example, hydrogen attached to a carbon atom on a heteroaryl ring may be substituted, or hydrogen attached to a heteroatom on a heteroaryl ring may be substituted.
The term "spiro" refers to a ring system in which two rings share 1 ring-forming atom.
The term "fused ring" refers to a ring system in which two rings share 2 ring atoms.
The term "bridged ring" refers to a ring system in which two rings share more than 3 ring members.
The term "halogen" means fluorine, chlorine, bromine or iodine.
"Halo" means substituted with one or more halogens.
The term "oxo (=o)" means that a hydrogen or lone pair of electrons on a substituted non-oxygen atom is replaced with oxygen, for example,Is oxo-substituted into Is oxo-substituted into
The term "halo C 1-10 alkyl" refers to an alkyl group as defined above which is substituted with one or more halogens as defined above, preferably "halo C 1-6 alkyl". The haloalkyl includes, but is not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 2-trifluoroethyl, 2-difluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl and the like.
Unless otherwise indicated, the definition of a term herein applies equally to a group containing that term, e.g., the definition of C 1-10 alkyl applies to the definition of C 1-10 alkyl oxy, C 1-10 alkylthio, C 1-10 alkylamino, C 1-10 alkylcarbonyl, etc., groups containing C 1-10 alkyl.
Crystallization often yields solvates of the compounds of the present invention, and the term "solvate" as used herein refers to a complex composed of one or more molecules of the compounds of the present invention and one or more molecules of a solvent.
The solvent may be water, in which case the solvate is a hydrate. In addition, an organic solvent is also possible. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may be true solvates, but in other cases the compounds of the invention may simply accidentally retain water or a mixture of water with some other solvent, the compounds of the invention may be reacted in one solvent or precipitated or crystallized in one solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.
The term "acceptable" in connection with a formulation, composition or ingredient as used herein means that there is no sustained detrimental effect on the overall health of the subject being treated.
The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.
Those skilled in the art will appreciate that the compounds of the present invention may exist in various pharmaceutically acceptable salt forms. These compounds may form acid addition salts if they have a basic center, base addition salts if they have an acidic center, and internal salts if they contain both an acidic center (e.g., carboxyl) and a basic center (e.g., amino).
The term "tautomer" refers to a functional group isomer that results from the rapid movement of an atom in a molecule at two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Proton-mobile tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium and attempts to isolate individual tautomers often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The location of the equilibrium depends on the chemical nature of the molecule. For example, among many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates, while among phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.
Depending on its molecular structure, the compound of the invention may be chiral and thus various enantiomeric forms may exist. These compounds may thus be present in racemic or optically active form. The compounds of the present invention encompass isomers or mixtures, racemates thereof wherein each chiral carbon is in the R or S configuration. The compounds of the invention or intermediates thereof may be isolated as enantiomer compounds by chemical or physical methods well known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g.N-benzoylproline or N-benzenesulfonylproline) or various optically active camphorsulfonic acids in R and S form. The chromatographic resolution can also advantageously be carried out with the aid of optically active resolving agents, such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers, immobilized on silica. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane/isopropanol/acetonitrile.
In the present application, "pharmaceutical composition" refers to a formulation of a compound of the present application with a medium commonly accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of organisms, facilitate the absorption of active ingredients and further exert biological activity.
In the present application, "pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonizing agent, solvent, or emulsifying agent that is approved by the relevant government regulatory agency as acceptable for human or livestock use.
In the present application, the term "solvate" means that the present darkling compound or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent which is bound by non-covalent intermolecular forces, and when the solvent is water, it is a hydrate.
In the present application, the term "prodrug" refers to a compound of the present application that can be converted into a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the application are prepared by modifying functional groups in the compounds, which modifications may be removed by conventional procedures or in vivo to give the parent compound. Prodrugs include compounds wherein a hydroxyl group or amino group of a compound of the application is attached to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl group, free amino group, respectively.
"Isotopes" are all isotopes of atoms that are present in compounds of the invention. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to 2H、3H、13C、14C、15N、18O、31P、32P、35S、18F and 36 C1, respectively. Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically-labeled reagent in place of a non-isotopically-labeled reagent. Such compounds have a variety of potential uses, for example as standards and reagents in assaying biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological or pharmacokinetic properties.
Herein, the term "tumor" includes benign tumors and malignant tumors (e.g., cancers).
The term "treatment" and other similar synonyms as used herein include the following meanings:
(i) Preventing the occurrence of a disease or disorder in a mammal, particularly when such mammal is susceptible to the disease or disorder, but has not been diagnosed as having the disease or disorder;
(ii) Inhibiting the disease or disorder, i.e., inhibiting its progression;
(iii) Alleviating a disease or condition, i.e. causing regression of the state of the disease or condition, or
(Iv) Alleviating symptoms caused by the disease or condition.
The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, most preferably humans.
The term "therapeutically effective amount" refers to that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought by a researcher, veterinarian, medical doctor or other clinician in a tissue, system, animal, individual or human, which includes one or more of (1) preventing a disease, disorder or condition, e.g., in an individual susceptible to the disease, disorder or condition but not yet experiencing or developing the pathology or symptomatology of the disease. (2) Inhibiting a disease, disorder or condition (i.e., preventing further development of pathology and/or symptoms), for example, in an individual experiencing or presenting with the pathology or symptoms of the disease, disorder or condition. (3) Alleviation of a disease, disorder or condition (i.e., reversing the pathology and/or symptomatology) such as in an individual experiencing or developing the pathology or symptomatology of the disease, disorder or condition.
Detailed Description
The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.
The method for synthesizing the quinoline skeleton compound of the present invention will be briefly described below. In the synthetic examples listed below, the synthesis of intermediates mainly involves the suzuki reaction, the reduction reaction, the acylation reaction, and the like.
Specifically, the synthetic methods of representative specific compounds of the present invention are given below.
Intermediate preparation method
Preparation example 1 the synthetic route for compound 1 is as follows:
7-nitroquinoline (1.0 g,5.75 mmol) was dissolved in 20mL of acetic acid, N-bromosuccinimide (NBS) (1.225 g,6.90mmol,1.2 eq) was added and reacted at 80℃for 10 hours, after the reaction was completed, the solution was placed in ice water to precipitate a large amount of white solid, and was filtered to give compound 1 (1.13 g,4.48mmol, calculated C 9H6BrN2O2[M+H]+ 252.9613 of yield 78％).1H NMR(400MHz,CDCl3)δ9.07(d,J＝2.2Hz,1H),8.99(d,J＝2.3Hz,1H),8.45(d,J＝2.3Hz,1H),8.37(dd,J＝9.0,2.3Hz,1H),7.92(d,J＝9.0Hz,1H).HRMS-ESI:, experimental value: 252.9605.
The synthetic route for preparation 2 compound 2 is as follows:
Compound 1 (0.5 g,2 mmol) was dissolved in 15mL of ethylene glycol dimethyl ether, 3, 4-methylenedimethoxy phenylboronic acid (0.390 g,2.4mmol,1.2 eq), tetrakis triphenylphosphine palladium (0.346 g,0.3mmol,0.15 eq), sodium carbonate (0.318 g,3mmol,1.5 eq) and water 5mL were added. The reaction was carried out at 80℃for 1.5h under argon. After the reaction, dichloromethane and water were added to the reaction solution, the organic phase after extraction was washed with water and saturated brine successively, concentrated by rotary evaporation, and dried to give a solid, which was subjected to column chromatography (100-200 mesh silica gel, mobile phase was V (petroleum ether): V (ethyl acetate) =10:1) to give compound 2 (0.529 g, yield 90%).
Preparation 3 the synthetic route for compound 3 is as follows:
Compound 2 (0.470 g,1.6 mmol) was dissolved in 20mL of ethanol, and iron powder (0.313 g,5.6mmol,3.5 eq) and 5mL (0.428 g,8mmol,5 eq) of aqueous ammonium chloride solution were added and reacted at 90℃for 2h. After the reaction, the reaction mixture was cooled to room temperature, then ammonia water was added to adjust the pH to 9, celite was added to filter, the filtrate was extracted 3 times with methylene chloride and water, the organic phase was collected, concentrated by rotary evaporation, and dried to give a solid, which was subjected to column chromatography (100-200 mesh silica gel, mobile phase was V (methylene chloride): V (methanol): V (ammonia water) =10:0.1:0.05) to give compound 3 (0.363 g, yield 86%).
Preparation 4 the synthetic route for compound 4 is shown below:
Compound 1 (0.5 g,2 mmol) was dissolved in 15mL of ethylene glycol dimethyl ether, 3, 4-dimethoxyphenylboronic acid (0.433 g,2.4mmo,1.2 eq), tetrakis triphenylphosphine palladium (0.348 g,0.3 mmole, 0.15 eq), sodium carbonate (0.318 g,3 mmole, 1.5 eq) and water 5mL were added. Stirred under argon at 80 ℃ for 1.5h. After the reaction, the organic phase was extracted with dichloromethane and water, washed successively with water and saturated brine, concentrated by rotary evaporation, and dried to give a solid, which was subjected to column chromatography (100-200 mesh silica gel, mobile phase V (petroleum ether): V (ethyl acetate) =10:1) to give compound 4 (0.520 g, yield 80%) as pale yellow powdery solid.
Preparation 5 the synthetic route for compound 5 is shown below:
Compound 4 was dissolved in 20mL of ethanol, and iron powder (0.620 g,11.1mmol,7 eq) and 5mL of aqueous ammonium chloride (0.850 g,15.9mmol,10 eq) were added and reacted at 90℃for 2h. After the reaction, the reaction solution was cooled to room temperature, then ammonia water was added to adjust the pH to 9, celite was added to filter, the filtrate was extracted 3 times with methylene chloride and water, the organic phase was collected, concentrated by rotary evaporation, and dried to give a solid, which was subjected to column chromatography (100-200 mesh silica gel, mobile phase was V (methylene chloride): V (methanol): V (ammonia water) =10:0.1:0.05) to give compound 5 (0.380 g, yield 85%).
Preparation 6 compound 6 was synthesized as follows:
Compound 1 (0.5 g,2 mmol) was dissolved in 15mL of ethylene glycol dimethyl ether, 3, 5-dimethoxyphenylboronic acid (0.433 g,2.4mmo,1.2 eq), tetrakis triphenylphosphine palladium (0.348 g,0.3 mmole, 0.15 eq), sodium carbonate (0.318 g,3 mmole, 1.5 eq) and water 5mL were added. Stirred under argon at 80 ℃ for 1.5h. After the reaction, the organic phase was extracted with dichloromethane and water, washed successively with water and saturated brine, concentrated by rotary evaporation, and dried to give a solid, which was subjected to column chromatography (100-200 mesh silica gel, mobile phase V (petroleum ether): V (ethyl acetate) =10:1) to give compound 6 (0.564 g, yield 90.9%) as pale yellow powdery solid. HRMS-ESI calculated C 17H15N2O4[M+H]+ 311.1032, experimental value ：311.1022.1H NMR(400MHz,CDCl3)δ9.33(d,J＝2.3Hz,1H),9.06(d,J＝2.3Hz,1H),8.52–8.30(m,2H),8.05(d,J＝9.0Hz,1H),6.86(d,J＝2.2Hz,2H),6.61(d,J＝2.3Hz,1H),3.92(s,6H).
Preparation 7 compound 7 was synthesized as follows:
Compound 6 (0.5 g,1.6 mmol) was dissolved in 20mL of ethanol, and iron powder (0.625 g,11.2mmol,7 eq) and 5mL (0.856 g,16mmol,10 eq) of aqueous ammonium chloride solution were added and reacted at 90℃for 2h. After the reaction, the reaction solution was cooled to room temperature, then added with ammonia water to adjust the pH to 9, added with diatomite for filtration, the filtrate was extracted 3 times with dichloromethane and water, the organic phase was collected for rotary evaporation and concentration, and dried to obtain a solid, which was subjected to column chromatography (100-200 mesh silica gel, mobile phase was V (dichloromethane): V (methanol): V (ammonia water) =10:0.1:0.05) to obtain pale yellow solid compound 7 (0.380 g, calculated value C 17H17N2O2[M+H]+ 281.1290 of yield 85％).1H NMR(400MHz,CD3OD)δ8.81(d,J＝2.3Hz,1H),8.23(d,J＝2.2Hz,1H),7.68(d,J＝9.4Hz,1H),7.10(dd,J＝9.4,2.4Hz,1H),7.08(d,J＝1.0Hz,1H),6.80(d,J＝2.2Hz,2H),6.49(t,J＝2.2Hz,1H),3.83(s,6H).HRMS-ESI：, experimental value: 281.1280).
Preparation 8 compound 8 was synthesized as follows:
Compound 1 (0.4 g,1.6 mmol) was dissolved in 20mL of ethanol, and iron powder (0.625 g,11.2mmol,7 eq) and 5mL (0.856 g,16mmol,10 eq) of aqueous ammonium chloride solution were added and reacted at 90℃for 2h. After the reaction, the reaction solution was cooled to room temperature, then added with ammonia water to adjust the pH to 9, added with diatomite for filtration, the filtrate was extracted 3 times with dichloromethane and water, the organic phase was collected for rotary evaporation and concentration, and dried to obtain a solid, which was subjected to column chromatography (100-200 mesh silica gel, mobile phase was V (dichloromethane): V (methanol): V (ammonia water) =10:0.1:0.05) to obtain pale yellow solid compound 8 (0.293 g, calculated value C 9H8N2Br[M+H]+ 222.9871 of yield 82％).1H NMR(400MHz,CDCl3)δ8.73(d,J＝2.3Hz,1H),8.11(d,J＝2.9Hz,1H),7.53(d,J＝8.7Hz,1H),7.17(d,J＝2.3Hz,1H),6.99(dd,J＝8.7,2.3Hz,1H),4.11(s,2H).HRMS-ESI：, experimental value: 222.9859).
Preparation 9 the synthetic route for compound 9 is as follows:
Compound 8 (0.1 g,0.36 mmol) was dissolved in 15mL of dichloromethane, carbonyl diimidazole (CDI, 0.065g,0.43mmol,1.2 eq) was added and reacted at room temperature for 12h. To the reaction mixture was added 4-aminomethyltetrahydropyran (0.54 mmol,1.5 eq) and the reaction was continued at room temperature for 0.5h. After the reaction was completed, the organic phase was washed with saturated ammonium chloride, collected, concentrated by rotary evaporation, and purified by silica gel column chromatography (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give solid compound 9. Yellow powder, yield 86％.1H NMR(400MHz,CD3OD)δ8.75(d,J＝2.3Hz,1H),8.43(dd,J＝2.3,0.8Hz,1H),8.12(d,J＝2.1Hz,1H),7.78(d,J＝8.9Hz,1H),7.67(dd,J＝8.9,2.2Hz,1H),4.02-3.92(m,2H),3.43(td,J＝11.8,2.1Hz,2H),3.16(d,J＝6.7Hz,2H),1.88–1.73(m,1H),1.72-1.63(m,2H),1.41-1.27(m,2H).HRMS-ESI： calculated C 16H19N3O2Br[M+H]+ 364.0661, experimental 364.0653.
Preparation 10 compound 10 was synthesized as follows:
compound 9 (0.5 g,1.37 mmol) was dissolved in 15mL of ethylene glycol dimethyl ether, 3-aminophenylboronic acid (0.226 g,1.65mmol,1.2 eq), tetrakis triphenylphosphine palladium (0.238 g,0.206mmol,0.15 eq), sodium carbonate (0.217 g,2.06mmol,1.5 eq) and water 5mL were added. Stirred under argon at 80 ℃ for 1.5h. After the reaction, the organic phase was extracted with dichloromethane and water, washed successively with water and saturated brine, concentrated by rotary evaporation, and dried to give a solid, which was subjected to column chromatography (V (dichloromethane): V (methanol): V (ammonia) =10:0.2:0.1) to give compound 10 (0.564 g, yield 90.9%) as a white powdery solid.
Preparation 11 compound 11 was synthesized as follows:
Compound 8 (0.1 g,0.36 mmol) was dissolved in 15mL of dichloromethane, and carbonyldiimidazole (0.065 g,0.43mmol,1.2 eq) was added and reacted at room temperature for 12h. To the reaction mixture was added 4-aminomethylpropionyl piperidine (0.54 mmol,1.5 eq) and the reaction was continued at room temperature for 0.5h. After the reaction was completed, the organic phase was washed with saturated ammonium chloride, collected, concentrated by rotary evaporation, and purified by silica gel column chromatography (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give solid compound 11. Yellow powder, yield 71％.1H NMR(400MHz,CDCl3)δ8.76(d,J＝2.3Hz,1H),8.66(s,1H),8.16(d,J＝2.3Hz,1H),7.97(dd,J＝9.0,2.1Hz,1H),7.78(d,J＝2.1Hz,1H),7.61(d,J＝9.0Hz,1H),6.33(t,J＝6.1Hz,1H),4.66-4.52(m,1H),3.92-3.77(m,1H),3.43-3.25(m,1H),3.16-3.06(m,1H),2.98(td,J＝13.1,2.4Hz,1H),2.53(td,J＝12.8,2.5Hz,1H),2.41-2.22(m,2H),1.83-1.57(m,3H),1.14(t,J＝7.4Hz,3H),1.17-1.07(m,2H).HRMS-ESI： calculated C 19H24N4O2Br[M+H]+ 419.1083, experimental 419.1081.
Preparation 12 compound 12 was synthesized as follows:
Compound 8 (0.1 g,0.36 mmol) was dissolved in 15mL of dichloromethane, and carbonyldiimidazole (0.065 g,0.43mmol,1.2 eq) was added and reacted at room temperature for 12h. 4-trifluoromethoxybenzylamine (0.54 mmol,1.5 eq) was added to the reaction mixture, and the reaction was continued at room temperature for 0.5h. After the reaction was completed, the organic phase was washed with saturated ammonium chloride, collected, concentrated by rotary evaporation, and purified by silica gel column chromatography (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give solid compound 12. Yellow powder, yield 65％.1H NMR(400MHz,CD3OD)δ8.78(d,J＝2.4Hz,1H),8.46(dd,J＝2.4,0.8Hz,1H),8.16(d,J＝2.1Hz,1H),7.81(d,J＝8.9Hz,1H),7.71(dd,J＝8.9,2.2Hz,1H),7.47(d,J＝8.6Hz,2H),7.26(d,J＝7.7Hz,1H),4.48(s,2H).HRMS-ESI： calculated C 18H14N3O2F3Br[M+H]+ 440.0221, experimental 440.0223.
Preparation 13 the synthesis of compound 13 was as follows:
6-nitroquinoline (1.0 g,5.75 mmol) was dissolved in 20mL of acetic acid, NBS (1.225, 6.90mmol,1.2 eq) was added and reacted at 80℃for 10h, after the reaction was completed the solution was placed in ice water to precipitate a large amount of white solid, which was filtered to give 3-bromo-6-nitroquinoline compound 13 (1.13 g,4.48mmol, calculated C 9H6BrN2O2[M+H]+ 252.9613, yield 75％).1H NMR(400MHz,DMSO-d6)δ9.18(d,J＝2.4Hz,1H),9.07(d,J＝2.4Hz,1H),9.04(d,J＝2.6Hz,1H),8.50(dd,J＝9.2,2.6Hz,1H),8.25(d,J＝9.2Hz,1H).HRMS-ESI：, experimental: 252.9599.
Preparation 14 the method for synthesizing compound 14 is as follows:
Compound 13 (0.5 g,2 mmol) was dissolved in 15mL of ethylene glycol dimethyl ether, 3,4- (methylenedioxy) phenylboronic acid (0.433 g,2.4mmo,1.2 eq), tetrakis triphenylphosphine palladium (0.346 g,0.3 mmole, 0.15 eq), sodium carbonate (0.318 g,3 mmole, 1.5 eq) and water 5mL were added. Stirred under argon at 80 ℃ for 1.5h. After the reaction, the organic phase was extracted with dichloromethane and water, washed successively with water and saturated brine, concentrated by rotary evaporation, and dried to give a solid, which was subjected to column chromatography (100-200 mesh silica gel, mobile phase V (petroleum ether): V (ethyl acetate) =10:1) to give compound 14 (0.520 g, yield 83%) as pale yellow powdery solid.
Preparation 15 compound 15 was synthesized as follows:
Compound 14 (0.5 g,1.6 mmol) was dissolved in 20mL of ethanol, and iron powder (0.625 g,11.2mmol,7 eq) and 5mL (0.856 g,16mmol,10 eq) of aqueous ammonium chloride solution were added and reacted at 90℃for 2h. After the reaction, the reaction solution was cooled to room temperature, then added with ammonia water to adjust the pH to 9, added with diatomite for filtration, the filtrate was extracted 3 times with dichloromethane and water, the organic phase was collected for rotary evaporation and concentration, dried to obtain a solid, and the solid was purified by column chromatography (100-200 mesh silica gel) with a mobile phase of V (dichloromethane): V (methanol): V (ammonia water) =10:0.1:0.05) to obtain a pale yellow solid compound 15 (0.358 g, calculated value C 16H13N2O2[M+H]+ 265.0977 of yield 81％).1H NMR(400MHz,DMSO-d6)δ8.74(d,J＝2.3Hz,1H),8.10(d,J＝2.3Hz,1H),7.69(d,J＝9.0Hz,1H),7.41(d,J＝1.8Hz,1H),7.30(dd,J＝8.1,1.8Hz,1H),7.13(dd,J＝9.0,2.5Hz,1H),7.05(d,J＝8.1Hz,1H),6.84(d,J＝2.5Hz,1H),6.09(s,2H),5.61(s,2H).HRMS-ESI：, experimental value: 265.0967).
Preparation 16 compound 16 was synthesized as follows:
M-nitrobenzaldehyde (39.70 mmol,6.00 g) was dissolved in 100mL of toluene, and ethylene glycol (79.41 mmol,4.34 mL) and p-toluenesulfonic acid (1.19 mmol,0.23 g) were added to react at 120℃for 2h. After completion of the reaction, the mixture was washed with a saturated sodium hydrogencarbonate solution and a saturated sodium chloride solution, and dried and concentrated to give a yellow oil (7.75 g, yield 100%). The intermediate is a pure product, and can be put into the next reaction without purification. To the autoclave was added 100mL of a methanol solution of a yellow oil (39.70 mmol,7.75 g), and palladium on carbon (0.77 g). After 3 times of hydrogen extraction and ventilation circulation, the mixture is reacted for 24 hours under the pressure of 60psi of hydrogen, after the reaction is finished, the mixture is filtered, and the organic phase is collected, concentrated by rotary evaporation and is subjected to silica gel column chromatography (V (petroleum ether): V (ethyl acetate) =5:1 to obtain pale yellow oily compound 16 (5.97 g, yield) 91％).1H NMR(400MHz,DMSO-d6)δ7.00(t,J＝7.7Hz,1H),6.65(t,J＝2.0Hz,1H),6.59–6.51(m,2H),5.55(s,1H),5.10(s,2H),4.04–3.82(m,4H).
Preparation 17 compound 17 was synthesized as follows:
Compound 16 (12.11 mmol,2.00 g) was redissolved in anhydrous DMF, NBS (13.32 mmol,2.37 g) was added in portions under ice-bath and the reaction was carried out at room temperature under argon atmosphere for 18h. After the completion of the reaction, the reaction was quenched by addition of water and extracted several times with ethyl acetate, the organic phases were combined and washed with half-saturated sodium chloride solution, the organic phases were collected and concentrated by rotary evaporation, and compound 17 (2.31 g, yield) was obtained as pale yellow oil by silica gel column chromatography V (petroleum ether): V (ethyl acetate) =5:1 78％).1H NMR(400MHz,DMSO-d6)δ7.17(d,J＝8.5Hz,1H),6.81(d,J＝2.9Hz,1H),6.50(dd,J＝8.5,2.9Hz,1H),5.78(s,1H),5.34(s,2H),4.15–3.87(m,4H).
Preparation 18 compound 18 was synthesized as follows:
Pyridine (24.58 mmol,1.98 mL), DMAP (0.82 mmol,0.10 g) and acetic anhydride (12.29 mmol,1.15 mL) were added sequentially to an anhydrous DCM solution of compound 17 (8.19 mmol,2.00 g), and the reaction was carried out at room temperature under argon atmosphere for 30min. After the completion of the reaction, the organic phase was washed with saturated ammonium chloride solution, water, saturated sodium bicarbonate solution and saturated brine in this order, the organic phase was collected, concentrated by rotary evaporation, and purified by beating with methylene chloride and n-hexane to give compound 18 (2.13 g, yield 91％).1H NMR(400MHz,CDCl3)δ7.63–7.52(m,2H),7.49(d,J＝8.4Hz,1H),7.35–7.30(m,1H),6.05(s,1H),4.22–3.98(m,4H),2.15(s,3H).13C NMR(100MHz,CDCl3)δ168.35,137.42,137.10,133.49,122.01,118.89,117.05,102.34,65.49,24.59.HRMS-ESI：, calculated C 11H12BrNNaO3[M+Na]+ 307.9893, experimental value: 307.9893) as a white solid.
Preparation 19 compound 19 was synthesized as follows:
Compound 18 (1.40 mmol,0.40 g), 3, 5-dimethoxyacetophenone (2.80 mmol,0.51 g) was dissolved in 20mL tetrahydrofuran, and palladium acetate (0.07 mmol,0.016 g), xantphos (0.14 mmol,0.081 g) and potassium phosphate (2.80 mmol,0.61 g) were sequentially added, and the reaction system was replaced with argon for 3 times and reacted at 90℃for 48 hours. Filtering after the reaction, collecting the organic phase, concentrating by rotary evaporation, and subjecting to silica gel column chromatography (silica gel 200-300 mesh, V (petroleum ether): V (ethyl acetate) =1:1) to obtain white solid compound 19(0.52g,96％).1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),7.67(d,J＝2.3Hz,1H),7.59(dd,J＝8.2,2.3Hz,1H),7.13(d,J＝2.3Hz,2H),7.09(d,J＝8.3Hz,1H),6.77(t,J＝2.3Hz,1H),5.74(s,1H),4.41(s,2H),3.97–3.82(m,4H),3.80(s,6H),2.03(s,3H).
Preparation 20 compound 20 was synthesized as follows:
20/10mL of an ethanol/water solution was measured and placed in a pressure-resistant bottle, followed by the addition of compound 19 (1.69 mmol,0.65 g) and ammonium chloride (1.07 g). The reaction was continued at 120℃for 48h at 90℃under a closed system for 48h. After the reaction, ethyl acetate was added to dilute the reaction solution, and saturated sodium hydrogencarbonate solution was added to wash the organic phase. The organic phase was collected, concentrated by rotary evaporation, and chromatographed on a silica gel column (V (dichloromethane): V (tetrahydrofuran): V (ammonia) =10:0.2:0.05) to give compound 20 (0.31 g, yield) as a pale yellow oil 65％).1H NMR(400MHz,CD3OD)δ8.89(s,1H),7.90(s,1H),7.68(d,J＝8.8Hz,1H),7.24(dd,J＝8.8,2.3Hz,1H),7.10(d,J＝2.3Hz,2H),7.06(d,J＝2.3Hz,1H),6.48(t,J＝2.3Hz,1H),3.84(s,6H).
The synthetic route for compound 21 of preparation 21 is as follows:
To a 100mL round bottom flask was added 4-nitroo-phenylenediamine (0.766 g,5.00 mmol) and piperonal (0.750 g,5.00mmol,1 eq) and dissolved with stirring with absolute ethanol (25 mL) as solvent and stirred under argon at 80℃for 24h. After the reaction was completed, the reaction solution was cooled to room temperature, and the reaction mixture was concentrated to half the original volume, and the precipitated crude product was recrystallized from petroleum ether (30 mL) to give schiff base compound (0.998 g, yield 70.0%). The intermediate was dissolved in 25mL absolute ethanol, then nitrobenzene (1 mL) was added and stirred under argon at 80℃for 24h. After the reaction was completed, the reaction solution was cooled to room temperature, the reaction mixture was concentrated to half the original volume, and a crude product precipitate was filtered to obtain compound 21 (0.496 g, yield 50％).1H NMR(400MHz,Methanol-d4)δ8.47(d,J＝2.2Hz,1H),8.19(dd,J＝8.8,2.2Hz,1H),7.68(dd,J＝8.1,1.7Hz,2H),7.59(d,J＝1.8Hz,1H),7.02(d,J＝8.2Hz,1H),6.09(s,2H).HRMS-ESI: calculated value C 14H10N3O4[M+H]+ 284.0671, experimental value: 284.0659.
The synthetic route for compound 22 of preparation 22 is as follows:
Compound 21 (0.181 g, 0.428 mmol) was dissolved in 12mL of ethanol, and iron powder (0.274 g,4.9mmol,7 eq) and 5mL (0.350 g,6.38mmol,10 eq) of aqueous ammonium chloride solution were added in this order and reacted at 80℃for 2h. After the reaction was completed, the reaction mixture was cooled to room temperature, then ammonia water was added to adjust the pH to 9, celite was added to filter, ethyl acetate was added to the filtrate and washed with saturated sodium hydrogencarbonate solution (30 mL), water (30 mL) and saturated sodium chloride solution (30 mL) in this order, the organic phase was concentrated by rotary evaporation and then subjected to column chromatography (100-200 mesh silica gel, mobile phase: V (petroleum ether): V (ethyl acetate) =1:1) to give reduced compound 22 (0.121 g, yield 75.0%).
Preparation 23 compound 23 was synthesized as follows:
Piperonal (0.500 g,3.33 mmol) and 2, 4-dinitrotoluene (0.606 g,3.33mmol,1 eq) were dissolved in 30mL toluene and piperidine (0.07 mL,0.666mmol,0.2 eq) was added and reacted at 110℃for 24h. After the reaction was completed, the organic phase was concentrated by rotary evaporation and then ethanol was added to precipitate a large amount of yellow solid, which was filtered to obtain intermediate (0.909 g, yield 87％).1H NMR(400MHz,DMSO-d6)δ8.71(d,J＝2.4Hz,1H),8.46(dd,J＝8.8,2.5Hz,1H),8.20(d,J＝8.8Hz,1H),7.53(d,J＝16.1Hz,1H),7.37(s,1H),7.34-7.29(m,1H),7.16(d,J＝8.1Hz,1H),6.98(d,J＝8.0Hz,1H),6.09(s,2H).HRMS-ESI: calculated as C 15H11N2O6[M+H]+ 315.0617, experimental value: 315.0617. Intermediate (0.500 g,1.6 mmol) was dissolved in 20mL of ethylene glycol dimethyl ether (DME), iron acetate (0.0152 g,0.08mmol,0.05 eq), phenanthroline (0.02 g,0.08mmol,0.05 eq), phenylsilane (0.6 mL,9.6mmol,6 eq) was added, and reacted at 85 ℃ for 15h after the reaction was completed, the organic phase was concentrated by rotary evaporation and then purified compound 23 (0.171 g, yield 38％).1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),8.24(d,J＝2.1Hz,1H),7.89(dd,J＝8.8,2.2Hz,1H),7.66(d,J＝8.7Hz,1H),7.53(s,1H),7.47(dd,J＝8.1,1.8Hz,1H),7.09(d,J＝8.1Hz,1H),7.05(s,1H),6.12(s,2H).HRMS-ESI: calculated as C 15H12N2O4[M+H]+ 283.0719, experimental value: 283.0713) was obtained by silica gel column chromatography V (dichloromethane) =10:0.05).
Preparation 24 compound 24 was synthesized as follows:
Compound 23 (0.200 g,0.7 mmol) was dissolved in 20mL of ethanol, and iron powder (0.274 g,4.9mmol,7 eq) and 5mL (0.374 g,7mmol,10 eq) of aqueous ammonium chloride solution were added and reacted at 90℃for 2h. After the reaction, the reaction solution was cooled to room temperature, then added with ammonia water to adjust the pH to 9, added with diatomite for filtration, extracted 3 times with dichloromethane and water, and the organic phase was collected, concentrated by rotary evaporation and dried to obtain a solid, which was subjected to column chromatography (100-200 mesh silica gel, mobile phase was V (dichloromethane): V (methanol): V (ammonia water) =10:0.1:0.05) to obtain pale yellow solid compound 24 (0.139 g, calculated value C 15H14N2O2[M+H]+ 253.0977 of yield 79％).1H NMR(400MHz,DMSO-d6)δ10.76(s,1H),7.32(d,J＝1.8Hz,1H),7.23(dd,J＝8.2,1.8Hz,1H),7.13(d,J＝8.3Hz,1H),6.94(s,1H),6.55(d,J＝2.2Hz,2H),6.37(dd,J＝8.3,1.8Hz,1H),6.03(s,2H),4.79(s,1H).HRMS-ESI:, experimental value: 253.0964).
Process for preparing compounds
The synthetic route for compound C1 of example 1 is as follows:
Compound 3 (0.1 g,0.38 mmol) was dissolved in 15mL of dichloromethane, and carbonyldiimidazole (0.065 g,0.45mmol,1.2 eq) was added and reacted at room temperature for 12h. Isobutylamine (0.054 mL,0.57mmol,1.5 eq) was added to the reaction solution, the reaction was continued at room temperature for 0.5H, after the completion of the reaction, the organic phase was washed with saturated ammonium chloride, collected, concentrated by rotary evaporation, and purified by silica gel column chromatography (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give Compound C1 (0.116 g, yield 85％).m.p.235.4-236.8℃.1H NMR(400MHz,DMSO-d6)δ9.06(d,J＝2.4Hz,1H),8.82(s,1H),8.40(d,J＝2.4Hz,1H),8.17(d,J＝2.1Hz,1H),7.85(d,J＝8.9Hz,1H),7.55(dd,J＝8.9,2.2Hz,1H),7.44(d,J＝1.8Hz,1H),7.32(dd,J＝8.1,1.8Hz,1H),7.06(d,J＝8.1Hz,1H),6.34(t,J＝5.8Hz,1H),6.09(s,2H),2.98(t,J＝6.3Hz,2H),1.75-1.72(m,1H),0.90(d,J＝6.7Hz,6H).13C NMR(100MHz,DMSO-d6)δ155.6,149.9,148.7,148.2,147.6,141.9,132.3,132.1,130.8,128.9,123.3,120.9,120.6,113.4,109.4,107.7,101.7,47.1,28.9,20.5.HRMS-ESI： calculated as C21H22N3O3[ M+H ] +364.1661, experimental value: 364.1660.
Example 2 the synthetic route for compound C2 is as follows:
Using 3- (3, 4-dimethoxyphenyl) quinolin-7-amine (compound 5,0.1g,0.36 mmol) and isobutylamine (0.54 mmol,1.5 eq) as starting materials, the product was purified by column chromatography on silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give compound C2 as a yellow oil (0.051g,37％).1H NMR(400MHz,CD3OD)δ8.98(d,J＝2.3Hz,1H),8.36(d,J＝2.3Hz,1H),8.10(d,J＝2.1Hz,1H),7.85(d,J＝8.9Hz,1H),7.65(dd,J＝8.9,2.2Hz,1H),7.34-7.29(m,H),7.28(d,J＝2.2Hz,1H),7.08(d,J＝8.2Hz,1H),3.94(s,3H),3.88(s,3H),3.08(d,J＝6.7Hz,2H),1.94-1.75(m,1H),0.97(d,J＝6.7Hz,6H).13C NMR(100MHz,DMSO-d6)δ155.7,149.8,149.4,149.0,146.9,142.6,133.3,130.9,130.1,129.1,123.5,120.9,119.6,112.9,111.9,111.0,56.2,56.1,47.0,28.9,20.5.HRMS-ESI：, calculated C 22H26N3O3[M+H]+ 380.1974, experimental value: 380.1960.
Example 3 the synthetic route for compound C3 is as follows:
Compound 7 (0.1 g,0.36 mmol) was dissolved in 15mL of dichloromethane, then carbonyldiimidazole (0.065 g,0.43mmol,1.2 eq) was added and reacted at room temperature for 12h. After the completion of the reaction of Compound 7, isobutyl amine (0.054 mL,0.54mmol,1.5 eq) was added to the reaction mixture, and the reaction was continued at room temperature for 0.5h. After the reaction was completed, the reaction solution was washed 3 times with saturated ammonium chloride, the organic phase was collected and concentrated by rotary evaporation, and compound C3 (0.116 g, yield 85％).mp.116.8-118.2℃.1H NMR(400MHz,CD3OD)δ8.93(d,J＝2.3Hz,1H),8.33(d,J＝2.3Hz,1H),8.10(d,J＝2.1Hz,1H),7.83(d,J＝8.9Hz,1H),7.63(dd,J＝8.9,2.1Hz,1H),6.81(d,J＝2.2Hz,2H),6.50(t,J＝2.2Hz,1H),3.84(s,6H),3.07(d,J＝6.8Hz,2H),1.81(dt,J＝13.4,6.7Hz,1H),0.97(d,J＝6.7Hz,6H).13C NMR(176MHz,DMSO-d6)δ161.6,155.6,148.6,143.2,139.3,130.8,129.5,123.5,121.1,105.4,100.4,47.00 28.9,20.5.HRMS-ESI： calculated as C 22H26N3O3[M+H]+ 380.1974, experimental value: 380.1959) was obtained by silica gel column chromatography (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05).
Example 4 compound C4 was synthesized as follows:
Using compound 7 (0.1 g,0.36 mmol) and (S) - (tetrahydrofuran-2-yl) methylamine (0.54 mmol,1.5 eq) as starting materials, the reaction was performed according to the method of example 1, and the product was purified by silica gel column chromatography (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give compound C4 as a yellow oil (0.069g,52％).1H NMR(400MHz,CD3OD)δ8.94(d,J＝2.3Hz,1H),8.33(d,J＝1.5Hz,1H),8.11(d,J＝2.1Hz,1H),7.83(d,J＝8.9Hz,1H),7.63(dd,J＝8.9,2.2Hz,1H),6.82(d,J＝2.2Hz,2H),6.51(t,J＝2.2Hz,1H),4.05-3.99(m,1H),3.90(dt,J＝8.2,6.7Hz,1H),3.84(s,6H),3.80-3.74(m,1H),3.42(dd,J＝13.8,4.0Hz,1H),3.26(dd,J＝13.8,6.6Hz,1H),1.88-2.08(m,3H),1.62-1.69(m,1H).13C NMR(100MHz,CD3OD)δ161.6,149.0,147.5,141.6,139.4,133.5,132.0,128.6,123.9,120.6,113.1,104.9,99.5,78.1,67.7,54.5,43.3,28.1,25.4.HRMS-ESI： as calculated C 23H26N3O4[M+H]+ 408.1923, experimental value: 408.1920.
Example 5 the synthetic route for compound C5 is as follows:
Using compound 7 (0.1 g,0.36 mmol) and 4-aminomethyltetrahydropyran (0.54 mmol,1.5 eq) as starting materials, the product was purified by column chromatography on silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give compound C5(0.114g,75％).m.p.115.2-117.0℃.1H NMR(400MHz,DMSO-d6)δ9.12(d,J＝2.3Hz,1H),8.86(s,1H),8.50(d,J＝2.3Hz,1H),8.20(d,J＝2.1Hz,1H),7.89(d,J＝8.8Hz,1H),7.57(dd,J＝8.9,2.2Hz,1H),6.98(d,J＝2.2Hz,2H),6.56(t,J＝2.2Hz,1H),6.40(t,J＝5.9Hz,1H),3.91-3.86(m,2H),3.85(s,6H),3.29-3.23(m,2H),3.06(t,J＝6.3Hz,2H),1.77-1.67(m,1H),1.62 -1.55(m,2H),1.31-1.13(m,2H).13C NMR(100MHz,CD3OD)δ161.6,156.5,149.1,147.5,141.7,139.5,133.6,132.1,128.6,123.9,120.7,113.1,104.9,99.5,67.4,54.5,45.1,35.6,30.3.HRMS-ESI： as calculated C 24H28N3O4[M+H]+ 422.2080, experimental value: 422.2071.
Example 6 the synthetic route for compound C6 is as follows:
Using compound 7 (0.1 g,0.36 mmol) and 4- (2-aminoethyl) tetrahydropyran (0.54 mmol,1.5 eq) as starting materials, the product was purified by column chromatography on silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give compound C6 as a white powder (0.114g,75％).m.p.165.6-167.5℃.1H NMR(400MHz,CDCl3)δ8.99(d,J＝2.3Hz,1H),8.37(s,1H),8.12(d,J＝2.3Hz,1H),7.95(dd,J＝8.9,2.1Hz,1H),7.80(d,J＝2.1Hz,1H),7.72(d,J＝8.9Hz,1H),6.73(d,J＝2.2Hz,2H),6.49(t,J＝2.2Hz,1H),5.72(t,J＝5.5Hz,1H),3.92-3.82(m,8H),3.34-3.17(m,4H),1.53-1.32(m,5H),1.28-1.25(m,2H).13C NMR(100MHz,CDCl3)δ161.4,155.9,149.8,147.9,141.3,139.7,133.3,132.2,128.9,124.1,121.4,114.7,105.5,99.7,67.9,55.5,37.5,37.1,32.8,32.6.HRMS-ESI:, calculated C 25H30N3O4[M+H]+ 436.2236, experimental value: 436.2216.
Example 7 compound C7 was synthesized as follows:
Using compound 7 (0.1 g,0.36 mmol) and methyl 4- (aminomethyl) cyclohexane-1-carboxylate (0.54 mmol,1.5 eq) as starting materials, the reaction was performed according to the synthesis method of example 1, and the product was purified by silica gel column chromatography (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give compound C7 as a yellow powder (0.134g,78％).m.p.217.1-218.5℃.1H NMR(400MHz,DMSO-d6)δ9.12(d,J＝2.3Hz,1H),8.84(s,1H),8.50(d,J＝2.4Hz,1H),8.20(d,J＝2.1Hz,1H),7.89(d,J＝8.9Hz,1H),7.55(dd,J＝8.8,2.1Hz,1H),6.98(d,J＝2.2Hz,2H),6.56(d,J＝2.2Hz,1H),6.37(t,J＝5.9Hz,1H),3.85(s,6H),3.59(s,3H),3.01(t,J＝6.2Hz,2H),2.34-2.22(m,1H),2.02-1.90(m,2H),1.84-1.75(m,2H),1.46-1.38(m,0H),1.36-1.28(m,2H),1.09-0.89(m,2H).13C NMR(100MHz,DMSO-d6)δ175.9,161.5,155.6,150.0,148.7,142.2,139.9,133.1,130.9,129.2,123.2,120.6,113.3,105.4,100.2,55.9,51.7,45.3,42.8,37.9,29.7,28.7.HRMS-ESI：, calculated as C 27H32N3O5[M+H]+ 478.2342, experimental value: 478.2335.
Example 8 the synthetic route for compound C8 is as follows:
Using compound 7 (0.1 g,0.36 mmol) and 4-amino-1-propionylpiperidine (0.54 mmol,1.5 eq) as raw materials, the product was purified by column chromatography on silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.3:0.05) to give compound C8 as a yellow powder (0.113g,68％).m.p.236.2-236.8℃.1H NMR(400MHz,CD3OD)δ8.96(d,J＝2.3Hz,1H),8.36(d,J＝2.3Hz,1H),8.12(d,J＝2.1Hz,1H),7.85(d,J＝8.9Hz,1H),7.61(dd,J＝8.9,2.1Hz,1H),6.84(d,J＝2.2Hz,2H),6.52(t,J＝2.2Hz,1H),4.44-4.34(m,1H),3.96-3.87(m,2H),3.85(s,6H),3.30-3.18(m,1H),2.97-2.83(m,1H),2.41(q,J＝7.5Hz,2H),2.13-1.93(m,2H),1.53-1.31(m,2H),1.12(t,J＝7.5Hz,3H).13C NMR(100MHz,CD3OD)δ173.3,161.6,155.6,148.9,147.4,141.5,139.4,133.7,132.0,128.6,124.0,120.7,113.0,104.9,99.5,54.6,46.8,44.1,40.4,32.6,31.7,25.9,8.6.HRMS-ESI：, calculated C 26H31N4O4[M+H]+ 463.2345, experimental value: 463.2347.
Example 9 the synthetic route for compound C9 is as follows:
Using compound 7 (0.1 g,0.36 mmol) and 4- (aminomethyl) -1-propionylpiperidine (0.54 mmol,1.5 eq) as starting materials, the reaction was performed according to the synthesis method of example 1, and the product was purified by silica gel column chromatography (V (dichloromethane): V (methanol): V (ammonia) =10:0.3:0.05) to give compound C9 as a yellow powder (0.096g,56％).m.p.91.7-93.2℃.1H NMR(400MHz,CD3OD)δ8.97(d,J＝2.3Hz,1H),8.40(d,J＝2.3Hz,1H),8.13(d,J＝2.1Hz,1H),7.88(d,J＝8.9Hz,1H),7.66(dd,J＝8.9,2.1Hz,1H),6.86(d,J＝2.2Hz,2H),6.53(t,J＝2.2Hz,1H),4.56-4.52(m,1H),3.99-3.95(m,1H),3.86(s,6H),3.17(t,J＝6.5Hz,2H),3.11-3.07(m,1H),2.63(td,J＝12.8,2.7Hz,1H),2.40(q,J＝7.5Hz,2H),1.86-1.78(m,3H),1.22-1.14(m,2H),1.11(t,J＝7.5Hz,4H).13C NMR(100MHz,CD3OD)δ174.7,163.1,157.9,150.4,148.8,143.1,140.9,135.2,133.5,130.0,125.4,122.2,114.4,106.3,101.0,56.0,46.8,46.0,42.9,38.2,31.5,30.7,27.4,10.1.HRMS-ESI：, calculated C 27H33N4O4[M+H]+ 477.2502, experimental value: 477.2502.
Example 10 compound C10 was synthesized as follows:
Using compound 7 (0.1 g,0.36 mmol) and 4-aminoethyl-1-propionylpiperidine (0.54 mmol,1.5 eq) as starting materials, the product was purified by column chromatography on silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.3:0.05) to give compound C10 as a yellow oil (0.104g,59％).1H NMR(400MHz,CD3OD)δ8.97(d,J＝2.3Hz,1H),8.39(d,J＝2.3Hz,1H),8.13(d,J＝2.1Hz,1H),7.87(d,J＝8.9Hz,1H),7.64(dd,J＝8.9,2.1Hz,1H),6.85(d,J＝2.2Hz,2H),6.52(t,J＝2.2Hz,1H),4.51(d,J＝13.2Hz,1H),3.92(d,J＝13.7Hz,1H),3.85(s,6H),3.28(d,J＝7.2Hz,2H),3.05(dt,J＝13.0,2.7Hz,1H),2.60(dt,J＝12.9,2.9Hz,1H),2.38(q,J＝7.5Hz,2H),1.85-1.80(m,2H),1.65-1.63(m,1H),1.51(q,J＝7.0Hz,2H),1.26-1.06(m,5H).13C NMR(100MHz,CD3OD)δ161.6,112.9,104.8,99.5,54.5,48.2,48.0,47.8,47.6,47.4,47.2,46.9,41.8,36.9,36.3,33.4,31.6,25.9.HRMS-ESI：, calculated C 28H35N4O4[M+H]+ 491.2658, experimental value 491.2639.
The synthetic route for compound C11 of example 11 is as follows:
using compound 7 (0.1 g,0.36 mmol) and 4-aminomethyl-1-acetylpiperidine (0.54 mmol,1.5 eq) as starting materials, the product was purified by column chromatography on silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.2:0.05) to give compound C11 as a yellow powder (0.125g,75％).m.p.65.5-66.2℃.1H NMR(400MHz,CD3OD)δ8.96(d,J＝2.3Hz,1H),8.37(d,J＝1.9Hz,1H),8.12(d,J＝2.1Hz,1H),7.86(d,J＝8.9Hz,1H),7.64(dd,J＝8.9,2.2Hz,1H),6.84(d,J＝2.2Hz,2H),6.52(t,J＝2.2Hz,1H),4.55-4.51(m,1H),3.95-3.91(m,1H),3.85(s,6H),3.21-3.06(m,3H),2.62(td,J＝12.9,2.7Hz,1H),2.09(s,3H),1.85-1.77(m,3H),1.27-1.11(m,2H).13C NMR(100MHz,CD3OD)δ170.0,161.6,156.5,149.1,147.5,141.6,139.4,133.6,132.0,128.6,123.9,120.7,113.1,104.9,99.5,54.6,46.2,44.6,41.4,36.6,29.9,29.2,19.9.HRMS-ESI：, calculated C 26H31N4O4[M+H]+ 463.2345, experimental value: 463.2338.
Example 12 the synthetic route for compound C12 is as follows:
Using compound 7 (0.1 g,0.36 mmol) and 4-aminomethyl-1-trifluoroacetyl piperidine (0.54 mmol,1.5 eq) as starting materials, the reaction was performed according to the synthesis method of example 1, and the product was purified by silica gel column chromatography (V (dichloromethane): V (methanol): V (ammonia) =10:0.2:0.05) to give compound C12 as a yellow oil (0.134g,72％).1H NMR(400MHz,CD3OD)δ8.98(d,J＝2.3Hz,1H),8.42(dd,J＝2.3,0.8Hz,1H),8.14(d,J＝2.1Hz,1H),7.89(d,J＝8.9Hz,1H),7.66(dd,J＝8.9,2.2Hz,1H),6.87(d,J＝2.2Hz,2H),6.54(t,J＝2.2Hz,1H),4.53-4.44(m,1H),4.08-3.97(m,1H),3.86(s,6H),3.25(ddd,J＝14.1,12.5,2.4Hz,1H),3.18(dd,J＝6.3,1.2Hz,2H),2.89(t,J＝12.6Hz,1H),1.98-1.84(m,3H),1.37-1.13(m,3H).13C NMR(100MHz,CD3OD)δ161.7,156.4,148.5,146.8,141.9,139.2,134.3,132.1,128.7,124.1,120.9,112.3,104.9,99.6,54.6,45.5,44.3,43.3,36.4,29.9,28.9.HRMS-ESI： as calculated C 26H28N4O4F3[M+H]+ 517.2063, experimental value: 517.2050.
Example 13 compound C13 was synthesized as follows:
Using compound 7 (0.1 g,0.36 mmol) and 4-aminomethyl-1-cyclopropylpiperidine (0.54 mmol,1.5 eq) as starting materials, the reaction was performed according to the synthesis method of example 1, and the product was purified by silica gel column chromatography (V (dichloromethane): V (methanol): V (ammonia) =10:0.2:0.05) to give compound C13 as a yellow oil (0.120g,68％).1H NMR(400MHz,CD3OD)δ8.96(d,J＝2.2Hz,1H),8.38(d,J＝2.3Hz,1H),8.13(d,J＝2.1Hz,1H),7.87(d,J＝8.9Hz,1H),7.65(dd,J＝8.9,2.1Hz,1H),6.85(d,J＝2.2Hz,2H),6.53(t,J＝2.4Hz,1H),4.56-4.48(m,1H),4.44-4.27(m,1H),3.85(s,6H),3.25-3.08(m,3H),2.66(t,J＝12.6Hz,1H),2.05-1.90(m,1H),1.90-1.69(m,3H),1.36-0.98(m,3H),0.90-0.81(m,2H),0.81-0.71(m,2H).13CNMR(100MHz,CDCl3)δ172.3,161.4,156.0,149.7,147.8,141.8,139.9,133.5,132.1,128.8,123.9,121.3,114.1,105.5,99.8,55.5,45.8,44.9,42.7,30.4,29.3,11.2,7.5.HRMS-ESI： as a calculated value C 28H33N4O4[M+H]+ 489.2502, experimental value 489.2489.
Example 14 the synthetic route for compound C14 is as follows:
using compound 7 (0.1 g,0.36 mmol) and benzyl 4- (aminomethyl) piperidine-1-carboxylate (0.54 mmol,1.5 eq) as starting materials, the reaction was performed according to the synthesis method of example 1, and the product was purified by silica gel column chromatography (V (dichloromethane): V (methanol): V (ammonia) =10:0.2:0.05) to give compound C14(0.148g,74％).m.p.189.5-191.0℃.1H NMR(400MHz,CDCl3)δ9.00(d,J＝2.2Hz,1H),8.14(d,J＝2.3Hz,1H),7.99(dt,J＝9.0,2.3Hz,1H),7.78-7.69(m,2H),7.36-7.18(m,5H),6.75(d,J＝2.2Hz,2H),6.49(t,J＝2.2Hz,1H),5.09(s,2H),4.13(s,2H),3.84(s,6H),3.16(d,J＝5.6Hz,2H),2.70(s,2H),1.66-1.63(m,3H),1.19-1.07(m,2H).13C NMR(100MHz,CDCl3)δ161.4,155.9,155.9,155.5,149.9,147.9,141.4,141.3,139.8,136.7,133.3,132.2,128.9,128.5,128.0,127.7,124.0,123.9,121.2,121.1,114.6,114.4,105.5,99.7,67.2,55.5,45.2,45.1,43.9,36.7,29.6.HRMS-ESI： as calculated C 32H35N4O5[M+H]+ 555.2607, experimental value: 555.2584.
Example 15 compound C15 was synthesized as follows:
Using compound 7 (0.1 g,0.36 mmol) and (S) -1- (4-aminopiperidin-1-yl) -2-methylbutan-1-one (0.54 mmol,1.5 eq) as starting materials, the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.2:0.05) to give compound C15 as a yellow oil (0.097g,55％).1H NMR(400MHz,CD3OD)δ8.97(d,J＝2.3Hz,1H),8.38(d,J＝2.1Hz,1H),8.14(d,J＝2.3Hz,1H),7.87(d,J＝8.9Hz,1H),7.63(dd,J＝8.9,2.2Hz,1H),6.85(d,J＝2.3Hz,2H),6.53(t,J＝2.2Hz,1H),4.49-4.36(m,1H),4.08-4.00(m,1H),3.92-3.87(m,1H),3.85(s,6H),3.31-3.27(m,1H),2.92-2.89(m,1H),2.81-2.77(m,1H),2.09-2.06(m,1H),2.03-1.93(m,1H),1.67-1.64(m,1H),1.44-1.38(m,3H),1.08(t,J＝7.8Hz,3H),0.89(dt,J＝10.8,7.3Hz,3H).13C NMR(100MHz,CD3OD)δ175.94,175.9,161.6,155.6,149.0,147.4,141.5,139.4,133.7,132.1,128.6,124.0,120.7,113.0,104.9,99.5,54.6,48.3,48.0,47.8,47.6,47.4,47.2,46.9,46.9,44.2,44.1,40.6,40.5,36.6,33.0,32.0,31.8,26.8,26.8,16.4,16.3,10.9,10.7.HRMS-ESI： as a calculated C 28H35N4O4[M+H]+ 491.2658, experimental value: 491.2654.
Example 16 compound C16 was synthesized as follows:
Compound 7 (0.1 g,0.36 mmol) was dissolved in 15mL of dichloromethane, and carbonyldiimidazole (0.065 g,0.43mmol,1.2 eq) was added and reacted at room temperature for 12h. Then, 4-trifluoromethoxy aniline (0.54 mmol,1.5 eq) was added to the reaction mixture, and the reaction was continued at room temperature for 0.5h. After the reaction was completed, the reaction solution was washed with saturated ammonium chloride, the organic phase was collected and concentrated by rotary evaporation, and compound C16 pale yellow powder (0.097g,56％).m.p.216.6-217.9℃.1H NMR(400MHz,DMSO-d6)δ9.24(s,1H),9.19(d,J＝2.3Hz,1H),9.09(s,1H),8.59(d,J＝2.4Hz,1H),8.30(d,J＝2.1Hz,1H),7.99(d,J＝8.9Hz,1H),7.66(dd,J＝8.9,2.2Hz,1H),7.62(d,J＝9.0Hz,2H),7.33(d,J＝8.7Hz,2H),7.01(d,J＝2.3Hz,2H),6.58(t,J＝2.2Hz,1H),3.86(s,6H).13C NMR(176MHz,DMSO)δ161.6,152.9,152.8,150.1,143.3,141.3,139.7,139.2,133.5,131.3,129.4,123.8,122.3,121.4,120.9,120.1,119.9,114.2,105.4,100.33,55.9.HRMS-ESI： calculated C 25H21N3O4F3[M+H]+ 484.1484, experimental value 484.1485 was obtained by silica gel column chromatography (V (dichloromethane): V (methanol): V (ammonia) =10:0.1:0.05).
Example 17 the synthetic route for compound C17 is as follows:
Using compound 7 (0.1 g,0.36 mmol) and 4-trifluoromethoxybenzylamine (0.54 mmol,1.5 eq) as starting materials, the product was purified by column chromatography on silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.1:0.05) to give compound C17 as a yellow powder (0.134g,75％).m.p.186.7-187.7℃.1H NMR(400MHz,DMSO-d6)δ9.13(d,J＝2.4Hz,1H),9.11(s,1H),8.50(d,J＝2.4Hz,1H),8.22(d,J＝2.1Hz,1H),7.91(d,J＝8.9Hz,1H),7.61(dd,J＝8.9,2.1Hz,1H),7.47(d,J＝8.4Hz,2H),7.35(d,J＝8.2Hz,2H),6.98(d,J＝2.2Hz,2H),6.91(t,J＝6.0Hz,1H),6.56(t,J＝2.2Hz,1H),4.39(d,J＝5.9Hz,2H),3.85(s,6H).13C NMR(176MHz,DMSO-d6)δ161.5,155.9,150.0,148.7,147.6,142.23,140.5,139.9,133.1,130.8,129.3,129.1,123.2,121.4,120.5,113.2,105.3,100.2,55.9,42.4.HRMS-ESI：, calculated C 26H23N3O4F3[M+H]+ 498.1641, experimental value 498.1649.
The synthetic route for compound C18 of example 18 is as follows:
Using compound 7 (0.1 g,0.36 mmol) and 3-trifluoromethoxybenzylamine (0.54 mmol,1.5 eq) as starting materials, the product was purified by column chromatography on silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.1:0.05) to give compound C18 as a yellow powder (0.118g,66％).m.p.176.2-178.1℃.1H NMR(400MHz,CD3OD)δ9.00(d,J＝2.4Hz,1H),8.44(s,1H),8.16(s,1H),7.92(d,J＝8.9Hz,1H),7.71(dd,J＝8.9,2.2Hz,1H),7.44(t,J＝7.9Hz,1H),7.37(d,J＝7.7Hz,1H),7.29(s,1H),7.17(d,J＝9.5Hz,1H),6.89(d,J＝2.3Hz,2H),6.55(t,J＝2.3Hz,1H),4.49(s,2H),3.87(s,6H).13C NMR(100MHz,DMSO-d6)δ161.6,155.6,150.1,149.0,148.6,143.9,142.0,139.9,133.1,131.0,130.7,129.2,126.7,123.4,120.7,119.9,119.6,113.7,105.4,100.3,55.9,42.8.HRMS-ESI：, calculated C 26H23N3O4F3[M+H]+ 498.1641, experimental value 498.1637.
The synthetic route for compound C19 of example 19 is as follows:
Using compound 7 (0.1 g,0.36 mmol) and 4-difluoromethoxybenzylamine (0.54 mmol,1.5 eq) as starting materials, the reaction was performed according to the synthetic method of example 1, and the product was purified by silica gel column chromatography (V (dichloromethane): V (methanol): V (ammonia) =10:0.1:0.05) to give compound C19 as a white powder (0.116g,67％).m.p.205.1-206.9℃.1H NMR(400MHz,DMSO-d6)δ9.13(d,J＝2.3Hz,1H),9.06(s,1H),8.51(d,J＝2.4Hz,1H),8.22(d,J＝2.1Hz,1H),7.90(d,J＝8.9Hz,1H),7.59(dd,J＝8.9,2.2Hz,1H),7.40(d,J＝8.6Hz,2H),7.20(t,J＝72Hz,1H),7.16(d,J＝8.6Hz,2H),6.98(d,J＝2.2Hz,2H),6.84(t,J＝6.0Hz,1H),6.56(t,J＝2.2Hz,1H),4.35(d,J＝5.9Hz,2H),3.85(s,6H).13C NMR(100MHz,DMSO-d6)δ160.9,154.9,149.6,148.1,141.4,139.4,137.3,132.5,130.4,128.7,122.8,120.1,118.9,116.3,113.8,113.1,104.8,99.7,55.3,42.1.HRMS-ESI： as calculated value C 26H24N3O4F2[M+H]+ 480.1735, experimental value 480.1728.
Example 20 the synthetic route for compound C20 is as follows:
Using compound 7 (0.1 g,0.36 mmol) and 4-trifluoromethylbenzylamine (0.54 mmol,1.5 eq) as starting materials, the product was purified by column chromatography on silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.1:0.05) to give compound C20 as a white powder (0.109g,63％).m.p.223.0-224.1℃.1H NMR(400MHz,DMSO-d6)δ9.15(s,1H),9.13(d,J＝1.7Hz,1H),8.51(d,J＝2.4Hz,1H),8.22(s,1H),7.91(d,J＝8.8Hz,1H),7.72(d,J＝8.0Hz,2H),7.61(dd,J＝9.0,2.1Hz,1H),7.57(d,J＝8.0Hz,2H),7.03-6.90(m,3H),6.56(t,J＝2.2Hz,1H),4.45(d,J＝5.9Hz,2H),3.85(s,6H).13C NMR(100MHz,DMSO-d6)δ160.9,154.9,149.4,147.9,145.1,141.3,139.2,132.4,130.3,128.5,127.5,127.3,124.9,124.9,124.9,122.7,120.0,113.1,104.7,99.5,55.2,42.2.HRMS-ESI： as calculated C 26H23N3O3F3[M+H]+ 482.1692, experimental value: 482.1687.
The synthetic route for compound C21 of example 21 is as follows:
Using compound 7 (0.1 g,0.36 mmol) and 4-methoxybenzylamine (0.54 mmol,1.5 eq) as starting materials, the product was purified by column chromatography on silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.1:0.05) to give compound C21 as a white powder (0.129g,81％).m.p.200.9-201.4℃.1H NMR(400MHz,DMSO-d6)δ9.17(d,J＝2.3Hz,1H),9.07(s,1H),8.61(s,1H),8.27(d,J＝2.2Hz,1H),7.94(d,J＝8.9Hz,1H),7.60(dd,J＝8.8,2.2Hz,1H),7.28(d,J＝8.7Hz,2H),7.00(d,J＝2.2Hz,2H),6.92(d,J＝8.7Hz,2H),6.77(t,J＝5.9Hz,1H),6.57(t,J＝2.2Hz,1H),4.29(d,J＝5.5Hz,2H),3.85(s,6H),3.74(s,3H).13C NMR(176MHz,DMSO-d6)δ161.6,158.7,155.3,132.4,130.9,129.6,129.1,123.7,114.2,105.5,100.5,55.9,55.6,42.8.HRMS-ESI：, calculated C 26H26N3O4[M+H]+ 444.1923, experimental value 444.1915.
The synthetic route for compound C22 of example 22 is as follows:
Using compound 7 (0.1 g,0.36 mmol) and 4-cyanobenzylamine (0.54 mmol,1.5 eq) as starting materials, the product was purified by column chromatography on silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.1:0.05) to give compound C22 as a white powder (0.131g,83％).m.p.219.1-220.7℃.1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),9.14(d,J＝2.4Hz,1H),8.51(d,J＝2.4Hz,1H),8.22(d,J＝2.1Hz,1H),7.91(d,J＝8.9Hz,1H),7.83(d,J＝8.3Hz,2H),7.61(dd,J＝8.9,2.2Hz,1H),7.54(d,J＝8.1Hz,2H),6.98(d,J＝2.3Hz,2H),6.95(t,J＝6.1Hz,1H),6.56(t,J＝2.2Hz,1H),4.45(s,2H),3.85(s,6H).13C NMR(176MHz,DMSO-d6)δ161.5,155.6,150.1,148.6,146.9,141.9,139.9,133.1,132.8,131.0,129.2,128.4,123.4,120.7,119.4,113.7,109.9,105.4,100.2,55.7,43.1.HRMS-ESI：, calculated C 26H23N4O3[M+H]+ 439.1770, experimental value 439.1768.
Example 23 the synthetic route for compound C23 is as follows:
Using compound 7 (0.1 g,0.36 mmol) and 4-sulfonylaminobenzylamine (0.54 mmol,1.5 eq) as starting materials, the product was purified by column chromatography on silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.2:0.05) to give compound C23 as a yellow powder (0.063g,36％).m.p.235.5-236.1℃.1H NMR(400MHz,DMSO-d6)δ9.17(s,1H),9.14(d,J＝2.3Hz,1H),8.52(d,J＝2.4Hz,1H),8.23(d,J＝2.1Hz,1H),7.91(d,J＝8.9Hz,1H),7.81(d,J＝8.2Hz,2H),7.61(dd,J＝8.9,2.2Hz,1H),7.52(d,J＝8.1Hz,2H),7.32(s,2H),7.02-6.87(m,3H),6.56(t,J＝2.2Hz,1H),4.44(d,J＝5.8Hz,2H),3.85(s,6H).13C NMR(100MHz,DMSO-d6)δ161.5,155.6,150.1,148.6,144.9,143.0,142.0,139.9,133.1,130.9,129.2,127.8,123.4,120.7,113.7,105.4,100.2,55.9,42.9.HRMS-ESI：, calculated C 25H25N4O5S[M+H]+ 493.1546, experimental value 493.1540.
Example 24 compound C24 was synthesized as follows:
Using compound 7 (0.1 g,0.36 mmol) and 4-methylsulfonylbenzylamine (0.54 mmol,1.5 eq) as starting materials, the reaction was performed according to the synthetic method of example 1, and the product was purified by silica gel column chromatography (V (dichloromethane): V (methanol): V (ammonia) =10:0.1:0.05) to give compound C24 as a white powder (0.067g,38％).m.p.184.3-185.6℃.1H NMR(400MHz,DMSO-d6)δ9.16(s,1H),9.14(d,J＝2.4Hz,1H),8.51(d,J＝2.4Hz,1H),8.22(d,J＝2.1Hz,1H),7.92(d,J＝8.4Hz,3H),7.61(d,J＝8.3Hz,3H),7.01-6.90(m,3H),6.56(t,J＝2.2Hz,1H),4.47(d,J＝6.0Hz,2H),3.85(s,6H),3.20(s,3H).13C NMR(100MHz,DMSO-d6)δ161.6,155.6,150.1,148.6,147.1,141.9,139.9,139.7,133.1,131.0,129.2,128.3,127.6,123.4,120.7,113.7,100.2,55.9,44.1,42.9.HRMS-ESI： as calculated value C 26H26N3O5S[M+H]+ 492.1593, experimental value 492.1588.
Example 25 compound C25 was synthesized as follows:
Using compound 7 (0.1 g,0.36 mmol) and 4-aminomethylpyridine (0.54 mmol,1.5 eq) as starting materials, the product was purified by silica gel column chromatography (V (dichloromethane): V (methanol): V (ammonia) =10:0.1:0.05) to give compound C25 as a yellow powder (0.092g,62％).m.p.205.3-207.1℃.1H NMR(400MHz,DMSO-d6)δ9.17(s,1H),9.13(d,J＝2.4Hz,1H),8.53(d,J＝6.1Hz,2H),8.51(d,J＝2.4Hz,1H),8.22(d,J＝2.1Hz,1H),7.91(d,J＝8.9Hz,1H),7.62(dd,J＝8.8,2.2Hz,1H),7.34(d,J＝6.1Hz,2H),6.98(d,J＝2.2Hz,2H),6.93(t,J＝6.1Hz,1H),6.56(t,J＝2.2Hz,1H),4.40(d,J＝6.0Hz,2H),3.85(s,6H).13C NMR(100MHz,DMSO-d6)δ161.6,155.7,150.1,150.0,149.9,148.6,141.9,139.9,133.1,131.0,129.2,123.4,122.5,120.7,113.8,105.4,100.3,55.9,42.4.HRMS-ESI：, calculated C 24H23N4O3[M+H]+ 415.1770, experimental value 415.1770.
The synthetic route for compound C26 of example 26 is as follows:
Compound 5 (0.1 g,0.36 mmol) was dissolved in 15mL of dichloromethane, carbonyldiimidazole (0.065 g,0.43mmol,1.2 eq) was added and reacted at room temperature for 12h 4-sulfonylaminobenzylamine (0.54 mmol,1.5 eq) was added to the reaction solution and the reaction was continued at room temperature for 0.5h. After the reaction was completed, the organic phase was washed with saturated ammonium chloride, collected, concentrated by rotary evaporation, and chromatographed on a silica gel column (V (dichloromethane): V (methanol): V (ammonia) =10:0.25:0.05) to give compound C26 as a yellow powder (0.074g,42％).m.p.224.1-225.3℃.1H NMR(400MHz,DMSO-d6)δ9.14(s,2H),8.46(d,J＝2.4Hz,1H),8.21(d,J＝2.1Hz,1H),7.89(d,J＝8.9Hz,1H),7.81(d,J＝8.4Hz,2H),7.60(dd,J＝8.8,2.2Hz,1H),7.52(d,J＝8.2Hz,2H),7.41(d,J＝2.2Hz,1H),7.38(dd,J＝8.3,2.1Hz,1H),7.32(s,2H),7.10(d,J＝8.4Hz,1H),6.94(t,J＝6.0Hz,1H),4.44(s,1H),4.43(s,1H),3.89(s,3H),3.82(s,3H).13C NMR(176MHz,DMSO)δ155.6,150.08,150.06,149.8,149.3,148.1,145.0 144.7,143.0,141.6,132.0,131.1,130.5,129.8,128.9,127.8,126.2,123.5,120.6,119.5,113.8,112.8,110.9,56.1,56.1,42.9.HRMS-ESI：, calculated C 25H25N4O5S[M+H]+ 493.1546, experimental value 493.1545.
The synthetic route for compound C27 of example 27 is as follows:
Using compound 5 (0.1 g,0.36 mmol) and 4-difluoromethoxybenzylamine (0.54 mmol,1.5 eq) as starting materials, the product was purified by column chromatography on silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give compound C27 as a white powder (0.119g,67％).m.p.181.1-182.0℃.1H NMR(400MHz,DMSO-d6)δ9.14(d,J＝2.3Hz,1H),9.02(s,1H),8.45(d,J＝2.4Hz,1H),8.20(d,J＝2.1Hz,1H),7.89(d,J＝8.9Hz,1H),7.58(dd,J＝8.8,2.2Hz,1H),7.40(d,J＝8.2Hz,3H),7.21(t,J＝72Hz,1H),7.17(d,J＝8.6Hz,2H),7.10(d,J＝8.4Hz,1H),6.83(t,J＝6.0Hz,1H),4.36(s,1H),4.34(s,1H),3.90(s,3H),3.82(s,3H).13C NMR(176MHz,DMSO)δ155.6,150.2,150.2,150.2,150.0,149.8,149.3,148.1,141.6,137.9,132.1,131.1,130.5,129.3,128.9,123.5,120.6,119.5,119.3,118.4,116.9,115.4(F-C),113.7,112.8,110.9,56.14 56.1,55.4,42.6.HRMS-ESI： as calculated C 26H24N3O4F2[M+H]+ 480.1735, experimental value: 480.1735.
The synthetic route for compound C28 of example 28 is as follows:
Compound 9 (0.073 g,0.2 mmol) was dissolved in 15mL of ethylene glycol dimethyl ether, 3,4- (methylenedioxy) phenylboronic acid (0.04 g,0.24mmol,1.2 eq), tetrakis triphenylphosphine palladium (0.035 g,0.03mmol,0.15 eq), sodium carbonate (0.32 g,0.3mmol,1.5 eq) and water 5mL. After completion of the reaction, stirred at 80℃for 1.5h under argon, extracted with dichloromethane and water, the organic phase was washed successively with water, saturated brine, concentrated by rotary evaporation, and dried to give a solid which was chromatographed on silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give a C28 yellow powder (0.061 g, calculated as yield 76％).m.p.200.4-202.2℃.1H NMR(400MHz,CD3OD)δ8.99(s,1H),8.40(d,J＝2.3Hz,1H),8.15(d,J＝2.1Hz,1H),7.89(d,J＝8.9Hz,1H),7.65(dd,J＝8.9,2.1Hz,1H),7.26(d,J＝1.7Hz,1H),7.24(dd,J＝8.0,1.9Hz,1H),6.97(d,J＝8.0Hz,1H),6.02(s,2H),4.01-3.94(m,2H),3.47-3.38(m,2H),3.16(d,J＝6.7Hz,2H),1.87-1.73(m,1H),1.72-1.66(m,2H),1.41-1.31(m,2H).13C NMR(100MHz,CD3OD)δ156.5,148.7,148.6,147.9,146.6,141.7,133.5,132.0,128.5,124.2,120.9,120.6,112.5,108.5,106.9,101.4,67.4,45.1,35.6,30.3.HRMS-ESI： C 23H24N3O4[M+H]+ 406.1767, experimental value: 406.1750.
The synthetic route for compound C29 of example 29 is as follows:
Starting from compound 9 (0.073 g,0.2 mmol) and 4-trifluoromethoxybenzeneboronic acid (0.049 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give compound C29 as a white powder (0.073 g, yield 82％).m.p.214.8-219.4℃.1H NMR(400MHz,CD3OD)δ9.02(d,J＝2.3Hz,1H),8.45(d,J＝2.3Hz,1H),8.14(d,J＝2.1Hz,1H),7.90(d,J＝8.9Hz,1H),7.86(d,J＝8.7Hz,2H),7.69(dd,J＝8.9,2.2Hz,1H),7.42(d,J＝7.9Hz,2H),3.99-3.92(m,2H),3.46-3.38(m,2H),3.16(d,J＝6.7Hz,2H),1.90-1.75(m,1H),1.73-1.64(m,2H),1.44-1.22(m,2H).13C NMR(100MHz,CD3OD)δ157.9,150.5,150.3,149.1,143.4,138.1,135.2,132.1,130.1,129.9,125.4,122.8,122.3,114.6,68.8,46.6,37.1,31.8.HRMS-ESI： calculated as C 23H23N3O3F3[M+H]+ 446.1692, experimental value 446.1687.
Example 30 the synthetic route for compound C30 is as follows:
Starting from compound 9 (0.073 g,0.2 mmol) and 3-trifluoromethoxybenzeneboronic acid (0.049 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give compound C30 as a white powder (0.068 g, yield 78％).m.p.199.9-201.2℃.1H NMR(400MHz,CD3OD)δ9.02(d,J＝2.4Hz,1H),8.48(d,J＝2.3Hz,1H),8.16(d,J＝2.3Hz,1H),7.92(d,J＝8.9Hz,1H),7.78(d,J＝8.0Hz,1H),7.69(dd,J＝2.4,9.0Hz,2H),7.62(t,J＝8.0Hz,1H),7.34(d,J＝8.3Hz,1H),4.03-3.92(m,2H),3.47-3.35(m,2H),3.16(d,J＝6.7Hz,2H),1.88-1.76(m,1H),1.72-1.65(m,2H),1.42-1.25(m,2H).13C NMR(100MHz,CD3OD)δ157.9,151.4,150.2,149.3,143.5,141.4,135.4,132.1,131.8,130.2,127.0,125.3,123.3,122.3,121.4,120.8,114.5,68.8,46.6,37.1,31.8.HRMS-ESI： calculated as C 23H23N3O3F3[M+H]+ 446.1692, experimental value: 446.1688.
Example 31 the synthetic route for compound C31 is as follows:
Starting from compound 9 (0.073 g,0.2 mmol) and 4-dimethylaminophenylboronic acid (0.043 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give compound C31 as a yellow oil (0.063 g, yield 76％).m.p.229.3-230.8℃.1H NMR(400MHz,DMSO-d6)δ9.08(d,J＝2.4Hz,1H),8.78(s,1H),8.33(d,J＝2.4Hz,1H),8.14(d,J＝2.1Hz,1H),7.84(d,J＝8.8Hz,1H),7.68(d,J＝8.9Hz,2H),7.53(dd,J＝8.8,2.2Hz,1H),6.86(d,J＝8.9Hz,2H),6.36(t,J＝5.9Hz,1H),3.86(dd,J＝11.5,2.6Hz,2H),3.27(dd,J＝11.6,2.1Hz,2H),3.05(t,J＝6.2Hz,2H),2.96(s,6H),1.66-1.72(m,1H),1.58-1.61(m,2H),1.21(qd,J＝12.0,4.4Hz,2H).13C NMR(100MHz,DMSO-d6)δ155.1,149.9,149.1,147.1,140.8,130.7,130.0,128.2,127.2,124.5,123.1,119.9,113.0,112.7,66.7,44.7,35.2,30.2.HRMS-ESI： calculated as C 24H29N4O2[M+H]+ 405.2291, experimental value 405.2290.
Example 32 the synthetic route for compound C32 is as follows:
Starting from compound 9 (0.073 g,0.2 mmol) and 3-dimethylaminophenylboronic acid (0.043 g,0.24mmol,1.2 eq) the product was purified by silica gel column chromatography (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give compound C32 as a yellow oil (0.064 g, yield 76％).m.p.177.5-178.9℃.1H NMR(400MHz,CD3OD)δ8.95(d,J＝2.2Hz,1H),8.32(d,J＝2.3Hz,1H),8.12(d,J＝2.1Hz,1H),7.82(d,J＝8.9Hz,1H),7.63(dd,J＝8.9,2.1Hz,1H),7.30(t,J＝8.0Hz,1H),7.00-6.98(m,2H),6.79(d,J＝7.1Hz,1H),3.96-3.92(m,2H),3.42-3.36(m,2H),3.14(d,J＝6.7Hz,2H),2.98(s,6H),1.77-1.76(m,1H),1.68-1.65(m,2H),1.36-1.24(m,2H).13C NMR(100MHz,CD3OD)δ156.5,151.4,149.2,147.1,141.5,138.0,133.5,133.0,129.5,128.5,124.1,120.6,115.2,112.9,112.3,110.9,67.4,45.1,39.6,35.6,30.3.
Example 33 the synthetic route for compound C33 is as follows:
Starting from compound 9 (0.073 g,0.2 mmol) and 4- (4-methyl-1-piperazinyl) phenylboronic acid (0.053 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.2:0.05) to give compound C33 as a yellow powder (0.060 g, yield 76％).m.p.217.9-219.8℃.1H NMR(400MHz,DMSO-d6)δ9.08(d,J＝2.4Hz,1H),8.81(s,1H),8.36(d,J＝2.4Hz,1H),8.15(d,J＝2.1Hz,1H),7.85(d,J＝8.9Hz,1H),7.70(d,J＝8.8Hz,2H),7.54(dd,J＝8.9,2.2Hz,1H),7.07(d,J＝8.7Hz,2H),6.37(t,J＝5.9Hz,1H),3.86(dd,J＝11.3,2.8Hz,2H),3.27(dd,J＝11.7,2.1Hz,2H),3.22(t,J＝5.0Hz,4H),3.05(t,J＝6.2Hz,2H),2.48(t,J＝4.9Hz,3H),2.24(s,3H),1.72-1.65(m,1H),1.61-1.57(m,2H),1.26-1.56(m,3H).13C NMR(100MHz,DMSO-d6)δ155.6,151.0,149.7,147.9,141.5,131.1,131.0,128.8,127.7,123.6,120.5,116.1,113.5,67.2,55.0,48.2,46.22,5.3,35.8,30.8.HRMS-ESI： calculated C 27H34N5O2[M+H]+ 460.2713, experimental value: 460.2722.
Example 34 the synthetic route for compound C34 is as follows:
Starting from compound 9 (0.073 g,0.2 mmol) and 4-acetylphenylboronic acid (0.039 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.2:0.05) to give compound C34 as a yellow powder (0.065 g, yield 81％).m.p.224.3-224.7℃.1H NMR(400MHz,DMSO-d6)δ9.20(d,J＝2.4Hz,1H),8.94(d,J＝4.0Hz,1H),8.60(s,1H),8.23(s,1H),8.10(d,J＝6.9Hz,1H),8.02(d,J＝8.5Hz,1H),7.93(d,J＝8.9Hz,1H),7.59(dd,J＝8.8,2.2Hz,1H),6.44(t,J＝6.0Hz,1H),3.88-3.85(m,2H),3.31-3.25(m,2H),3.06(t,J＝6.3Hz,2H),2.64(s,3H),1.74-1.68(m,1H),1.617-1.58(m,2H),1.26-1.16(m,2H).13C NMR(100MHz,DMSO-d6)δ197.4,154.9,149.2,148.3,142.0,141.7,135.7,132.9,129.1,128.9,128.8,122.6,120.2,112.7,66.7,44.7,35.2,30.2,26.7.HRMS-ESI： calculated as C 24H26N3O3[M+H]+ 404.1974, experimental value: 404.1967.
Example 35 the synthetic route for compound C35 is as follows:
2-Pyridineacetic acid (0.041 g,0.3mmol,1.2 eq) was dissolved in 10mL of dry dichloromethane, N-diisopropylethylamine (DIEA, 0.087mL,0.5mmol,2 eq) and HATU (0.114 g,0.3mmol,1.2 eq) were added, after stirring for 1h, compound 10 (0.1 g,0.25mmol,1 eq) was added, and after completion of the reaction at room temperature, the reaction mixture was washed successively with saturated ammonium chloride, saturated sodium carbonate, saturated brine, concentrated by rotary evaporation, and dried to give a solid, which was chromatographed (V (dichloromethane): V (methanol): V (ammonia) =10:0.1:0.05) as a yellow powder, compound C35 (0.080 g, calculated C 29H30N5O3[M+H]+ 496.2349, experimental value: 496.2341, yield 65％).m.p.175.6-176.2℃.1H NMR(400MHz,CD3OD)δ8.99(d,J＝2.3Hz,1H),8.53(dd,J＝5.0,1.8Hz,1H),8.39(d,J＝2.3Hz,1H),8.14(s,1H),8.05(t,J＝1.9Hz,1H),7.86(d,J＝8.8Hz,1H),7.83(dd,J＝7.7,1.8Hz,1H),7.67(dd,J＝8.9,2.2Hz,1H),7.61(dt,J＝7.3,1.9Hz,1H),7.54-7.46(m,3H),7.35(ddd,J＝7.6,5.0,1.2Hz,1H),4.02-3.94(m,2H),3.98(s,2H),3.48-3.37(m,2H),3.16(d,J＝6.7Hz,2H),1.89-1.77(m,1H),1.74-1.66(m,2H),1.43-1.27(m,2H).13C NMR(100MHz,CD3OD)δ169.3,156.5,155.3,148.9,148.5,147.5,141.7,139.3,138.1,137.4,133.5,131.7,129.4,128.6,124.5,123.9,122.5,122.3,120.7,119.3,118.3,113.1,67.4,45.1,35.6,30.3.HRMS-ESI：.
Example 36 the synthetic route for compound C36 is as follows:
3-Pyridineacetic acid (0.041 g,0.3mmol,1.2 eq) was dissolved in 10mL of dry dichloromethane, N-diisopropylethylamine (0.087 mL,0.5mmol,2 eq) and HATU (0.114 g,0.3mmol,1.2 eq) were added, after stirring for 1h, compound 10 (0.1 g,0.25mmol,1 eq) was added, after completion of the reaction at normal temperature for 12h, the reaction mixture was washed successively with saturated ammonium chloride, saturated sodium carbonate, saturated brine, concentrated by rotary evaporation and dried to give a solid, which was chromatographed over column (V (dichloromethane): V (methanol): V (ammonia) =10:0.1:0.05) to give compound C36 as a yellow powder (0.099 g, yield 80％).m.p.>250℃.1H NMR(400MHz,CD3OD)δ8.92(d,J＝2.3Hz,1H),8.56(d,J＝2.2Hz,1H),8.44(dd,J＝5.0,1.6Hz,1H),8.28(d,J＝2.3Hz,1H),8.11(d,J＝2.1Hz,1H),7.96(d,J＝1.2Hz,1H),7.87(dt,J＝7.9,2.0Hz,1H),7.77(d,J＝8.9Hz,1H),7.60(dd,J＝8.9,2.2Hz,1H),7.55(td,J＝3.7,1.6Hz,1H),7.48-7.32(m,3H),3.99-3.90(m,2H),3.79(s,2H),3.48-3.34(m,2H),3.13(d,J＝6.8Hz,2H),1.83-1.71(m,1H),1.69-1.60(m,2H),1.39-1.20(m,2H).13C NMR(100MHz,DMSO-d6)δ169.2,155.6,150.7,149.8,148.6,148.3,142.2,140.3,138.5,137.3,132.8,132.0,130.9,130.1,129.2,123.9,123.3,122.4,120.7,118.9,117.9,113.3,67.2,45.3,40.6,35.8,30.8.HRMS-ESI： calculated as C 29H30N5O3[M+H]+ 496.2349, experimental value: 496.2338).
The synthetic route for compound C37 of example 37 is as follows:
2- (6-Chloropyridin-3-yl) acetic acid (0.041 g,0.3mmol,1.2 eq) was dissolved in 10mL of dried dichloromethane, N-diisopropylethylamine (0.087 mL,0.5mmol,2 eq) and HATU (0.114 g,0.3mmol,1.2 eq) were added, and after stirring for 1h compound 10 (0.1 g,0.25mmol,1 eq) was added and reacted at room temperature for 12h. After the reaction, the reaction mixture was washed with saturated ammonium chloride, saturated sodium carbonate and saturated brine in this order, concentrated by rotary evaporation, and dried to give a solid, which was subjected to column chromatography (V (dichloromethane): V (methanol): V (aqueous ammonia) =10:0.15:0.05) to give compound C37 as a yellow powder (0.115 g, yield 87％).m.p.>250℃.1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),9.06(d,J＝2.3Hz,1H),8.89(s,1H),8.43(d,J＝2.4Hz,1H),8.39(d,J＝2.5Hz,1H),8.21(d,J＝2.1Hz,1H),8.06(d,J＝2.0Hz,1H),7.93(d,J＝8.9Hz,1H),7.85(dd,J＝8.2,2.5Hz,1H),7.62(dt,J＝7.9,1.5Hz,1H),7.58(dd,J＝8.9,2.2Hz,1H),7.55-7.45(m,3H),6.41(t,J＝5.9Hz,1H),3.93-3.82(m,2H),3.79(s,2H),3.30-3.23(m,2H),3.06(t,J＝6.1Hz,2H),1.74 -1.65(m,1H),1.64-1.55(m,2H),1.29-1.14(m,2H).13C NMR(176MHz,DMSO-d6)δ168.9,155.6,150.9,149.1,142.3,141.2,140.3,138.4,131.6,130.9,130.2,129.2,124.3,123.3,122.5,120.7,119.0,117.9,67.2,45.3,40.5,35.8,30.8.HRMS-ESI：, calculated C 29H29N5O3Cl[M+H]+ 530.1959, experimental value: 530.1953).
Example 38 the synthetic route for compound C38 is as follows:
Starting from compound 11 (0.083 g,0.2 mmol) and 3, 4-methylenedioxyphenylboronic acid (0.039 g,0.24 mmole, 1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.2:0.05) to give compound C38 as a yellow powder (0.075 g, yield 82％).m.p.191.3-192.7℃.1H NMR(400MHz,CDCl3)δ8.88(d,J＝2.3Hz,1H),8.50(s,1H),8.00(d,J＝2.3Hz,1H),7.91(dd,J＝8.9,2.1Hz,1H),7.72(d,J＝2.1Hz,1H),7.64(d,J＝8.9Hz,1H),6.97-7.05(m,2H),6.83(d,J＝8.5Hz,1H),6.21(t,J＝6.1Hz,1H),4.33-4.62(m,1H),3.81-3.61(m,1H),3.17-3.12(m,1H),3.12-2.99(m,1H),2.96-2.78(m,1H),2.54-2.34(m,1H),2.31-2.20(m,2H),1.78-1.59(m,3H),1.05(t,J＝7.5Hz,5H).13C NMR(100MHz,CDCl3)δ172.6,156.3,149.7,148.5,147.7,147.6,141.3,132.5,131.9,131.8,128.6,123.9,121.2,120.8,114.4,108.9,107.5,101.4,45.6,44.9,41.9,36.8,30.3,29.6,26.6,9.71.HRMS-ESI： calculated as C 26H29N4O4[M+H]+ 461.2189, experimental value: 461.2177.
The synthetic route for compound C39 of example 39 is as follows:
Starting from compound 11 (0.083 g,0.2 mmol) and 3, 4-dimethoxyphenylboronic acid (0.044 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give compound C39 as a yellow powder (0.079 g, yield 83％).m.p.92.2-93.0℃.1H NMR(400MHz,CD3OD)δ9.03(d,J＝2.3Hz,1H),8.42(d,J＝1.6Hz,1H),8.15(d,J＝2.1Hz,1H),7.90(d,J＝8.9Hz,1H),7.68(dd,J＝8.9,2.1Hz,1H),7.38-7.29(m,2H),7.12(d,J＝8.2Hz,1H),4.58(d,J＝13.2Hz,1H),4.06-3.95(m,4H),3.91(s,3H),3.24-3.16(m,2H),3.16-3.06(m,1H),2.73-2.61(m,1H),2.43(q,J＝7.5Hz,2H),1.91-1.73(m,3H),1.35-1.17(m,2H),1.13(t,J＝7.5Hz,3H).13C NMR(175MHz,CD3OD)δ173.25,156.53,149.75,149.43,149.07,147.06,141.33,132.83,132.04,130.42,128.41,124.17,120.69,119.45,113.15,112.13,110.47,55.25,55.11,45.40,44.58,41.54,36.76,30.08,29.27,25.99,8.65.HRMS-ESI： calculated as C 27H33N4O4[M+H]+ 477.2502, experimental value: 477.2493.
Example 40 compound C40 was synthesized as follows:
Starting from compound 11 (0.083 g,0.2 mmol) and 3-methoxyphenylboronic acid (0.037 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.2:0.05) to give compound C40 (0.067 g, yield 75％).m.p.89.1-90.6℃.1H NMR(400MHz,CD3OD)δ9.02(d,J＝2.3Hz,1H),8.45(s,1H),8.16(s,1H),7.91(d,J＝8.9Hz,1H),7.69(dd,J＝8.9,2.2Hz,1H),7.44(t,J＝7.9Hz,1H),7.33(d,J＝7.6Hz,1H),7.30(d,J＝2.3Hz,1H),7.01(dd,J＝8.2,1.0Hz,1H),4.62-4.53(m,1H),4.08-3.95(m,1H),3.90(d,J＝1.4Hz,3H),3.19(s,2H),3.15-3.06(m,1H),2.71-2.60(m,1H),2.42(q,J＝7.5Hz,2H),1.90-1.74(m,3H),1.30-1.17(m,2H),1.13(t,J＝7.5Hz,3H).13C NMR(100MHz,CD3OD)δ173.2,160.5,156.4,149.0,147.4,141.6,138.8,133.5,131.9,129.9,128.6,124.0,120.7,119.0,113.1,113.0,112.3,54.4,45.4,44.6,41.5,36.7,30.1,29.3,26.0,8.7.HRMS-ESI：, calculated C 26H31N4O3[M+H]+ 447.2396, experimental value: 447.2391.
Example 41 the synthetic route for compound C41 is as follows:
Starting from compound 11 (0.083 g,0.2 mmol) and 3-trifluoromethoxybenzeneboronic acid (0.049 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.2:0.05) to give compound C41 as a yellow powder (0.071 g, yield 71％).m.p.158.2-159.2℃.1H NMR(400MHz,CD3OD)δ9.00(d,J＝2.3Hz,1H),8.44(d,J＝2.2Hz,1H),8.16(d,J＝2.1Hz,1H),7.89(d,J＝8.9Hz,1H),7.75(dd,J＝7.8,1.0Hz,1H),7.67(dd,J＝8.8,2.0Hz,2H),7.61(t,J＝8.0Hz,1H),7.33(dd,J＝8.2,1.2Hz,1H),4.60-4.51(m,1H),4.03-3.94(m,1H),3.17(t,J＝6.9Hz,2H),3.13-3.02(m,1H),2.67-2.59(m,1H),2.40(q,J＝7.5Hz,2H),1.91-1.77(m,3H),1.33-1.15(m,2H),1.12(t,J＝7.5Hz,3H).13C NMR(100MHz,CD3OD)δ173.2,156.4,149.8,148.7,147.8,142.0,139.8,133.9,130.6,130.3,128.7,125.5,123.8,121.9,120.8,119.9,119.3,113.0,45.4,44.6,41.5,36.7,30.1,29.3,26.0,8.7.HRMS-ESI： calculated as C 26H28N4O3F3[M+H]+ 501.2114, experimental value: 501.2102.
Example 42 the synthetic route for compound C42 is as follows:
Starting from compound 11 (0.083 g,0.2 mmol) and 4-trifluoromethoxybenzeneboronic acid (0.049 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.2:0.05) to give compound C42 as a white powder (0.083 g, yield 83％).m.p.178.8-180.0℃.1H NMR(400MHz,CD3OD)δ9.03(d,J＝2.3Hz,1H),8.47(d,J＝2.3Hz,1H),8.18(d,J＝2.1Hz,1H),7.91(d,J＝8.9Hz,1H),7.87(d,J＝8.8Hz,2H),7.69(dd,J＝8.9,2.1Hz,1H),7.43(d,J＝7.7Hz,1H),4.62-4.55(m,1H),4.04-3.93(m,1H),3.19(t,J＝6.5Hz,2H),3.15-3.03(m,1H),2.71-2.57(m,1H),2.42(q,J＝7.5Hz,2H),1.88-1.80(m,4H),1.30-1.16(m,2H),1.13(t,J＝7.5Hz,3H).13C NMR(100MHz,CD3OD)δ173.3,156.5,149.0,148.8,147.5,141.9,136.6,133.9,130.6,128.6,128.5,123.9,121.4,120.9,113.0,45.4,44.6,41.5,36.8,30.1,29.3,26.0,8.7.HRMS-ESI： calculated as C 26H28N4O3F3[M+H]+ 501.2114, experimental value: 501.2114.
Example 43 the synthetic route for compound C43 is as follows:
Starting from compound 11 (0.083 g,0.2 mmol) and 4-cyanobenzylboronic acid (0.036 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.2:0.05) to give compound C43 as a yellow powder (0.075 g, yield 85％).m.p.243.8-244.9℃.1H NMR(400MHz,DMSO-d6)δ9.19(d,J＝2.4Hz,1H),8.93(s,1H),8.62(d,J＝2.4Hz,1H),8.23(s,1H),8.08(d,J＝8.5Hz,2H),7.99(d,J＝8.5Hz,2H),7.92(d,J＝8.9Hz,1H),7.59(dd,J＝8.9,2.2Hz,1H),6.43(t,J＝5.9Hz,1H),4.42-4.39(m,1H),3.88-3.85(m,1H),3.10-3.03(m,2H),3.00-2.84(m,1H),2.58-2.52(m,1H),2.30(q,J＝7.4Hz,2H),1.73-1.70(m,3H),1.10-1.09(m,1H),0.98(t,J＝7.4Hz,4H).13C NMR(100MHz,DMSO-d6)δ170.9,154.9,149.1,148.5,142.2,141.9,133.4,132.9,128.9,128.5,127.5,122.5,120.3,118.7,112.7,110.1,44.6,44.3,40.8,36.3,29.9,29.2,25.5,9.4.HRMS-ESI： calculated as C 26H28N5O2[M+H]+ 442.2243, experimental value: 442.2232.
Example 44 the synthetic route for compound C44 is as follows:
Starting from compound 11 (0.083 g,0.2 mmol) and 4- [ (dimethylamino) methyl ] phenylboronic acid (0.043 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.2:0.05) to give compound C44 as a yellow powder (0.064 g, yield 68％).m.p.118.9-119.3℃.1H NMR(400MHz,CD3OD)δ9.06(d,J＝2.3Hz,1H),8.49(dd,J＝2.4,0.8Hz,1H),8.17(d,J＝2.1Hz,1H),7.93(d,J＝8.9Hz,1H),7.79(d,J＝8.2Hz,2H),7.70(dd,J＝8.9,2.1Hz,1H),7.52(d,J＝8.3Hz,2H),4.54-4.63(m,1H),3.95-4.05(m,1H),3.64(s,2H),3.20(t,J＝6.4Hz,2H),3.17-3.04(m,1H),2.71-2.61(m,1H),2.44(q,J＝7.5Hz,2H),2.36(s,6H),1.92-1.79(m,3H),1.30-1.17(m,2H),1.13(t,J＝7.5Hz,3H).13C NMR(100MHz,CD3OD)δ173.3,156.5,149.0,147.4,141.7,136.9,133.4,131.7,130.3,128.6,126.8,124.1,120.8,113.1,62.9,45.4,44.6,43.7,41.6,36.8,30.1,29.3,26.0,8.6.HRMS-ESI： calculated as C 28H36N5O2[M+H]+ 474.2869, experimental value: 474.2862.
Example 45 compound C45 was synthesized as follows:
Starting from compound 11 (0.083 g,0.2 mmol) and 4- (4-methyl-1-piperazinyl) phenylboronic acid (0.053 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.2:0.05) to give compound C45 as an orange-yellow powder (0.081 g, yield 79％).m.p.221.0-222.3℃.1H NMR(400MHz,CD3OD)δ8.98(d,J＝2.3Hz,1H),8.33(d,1H),8.10(d,J＝2.1Hz,1H),7.84(d,J＝8.9Hz,1H),7.63(d,J＝8.6Hz,3H),7.07(d,J＝8.4Hz,2H),4.56-4.53(m,2H),3.98-3.95(m,1H),3.28-3.25(m,4H),3.19-3.01(m,3H),2.65-2.59(m,5H),2.42-2.37(m,5H),1.78-1.91(m,3H),1.25-1.22(m,2H),1.10(t,J＝7.5Hz,3H).13C NMR(176MHz,CD3OD)δ173.3,156.6,151.0,148.9,146.8,141.1,132.2,131.9,128.3,127.3,124.3,120.7,116.2,113.2,54.5,45.4,44.7,44.6,41.6,36.8,30.1,29.3,26.0,8.7.HRMS-ESI： calculated as C 30H39N6O2[M+H]+ 515.3134, experimental value: 515.3130.
Example 46 compound C46 was synthesized as follows:
Starting from compound 11 (0.083 g,0.2 mmol) and 4-acetylphenylboronic acid (0.039 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.2:0.05) to give compound C46 as a yellow powder (0.059 g, yield 65％).m.p.229.7-230.4℃.1H NMR(400MHz,DMSO-d6)δ9.20(d,J＝2.4Hz,1H),8.91(s,1H),8.60(d,J＝2.4Hz,1H),8.23(d,J＝2.1Hz,1H),8.10(d,J＝8.5Hz,2H),8.02(d,J＝8.5Hz,2H),7.93(d,J＝8.9Hz,1H),7.59(dd,J＝8.9,2.2Hz,1H),6.43(t,J＝5.9Hz,1H),4.46-4.33(m,1H),3.93-3.80(m,1H),3.13-3.01(m,2H),3.00-2.93(m,1H),2.64(s,3H),2.58-2.52(m,1H),2.30(q,J＝7.4Hz,2H),1.78-1.63(m,3H),1.18-1.01(m,2H),0.98(t,J＝7.4Hz,4H).13C NMR(100MHz,DMSO-d6)δ197.4,170.9,154.9,149.3,148.3,142.0,141.7,135.7,133.0,129.1,128.9,128.8,126.8,122.6,120.2,112.8,44.6,44.3,40.8,36.3,29.9,29.2,26.7,25.5,9.4.HRMS-ESI： calculated as C 27H31N4O3[M+H]+ 459.2396, experimental value: 459.2389.
Example 47 the synthetic route for compound C47 is as follows:
Starting from compound 11 (0.083 g,0.2 mmol) and 4- (aminosulfonyl) phenylboronic acid (0.048 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.2:0.05) to give compound C47 as a white powder (0.058 g, yield 68％).m.p.204.2-204.8℃.1H NMR(400MHz,DMSO-d6)δ9.19(d,J＝2.4Hz,1H),8.92(s,1H),8.61(d,J＝2.4Hz,1H),8.24(d,J＝2.1Hz,1H),8.06(d,J＝8.5Hz,2H),7.96(d,J＝8.8Hz,2H),7.92(d,J＝8.9Hz,1H),7.59(dd,J＝8.8,2.2Hz,1H),7.44(s,2H),6.44(t,J＝5.9Hz,1H),4.49-4.32(m,1H),3.94-3.74(m,1H),3.12-3.04(m,2H),3.02-2.90(m,1H),2.59-2.54(m,1H),2.31(q,J＝7.4Hz,2H),1.81-1.60(m,3H),1.18-1.04(m,2H),0.99(t,J＝7.4Hz,3H).13C NMR(100MHz,DMSO-d6)δ171.5,155.6,149.8,148.9,143.6,142.6,141.1,133.6,129.5,129.4,127.7,126.9,123.2,120.8,113.3,45.1,44.9,41.4,36.8,30.5,29.8,26.1.HRMS-ESI： calculated as C 25H30N4O4S[M+H]+ 496.2019, experimental value: 496.2013.
Example 48 compound C48 was synthesized as follows:
Starting from compound 11 (0.083 g,0.2 mmol) and 4- (methylsulfonyl) phenylboronic acid (0.048 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.2:0.05) to give compound C48 as a white powder (0.060 g, yield 61％).m.p.253.0-254.1℃.1H NMR(400MHz,DMSO-d6)δ9.20(d,J＝2.4Hz,1H),8.93(s,1H),8.63(d,J＝2.4Hz,1H),8.24(d,J＝2.1Hz,1H),8.14(d,J＝8.6Hz,2H),8.06(d,J＝8.6Hz,2H),7.94(d,J＝8.9Hz,1H),7.60(dd,J＝8.9,2.2Hz,1H),6.44(t,J＝5.8Hz,1H),4.47–4.38(m,1H),3.93–3.81(m,1H),3.29(s,3H),3.07(td,J＝6.1,2.1Hz,2H),3.04–2.91(m,1H),2.57–2.53(m,1H),2.31(q,J＝7.4Hz,2H),1.79–1.62(m,3H),1.19–1.03(m,2H),0.98(t,J＝7.4Hz,3H).13C NMR(176MHz,DMSO-d6)δ171.5,155.5,149.8,149.0,142.9,142.7,140.2,134.0,129.5,129.2,128.2,128.1,123.1,120.9,113.2,45.1,44.9,44.0,41.4,40.5,36.8,30.5,29.7,26.1,10.0.HRMS-ESI： calculated C 21H31N4O4S[M+H]+ 495.2066, experimental value 495.2061.
Example 49 the synthetic route for compound C49 is as follows:
Starting from compound 12 (0.087 g,0.2 mmol) and 3, 4-methylenedioxyphenylboronic acid (0.039 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.1:0.05) to give compound C49 as a white powder (0.066 g, yield 69％).m.p.230.8-231.4℃.1H NMR(400MHz,DMSO-d6)δ9.08(d,J＝2.4Hz,2H),8.43(d,J＝2.4Hz,1H),8.20(d,J＝2.1Hz,1H),7.88(d,J＝8.8Hz,1H),7.59(dd,J＝8.9,2.2Hz,1H),7.47(d,J＝8.7Hz,2H),7.45(d,J＝1.9Hz,1H),7.39-7.29(m,3H),7.07(d,J＝8.1Hz,1H),6.88(t,J＝6.0Hz,1H),6.10(s,2H),4.40(s,2H).13C NMR(176MHz,DMSO-d6)δ155.6,149.9,148.7,148.1,147.6,141.7,140.4,132.4,132.0,130.9,129.4,129.0,123.5,121.5,121.3,121.0,120.7,113.6,109.4,107.7,101.7,42.6.HRMS-ESI： calculated as C 25H19N3O4F3[M+H]+ 482.1328, experimental value: 482.1323.
Example 50 compound C50 was synthesized as follows:
Starting from compound 12 (0.087 g,0.2 mmol) and 3, 4-dimethoxyphenylboronic acid (0.044 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give compound C50 as a yellow powder (0.079 g, yield 83％).m.p.199.9-200.8℃.1H NMR(400MHz,DMSO-d6)δ9.17(d,J＝2.3Hz,1H),9.12(s,1H),8.53(d,J＝2.4Hz,1H),8.25(d,J＝2.1Hz,1H),7.92(d,J＝9.0Hz,1H),7.60(dd,J＝8.9,2.2Hz,1H),7.48(d,J＝8.7Hz,2H),7.43(d,J＝2.2Hz,1H),7.39(dd,J＝8.3,2.2Hz,1H),7.35(d,J＝7.9Hz,2H),7.11(d,J＝8.4Hz,1H),6.91(t,J＝6.0Hz,1H),4.39(d,J＝5.7Hz,2H),3.90(s,3H),3.83(s,3H).13CNMR(100MHz,DMSO-d6)δ155.6,149.8,149.7,149.34 147.6,141.8,140.4,132.6,131.1,130.3,129.4,129.0,123.6,121.5,120.8,119.6,113.3,112.9,111.0,56.2,56.1,42.6.HRMS-ESI： calculated as C 26H23N3O4F3[M+H]+ 498.1641, experimental value 498.1635.
Example 51 the synthetic route for compound C51 is as follows:
Starting from compound 12 (0.087 g,0.2 mmol) and 2, 4-dimethoxyphenylboronic acid (0.044 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.1:0.05) to give compound C51 as a yellow powder (0.056 g, yield 56％).m.p.188.6-189.7℃.1H NMR(400MHz,CDCl3)δ8.86(d,J＝2.2Hz,1H),8.44(s,1H),8.01(d,J＝2.2Hz,1H),7.89–7.71(m,2H),7.60(d,J＝8.8Hz,1H),7.21(d,J＝8.6Hz,2H),7.18(d,J＝9.2Hz,1H),7.04-6.98(m,2H),6.62-6.53(m,2H),6.20(t,J＝5.9Hz,1H),4.36(s,1H),4.35(s,2H),3.86(s,3H),3.75(s,3H).13C NMR(100MHz,CDCl3)δ161.0,157.7,156.0,151.9,148.2,146.7,140.5,137.8,135.2,131.3,130.1,128.8,128.6,124.4,121.2,121.0,120.0,119.1,115.3,105.1,99.0,55.5,43.2.HRMS-ESI： calculated as C 26H23N3O4F3[M+H]+ 498.1641, experimental value: 498.1641.
Example 52 the synthetic route for compound C52 is as follows:
Starting from compound 12 (0.087 g,0.2 mmol) and 4-methoxyphenylboronic acid (0.049 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.1:0.05) to give compound C52 as a yellow powder (0.083 g, yield 89％).m.p.212.8-213.8℃.1H NMR(400MHz,CD3OD)δ8.98(d,J＝2.3Hz,1H),8.35(d,J＝2.3Hz,1H),8.10(d,J＝2.1Hz,1H),7.87(d,J＝8.9Hz,2H),7.72(dd,J＝8.9,2.2Hz,1H),7.68(d,J＝8.8Hz,2H),7.45(d,J＝8.7Hz,2H),7.24(d,J＝8.0Hz,1H),7.07(d,J＝8.8Hz,2H),4.47(s,2H),3.86(s,3H).13C NMR(176MHz,MeOD)δ159.9,156.4,149.0,148.3,146.9,141.2,138.8,132.7,132.0,129.8,128.6,128.4,127.9,124.3,120.8,119.8,114.4,113.44,42.5.HRMS-ESI： calculated as C 25H21N3O3F3[M+H]+ 468.1535, experimental value: 468.1516.
Example 53 the synthetic route for compound C53 is as follows:
Starting from compound 12 (0.087 g,0.2 mmol) and 3-methoxyphenylboronic acid (0.049 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give compound C53 as a brown powder (0.064 g, yield 68％).m.p.210.3-211.4℃.1H NMR(400MHz,DMSO-d6)δ9.16(s,2H),8.56(s,1H),8.25(s,1H),7.94(d,J＝8.9Hz,1H),7.60(d,J＝2.1Hz,1H),7.48(d,J＝8.4Hz,2H),7.45(d,J＝8.1Hz,1H),7.42(s,1H),7.40(d,J＝2.7Hz,1H),7.36(d,J＝8.2Hz,2H),7.01(d,J＝7.2Hz,1H),6.92(t,J＝6.0Hz,1H),4.39(d,J＝5.6Hz,2H),3.87(s,3H).13C NMR(100MHz,DMSO-d6)δ160.4,155.6,149.9,148.3,147.6,142.1,140.4,139.3,133.2,131.0,130.7,129.4,129.2,123.4,121.5,120.8,119.6,114.0,113.5,112.7,55.7,42.6.HRMS-ESI： calculated as C 25H21N3O3F3[M+H]+ 468.1535, experimental value: 468.1532.
Example 54 the synthetic route for compound C54 is as follows:
starting from compound 12 (0.087 g,0.2 mmol) and 3-methylphenylboronic acid (0.033 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.1:0.05) to give compound C54 as a yellow powder (0.061 g, yield 67％).m.p.206.4-207.8℃.1H NMR(400MHz,DMSO-d6)δ9.12(d,J＝2.3Hz,1H),9.08(s,1H),8.48(d,J＝2.4Hz,1H),8.22(d,J＝2.1Hz,1H),7.91(d,J＝8.9Hz,1H),7.67(s,1H),7.62(d,J＝8.5Hz,1H),7.60(dd,J＝8.8,2.2Hz,1H),7.48(d,J＝8.7Hz,2H),7.42(t,J＝7.6Hz,1H),7.35(d,J＝7.8Hz,2H),7.24(d,J＝7.7Hz,1H),6.88(t,J＝6.0Hz,1H),4.39(d,J＝5.9Hz,2H),2.42(s,3H).13C NMR(100MHz,DMSO-d6)δ155.6,150.0,148.4,141.9,140.4,138.8,137.8,132.8,131.2,129.5,129.4,129.1,128.9,127.9,124.4,123.5,121.5,120.7,113.7,42.6,21.6.HRMS-ESI： calculated as C 25H21N3O2F3[M+H]+ 452.1586, experimental value: 452.1572.
The synthetic route for compound C55 of example 55 is as follows:
Starting from compound 12 (0.087 g,0.2 mmol) and 3-trifluoromethoxybenzeneboronic acid (0.049 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.1:0.05) to give compound C55 as a brown powder (0.067 g, yield 64％).m.p.170.1-171.8℃.1H NMR(400MHz,DMSO-d6)δ9.17(d,J＝2.4Hz,1H),9.13(s,1H),8.59(d,J＝2.4Hz,1H),8.24(d,J＝2.1Hz,1H),7.97-7.89(m,2H),7.86(s,1H),7.67(t,J＝8.0Hz,1H),7.62(dd,J＝8.9,2.2Hz,1H),7.48(d,J＝8.7Hz,2H),7.43(d,J＝8.3Hz,1H),7.35(d,J＝7.8Hz,2H),6.90(t,J＝6.0Hz,1H),4.39(d,J＝5.9Hz,2H).13C NMR(100MHz,DMSO-d6)δ155.6,149.8,149.6,148.8,147.6,142.4,140.4,140.3,133.5,131.6,129.5,129.4,126.4,123.3,121.5,120.9,120.5,119.9,113.6,42.6.HRMS-ESI： calculated as C 25H18N3O3F6[M+H]+ 522.1252, experimental value: 522.1243.
Example 56 the synthetic route for compound C56 is as follows:
Starting from compound 12 (0.087 g,0.2 mmol) and 4- (aminosulfonyl) phenylboronic acid (0.048 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.2:0.05) to give compound C56 as a yellow powder (0.068 g, yield 66％).m.p.>270℃.1H NMR(400MHz,DMSO-d6)δ9.19(d,J＝2.4Hz,1H),9.15(s,1H),8.61(d,J＝2.4Hz,1H),8.25(d,J＝2.1Hz,1H),8.06(d,J＝8.5Hz,2H),7.97-7.93(m,3H),7.63(dd,J＝8.9,2.2Hz,1H),7.48(d,J＝8.7Hz,2H),7.44(s,2H),7.36(d,J＝8.2Hz,2H),6.91(t,J＝6.0Hz,1H),4.40(s,1H),4.39(s,1H).13C NMR(100MHz,DMSO-d6)δ155.6,149.9,148.8,147.6,143.6,142.4,141.1,140.3,133.6,129.6,129.5,129.4,127.7,126.9,123.3,121.5,120.9,113.6,42.6.HRMS-ESI： calculated as C 24H20N4O4F3S[M+H]+ 517.1157, experimental value: 517.1162.
The synthetic route for compound C57 of example 57 is as follows:
Starting from compound 12 (0.087 g,0.2 mmol) and 4-methanesulfonyl phenylboronic acid (0.055 g,0.24mmol,1.2 eq) the product was purified by column chromatography over silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.1:0.05) to give compound C57 as a yellow powder (0.048 g, yield 47％).m.p.236.3-237.4℃.1H NMR(400MHz,DMSO-d6)δ9.21(d,J＝2.3Hz,1H),9.17(s,1H),8.65(d,J＝2.4Hz,1H),8.27(d,J＝2.1Hz,1H),8.15(d,J＝8.6Hz,2H),8.07(d,J＝8.6Hz,2H),7.96(d,J＝8.9Hz,1H),7.64(dd,J＝8.9,2.2Hz,1H),7.48(d,J＝8.7Hz,2H),7.36(d,J＝7.6Hz,2H),6.92(t,J＝6.0Hz,1H),4.40(d,J＝5.9Hz,2H),3.29(s,3H).13C NMR(100MHz,DMSO-d6)δ155.53,149.76,148.84,147.63,142.85,142.67,140.33,140.26,134.14,129.51,129.45,129.31,128.24,128.11,123.24,121.47,120.97,113.40,44.04,42.61.HRMS-ESI： calculated as C 25H21N3O4F3S[M+H]+ 516.1205, experimental value: 516.1157.
The synthetic route for compound C58 of example 58 is as follows:
Compound 15 (0.1 g,0.36 mmol) was dissolved in 15mL of dichloromethane, and carbonyldiimidazole (0.065 g,0.43mmol,1.2 eq) was added and reacted at room temperature for 12h. To the reaction mixture was added isobutylamine (0.54 mmol,1.5 eq) and the reaction was continued at room temperature for 0.5h. After the reaction was completed, the organic phase was washed with saturated ammonium chloride, collected, concentrated by rotary evaporation, and chromatographed on a silica gel column (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give compound C58 (0.079 g, yield 61％).m.p.>280℃.1H NMR(400MHz,DMSO-d6)δ8.98(d,J＝2.3Hz,1H),8.78(s,1H),8.36(d,J＝2.3Hz,1H),8.12(d,J＝2.4Hz,1H),7.89(d,J＝9.0Hz,1H),7.65(dd,J＝9.1,2.4Hz,1H),7.48(d,J＝1.8Hz,1H),7.36(dd,J＝8.1,1.9Hz,1H),7.07(d,J＝8.1Hz,1H),6.32(t,J＝5.8Hz,1H),6.10(s,2H),2.98(t,2H),1.87-1.66(m,1H),0.90(d,J＝6.7Hz,6H).13C NMR(100MHz,DMSO-d6)δ155.7,148.7,147.9,147.2,143.2,139.5,133.2,131.9,131.6,129.5,128.9,122.9,121.4,112.6,109.4,107.9,101.8,47.0,28.9,20.5.HRMS-ESI： calculated C 21H22N3O3[M+H]+ 364.1661, experimental value: 364.1661.
Example 59 the synthetic route for compound C59 is as follows:
Compound 15 (0.1 g,0.36 mmol) was dissolved in 15mL of dichloromethane, and carbonyldiimidazole (0.065 g,0.43mmol,1.2 eq) was added and reacted at room temperature for 12h. To the reaction mixture was added 4-aminomethyltetrahydropyran (0.54 mmol,1.5 eq) and the reaction was continued at room temperature for 0.5h. After completion of the reaction, the organic phase was washed with saturated ammonium chloride, collected, concentrated by rotary evaporation, and chromatographed on a silica gel column (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give compound C59 (0.119 g, yield 82％).m.p.283.3-284.5℃.1H NMR(400MHz,DMSO-d6)δ8.98(d,J＝2.4Hz,1H),8.78(s,1H),8.36(d,J＝2.3Hz,1H),8.11(d,J＝2.4Hz,1H),7.88(d,J＝9.0Hz,1H),7.64(dd,J＝9.1,2.4Hz,1H),7.47(d,J＝1.9Hz,1H),7.36(dd,J＝8.1,1.9Hz,1H),7.07(d,J＝8.1Hz,1H),6.34(t,J＝5.9Hz,1H),6.10(s,2H),3.97–3.80(m,2H),3.30-3.22(m,2H),3.05(t,J＝6.2Hz,2H),1.68-1.57(m,1H),1.64-1.52(m,2H),1.30-1.10(m,2H).13C NMR(100MHz,DMSO-d6)δ155.7,148.7,147.9,147.3,143.2,139.4,133.2,131.9,131.6,129.5,128.9,122.9,121.4,112.6,109.4,107.9,101.8,67.3,45.3,35.8,30.8.HRMS-ESI： calculated as C 23H24N3O4[M+H]+ 406.1767, experimental value: 406.1764.
Example 60 the synthetic route for compound C60 is as follows:
Compound 15 (0.1 g,0.36 mmol) was dissolved in 15mL of dichloromethane, and carbonyldiimidazole (0.065 g,0.43mmol,1.2 eq) was added and reacted at room temperature for 12h. To the reaction solution was added 4-amino-1-propionyl piperidine (0.54 mmol,1.5 eq) and the reaction was continued at room temperature for 0.5h after the completion of the reaction, the organic phase was washed with saturated ammonium chloride, collected and concentrated by rotary evaporation, and Compound C60 (0.117 g, calculated as yield 73％).m.p.241.1-242.5℃.1H NMR(400MHz,DMSO-d6)δ8.99(d,J＝2.3Hz,1H),8.74(s,1H),8.37(d,J＝2.3Hz,1H),8.11(d,J＝2.4Hz,1H),7.90(d,J＝9.0Hz,1H),7.66(dd,J＝9.1,2.4Hz,1H),7.48(d,J＝1.8Hz,1H),7.36(dd,J＝8.1,1.8Hz,1H),7.07(d,J＝8.1Hz,1H),6.33(d,J＝7.6Hz,1H),6.11(s,2H),4.30-4.11(m,1H),3.86-3.70(m,2H),3.23-3.10(m,1H),2.91-2.78(m,1H),2.33(q,J＝7.4Hz,2H),1.97-1.79(m,2H),1.47-1.16(m,2H),1.00(t,J＝7.4Hz,3H).13C NMR(100MHz,DMSO-d6)δ171.6,154.9,148.7,147.9,147.3,143.3,139.3,133.2,129.6,128.9,122.9,121.4,112.7,109.4,107.9,101.8,46.8,43.9,33.0,32.3,26.0,9.9.HRMS-ESI： C 25H27N4O4[M+H]+ 447.2032, experimental value: 447.2035) was obtained by silica gel column chromatography (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05).
Example 61 the synthetic route for compound C61 is as follows:
Compound 15 (0.1 g,0.36 mmol) was dissolved in 15mL of dichloromethane, and carbonyldiimidazole (0.065 g,0.43mmol,1.2 eq) was added and reacted at room temperature for 12h. To the reaction solution was added 4-aminomethyl-1-propionylpiperidine (0.54 mmol,1.5 eq) and the reaction was continued at room temperature for 0.5h after completion of the reaction, the organic phase was washed with saturated ammonium chloride, collected and concentrated by rotary evaporation, and chromatographed on silica gel (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give compound C61 as a yellow powder (0.134 g, yield 81％).m.p.160.4-161.2℃.1HNMR(400MHz,DMSO-d6)δ8.98(d,J＝2.3Hz,1H),8.80(s,1H),8.37(d,J＝2.3Hz,1H),8.12(d,J＝2.4Hz,1H),7.89(d,J＝9.1Hz,1H),7.65(dd,J＝9.1,2.4Hz,1H),7.48(d,J＝1.9Hz,1H),7.36(dd,J＝8.1,1.9Hz,1H),7.07(d,J＝8.1Hz,1H),6.37(t,J＝5.9Hz,1H),6.10(s,2H),4.44-4.36(m,1H),3.90-3.80(m,1H),3.06(t,J＝6.1Hz,2H),2.96-2.93(m,1H),2.54-2.47(m,1H),2.30(q,J＝7.4Hz,2H),1.77-1.60(m,3H),1.18-1.00(m,2H),0.98(t,J＝7.4Hz,3H).13C NMR(100MHz,DMSO-d6)δ170.9,155.2,148.1,147.3,146.7,142.6,138.8,132.6,131.3,131.0,128.9,128.4,122.4,120.8,112.1,108.8,107.4,101.2,44.6,44.3,40.8,36.3,29.9,29.2,25.5,9.4.HRMS-ESI： calculated as C 26H29N4O4[M+H]+ 461.2189, experimental value: 461.2181).
The method for synthesizing the tetrahydroquinoline compound of the present invention will be briefly described below. In the synthetic examples listed below, the synthesis of intermediates mainly involves the suzuki reaction, the reduction reaction, the acylation reaction, and the like.
Specifically, the synthetic methods of representative specific compounds of the present invention are given below.
Example 62 compound C62 was synthesized as follows:
Compound C1 (0.1 g,0.328 mmol) was dissolved in 10mL of methanol, nickel chloride (0.435 g,3.36mmol,12 eq) was added, followed by the addition of sodium borohydride (0.428 g,19.26mmol,70 eq) in portions and reacted at room temperature for 2h. After the reaction was completed, water was added, after filtration with celite, methylene chloride was added to the filtrate, after extraction for 3 times, the organic phase was collected and concentrated by rotary evaporation, and compound C62 yellow powder (0.080 g, yield 66％).m.p.197.8-199.2℃.1H NMR(400MHz,DMSO-d6)δ8.01(s,1H),6.88(d,J＝1.7Hz,1H),6.83(d,J＝7.9Hz,1H),6.74(dd,J＝8.1,1.7Hz,1H),6.70(d,J＝8.1Hz,1H),6.65(d,J＝2.1Hz,1H),6.41(dd,J＝8.1,2.1Hz,1H),6.00(t,J＝5.9Hz,1H),5.96(s,2H),5.80(d,J＝3.6Hz,1H),3.25-3.18(m,1H),3.16-3.06(m,1H),2.94-2.82(m,3H),2.78(d,J＝15.3Hz,1H),2.73-2.67(m,1H),1.73-1.61(m,1H),0.86(d,J＝6.7Hz,6H).13C NMR(100MHz,DMSO-d6)δ155.7,147.8,146.0,145.2,139.6,138.7,129.4,120.6,113.6,108.6,108.2,105.9,102.9,101.1,47.9,46.9,38.2,34.5,28.9,20.5.HRMS-ESI： calculated C 21H26N3O3[M+H]+ 368.1974, experimental value: 368.1960) was obtained by silica gel column chromatography (V (methylene chloride): V (methanol): V (ammonia) =10:0.08:0.05).
Example 63 compound C63 was synthesized as follows:
Compound C62 (0.150 g,0.328 mmol) was dissolved in 10mL of methanol, nickel chloride (0.435 g,3.36mmol,12 eq) was added, followed by the addition of sodium borohydride (0.328 g,19.26mmol,70 eq) in portions and reacted at room temperature for 2h. After the reaction was completed, water was added, after filtration with celite, methylene chloride was added to the filtrate, after extraction for 3 times, the organic phase was collected and concentrated by rotary evaporation, and compound C63 orange-yellow powder (0.085 g, yield 56％).m.p.182.4-184.2℃.1H NMR(400MHz,CD3OD)δ6.91(d,J＝2.4Hz,1H),6.88(dd,J＝8.4,2.5Hz,1H),6.71-6.80(m,3H),6.52(d,J＝8.5Hz,1H),5.90(s,2H),4.57-4.48(m,1H),4.00-3.89(m,1H),3.17(t,J＝10.5Hz,1H),3.13-3.03(m,3H),2.99-2.93(m,1H),2.85(m,2H),2.65-2.56(m,1H),2.39(q,J＝7.5Hz,2H),1.82-1.69(m,3H),1.10(t,J＝7.5Hz,5H).13C NMR(100MHz,CDCl3)δ172.2,157.4,147.9,146.3,142.3,137.3,126.9,126.5,124.2,122.1,120.1,114.6,108.4,107.5,100.9,48.5,45.5,41.6,38.1,36.9,34.7,30.4,29.5,26.6,9.6.HRMS-ESI： calculated C 26H33N4O4[M+H]+ 465.2502, experimental value: 465.2492) was obtained by silica gel column chromatography (V (methylene chloride): V (methanol): V (ammonia) =10:0.08:0.05).
Example 64 compound C64 was synthesized as follows:
Compound C39 (0.150 g,0.328 mmol) was dissolved in 10mL of methanol, nickel chloride (0.435 g,3.36mmol,12 eq) was added, followed by the addition of sodium borohydride (0.328 g,19.26mmol,70 eq) in portions and reacted at room temperature for 2h. After the reaction was completed, water was added, after filtration through celite, methylene chloride was added to the filtrate, after extraction 3 times, the organic phase was collected and concentrated by rotary evaporation, and compound C64 was obtained as a yellow oil (0.096 g, yield 63％).1H NMR(400MHz,CD3OD)δ6.81(d,J＝8.1Hz,1H),6.79-6.69(m,3H),6.66(d,J＝2.1Hz,1H),6.47(dd,J＝8.0,2.2Hz,1H),5.89(s,2H),4.60-4.35(m,1H),4.02-3.79(m,1H),3.16(t,J＝10.8Hz,1H),3.09-2.99(m,3H),2.98-2.88(m,1H),2.84-2.74(m,2H),2.67-2.55(m,1H),2.39(q,J＝7.5Hz,2H),1.91-1.69(m,3H),1.22-1.04(m,5H).13C NMR(100MHz,CD3OD)δ174.5,158.5,149.1,147.4,145.8,139.4,130.3,121.1,117.3,109.7,109.1,108.5,106.3,46.8,45.9,42.9,39.9,38.1,35.5,31.4,30.6,27.4,10.1.HRMS-ESI：, calculated C 26H33N4O4[M+H]+ 465.2502, experimental value: 465.2493) by silica gel column chromatography (V (methylene chloride): V (methanol): V (ammonia) =10:0.08:0.05).
The synthetic methods of the isoquinoline compounds and tetrahydroisoquinolines of the present invention will be briefly described below. Specifically, the synthetic methods of representative specific compounds of the present invention are given below.
Ethylene glycol, p-toluenesulfonic acid, toluene at 110 ℃, b Pd/C, methanol and hydrogen at room temperature, C N-bromosuccinimide, DMF at room temperature, d acetic anhydride, DMAP, pyridine, methylene dichloride at room temperature, e palladium acetate, xanphos, potassium phosphate, THF at 90 ℃, f ammonium chloride, ethanol/water solution at 90-120 ℃, g carbonyl diimidazole, DCM at room temperature, h amine, DCM at room temperature, i platinum dioxide, hydrochloric acid, ethanol and hydrogen at room temperature.
Example 65 compound C65 was synthesized as follows:
Compound 20 (0.1 g,0.36 mmol) was dissolved in 15mL of dry dichloromethane, carbonyl diimidazole (0.073 g,0.43mmol,1.2 eq) was added and reacted at room temperature for 5d. 4-trifluoromethoxybenzylamine (0.54 mmol,1.5 eq) was added to the reaction mixture, the reaction was continued at room temperature for 12 hours, after the completion of the reaction, the organic phase was washed with saturated ammonium chloride, collected, concentrated by rotary evaporation, and subjected to silica gel column chromatography (V (dichloromethane): V (ethanol) =10:0.15) to give compound C65 (0.15 g, yield 83％).m.p.179.6-180.3℃.1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),9.08(s,1H),8.35–8.28(m,2H),7.92(d,J＝8.9Hz,1H),7.68(dd,J＝8.9,2.2Hz,1H),7.51–7.43(m,2H),7.39–7.31(m,4H),6.90(t,J＝6.0Hz,1H),6.54(t,J＝2.3Hz,1H),4.38(d,J＝5.9Hz,2H),3.84(s,6H).13C NMR(100MHz,DMSO-d6)δ161.32,155.67,151.49,147.87,147.62,141.67,140.42,139.88,132.09,129.47,129.01,128.19,124.59,121.86,121.46,116.52,112.19,104.55,100.88,55.77,42.63.HRMS-ESI：, calculated C 26H23F3N3O4[M+H]+ 498.1635, experimental value: 498.1649).
Example 66 the synthetic route for compound C66 is as follows:
Compound 20 (0.1 g,0.36 mmol) was dissolved in 15mL of dry dichloromethane, carbonyl diimidazole (0.073 g,0.43mmol,1.2 eq) was added and reacted at room temperature for 5d. To the reaction solution was added 4-aminomethyl-1-propionylpiperidine (0.54 mmol,1.5 eq) and the reaction was continued at room temperature for 12 hours, after the completion of the reaction, the organic phase was washed with saturated ammonium chloride, collected and concentrated by rotary evaporation, and Compound C66 (0.12 g, yield 72％).m.p.142.1-143.3℃.1H NMR(400MHz,CD3OD)δ9.11(s,1H),8.16(d,J＝2.2Hz,1H),8.08(s,1H),7.88(d,J＝8.8Hz,1H),7.68(dd,J＝8.9,2.2Hz,1H),7.18(d,J＝2.2Hz,2H),6.53(t,J＝2.3Hz,1H),4.55(d,J＝13.2Hz,1H),3.97(d,J＝13.6Hz,1H),3.86(s,6H),3.16(t,J＝6.4Hz,2H),3.08(t,J＝12.6Hz,1H),2.69–2.57(m,1H),2.40(q,J＝7.5Hz,2H),1.87–1.75(m,3H),1.23–1.07(m,5H).13C NMR(100MHz,CD3OD)δ173.24,161.33,156.61,150.76,149.06,141.33,139.10,132.76,128.69,127.47,124.70,117.02,112.84,104.57,100.13,54.49,45.38,44.59,41.53,36.77,30.09,29.28,25.99,8.65.HRMS-ESI： calculated as C 27H33N4O4[M+H]+ 477.2496, experimental value: 477.2508) was obtained by silica gel column chromatography (V (dichloromethane): V (ethanol) =10:0.5).
Example 67 compound C67 was synthesized as follows:
To the autoclave, 50mL of an ethanol solution of Compound C65 (0.40 mmol,0.2 g) was added, followed by several drops of 2M aqueous hydrochloric acid solution and platinum dioxide (0.02 g). After 3 times of hydrogen extraction and ventilation circulation, the mixture is reacted for 24 hours under the pressure of 60psi of hydrogen, after the reaction is finished, the mixture is filtered, the organic phase is collected, concentrated by rotary evaporation, and the compound C67 (0.19 g, yield 95％).m.p.125.9-126.5℃.1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),7.45–7.38(m,2H),7.36–7.29(m,2H),7.19(d,J＝2.2Hz,1H),7.10(dd,J＝8.2,2.2Hz,1H),6.93(d,J＝8.3Hz,1H),6.68–6.59(m,3H),6.38(t,J＝2.3Hz,1H),4.31(d,J＝6.0Hz,2H),3.97(q,J＝16.0Hz,2H),3.80(dd,J＝10.8,3.9Hz,1H),3.73(s,6H),3.00(s,1H),2.81(dd,J＝16.0,3.8Hz,1H),2.65(dd,J＝15.9,10.7Hz,1H).13C NMR(100MHz,DMSO)δ160.81,155.76,147.82,147.56,140.66,138.43,136.11,129.37,129.32,128.19,121.86,121.42,119.31,116.37,115.47,104.93,99.05,58.18,55.55,48.97,42.52,37.04.HRMS-ESI： calculated value C 26H27F3N3O4[M+H]+ 502.1948 and experimental value 502.1978) is obtained through silica gel column chromatography (V (dichloromethane): V (ethanol) =10:0.45).
Example 68 the synthetic route for compound C68 is as follows:
50mL of a solution of C66 (0.42 mmol,0.2 g) in ethanol was added to the autoclave, followed by several drops of 2M aqueous hydrochloric acid and platinum dioxide (0.02 g). After 3 times of hydrogen extraction and ventilation circulation, the mixture is reacted for 16 hours under the pressure of 60psi of hydrogen, after the reaction is finished, the mixture is filtered, the organic phase is collected, concentrated by rotary evaporation, and compound C68 (0.19 g, yield 96％).m.p.110.7-111.9℃.1H NMR(400MHz,CD3OD)δ7.16(d,J＝2.2Hz,1H),7.10(dd,J＝8.3,2.2Hz,1H),7.01(d,J＝8.3Hz,1H),6.60(d,J＝2.3Hz,2H),6.40(t,J＝2.3Hz,1H),4.58–4.49(d,J＝13.1Hz,1H),4.16 -4.00(q,J＝15.9Hz,2H),4.00–3.85(m,2H),3.77(s,6H),3.13–3.02(m,3H),2.90(d,J＝7.5Hz,2H),2.61(td,J＝12.9,2.7Hz,1H),2.40(q,J＝7.5Hz,2H),1.78(td,J＝14.2,11.9,7.6Hz,3H),1.21–1.07(m,5H).13C NMR(100MHz,CD3OD)δ173.25,161.16,157.04,145.66,137.55,134.31,128.95,128.40,117.44,116.31,104.26,98.90,58.68,54.37,45.40,44.55,41.54,36.81,35.95,30.08,29.27,25.99,8.66.HRMS-ESI： calculated value C 27H37N4O4[M+H]+ 481.2809 and experimental value 481.2801) is obtained through silica gel column chromatography (V (dichloromethane): V (ethanol) =10:1.2).
The method for synthesizing the benzimidazole compound of the present invention will be briefly described below. In the synthetic examples listed below, the synthesis of intermediates mainly involves coupling, ring closure, reduction, and acylation reactions, etc.
Specifically, the synthetic methods of representative specific compounds of the present invention are given below.
A, 4-nitro-o-phenylenediamine, aldehyde, absolute ethyl alcohol and 80 ℃, b, nitrobenzene, absolute ethyl alcohol and 80 ℃, C, iron powder, ammonium chloride, water and ethanol, and 90 ℃, d, carbonyl diimidazole and dichloromethane are reacted at room temperature, and e, amine and dichloromethane are reacted at room temperature.
The synthetic route for compound C69 of example 69 is as follows:
Compound 22 (0.1 g,0.40 mmol) was dissolved in 15mL of dry dichloromethane, carbonyl diimidazole (0.073 g,0.48mmol,1.2 eq) was added and reacted at room temperature for 12h. To the reaction mixture was added isobutylamine (0.60 mmol,1.5 eq) and the reaction was continued at room temperature for 0.5h. After the reaction was completed, the organic phase was washed with saturated ammonium chloride, collected, concentrated by rotary evaporation, and purified by silica gel column chromatography (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give compound C69 (0.099 g, yield 71％).m.p.147.5-149.3℃.1H NMR(400MHz,Methanol-d4)δ7.77(d,J＝2.0Hz,1H),7.56(dd,J＝8.1,1.8Hz,1H),7.52(d,J＝1.8Hz,1H),7.44(d,J＝8.6Hz,1H),7.05(dd,J＝8.6,2.0Hz,1H),6.95(d,J＝8.1Hz,1H),6.04(s,2H),3.04(d,J＝6.8Hz,2H),1.88-1.70(m,1H),0.96(d,J＝6.7Hz,6H).13C NMR(100MHz,Methanol-d4)δ157.4,151.8,149.5,148.5,135.2,123.7,120.8,115.8,108.3,106.3,101.7,28.8,19.0.HRMS-ESI: calculated C 19H21N4O3[M+H]+ 353.1614, experimental value: 353.1604.
Example 70 the synthetic route for compound C70 is as follows:
Compound 22 (0.1 g,0.40 mmol) was dissolved in 15mL of dry dichloromethane, carbonyl diimidazole (0.073 g,0.48mmol,1.2 eq) was added and reacted at room temperature for 12h. To the reaction mixture was added 4-aminomethyl-1-propionylpiperidine (0.60 mmol,1.5 eq) and the reaction was continued at room temperature for 0.5h. After the reaction was completed, the organic phase was washed with saturated ammonium chloride, collected, concentrated by rotary evaporation, and chromatographed on a silica gel column (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give compound C70 as a white oil (0.149 g, yield 83％).1H NMR(400MHz,Methanol-d4)δ7.76(d,J＝2.1Hz,1H),7.52(dd,J＝8.2,1.5Hz,1H),7.47(d,J＝1.5Hz,1H),7.42(d,J＝8.6Hz,1H),7.05(dd,J＝8.6,2.1Hz,1H),6.87(d,J＝8.2Hz,1H),5.97(s,2H),4.55-4.41(m,1H),3.91-3.79(m,1H),3.16-3.03(m,2H),3.02-2.88(m,1H),2.54(td,J＝12.7,2.7Hz,1H),2.38-2.27(m,2H),1.80-1.65(m,3H),1.06(td,J＝7.5,1.3Hz,5H).13C NMR(100MHz,Methanol-d4)δ173.2,157.3,151.9,149.4,148.4,138.1,135.7,135.0,123.5,120.8,115.9,114.9,108.3,106.3,104.6,101.7,45.3,44.7,41.5,36.8,30.1,29.3,25.9,8.7.HRMS-ESI: calculated C 24H28N5O4[M+H]+ 450.2141, experimental value: 450.2136.
Example 71 the synthetic route for compound C71 is as follows:
Compound 22 (0.1 g,0.40 mmol) was dissolved in 15mL of dry dichloromethane, carbonyl diimidazole (0.073 g,0.48mmol,1.2 eq) was added and reacted at room temperature for 12h. To the reaction solution was added 4-aminomethyltetrahydropyran (0.60 mmol,1.5 eq) and the reaction was continued at room temperature for 0.5h, after the completion of the reaction, the organic phase was washed with saturated ammonium chloride, collected and concentrated by rotary evaporation, and compound C71 brown oil (0.085 g, yield 54％).1H NMR(400MHz,Methanol-d4)δ7.79(d,J＝2.0Hz,1H),7.60(dd,J＝8.2,1.8Hz,1H),7.55(d,J＝1.8Hz,1H),7.48(d,J＝8.6Hz,1H),7.09(dd,J＝8.7,2.1Hz,1H),6.99(d,J＝8.2Hz,1H),6.07(s,2H),4.05-3.93(m,2H),3.47-3.41(m,2H),3.14(d,J＝6.7Hz,2H),1.85-1.74(m,1H),1.74-1.66(m,2H),1.44-1.25(m,2H).13C NMR(100MHz,Methanol-d4)δ157.4,151.8,149.5,148.5,135.2,123.5,120.8,115.9,114.9,108.3,106.3,101.7,67.4,45.1,35.7,30.3.HRMS-ESI: calculated as C 21H23N4O4[M+H]+ 395.1719, experimental value: 395.1712) was obtained by silica gel column chromatography (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05).
The method for synthesizing the indole compound of the present invention will be briefly described below. In the synthetic examples listed below, the synthesis of intermediates mainly involves coupling, ring closure, reduction, and acylation reactions, etc.
Specifically, the synthetic methods of representative specific compounds of the present invention are given below.
A, piperonal, 2, 4-dinitrotoluene, piperidine and toluene at 110 ℃, b, iron (II) acetate, phenanthroline, phenylsilane, ethylene glycol dimethyl ether at 80 ℃, C, iron powder, ammonium chloride, water, ethanol at 90 ℃, d, carbonyl diimidazole and dichloromethane at room temperature, and e, amine and dichloromethane at room temperature.
Example 72 the synthetic route for compound C72 is as follows:
Compound 24 (0.1 g,0.40 mmol) was dissolved in 15mL of dry dichloromethane, carbonyl diimidazole (0.073 g,0.48mmol,1.2 eq) was added and reacted at room temperature for 12h. Isobutylamine (0.60 mmol,1.5 eq) was added to the reaction solution, the reaction was continued at room temperature for 0.5h, after completion of the reaction, the organic phase was washed with saturated ammonium chloride, concentrated by rotary evaporation, and Compound C72 (0.088 g, yield 63％).m.p.233.8-234.1℃.1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),8.30(d,J＝5.8Hz,1H),7.74(d,J＝1.8Hz,1H),7.37(d,J＝1.8Hz,1H),7.30(dd,J＝8.3,2.3Hz,2H),6.98(d,J＝8.1Hz,1H),6.76(d,J＝8.4Hz,1H),6.66(d,J＝2.2Hz,1H),6.11-6.07(m,1H),6.05(s,2H),2.94(t,J＝6.2Hz,2H),1.75-1.65(m,1H),0.89(d,J＝6.7Hz,6H).13C NMR(100MHz,DMSO-d6)δ155.5,147.7,146.2,137.4,136.4,135.1,126.8,123.4,119.5,118.0,111.8,108.6,105.1,100.9,99.9,97.8,46.5,28.4,19.9.HRMS-ESI: calculated as C 20H22N3O3[M+H]+ 352.1661, experimental value: 352.1653) was obtained by silica gel column chromatography (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05).
Example 73 compound C73 was synthesized as follows:
Compound 24 (0.1 g,0.40 mmol) was dissolved in 15mL of dry dichloromethane, carbonyl diimidazole (0.073 g,0.48mmol,1.2 eq) was added and reacted at room temperature for 12h. To the reaction mixture was added 4-aminomethyltetrahydropyran (0.60 mmol,1.5 eq) and the reaction was continued at room temperature for 0.5h. After the reaction was completed, the organic phase was washed with saturated ammonium chloride, collected, concentrated by rotary evaporation, and purified by silica gel column chromatography (V (dichloromethane): V (methanol): V (ammonia) =10:0.15:0.05) to give compound C73 (0.099 g, yield 63％).m.p.237.1-237.9℃.1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),8.28(s,1H),7.74(s,1H),7.37(s,1H),7.30(dd,J＝8.6,3.9Hz,2H),6.98(d,J＝8.1Hz,1H),6.76(d,J＝8.3Hz,1H),6.62-6.70(m,1H),6.11(t,J＝5.9Hz,1H),6.05(s,2H),3.85-3.83(m,2H),3.29(dd,J＝21.8,10.3Hz,3H),3.01(t,J＝6.2Hz,2H),1.65-1.64(m,1H),1.59-1.56(m,2H),1.23-1.14(m,2H).13C NMR(100MHz,DMSO-d6)δ155.4,147.7,146.2,137.3,136.4,135.0,126.8,123.5,119.5,118.0,111.8,108.6,105.1,100.9,99.9,97.8,66.7,44.7,35.3,30.2.HRMS-ESI: calculated C 22H24N3O4[M+H]+ 394.1767, experimental value: 394.1762.
Test example 1
The technical effects and advantages of the present invention are demonstrated by the application of the quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, indole, benzimidazole and other compounds of the present invention in inhibiting soluble epoxide hydrolase.
Specifically, the compound in the embodiment of the invention is incubated with a sample containing soluble epoxide hydrolase and an endogenous hydrolysis substrate 14,15-EET of the hydrolase, the content of the hydrolysis product 14,15-DHET is detected, and the relative generation amount is used for reflecting the inhibition effect of the compound on the soluble epoxide hydrolase, and the specific steps are as follows:
To the collected brain tissue samples of adult (25-30 g of body weight) male C57BL/6J mice, 1:10 (mg/. Mu.L) pre-chilled PBS (phosphate buffer solution, phosphate buffer saline) (pH=7.4) was added, and the mixture was broken for 30 seconds (4 ℃ C., 4500 rpm) by a homogenizer (Bertin Precellys-Dual, bertin Technologies), and then centrifuged at 9000g for 15 minutes by a small-sized low-temperature centrifuge, and the supernatant was diluted 20-fold. 160. Mu.L of PBS and 20. Mu.L of 20-fold diluted tissue fluid as well as 2. Mu.L of compound with concentration gradient 10000, 5000, 1000, 500, 100, 50, 10, 1, 0.1, 0.01. Mu.g/mL (final concentration 100, 50, 10, 5, 1, 0.5, 0.1, 0.01, 0.001, 0.0001. Mu.g/mL) were added to an EP (eppendorf) tube, incubated at room temperature for 15 minutes, negative control was PBS without tissue dilution but with solvent (180. Mu.L of PBS plus 2. Mu LDMSO), positive control was the same concentration of sample dilution plus an equal volume of solvent (160. Mu.L of PBS plus 20. Mu.L of diluted tissue fluid plus 2. Mu. LDMSO). After the incubation at room temperature was completed, all samples were placed on ice, and after rapid addition of enzyme substrates (10. Mu.L of 14,15-EET (10. Mu.g/mL)) and mixing, incubation was performed in a shaking table at 37℃and after the incubation was completed, the samples were placed on ice and rapid addition of 10. Mu.L of 800nM t-TUCB (No. 6757, tocris Bioscience, UK, bristol) to terminate the reaction, and finally a post-reaction system volume of 200. Mu.L was obtained. To detect enzyme activity, the concentration of the reaction product 14,15-DHET was detected using high performance liquid-mass spectrometry. The pretreatment is specifically 1, adding an equal volume (200. Mu.L) of a mixture of methanol and acetonitrile (50/50, v/v) containing 0.4% acetic acid and internal standards 11,12-EET-d 11 and 11,12-DHET-d 11 (20 ng/mL) to the sample, 2, homogenizing at 4500rpm for 10 minutes with a homogenizer and standing at-20℃for 2 hours to precipitate the protein, 3, after centrifugation of the sample for 10 minutes (14000 rpm), the supernatant was collected for UPLC-MS/MS analysis. The relative enzyme activity of sEH was calculated by comparing the amount of 14,15-DHET produced at a concentration of the test compound with that produced in the absence of the inhibitor, with the inhibition rate being 100% minus the relative enzyme activity. Inhibition = 100- (C t/C0) x 100, where C t is the amount of 14,15-DHET produced by the test compound and C 0 is the amount of 14,15-DHET produced in the absence of inhibitor.
Among the positive control compounds are TPPU and EC5026.
The verification results of the compounds prepared by the invention are shown in tables 1,2 and 3:
TABLE 1 inhibitory Activity of Compounds of general formulas I-1 and I-2 on sEH
TABLE 2 inhibitory Activity of Compounds of general formulas I-3 and I-4 on sEH
Numbering device IC50(nM)
C62 11.5±1.73
C63 33.3±0.5248
C64 3.14±0.177
TABLE 3 inhibitory Activity of Compounds of general formulas I-5 and I-6 on sEH
TABLE 4 inhibitory Activity of Compounds of general formulas I-8 and I-10 on sEH
According to the test results, the compounds prepared by the invention have better sEH inhibitory activity.
Test example 2
The technical effects and advantages of the present invention are demonstrated below by the use of the compounds of the present invention in inhibiting carrageenan-induced inflammation of foot swelling in mice.
The specific steps are that BALBC male mice are selected, 23-25g of male mice are adaptively fed for 5-7 days, experiments are started, 20mg/kg of oral administration (three doses of C17 are 1mg/kg, 10mg/kg and 20mg/kg respectively) is carried out, the administration solvent is 5% DMSO+95% soybean oil, and the administration volume is 10mL/kg. Animals were randomized into groups of 10 animals each after 12h of fasted prior to the experiment, and 0.05ml of 1% carrageenan (sterile saline) was administered to the sole of the rat after 1h of oral administration. The pre-and post-inflammatory 15min,30min,1h,2h,3h,4h,5h,6h post-plantar volumes were measured and the extent of swelling was observed to reach peak time and fade time, taking the difference in pre-and post-inflammatory plantar thickness as the extent of swelling. Each set of data was t-checked and the significance of the differences between the sets was compared. Swelling degree = inflammatory hind foot thickness-inflammatory forefoot thickness, inhibition ratio = (blank swelling degree-experimental swelling degree)/blank swelling degree.
The results of the in vivo anti-inflammatory activity verification of the compounds prepared by the invention are shown in table 5:
TABLE 5 anti-inflammatory Activity in oral drug bodies
As can be seen from Table 5, the quinoline compounds prepared according to the present invention have a superior oral anti-inflammatory activity. The dose-effect experiment shows that the compound has a wider medicinal effect range (1-20 mg/kg is effective), and has the effects of good in vivo oral anti-inflammatory activity, quick response, high anti-inflammatory activity, long duration and the like.
Test example 3
The technical effects and advantages of the present invention are verified by the following application of the compound C17 of the present invention in inhibiting ranpirin-induced acute pancreatitis in mice.
The specific procedure is as follows, CD-1 male mice (33-39 g,8 weeks) were used for the acute pancreatitis experiment. After 3 days of adaptive feeding, the mice were randomly divided into vehicle, model and experimental groups (C17), 8 animals per group. The dosage is 10mg/kg, the medicine is dissolved in 5% DMSO+95% 2-hydroxypropyl-beta-cyclodextrin. Mice were fasted for 6-8 hours prior to the experiment. In the model group and the experimental group, ranpirin (50. Mu.g/kg, 0.05mL,0-5 h) was intraperitoneally injected every one hour for 6 times in total, and used for inducing Acute Pancreatitis (AP), and the vehicle group was injected with an equal volume of physiological saline. Subsequently, 30 minutes and 2.5 hours after the first injection of ranpirin, the model group was intraperitoneally injected with vehicle and the administration group was intraperitoneally injected with the test drug for treating pancreatitis (see fig. 1 and 2).
From pathological changes in HE stained sections of mouse pancreatic tissue, it was observed that inflammatory infiltrates of mouse pancreas were significantly reduced after treatment with compound C17. Further, testing for markers of inflammation in plasma revealed that compound C17 reduced IL-6 and TNF- α levels by 24.6% and 32.7%, respectively. In conclusion, compound C17 significantly reduced the level of inflammation in the pancreas and plasma, prevented the occurrence of subsequent linked systemic inflammatory responses in time, and prevented further exacerbation of pancreatitis.
Test example 4
The technical effects and advantages of the invention are verified by the following application of the compound C17 of the invention in analgesic tests in the acetic acid torsion inhibition experiments.
The method comprises the following specific steps:
The analgesia experiments were performed using BALB/c male mice (6-8 weeks old, weighing approximately 23-25 g). Mice were randomly divided into model, experimental and positive control groups of 8 mice each. The oral administration dose of the mice was set to 20mg/kg, the administration volume was 10mL/kg, and the administration solvent was 5% dimethyl sulfoxide+95% 2-hydroxypropyl-beta-cyclodextrin (0.2 g/mL). Mice were fasted for 12 hours prior to the experiment, and at the beginning of the experiment, the mice of the experimental group and the control group were orally dosed with the drug, and the mice of the model group were orally dosed with the solvent only. 1h after administration, acetic acid solution (0.6% v/v, 0.01 mL/g) was injected intraperitoneally to induce pain. Animals were observed 5 minutes after pain induction and the number of back arches, body extension and hindlimb extension in mice was recorded and counted for 30 minutes. The analgesic effect is shown in figure 3.
According to the experimental result of anti-inflammatory of the foot swelling, compounds C5, C9, C17 and C30 with better anti-inflammatory activity, quick effect and long drug effect time are selected, a mouse acetic acid torsion analgesia experiment is carried out, the positive control drug is celecoxib, and the oral dosage is 20mg/kg. Experimental results show that after the four compounds are orally taken, the frequency of twisting of mice caused by acetic acid is obviously reduced, wherein the analgesic effect of C9 and C17 is particularly remarkable, the frequency of twisting can be reduced by 50 percent (compared with a model group), and the analgesic effect of the compound is comparable to that of celecoxib. The anti-inflammatory and analgesic experiments show that the sEH compound has potential of being developed into anti-inflammatory and analgesic drugs.
In conclusion, the compound prepared by the invention has better sEH inhibitory activity, and the IC 50 value of the individual high-activity compound even reaches below 1nM, which indicates the high-efficiency inhibition effect of the compound on sEH. The in vivo foot swelling anti-inflammatory activity experiment shows that the compound has good in vivo oral anti-inflammatory activity, and has the advantages of quick response, long duration and wide drug effect range after being taken orally, thereby realizing the anti-inflammatory effect by inhibiting sEH. In addition, the compound also shows good anti-inflammatory and analgesic activity in a mouse acute pancreatitis model and an acetic acid torsion model, and has good application prospect.
The embodiments of the technical solution of the present application have been described above by way of example. It should be understood that the protection scope of the present application is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made by those skilled in the art within the spirit and principles of the present application should be included in the scope of the present application as defined in the appended claims.

Claims (10)

1.式(I)所示的化合物、其互变异构体、立体异构体、同位素标记物、水合物、溶剂化物、药学上可接受的盐或前药：1. The compound represented by formula (I), its tautomers, stereoisomers, isotopic labels, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs: 其中，环B选自5-6元杂环、5-6元杂芳环；Among them, ring B is selected from 5-6 membered heterocyclic rings and 5-6 membered heteroaromatic rings; R1选自无取代或任选被一个、两个或更多个R11取代的下列基团：C1-10烷基、3-14元杂环基、C6-14芳基、5-14元杂芳基；每个R11相同或不同，彼此独立地选自H、无取代或任选被一个、两个或更多个R12取代的下列基团：C1-10烷氧基、C3-10环烷基、C1-10烷基-C(＝O)-、3-14元杂环基、C6-14芳基、5-14元杂芳基；每个R12相同或不同，彼此独立地选自H、CN、卤素、无取代或任选被一个、两个或更多个R13取代的下列基团：C1-10烷基、C1-10烷氧基、C1-10烷基-C(＝O)-、C1-10烷氧基-C(＝O)-、C3-10环烷基-C(＝O)-、C1-10烷基-S(＝O)2-、H2N-S(＝O)2-；每个R13相同或不同，彼此独立地选自H、卤素、C1-10烷基、C1-10烷氧基、C6-14芳基； R1 is selected from the following groups that are unsubstituted or optionally substituted with one, two or more R11s : C1-10 alkyl, 3-14 heterocyclic, C6-14 aryl, 5-14 heteroaryl; each R11 may be the same or different and is independently selected from H, unsubstituted or optionally substituted with one, two or more R12s : C1-10 alkoxy, C3-10 cycloalkyl, C1-10 alkyl-C(=O)-, 3-14 heterocyclic, C6-14 aryl, 5-14 heteroaryl; each R12 may be the same or different and is independently selected from H, CN, halogen, unsubstituted or optionally substituted with one, two or more R13s : C1-10 alkyl, C1-10 alkoxy, C1-10 alkyl-C(=O)-, C1-10 alkoxy-C(=O)-, C 3-10 cycloalkyl-C(=O)-, C1-10 alkyl-S(=O) 2- , H2NS (=O) 2- ; each R13 may be the same or different, and is independently selected from H, halogen, C1-10 alkyl, C1-10 alkoxy, C6-14 aryl; 每个R2相同或不同，彼此独立地选自H、C1-10烷基、C1-10烷氧基；Each R2 may be the same or different, and is independently selected from H, C1-10 alkyl, and C1-10 alkoxy. 每个R3相同或不同，彼此独立地选自H、CN、无取代或任选被一个、两个或更多个R31取代的下列基团：氨基、C1-10烷基、C1-10烷氧基、3-14元杂环基、C1-10烷基-S(＝O)2-、H2N-S(＝O)2-、C1-10烷基-C(O)NH-；每个R31相同或不同，彼此独立地选自H、卤素、氧代(＝O)、C1-10烷基、C1-10烷氧基、-NH(C1-10烷基)、N(C1-10烷基)(C1-10烷基)、5-14元杂芳基、卤代5-14元杂芳基；Each R 3 may be the same or different, and is independently selected from H, CN, unsubstituted or optionally substituted by one, two or more R 31 groups of the following groups: amino, C1-10 alkyl, C1-10 alkoxy, 3-14 membered heterocyclic, C1-10 alkyl-S(=O) 2- , H2NS (=O) 2- , C1-10 alkyl-C(O)NH-; each R 31 may be the same or different, and is independently selected from H, halogen, oxo(=O), C1-10 alkyl, C1-10 alkoxy, -NH( C1-10 alkyl), N( C1-10 alkyl)( C1-10 alkyl), 5-14 membered heteroaryl, halo-5-14 membered heteroaryl; 或者，两个相邻的R3与其各自连接的原子形成无取代或任选被一个、两个或更多个R32取代的3-14元杂环基；每个R32相同或不同，彼此独立地选自H、C1-10烷基、C1-10烷氧基；Alternatively, two adjacent R 3 and the atoms they are attached to form a 3-14 membered heterocyclic group that is unsubstituted or optionally substituted by one, two or more R 32 ; each R 32 may be the same or different and is independently selected from H, C 1-10 alkyl, C 1-10 alkoxy; 每个Rb相同或不同，彼此独立地选自H、C1-10烷基、C1-10烷氧基；Each Rb may be the same or different, and is independently selected from H, C1-10 alkyl, and C1-10 alkoxy groups; m选自0、1、2或3；m is selected from 0, 1, 2, or 3; n选自0、1、2、3、4或5；n is selected from 0, 1, 2, 3, 4 or 5; p选自0、1或2。p is selected from 0, 1, or 2. 2.根据权利要求1所述式(I)所示的化合物、其互变异构体、立体异构体、同位素标记物、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，环B选自5元含氮杂环、5元含氮杂芳环、6元含氮杂环、6元含氮杂芳环；2. The compound represented by formula (I) according to claim 1, its tautomers, stereoisomers, isotope labels, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, characterized in that ring B is selected from 5-membered nitrogen-containing heterocycles, 5-membered nitrogen-containing heteroaromatic rings, 6-membered nitrogen-containing heterocycles, and 6-membered nitrogen-containing heteroaromatic rings. 优选地，环B选自咪唑环、吡咯环、吡啶环或哌啶环；Preferably, ring B is selected from imidazole ring, pyrrole ring, pyridine ring or piperidine ring; 优选地，选自 Preferably, Selected from 优选地，选自 Preferably, Selected from 3.根据权利要求1或2所述式(I)所示的化合物、其互变异构体、立体异构体、同位素标记物、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，R1选自无取代或任选被一个、两个或更多个R11取代的下列基团：C1-6烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基；每个R11相同或不同，彼此独立地选自H、无取代或任选被一个、两个或更多个R12取代的下列基团：C1-6烷氧基、C3-8环烷基、C1-6烷基-C(＝O)-、3-8元杂环基、C6-10芳基、5-10元杂芳基；每个R12相同或不同，彼此独立地选自H、CN、卤素、无取代或任选被一个、两个或更多个R13取代的下列基团：C1-6烷基、C1-6烷氧基、C1-6烷基-C(＝O)-、C1-6烷氧基-C(＝O)-、C3-8环烷基-C(＝O)-、C1-6烷基-S(＝O)2-、H2N-S(＝O)2-；每个R13相同或不同，彼此独立地选自H、卤素、C1-6烷基、C1-6烷氧基、C6-10芳基；3. The compound of formula (I) according to claim 1 or 2, its tautomers, stereoisomers, isotopic labels, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, characterized in that R1 is selected from unsubstituted or optionally substituted by one, two, or more R11 groups: C1-6 alkyl, 3-8 heterocyclic, C6-10 aryl, 5-10 heteroaryl; each R11 may be the same or different, and is independently selected from H, unsubstituted or optionally substituted by one, two, or more R12 groups: C1-6 alkoxy, C3-8 cycloalkyl, C1-6 alkyl-C(=O)-, 3-8 heterocyclic, C6-10 aryl, 5-10 heteroaryl; each R12 may be the same or different, and is independently selected from H, CN, halogen, unsubstituted or optionally substituted by one, two, or more R13 groups: C1-6 alkyl, C3-8 cycloalkyl, C6-10 alkyl, 5-10 heteroaryl; each R12 may be the same or different, and is independently selected from H, CN, halogen, unsubstituted or optionally substituted by one, two, or more R13 groups: C1-6 alkyl, C3-8 cycloalkyl, C6-10 ... 1-6 alkoxy, C1-6 alkyl-C(=O)-, C1-6 alkoxy-C(=O)-, C3-8 cycloalkyl-C(=O)-, C1-6 alkyl-S(=O) 2- , H2NS (=O) 2- ; each R13 may be the same or different, and is independently selected from H, halogen, C1-6 alkyl, C1-6 alkoxy, C6-10 aryl; 优选地，R1选自无取代或任选被一个、两个或更多个R11取代的下列基团：C1-6烷基、3-8元杂环基、C6-10芳基；每个R11相同或不同，彼此独立地选自H、C1-6烷基-C(＝O)-、卤代C1-6烷氧基、无取代或任选被一个、两个或更多个R12取代的下列基团：C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基；每个R12相同或不同，彼此独立地选自H、CN、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷基-C(＝O)-、卤代C1-6烷基-C(＝O)-、C1-6烷氧基-C(＝O)-、C6-10芳基-C1-6烷氧基-C(＝O)-、C3-8环烷基-C(＝O)-、C1-6烷基-S(＝O)2-、H2N-S(＝O)2-；Preferably, R1 is selected from the following groups that are unsubstituted or optionally substituted by one, two or more R11s : C1-6 alkyl, 3-8 membered heterocyclic, C6-10 aryl; each R11 may be the same or different and is independently selected from H, C1-6 alkyl-C(=O)-, halo- C1-6 alkoxy, and the following groups that are unsubstituted or optionally substituted by one, two or more R12s : C3-8 cycloalkyl, 3-8 membered heterocyclic, C6-10 aryl, 5-10 membered heteroaryl; each R12 may be the same or different and is independently selected from H, CN, halogen, C1-6 alkyl, C1-6 alkoxy, halo- C1-6 alkoxy, C1-6 alkyl-C(=O)-, halo- C1-6 alkyl-C(=O)-, C1-6 alkoxy-C(=O)-, C6-10 aryl-C 1-6 alkoxy-C(＝O)-, C3-8 cycloalkyl-C(＝O)-, C1-6 alkyl-S(＝O) 2- , H2NS (＝O) 2- ; 优选地，R1选自-CH2-R11；Preferably, R1 is selected from -CH2 - R11 ; 优选地，每个R11相同或不同，彼此独立地选自三氟甲氧基、无取代或任选被一个、两个或更多个R12取代的下列基团：四氢呋喃基、四氢吡喃基、环己基、哌啶基、苯基；Preferably, each R 11 may be the same or different, and is independently selected from trifluoromethoxy, The following groups are unsubstituted or optionally substituted with one, two or more R12 groups: tetrahydrofuranyl, tetrahydropyranyl, cyclohexyl, piperidinyl, phenyl; 优选地，每个R11相同或不同，彼此独立地选自 Preferably, each R 11 may be the same or different, and is selected independently from each other. 优选地，每个R12相同或不同，彼此独立地选自H、CN、甲氧基、-C(O)OCH3、苄氧羰基、三氟甲氧基、二氟甲氧基、三氟甲基、甲基磺酰基、氨基磺酰基、 Preferably, each R 12 may be the same or different, and is independently selected from H, CN, methoxy, -C(O)OCH 3 , benzyloxycarbonyl, trifluoromethoxy, difluoromethoxy, trifluoromethyl, methylsulfonyl, aminosulfonyl, etc. 优选地，R1选自C1-6烷基、5-6元杂环基-C1-3烷基、C1-6烷基-C(＝O)-哌啶基、卤代C1-3烷氧基苯基、C1-3烷氧基-C(＝O)-环己基-C1-3烷基、C1-3烷基-C(＝O)-哌啶基-C1-3烷基、卤代C1-3烷基-C(＝O)-哌啶基-C1-3烷基、C3-6环烷基-C(＝O)-哌啶基-C1-3烷基、苯基C1-3烷基-C(＝O)-哌啶基-C1-3烷基、C1-3烷氧基苯基C1-3烷基、卤代C1-3烷氧基苯基C1-3烷基、卤代C1-3烷基苯基C1-3烷基、氰基苯基C1-3烷基、H2N-S(O)2-苯基C1-3烷基、C1-3烷基-S(O)2-苯基C1-3烷基、吡啶基C1-3烷基；Preferably, R1 is selected from C1-6 alkyl, 5-6 membered heterocyclic- C1-3 alkyl, C1-6 alkyl-C(=O)-piperidinyl, halo- C1-3 alkoxyphenyl, C1-3 alkoxy-C(=O)-cyclohexyl- C1-3 alkyl, C1-3 alkyl-C(=O)-piperidinyl- C1-3 alkyl, halo-C1-3 alkyl -C(=O)-piperidinyl- C1-3 alkyl, C3-6 cycloalkyl-C(=O)-piperidinyl- C1-3 alkyl, phenyl- C1-3 alkyl-C(=O)-piperidinyl- C1-3 alkyl, C1-3 alkoxyphenyl- C1-3 alkyl, halo- C1-3 alkoxyphenyl- C1-3 alkyl, halo- C1-3 alkylphenyl- C1-3 alkyl, cyanophenyl- C1-3 alkyl, H2 NS(O) 2 -phenyl C1-3alkyl , C1-3alkyl -S(O) 2 -phenyl C1-3alkyl , pyridyl C1-3alkyl ; 优选地，R1选自 Preferably, R1 is selected from 4.根据权利要求1-3任一项所述式(I)所示的化合物、其互变异构体、立体异构体、同位素标记物、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，每个R2相同或不同，彼此独立地选自彼此独立地选自H、C1-6烷基、C1-6烷氧基。4. The compound of formula (I) according to any one of claims 1-3, its tautomers, stereoisomers, isotopic labels, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, characterized in that each R2 is the same or different and is independently selected from each other from H, C1-6 alkyl, C1-6 alkoxy. 5.根据权利要求1-4任一项所述式(I)所示的化合物、其互变异构体、立体异构体、同位素标记物、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，每个R3相同或不同，彼此独立地选自H、CN、无取代或任选被一个、两个或更多个R31取代的下列基团：氨基、C1-6烷基、C1-6烷氧基、3-8元杂环基、C1-6烷基-S(＝O)2-、H2N-S(＝O)2-、C1-6烷基-C(O)NH-；每个R31相同或不同，彼此独立地选自H、卤素、氧代(＝O)、C1-6烷基、C1-6烷氧基、-NH(C1-6烷基)、N(C1-6烷基)(C1-6烷基)、5-10元杂芳基、卤代5-10元杂芳基；5. The compound of formula (I) according to any one of claims 1-4, its tautomers, stereoisomers, isotopic labels, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, characterized in that each R3 is the same or different, and is independently selected from H, CN, unsubstituted or optionally substituted by one, two or more R31 groups: amino, C1-6 alkyl, C1-6 alkoxy, 3-8 membered heterocyclic, C1-6 alkyl-S(=O) 2- , H2NS (=O) 2- , C1-6 alkyl-C(O)NH-; each R31 is the same or different, and is independently selected from H, halogen, oxo(=O), C1-6 alkyl, C1-6 alkoxy, -NH( C1-6 alkyl), N( C1-6 alkyl)( C1-6 alkyl), 5-10 membered heteroaryl, halogenated 5-10 membered heteroaryl; 或者，两个相邻的R3与其各自连接的原子形成无取代或任选被一个、两个或更多个R32取代的3-8元杂环基；每个R32相同或不同，彼此独立地选自H、C1-6烷基、C1-6烷氧基；Alternatively, two adjacent R 3s and their respective attached atoms form a 3-8 membered heterocyclic group that is unsubstituted or optionally substituted by one, two or more R 32s ; each R 32 may be the same or different and is independently selected from H, C 1-6 alkyl, and C 1-6 alkoxy groups; 优选地，每个R31相同或不同，彼此独立地选自H、卤素、氧代(＝O)、C1-3烷基、C1-3烷氧基、-NH(C1-3烷基)、N(C1-3烷基)(C1-3烷基)、吡啶基、卤代吡啶基；Preferably, each R 31 may be the same or different, and is independently selected from H, halogen, oxo (=O), C1-3 alkyl, C1-3 alkoxy, -NH ( C1-3 alkyl), N ( C1-3 alkyl)( C1-3 alkyl), pyridinyl, and halopyridinyl; 优选地，每个R3相同或不同，彼此独立地选自H、CN、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6烷基-C(O)-、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)、-C1-6烷基-NH(C1-6烷基)、-C1-6烷基-N(C1-6烷基)(C1-6烷基)、C1-6烷基-3-8元杂环基、C1-6烷基-S(＝O)2-、H2N-S(＝O)2-、5-10元杂芳基-C1-6烷基-C(O)NH-、卤代5-10元杂芳基-C1-6烷基-C(O)NH-；Preferably, each R3 may be the same or different, and is independently selected from H, CN, C1-6 alkyl, C1-6 alkoxy, halo- C1-6 alkyl, halo- C1-6 alkoxy, C1-6 alkyl-C(O)-, -NH( C1-6 alkyl), -N( C1-6 alkyl)( C1-6 alkyl), -C1-6 alkyl-NH( C1-6 alkyl), -C1-6 alkyl-N( C1-6 alkyl)( C1-6 alkyl), C1-6 alkyl-3-8-membered heterocyclic group, C1-6 alkyl-S(=O) 2- , H2NS (=O) 2- , 5-10-membered heteroaryl- C1-6 alkyl-C(O)NH-, halo-5-10-membered heteroaryl- C1-6 alkyl-C(O)NH-; 或者，两个相邻的R3与其各自连接的原子形成3-8元杂环基；Alternatively, two adjacent R3 atoms and their respective connected atoms form 3-8 membered heterocyclic groups; 优选地，R3选自H、CN、氨基、甲基、甲氧基、三氟甲氧基、乙酰基、二甲氨基、 Preferably, R3 is selected from H, CN, amino, methyl, methoxy, trifluoromethoxy, acetyl, dimethylamino, ... 或者，两个相邻的R3与其各自连接的原子形成 Alternatively, two adjacent R3 atoms and their respective connected atoms form 优选地，选自 Preferably, Selected from 优选地，每个Rb相同或不同，彼此独立地选自彼此独立地选自H、C1-6烷基、C1-6烷氧基。Preferably, each Rb is the same or different and is independently selected from H, C1-6 alkyl, and C1-6 alkoxy. 6.根据权利要求1-5任一项所述式(I)所示的化合物、其互变异构体、立体异构体、同位素标记物、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，式(I)所示的化合物具有如下所示的结构：6. The compound represented by formula (I) according to any one of claims 1-5, its tautomers, stereoisomers, isotopic labels, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, characterized in that the compound represented by formula (I) has the following structure: 其中，R1、R2、R3、Rb、m、n、p彼此独立地具有权利要求1-5任一项所述的定义；Wherein, R1 , R2 , R3 , Rb , m, n, and p independently have the definitions described in any one of claims 1-5; 优选地，式(I)所示的化合物具有如下所示的结构：Preferably, the compound represented by formula (I) has the following structure: 其中，环B、R1、R2、R31、Rb、m、p彼此独立地具有权利要求1-5任一项所述的定义；Among them, rings B, R1 , R2 , R31 , Rb , m, and p independently have the definitions described in any one of claims 1-5; 优选地，式(I)所示的化合物具有如下所示的结构：Preferably, the compound represented by formula (I) has the following structure: 其中，环B、R2、R3、R12、Rb、m、p彼此独立地具有权利要求1-5任一项所述的定义；Among them, rings B, R2 , R3 , R12 , Rb , m, and p independently have the definitions described in any one of claims 1-5; 优选地，式(I)所示的化合物具有如下所示的结构：Preferably, the compound represented by formula (I) has the following structure: 其中，环B、R2、R3、R11、Rb、m、n、p彼此独立地具有权利要求1-5任一项所述的定义；Among them, rings B, R2 , R3 , R11 , Rb , m, n, and p independently have the definitions described in any one of claims 1-5; 优选地，式(I)所示的化合物具有如下所示的结构：Preferably, the compound represented by formula (I) has the following structure: 其中，R3、R12彼此独立地具有上文所述的定义。Among them, R3 and R12 have the definitions described above independently of each other. 7.根据权利要求1-6任一项所述式(I)所示的化合物、其互变异构体、立体异构体、同位素标记物、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，式(I)所示的化合物选自如下结构中的一种：7. The compound represented by formula (I) according to any one of claims 1-6, its tautomers, stereoisomers, isotopic labels, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, characterized in that the compound represented by formula (I) is selected from one of the following structures: 8.权利要求1-7任一项所述式(I)所示的化合物、其互变异构体、立体异构体、同位素标记物、水合物、溶剂化物、药学上可接受的盐或前药的制备方法，所述制备方法包括以下步骤：将如下化合物a与化合物b在羰基二咪唑存在下反应，得到式(I)所示化合物；8. A method for preparing the compound of formula (I) according to any one of claims 1-7, its tautomers, stereoisomers, isotope labels, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, said preparation method comprising the following steps: reacting compound a with compound b in the presence of carbonyl diimidazole to obtain the compound of formula (I); 其中，环B、R1、R2、R3、Rb、m、n、p彼此独立地具有权利要求1-7任一项所述的定义。Among them, rings B, R1 , R2 , R3 , Rb , m, n, and p independently have the definitions described in any one of claims 1-7. 9.一种药物组合物，其中所述药物组合物包含权利要求1-7任一项所述式(I)所示化合物、其互变异构体、立体异构体、同位素标记物、水合物、溶剂化物、药学上可接受的盐或前药。9. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-7, a tautomer, a stereoisomer, an isotope label, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug. 10.权利要求1-7任一项所述式(I)所示的化合物、其互变异构体、立体异构体、同位素标记物、水合物、溶剂化物、药学上可接受的盐或前药，或权利要求9所述药物组合物在制备药物中的用途；10. The use of the compound of formula (I) according to any one of claims 1-7, its tautomers, stereoisomers, isotope labels, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the use of the pharmaceutical composition of claim 9 in the preparation of a medicament; 优选地，所述药物用于治疗与sEH抑制相关的疾病，如用于治疗炎症(如足肿胀炎症、胰腺炎、神经炎症)、镇痛、心肌缺血、纤维化、肾功能衰竭、糖尿病、高血压和心血管疾病。Preferably, the drug is used to treat diseases associated with sEH inhibition, such as inflammation (e.g., foot edema, pancreatitis, neuroinflammation), analgesia, myocardial ischemia, fibrosis, renal failure, diabetes, hypertension, and cardiovascular diseases.
CN202410620234.XA 2024-05-17 2024-05-17 sEH inhibitor compounds, pharmaceutical compositions, their preparation methods and applications Pending CN120965663A (en)

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