CN104774188B - Benzoheterocycles or benzoheteroaromatic derivatives, their preparation method and their application in medicine - Google Patents

Abstract

The present invention relates to benzo-heterocycle or benzo hetero-aromatic ring analog derivative, preparation method and its applications in medicine.Specifically, the present invention relates to benzo-heterocycle shown in a kind of logical formula (I) or benzo hetero-aromatic ring analog derivatives and its officinal salt, preparation method and they as mek inhibitor especially as the purposes of cancer therapeutic agent, definition is the same as that in the specification for each substituent group in formula of (I).Compound provided by the invention has good activity, and shows the effect of excellent anti-tumour cell proliferative.

Description

Benzoheterocycles or benzoheteroaromatic derivatives, their preparation method and their use in medicine application on

technical field

The present invention relates to a novel benzoheterocyclic or benzoheteroaromatic derivative and a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as an MEK inhibitor, especially as a cancer therapy use of the agent.

Background technique

The abnormality of the kinase pathway of MAPKs is closely related to the occurrence of tumors, and has become the preferred target for tumor drug development because it leads to uncontrolled cell proliferation and differentiation block.

Ser/threonine mitogen-activated protein kinases (MAPKs, also known as extracellular signal-regulated kinases, ERKs) are associated with tyrosine kinase receptors (eg, EGF receptors) and/or G protein heterotrimers in cells Activated by factor receptors, it can interact with a variety of intracellular signals stimulated by different second messengers, phosphorylate and regulate the activities of various enzymes and transcription factors (such as NF-κB, Rsk 90, phospholipase A2, c- Myc, CREB, Ets-1, AP-1 and c-jun, etc.). Among the MAPK pathways involved in normal and abnormal cell growth, the Ras/Raf/MEK/Erk kinase pathway is one of the most well-studied and most important pathways. More than a decade ago, scientists discovered that the protein kinase family Erks has a pro-proliferative effect. Subsequent studies quickly identified the MEK family of kinases upstream of Erk, and then found that Raf can activate MEKs. Its upstream Ras is a G protein, and the activated GTP binds to Ras. , which activates Raf indirectly. About 30% of malignant tumor patients have Ras gene mutation, and in pancreatic cancer, the Ras gene mutation rate can reach up to 90%. The mutation rate of B-Raf is as high as 50%-70% in melanoma, 35% in ovarian cancer, 30% in thyroid cancer, and 10% in colon cancer. MEKs can also be activated by a Raf-independent kinase, MEK kinase (also known as MEKK).

MEKs, also known as MAP kinases (MAPKK or Erk kinases), are dual specificity kinases that phosphorylate the serine/threonine residues and tyrosine residues of MAPKs (p44 ^MAPK (Erk 1) and p42 ^MAPK (Erk 2)) The MEK family consists of five genes: MEK1, MEK2, MEK3, MEK4 and MEK5. The N-terminus of MEKs is a negative regulatory region, and the catalytic region of the C-terminus has the function of binding to Erks and activating Erks. It was found that knocking out the regulatory region of MEK1 resulted in the inhibition of the intrinsic activity of MEK1 and Erk.

The molecular weight of MEK1 is about 44kDa, and it contains 393 amino acids. It is mainly expressed in adult tissues, especially brain tissues. A small amount of MEK1 expression can also be detected during embryonic development. MEK1 triggers its activity through phosphorylation at S218 and S222, and it was found that in NIH3T3 cells, replacing these two residues with aspartate or glutamate increased its activity and increased colony formation. Intrinsic activity of MEK1 in primary cell cultures promotes cellular senescence and expression of p53 and p16 ^INK4a , whereas in immortalized cells and cells depleted of p53 or p16 ^INK4a , MEK1 has the opposite effect. MEK2 has a molecular weight of about 45 kDa, shares 79% sequence similarity with MEK1, and its activity is triggered by phosphorylation at S222 and S226. MEK1 and MEK2 have different phosphorylation catalytic activities for different MAPK isoforms, Erk1 and Erk2. MEK3, MEK4 and MEK5 do not exert their effects by acting on Erks.

For the MAPK signaling pathway, a number of compounds that specifically inhibit the activity of Raf and MEK are currently in clinical and marketing stages. Among them, sorafenib (Bay 43-9006), which was launched in 2006, is a non-specific serine/threonine and tyrosine kinase inhibitor, and its targets include Raf, MEK, VEGFR2/3, Flt-3, PDGFR, c -Kit etc. B-Raf specific inhibitors such as dabrafenib (GSK2118436) and vemurafenib (PLX4032) show good clinical effects, but the duration is not long. At the same time, clinical studies have found that most of the symptoms of patients receiving effective treatment with PLX4032 recur, suggesting that Long-term treatment with B-Raf inhibitors can lead to acquired resistance in patients who are no longer sensitive to B-Raf inhibitors. In order to overcome the drug resistance of patients, MEK inhibitors are often used in combination with B-Raf inhibitors. The specific inhibitor of MEK1/2, Trametinib (GSK-1120212), was developed by GSK and is now on the market. Other MEK1/2 inhibitors, Selumetinib (AZD-6244), Pimasertib hydrochloride (AS-703026), TAK-733, etc. have entered In clinical trials, these MEK inhibitors have not published data on their interaction with Erk1 or Erk2.

Currently, a series of patent applications for MEK inhibitors have been disclosed, including WO2007096259, WO2010003022, and WO2012162293, among others.

In order to achieve better tumor treatment effect and better meet market demand, we hope to develop a new generation of high-efficiency and low-toxicity inhibitors targeting MAPKs signaling pathway, especially MEK target inhibitors. The present invention will provide a MEK inhibitor with a novel structure, and it is found that the compound with such a structure has good activity and exhibits excellent anti-tumor cell proliferation effect.

SUMMARY OF THE INVENTION

The object of the present invention is to provide the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

in:

is a single bond or a double bond;

P is selected from O, CR ⁶ or -CR ⁶ R ⁷ -;

R ¹ is selected from hydrogen atom, halogen, cyano, nitro, alkyl or haloalkyl;

R ² , R ³ or R ⁴ are each independently selected from a hydrogen atom, an alkyl group, a halogen, a cyano group, a nitro group, or a haloalkyl group;

R ⁵ is selected from heterocyclyl, heteroaryl, -NHS(O) _m R ⁸ , -C(O)NR ⁹ R ¹⁰ , -C(O)R ¹¹ , -C(O)NHNR ⁹ R ¹⁰ , - C(O)NHNHC(O)R ⁹ , -C(O)NHNHC(O)NR ⁹ R ¹⁰ , -NHC(O)R ⁹ , -NHC(O)OR ⁹ , -NHC(O)NR ⁹ R ¹⁰ , -NHC(O)NR ⁹ OR ¹⁰ or -OC(O)R ⁹ , wherein the heterocyclyl or heteroaryl groups are each independently optionally further selected from one or more groups selected from halogen, cyano, nitro , alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁹ , -C(O)OR ⁹ , -OC(O)R ⁹ , -NHS(O ) _m R ⁹ , -C(O)R ⁹ , -NHC(O)R ⁹ , -NHC(O)OR ⁹ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O) Substituents of NR ⁹ R ¹⁰ are substituted;

R ⁶ or R ⁷ are each independently selected from a hydrogen atom or an alkyl group, wherein the alkyl group is optionally further selected from one or more of alkyl, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclyl , aryl, heteroaryl, carboxylate or carboxylate substituent;

R ^is selected from cycloalkyl, wherein said cycloalkyl is further substituted by alkyl, and said alkyl is optionally further substituted by one or more substituents selected from hydroxy, halogen or alkoxy;

R ⁹ or R ¹⁰ are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, alkoxy group alkynyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently optionally further selected from one or more of alkyl, halogen, hydroxy, hydroxyalkyl, alkoxy, Substituted by substituents of vinyloxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylate or carboxylate;

Alternatively, R ⁹ or R ¹⁰ together with the attached nitrogen atom forms a 5-8 membered heterocyclic group, wherein the heterocyclic group contains one or more N, O or S(O) _m heteroatoms, and the The heterocyclyl group is optionally further selected from one or more groups selected from alkyl, halogen, hydroxy, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid substituted by the substituent of the ester group;

R ¹¹ is selected from hydrogen atom, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group, wherein said alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, Aryl or heteroaryl groups are each independently optionally further selected from one or more groups selected from alkyl, halogen, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy Substituted by the substituent of acid group or carboxylate group;

m is 0, 1 or 2; and

n is 0 or 1.

In a preferred embodiment of the present invention, a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer isomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, non-pair Enantiomers or mixtures thereof, or pharmaceutically acceptable salts thereof:

in: The definitions of P, R ¹ to R ³ and R ⁵ are as described in the general formula (I).

In a preferred embodiment of the present invention, a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer isomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (III) or its tautomer, meso, racemate, enantiomer, non-pair Enantiomers or mixtures thereof, or pharmaceutically acceptable salts thereof:

Wherein: the definitions of R ¹ to R ³ and R ⁵ are as described in the general formula (I).

In a preferred embodiment of the present invention, a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer isomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (IV) or its tautomer, meso, racemate, enantiomer, non-pair Enantiomers or mixtures thereof, or pharmaceutically acceptable salts thereof:

in: The definitions of n, P, R ¹ to R ³ and R ¹¹ are as described in the general formula (I).

In a preferred embodiment of the present invention, a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer isomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (V) or its tautomer, meso, racemate, enantiomer, non-pair Enantiomers or mixtures thereof, or pharmaceutically acceptable salts thereof:

Wherein: the definitions of R ¹ to R ³ and R ¹¹ are as described in the general formula (I).

In a preferred embodiment of the present invention, a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer form or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from halogen, preferably F or Cl.

In a preferred embodiment of the present invention, a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² or R ³ is selected from halogen, R ² is preferably Br or I, and R ³ is preferably F or Cl.

In a preferred embodiment of the present invention, a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer form or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ^R4 is selected from hydrogen atoms.

In a preferred embodiment of the present invention, a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from heteroaryl, wherein said heteroaryl is optionally further substituted by halogen, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl , cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁹ , -C(O)OR ⁹ , -OC(O)R ⁹ , -NHS(O) _m R ⁹ , -C(O) R ⁹ , -NHC(O)R ⁹ , -NHC(O)OR ⁹ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ substituents, It is preferably -NR ⁹ R ¹⁰ , wherein m, R ⁹ to R ¹⁰ are as defined in the general formula (I).

In a preferred embodiment of the present invention, a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer form or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is -C(O)NR ⁹ R ¹⁰ , wherein the definitions of R ⁹ to R ¹⁰ are as described in the general formula (I).

In a preferred embodiment of the present invention, a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer form or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁹ is selected from a hydrogen atom; R ¹⁰ is selected from an alkoxy group, wherein the alkoxy group is optionally further represented by one or two hydroxyl groups or cycloalkyl groups replace.

Typical compounds of the present invention include, but are not limited to:

or a tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound represented by the general formula (IA) or a tautomer, meso, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

in:

PG is selected from -NR ⁹ R ¹⁰ , -C(O)R ^d , -OH or -S(O) _m R ^d ;

R ^d is selected from hydroxy or halogen; and

The definitions of m, n, P, R ¹ to R ⁴ , R ⁹ and R ¹⁰ are as described in the general formula (I).

Typical compounds of general formula (IA) of the present invention include, but are not limited to:

or a tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof.

The present invention also provides a preparation of the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof , or a method of a pharmaceutically acceptable salt thereof, the method comprising:

The compound of the general formula (IA) is reacted with the compound of the formula G or its salt, and optionally further deprotected, hydroxylated or cyclized to obtain the compound of the general formula (I);

in:

PG is selected from -NR ⁹ R ¹⁰ , -C(O)R ^d , hydroxyl or -S(O) _m R ^d ;

Compound G is selected from heterocyclic compounds, heteroaromatic compounds, acid halides, sulfonyl halides, hydrazines, amines or alcohol compounds;

R ^d is selected from hydroxyl or halogen;

Preferably, when PG is selected from -NR ⁹ R ¹⁰ or hydroxyl, compound G is selected from acid halides, sulfonyl halides;

When PG is selected from -C(O)R ^d or -S(O) _m R ^d , compound G is selected from heterocyclic compounds, heteroaromatic compounds, hydrazines, amines or alcohol compounds;

The definitions of m, n, P, R ¹ to R ⁵ , R ⁹ and R ¹⁰ are as described in the general formula (I);

The protecting group of hydroxyl is preferably isopropylidene or vinyl;

The protecting group of the amino group is preferably tert-butoxycarbonyl;

The bishydroxylation reagent is preferably osmium tetroxide.

The present invention also provides a compound represented by the general formula (IIA) or a tautomer, meso, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

in:

PG is selected from -NR ⁹ R ¹⁰ , -C(O)R ^d , hydroxyl or -S(O) _m R ^d ;

R ^d is selected from hydroxyl or halogen;

and m, R ¹ to R ³ , R ⁹ and R ¹⁰ are as defined in the general formula (I).

The present invention also provides a compound represented by the general formula (II) or a tautomer, meso, racemate, enantiomer, diastereomer or a mixture thereof, Or a synthetic method of a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (IIA) is reacted with compound G or its salt, and optionally further deprotected, hydroxylated or cyclized to obtain the compound of general formula (II);

in:

PG is selected from -NR ⁹ R ¹⁰ , -C(O)R ^d , hydroxyl or -S(O) _m R ^d ;

Compound G is selected from heterocyclic compounds, heteroaromatic compounds, acid halides, sulfonyl halides, hydrazines, amines or alcohol compounds;

R ^d is selected from hydroxyl or halogen;

Preferably, when PG is selected from -NR ⁹ R ¹⁰ or hydroxyl, compound G is selected from acid halides, sulfonyl halides;

When PG is selected from -C(O)R ^d or -S(O) _m R ^d , compound G is selected from heterocyclic compounds, heteroaromatic compounds, hydrazines, amines or alcohol compounds;

The definitions of m, P, R ¹ to R ³ , R ⁵ and R ⁹ to R ¹⁰ are as described in the general formula (I);

The protecting group of hydroxyl is preferably isopropylidene or vinyl;

The protecting group of the amino group is preferably tert-butoxycarbonyl;

The bishydroxylation reagent is preferably osmium tetroxide.

The present invention also provides a compound represented by the general formula (IIIA) or a tautomer, meso, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

in:

PG is selected from -NR ⁹ R ¹⁰ , -C(O)R ^d , hydroxyl or -S(O) _m R ^d ;

R ^d is selected from hydroxy or halogen; and

m, R ¹ to R ³ , R ⁹ and R ¹⁰ are as defined in the general formula (I).

The present invention also provides a compound represented by the general formula (III) or a tautomer, meso, racemate, enantiomer, diastereomer or a mixture thereof, Or a synthetic method of a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (IIIA) is reacted with compound G or its salt, and optionally further deprotected, hydroxylated or cyclized to obtain the compound of general formula (III);

in:

PG is selected from -NR ⁹ R ¹⁰ , -C(O)R ^d , hydroxyl or -S(O) _m R ^d ;

Compound G includes but is not limited to heterocyclic compounds, heteroaromatic compounds, acid halides, sulfonyl halides, hydrazine, amine or alcohol compounds;

R ^d is selected from hydroxyl or halogen;

Preferably, when PG is selected from -NR ⁹ R ¹⁰ or hydroxyl, compound G is selected from acid halides, sulfonyl halides;

When PG is selected from -C(O)R ^d or -S(O) _m R ^d , compound G is selected from heterocyclic compounds, heteroaromatic compounds, hydrazines, amines or alcohol compounds;

m, R ¹ to R ³ , R ⁵ and R ⁹ to R ¹⁰ are defined as described in the general formula (I);

The protecting group of hydroxyl is preferably isopropylidene or vinyl;

The protecting group of the amino group is preferably tert-butoxycarbonyl;

The bishydroxylation reagent is preferably osmium tetroxide.

The present invention also provides a compound represented by the general formula (IVA) or a tautomer, meso, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

in: The definitions of n, P, R ¹ to R ³ and R ¹¹ are as described in claim 1 .

The present invention also provides a preparation of the compound represented by the general formula (IV) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof , or a method of a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (IVA) is reacted with compound G or its salt, and optionally further deprotected, hydroxylated or cyclized to obtain the compound of general formula (IV);

in:

Compound G is preferably a heterocyclic compound, a heteroaromatic compound, a hydrazine, an amine or an alcohol compound;

R ^d is selected from hydroxyl or halogen;

The definitions of n, P, R ¹ to R ³ and R ¹¹ are as described in the general formula (I);

The protecting group of hydroxyl is preferably isopropylidene or vinyl;

The protecting group of the amino group is preferably tert-butoxycarbonyl;

The bishydroxylation reagent is preferably osmium tetroxide.

The present invention also provides a compound represented by the general formula (VA) or a tautomer, meso, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein: R ¹ to R ³ are as defined in the general formula (I); and

R ^d is selected from hydroxy or halogen.

The present invention also provides a preparation of the compound represented by the general formula (V) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof , or a method of a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (VA) is reacted with compound G or its salt, and optionally further deprotected, hydroxylated or cyclized to obtain the compound of general formula (V);

in:

Compound G is preferably a heterocyclic compound, a heteroaromatic compound, a hydrazine, an amine or an alcohol compound;

R ^d is selected from hydroxyl or halogen;

The definitions of R ¹ to R ³ and R ¹¹ are as described in the general formula (I);

The protecting group of hydroxyl is preferably isopropylidene or vinyl;

The protecting group of the amino group is preferably tert-butoxycarbonyl;

The bishydroxylation reagent is preferably osmium tetroxide.

The present invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by the general formula (I) of the present invention or its tautomer, meso, racemate and enantiomer , a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present invention further relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting MEK.

The present invention further relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment of an inflammatory disorder, an autoimmune disease, a cardiovascular disorder, a proliferative disease or a nociceptive disorder, wherein the proliferative disease may be is cancer (as defined below).

The present invention further relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment of cancer, wherein the cancer is selected from the group consisting of melanoma, brain tumor (astroglial with malignant and oligodendroglioma) glioma, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, primary or metastatic squamous cell carcinoma etc.), kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer (cervical cancer, Endometrial cancer, etc.), head and neck tumors (maxillary cancer, laryngeal cancer, pharyngeal cancer, tongue cancer, intraoral cancer, etc.), multiple myeloma, malignant lymphoma (reticular cell sarcoma, lymphosarcoma, Hodgkin lymphoma, etc.) etc.), polycythemia vera, leukemia (acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, etc.), thyroid tumors, ureteral tumors, bladder tumors, gallbladder cancer, cholangiocarcinoma, chorionic epithelium Cancer or pediatric tumors (Ewing familial sarcoma, Wilms sarcoma, rhabdomyosarcoma, hemangiosarcoma, embryonic testicular cancer, neuroblastoma, retinoblastoma, hepatoblastoma, Wilms tumor, etc.), etc.

The present invention further relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment of cancer, wherein the cancer is preferably colorectal cancer or lung cancer.

The present invention further relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the preparation of a medicament for the treatment of cancer, wherein the medicament is further used in combination with another one or more anticancer agents selected from alkylating agents Agents (cyclophosphamide, ifosfamide, melphalan, busulfan, nimustine, ramustine, dacarbazine, temozolomide, nitrogen mustard hydrochloride, dibromomannitol, etc.), platinum complexing agents (cisplatin, carboplatin, oxaliplatin, etc.), metabolic antagonists (methotrexate, 5-fluorouracil, tegafur, gemcitabine, capecitabine, fulvestrant, pemetrexed, etc.), Plant alkaloids (vincristine, vinblastine, vindesine, etoposide, docetaxel, paclitaxel, irinotecan, vinorelbine, mitoxantrone, vinflunine, topotecan, etc.), hormones Anticancer agents (leuprolide, goserelin, exemestane, letrozole, anastrozole, dutasteride, etc.), antibody drugs (trastuzumab, pertuzumab, rituximab) ciximab, cetuximab, panitumumab, bevacizumab, etc.), VEGFR or EGFR inhibitors (sunitinib, sorafenib, imatinib, gefitinib, errol) tinib, vandetanib, pazopanib, lapatinib, etc.), mTOR inhibitors (everolimus, sirolimus, zotarolimus, etc.), PI3K kinase inhibitors (BKM-120, XL-147, BEZ-235, etc.), B-Raf inhibitors (vemurafenib, GSK-2118436, etc.) or AKT inhibitors (perifoxine, MK-2206, etc.), etc.

The present invention also relates to a method for inhibiting MEK activity, which comprises administering to a patient in need a therapeutically effective amount of the compound represented by the general formula (I) or its tautomer, meso, racemate, para- Enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same.

In other words, the present invention relates to a method of treating an inflammatory disorder, an autoimmune disease, a cardiovascular disorder, a proliferative disease or a nociceptive disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) A compound or a tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same , wherein the proliferative disease may be cancer (as defined below).

The present invention further relates to a method of treating cancer, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer Isomers, diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the cancer is selected from the group consisting of melanoma, brain tumor (with malignant astroglial and oligodendroglioma component glioma, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, primary or metastatic squamous carcinoma, etc.), kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor , uterine cancer (cervical cancer, endometrial cancer, etc.), head and neck tumors (maxillary cancer, laryngeal cancer, pharyngeal cancer, tongue cancer, intraoral cancer, etc.), multiple myeloma, malignant lymphoma (reticular cell sarcoma, Lymphosarcoma, Hodgkin lymphoma, etc.), polycythemia vera, leukemia (acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, etc.), thyroid tumor, ureteral tumor, bladder tumor, gallbladder carcinoma, cholangiocarcinoma, choriocarcinoma, or pediatric tumor (Ewing familial sarcoma, Wilms sarcoma, rhabdomyosarcoma, angiosarcoma, embryonal testicular carcinoma, neuroblastoma, retinoblastoma, hepatoblastoma, renal blastoma, etc.) etc.

The present invention also relates to a method for treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, and one or more additional anticancer agents selected from alkylating agents (cyclophosphamide, ifosfamide, melphalan, busulfan, nimustine, ramustine, dacarbazine, temozolomide, nitrogen mustard hydrochloride, dibromomannitol, etc.), platinum complexing agents ( Cisplatin, carboplatin, oxaliplatin, etc.), metabolic antagonists (methotrexate, 5-fluorouracil, tegafur, gemcitabine, capecitabine, fulvestrant, pemetrexed, etc.), plants Alkaloids (vincristine, vinblastine, vindesine, etoposide, docetaxel, paclitaxel, irinotecan, vinorelbine, mitoxantrone, vinflunine, topotecan, etc.), hormone resistance Cancer agents (leuprolide, goserelin, exemestane, letrozole, anastrozole, dutasteride, etc.), antibody drugs (trastuzumab, pertuzumab, rituximab) mAb, cetuximab, panitumumab, bevacizumab, etc.), VEGFR or EGFR inhibitors (sunitinib, sorafenib, imatinib, gefitinib, erlotinib) Acetaminophen, vandetanib, pazopanib, lapatinib, etc.), mTOR inhibitors (everolimus, sirolimus, zotarolimus, etc.), PI3K kinase inhibitors (BKM-120, XL -147, BEZ-235, etc.), B-Raf inhibitors (vemurafenib, GSK-2118436, etc.) or AKT inhibitors (perifoxine, MK-2206, etc.), etc.

The present invention also relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer and diastereomer as a drug for inhibiting MEK activity or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present invention also relates to a compound of general formula (I) or a tautomer, meso isomer thereof, as a medicament for the treatment of inflammatory disorders, autoimmune diseases, cardiovascular disorders, proliferative diseases or nociceptive disorders body, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the proliferative disease may be cancer ( as defined below).

The present invention further relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or tautomer, meso, racemate, enantiomer, or A mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the cancer is selected from the group consisting of melanoma, brain tumor (nerve with malignant astroglial and oligodendroglioma components); glioma, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, primary or metastatic squamous cell carcinoma, etc.), Kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer (cervical cancer, endometrial cancer cancer, etc.), head and neck tumors (maxillary cancer, laryngeal cancer, pharyngeal cancer, tongue cancer, intraoral cancer, etc.), multiple myeloma, malignant lymphoma (reticular cell sarcoma, lymphosarcoma, Hodgkin lymphoma, etc.), Polycythemia vera, leukemia (acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, etc.), thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, cholangiocarcinoma, choriocarcinoma or pediatric Tumors (Ewing familial sarcoma, Wilms sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testicular cancer, neuroblastoma, retinoblastoma, hepatoblastoma, Wilms tumor, etc.), etc.

The present invention also relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or tautomer, meso, racemate, enantiomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, and another one or more anticancer agents selected from the group consisting of alkylating agents (cyclophosphamide, ifosfamide, Melphalan, busulfan, nimustine, ramustine, dacarbazine, temozolomide, nitrogen mustard hydrochloride, dibromomannitol, etc.), platinum complexing agents (cisplatin, carboplatin, oxaliplatin etc.), metabolic antagonists (methotrexate, 5-fluorouracil, tegafur, gemcitabine, capecitabine, fulvestrant, pemetrexed, etc.), plant alkaloids (vincristine, vinblastine, Vindesine, etoposide, docetaxel, paclitaxel, irinotecan, vinorelbine, mitoxantrone, vinflunine, topotecan, etc.), hormone anticancer agents (leuprolide, gosher, etc.) Relin, exemestane, letrozole, anastrozole, dutasteride, etc.), antibody drugs (trastuzumab, pertuzumab, rituximab, cetuximab, Nituzumab, bevacizumab, etc.), VEGFR or EGFR inhibitors (sunitinib, sorafenib, imatinib, gefitinib, erlotinib, vandetanib, pazopanib Nitrate, lapatinib, etc.), mTOR inhibitors (everolimus, sirolimus, zotarolimus, etc.), PI3K kinase inhibitors (BKM-120, XL-147, BEZ-235, etc.), B -Raf inhibitors (vemurafenib, GSK-2118436, etc.) or AKT inhibitors (perifoxine, MK-2206, etc.) and the like.

Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs. Oral compositions may be prepared according to any method known in the art for the preparation of pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweetening, flavoring, coloring and preservative agents, to provide pleasing and palatable medicinal preparations. Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or acacia and lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time. For example, water soluble taste masking materials such as hydroxypropyl methylcellulose or hydroxypropyl cellulose, or time prolonging materials such as ethyl cellulose, cellulose acetate butyrate can be used.

Hard gelatin capsules are also available wherein the active ingredient is in admixture with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil. Soft gelatin capsules provide an oral preparation.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be naturally occurring phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols such as heptadecaethyleneoxycetyl alcohol (heptadecaethyleneoxy cetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyethylene oxide sorbitan monooleate, or ethylene oxide with fatty acids and hexitol anhydrides Condensation products of partial esters such as polyethylene oxide sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives such as ethyl or n-propyl paraben, one or more coloring agents, one or more flavoring agents and one or more sweetening agents. Flavoring agents such as sucrose, saccharin or aspartame.

Oily suspensions can be formulated by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or mineral oils such as liquid paraffin. The oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The aforementioned sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueous suspension can be provided by the addition of water to provide the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives for mixing. Suitable dispersing or wetting agents and suspending agents are exemplified by those mentioned above. Other excipients such as sweetening, flavouring and colouring agents may also be added. These compositions are preserved by the addition of antioxidants such as ascorbic acid.

The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as olive or peanut oil, or a mineral oil such as liquid paraffin or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids such as soybean lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of said partial esters and ethylene oxide, For example polyethylene oxide sorbitan monooleate. The emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Syrups and elixirs can be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.

The pharmaceutical compositions may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then processed into a mixture of water and glycerol to form a microemulsion. Injections or microemulsions can be injected into a patient's bloodstream by local bolus injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain this constant concentration, a continuous intravenous drug delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.

The pharmaceutical compositions may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can also be used in the preparation of injectables.

The compounds of the present invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.

As is well known to those skilled in the art, the dosage of a drug to be administered depends on a variety of factors, including but not limited to the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the condition of the patient, The patient's diet, administration time, administration mode, rate of excretion, combination of drugs, etc.; in addition, the optimal treatment mode such as the mode of treatment, the daily dosage of the general formula (I) or the type of pharmaceutically acceptable salts It can be verified according to the traditional treatment plan.

Detailed description of the invention

Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.

"Alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms. Preferred are alkyl groups containing 1 to 10 carbon atoms, more preferably alkyl groups containing 1 to 6 carbon atoms, most preferably alkyl groups containing 1 to 4 carbon atoms, and most preferably methyl. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4- Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3- Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof, etc. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl, Alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkane Oxy group, cycloalkylthio, heterocycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxylate, carboxylate, -OR ¹¹ , -C(O)OR ¹¹ , -OC (O)R ¹¹ , -NHS(O) _m R ¹¹ , -C(O)R ¹¹ , -NHC(O)R ¹¹ , -NHC(O)OR ¹¹ , -NR ⁹ R ¹⁰ , -OC(O) NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ .

The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3 -Butenyl, etc. Preferred is _C2-10 alkenyl, more preferred is _C2-6 alkenyl, and most preferred is _C2-4 alkenyl. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxylate, carboxylate, -OR ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , -NHS(O ) _m R ¹¹ , -C(O)R ¹¹ , -NHC(O)R ¹¹ , -NHC(O)OR ¹¹ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O) NR ⁹ R ¹⁰ .

The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, eg ethynyl, 1-propynyl, 2-propynyl, 1-, 2- Or 3-butynyl, etc. A _C2-10 alkynyl group is preferred, a _C2-6 alkynyl group is more preferred, and a _C2-4 alkynyl group is most preferred. Alkynyl groups can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxylate, carboxylate, -OR ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , -NHS(O ) _m R ¹¹ , -C(O)R ¹¹ , -NHC(O)R ¹¹ , -NHC(O)OR ¹¹ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O) NR ⁹ R ¹⁰ .

"Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably the cycloalkyl ring comprising 3 to 10 carbon atoms, most preferably the cycloalkyl ring contains 3 to 6 carbon atoms, most preferably cyclopropyl. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc., preferably cyclopropyl and cyclohexenyl. Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxylate, carboxylate, -OR ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , -NHS ( O) _m R ¹¹ , -C(O)R ¹¹ , -NHC(O)R ¹¹ , -NHC(O)OR ¹¹ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O ) NR ⁹ R ¹⁰ .

"Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen, or S(O) _m ( wherein m is an integer 0 to 2) heteroatoms, excluding ring moieties of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably includes 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, more preferably the heterocyclyl ring contains 3 to 10 ring atoms, more preferably the heterocyclyl ring contains 5 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl, oxazolyl, Isoxazolyl, etc. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls. Heterocyclyl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxylate, carboxylate, -OR ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , -NHS ( O) _m R ¹¹ , -C(O)R ¹¹ , -NHC(O)R ¹¹ , -NHC(O)OR ¹¹ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O ) NR ⁹ R ¹⁰ .

"Aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably a 6- to 10-membered aryl group, More preferred are phenyl and naphthyl, and most preferred is phenyl. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples include:

Aryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkane amino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkane Thio, -OR ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , -NHS(O) _m R ¹¹ , -C(O)R ¹¹ , -NHC(O)R ¹¹ , -NHC (O)OR ¹¹ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ .

"Heteroaryl" refers to a 5- to 14-membered aryl group having 1 to 4 heteroatoms as ring atoms, the remaining ring atoms being carbon, further comprising 1 to 4 heteroatoms, wherein the heteroatoms are selected from one or more Oxygen, Sulfur or Nitrogen. Preferably it is a 5- to 10-membered heteroaryl, more preferably a 5- to 6-membered heteroaryl, even more preferably furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyridyl oxazinyl, imidazolyl, tetrazolyl, oxadiazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples include:

Heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, -OR ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , -NHS(O) _m R ¹¹ , -C(O)R ¹¹ , -NHC(O)R ¹¹ , -NHC(O)OR ¹¹ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ .

"Alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl, cycloalkyl are as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxylate, carboxylate, -OR ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , -NHS(O) _m R ¹¹ , -C(O)R ¹¹ , -NHC(O)R ¹¹ , -NHC(O)OR ¹¹ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ .

"Haloalkyl" means an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

"Hydroxy" refers to the -OH group.

"Hydroxyalkyl" refers to an alkyl group substituted with hydroxy, wherein alkyl is as defined above.

"Halogen" refers to fluorine, chlorine, bromine or iodine.

"Amino" refers to _-NH2 .

"Cyano" refers to -CN.

"Nitro" refers to _-NO2 .

"Oxo" refers to =O.

"Carboxylic acid group" refers to -C(O)OH.

"Carboxylate" means -C(O)O(alkyl) or (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

"Hydroxy protecting group" refers to a molecule containing two or more functional groups in organic synthesis. In order to prevent the hydroxyl from being destroyed by the reaction, a certain reagent is commonly used to protect it first, and then the protecting group is removed after the reaction is completed. Hydroxyl protecting groups include, but are not limited to, methyl, ethyl, isopropylidene, t-butyldiphenylsilyl, t-butyl, benzyl, acetyl, benzoyl, or vinyl.

"Amino protecting group" refers to a molecule containing two or more functional groups in organic synthesis. In order to prevent the amino group from being destroyed by the reaction, a certain reagent is commonly used to protect it first, and then the protecting group is removed after the reaction is completed. Amino protecting groups include, but are not limited to, t-butoxycarbonyl, benzyloxycarbonyl, formyl, or trifluoroacetyl.

"Heterocyclic compound" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon comprising from 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen, or S(O) _m (wherein m is a heteroatom of the integers 0 to 2), excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably it includes 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, more preferably the heterocyclyl ring contains 3 to 10 ring atoms, and more preferably the heterocyclic compound contains 5 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclic compounds include pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, homopiperazine, pyran, tetrahydrofuran, and the like. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls. Heterocyclic compounds can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxylate, carboxylate, -OR ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , -NHS ( O) _m R ¹¹ , -C(O)R ¹¹ , -NHC(O)R ¹¹ , -NHC(O)OR ¹¹ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O ) NR ⁹ R ¹⁰ .

"Heteroaromatic compound" refers to a 5- to 14-membered aromatic ring having 1 to 4 heteroatoms as ring atoms and the remaining ring atoms being carbon, further comprising 1 to 4 heteroatoms, wherein the heteroatoms are selected from one or more oxygen, sulfur or nitrogen. Preferably it is a 5- to 10-membered heteroaromatic ring, more preferably a 5- to 6-membered heteroaromatic ring, even more preferably furan, thiophene, pyridine, pyrrole, N-alkylpyrrole, pyrimidine, pyrazine, imidazole, tetrazole Wait.

"Acyl halide" refers to a compound containing a group -C(O)-halogen;

"Sulfonyl halide" refers to a compound containing a group -S(O) ₂ -halogen;

"Hydrazine" refers to compounds having the structure of R ^9- NHNH-R ¹⁰ ;

"Amines" refer to compounds having the structure of R ⁹ -NH-R ¹⁰ ;

"Alcohols" refer to compounds in which the hydrogen atom in the alkane molecule is replaced by a hydroxyl group, preferably a compound of R ⁹ -OH. The alkane can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or A plurality of the following groups, independently selected from alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl , heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxylate, carboxylate, - OR ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , -NHS(O) _m R ¹¹ , -C(O)R ¹¹ , -NHC(O)R ¹¹ , -NHC(O)OR ¹¹ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ .

"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .

"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

m, R ⁹ to R ¹¹ are as defined in the general formula (I).

The synthetic method of the present invention

In order to complete the synthetic purpose of the present invention, the present invention adopts following synthetic technical scheme:

A preparation of the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or its A method of pharmaceutically acceptable salt, the method comprising:

The compound of the general formula (IA) is reacted with the compound of the formula G or its salt, and optionally further deprotected, hydroxylated or cyclized to obtain the compound of the general formula (I);

in:

PG is selected from -NR ⁹ R ¹⁰ , -C(O)R ^d , -OH or -S(O) _m R ^d ;

Compound G is selected from heterocyclic compounds, heteroaromatic compounds, acid halides, sulfonyl halides, hydrazines, amines or alcohol compounds;

R ^d is selected from hydroxyl or halogen;

Preferably, when PG is selected from -NR ⁹ R ¹⁰ or -OH, compound G is selected from acid halides, sulfonyl halides;

When PG is selected from -C(O)R ^d or -S(O) _m R ^d , compound G is selected from heterocyclic compounds, heteroaromatic compounds, hydrazines, amines or alcohol compounds;

The definitions of m, n, P, R ¹ to R ⁵ and R ⁹ to R ¹⁰ are as described in the general formula (I);

The protecting group of hydroxyl is preferably isopropylidene or vinyl;

The protecting group of the amino group is preferably tert-butoxycarbonyl;

The bishydroxylation reagent is preferably osmium tetroxide.

A preparation of the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer or its mixture form, or its A method of pharmaceutically acceptable salt, the method comprising:

The compound of general formula (IIA) is reacted with compound G or its salt, and optionally further hydrolyzed, hydroxylated or cyclized to obtain the compound of general formula (II);

in:

PG is selected from -NR ⁹ R ¹⁰ , -C(O)R ^d , -OH or -S(O) _m R ^d ;

Compound G is selected from heterocyclic compounds, heteroaromatic compounds, acid halides, sulfonyl halides, hydrazines, amines or alcohol compounds;

R ^d is selected from hydroxyl or halogen;

Preferably, when PG is selected from -NR ⁹ R ¹⁰ or -OH, compound G is selected from acid halides, sulfonyl halides;

When PG is selected from -C(O)R ^d or -S(O) _m R ^d , compound G is selected from heterocyclic compounds, heteroaromatic compounds, hydrazines, amines or alcohol compounds;

The definitions of m, P, R ¹ to R ³ , R ⁵ and R ⁹ to R ¹⁰ are as described in the general formula (I);

The protecting group of hydroxyl is preferably isopropylidene or vinyl;

The protecting group of amino is preferably tert-butoxycarbonyl;

The bishydroxylation reagent is preferably osmium tetroxide.

A preparation of the compound represented by the general formula (III) or its tautomer, meso, racemate, enantiomer, diastereomer or its mixture form, or its A method of pharmaceutically acceptable salt, the method comprising:

The compound of general formula (IIIA) is reacted with compound G or its salt, and optionally further hydrolyzed, hydroxylated or cyclized to obtain the compound of general formula (III);

in:

PG is selected from -NR ⁹ R ¹⁰ , -C(O)R ^d , -OH or -S(O) _m R ^d ;

Compound G includes but is not limited to heterocyclic compounds, heteroaromatic compounds, acid halides, sulfonyl halides, hydrazine, amine or alcohol compounds;

R ^d is selected from hydroxyl or halogen;

Preferably, when PG is selected from -NR ⁹ R ¹⁰ or -OH, compound G is selected from acid halides, sulfonyl halides;

When PG is selected from -C(O)R ^d or -S(O) _m R ^d , compound G is selected from heterocyclic compounds, heteroaromatic compounds, hydrazines, amines or alcohol compounds;

m, R ¹ to R ³ , R ⁵ and R ⁹ to R ¹⁰ are defined as described in the general formula (I);

The protecting group of hydroxyl is preferably isopropylidene or vinyl;

The protecting group of the amino group is preferably tert-butoxycarbonyl;

The bishydroxylation reagent is preferably osmium tetroxide.

A preparation of the compound represented by the general formula (IV) or its tautomer, meso, racemate, enantiomer, diastereomer or its mixture form, or its A method of pharmaceutically acceptable salt, the method comprising:

The compound of general formula (IVa) is oxidized to obtain the compound of general formula (IVb); the compound of general formula (IVb) is reacted with substituted aniline to obtain the compound of general formula (IVA); the compound of general formula (IVA) and compound G or its salt Reaction, optionally further deprotection, hydroxylation or cyclization to obtain the compound of general formula (IV);

in:

Compound G is selected from heterocyclic compounds, heteroaromatic compounds, hydrazine compounds, amine compounds or alcohol compounds;

R ^d is selected from hydroxyl or halogen;

X is selected from halogen;

The definitions of n, P, R ¹ to R ³ and R ¹¹ are as described in the general formula (I);

The protecting group of hydroxyl is preferably isopropylidene or vinyl;

The protecting group of the amino group is preferably tert-butoxycarbonyl;

The bishydroxylation reagent is preferably osmium tetroxide.

Specifically, a preparation of the compound represented by the general formula (V) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a method of a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (Va) is heated and reacted with 2-bromo-1,1-diethoxyethane under alkaline conditions to obtain the compound of general formula (Vb); the compound of general formula (Vb) is reacted with polyphosphoric acid to obtain The compound of general formula (Vc); the compound of general formula (Vc) is subjected to catalytic hydrogenation to obtain the compound of general formula (Vd); the compound of general formula (Vd) is added with titanium tetrachloride and 1,1-dichloride under ice bath conditions Methyl ether reacts to obtain the compound of the general formula (Ve); the compound of the general formula (Ve) reacts with isopentene, sodium dihydrogen phosphate and sodium chlorite to obtain the compound of the general formula (Vf); the compound of the general formula (Vf) and the substituted The aniline is reacted under basic conditions to obtain the compound of general formula (Vg); the compound of general formula (Vg) is reacted with 2,3-dichloro-5,6-dicyano-p-benzoquinone to obtain the compound of general formula (VA); The compound of formula (VA) is subjected to condensation reaction with compound G or its salt under the condition of a condensation reagent, and optionally further deprotecting group, hydroxylation or cyclization reaction is carried out to obtain the compound of general formula (V);

in:

Compound G is selected from heterocyclic compounds, heteroaromatic compounds, hydrazine compounds, amine compounds or alcohol compounds;

R ^d is selected from hydroxyl or halogen;

X is selected from halogen;

The definitions of R ¹ to R ³ and R ¹¹ are as described in the general formula (I);

The protecting group of hydroxyl is preferably isopropylidene or vinyl;

The protecting group of the amino group is preferably tert-butoxycarbonyl;

The bishydroxylation reagent is preferably osmium tetroxide.

Reagents for alkaline conditions include organic bases and inorganic bases, and the organic bases include but are not limited to N,N-diisopropylethylamine, triethylamine, lithium amide, n-butyllithium or potassium tert-butoxide , the inorganic bases include but are not limited to cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, sodium dihydrogen phosphate, potassium bicarbonate or sodium hydride, preferably potassium carbonate.

Catalysts include, but are not limited to, 10% palladium on carbon, palladium dichloride, palladium acetate, or tris(dibenzylideneacetone)dipalladium.

Condensation reagents include but are not limited to N,N-dicyclohexylcarbodiimide, N,N-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyl base urea tetrafluoroborate (TBTU), etc., preferably O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU), 2-(7- Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), preferably 2-(7-azobenzotriazole)-N,N ,N',N'-tetramethylurea hexafluorophosphate (HATU).

The solvents used include but are not limited to: ethyl acetate, dichloromethane, toluene, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, tert-butanol and water, or a mixed solvent of the above solvents.

Detailed ways

The present invention is further described below in conjunction with the examples, but these examples do not limit the scope of the present invention.

The experimental methods that do not specify specific conditions in the examples of the present invention generally follow conventional conditions or conditions suggested by raw material or commodity manufacturers. Reagents with no specific source indicated are conventional reagents purchased in the market.

Example

The structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" ⁶ > (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four Methylsilane (TMS).

The MS was measured with a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQadvantage MAX).

The determination of HPLC used an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150×4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150×4.6mm column).

The average inhibition rate and IC ₅₀ value of kinases were measured with NovoStar microplate reader (BMG, Germany).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ~ 0.2mm, and the size of the TLC separation and purification products is 0.9mm ~1.0mm.

Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

The known starting materials of the present invention can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals products and other companies.

There is no special description in the examples, and the reactions can all be carried out in an argon atmosphere or a nitrogen atmosphere.

Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

The pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.

The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

The microwave reaction used a CEM Discover-S 908860 microwave reactor.

There is no special description in the examples, and the solution refers to an aqueous solution.

There is no special description in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.

The monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), and the systems of the developing solvent used in the reaction are: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted according to the polarity of the compound.

The eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying the compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and acetone System, D: n-hexane and dichloromethane system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

Example 1

(R)-N-(2,3-Dihydroxypropoxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-5-carboxamide

first step

1-(2,2-diethoxyethoxy)-2,3-difluorobenzene

2,3-Difluorophenol 1a (50g, 0.39mol) was dissolved in 400mL dimethyl sulfoxide, 2-bromo-1,1-diethoxyethane (79.50g, 0.40mol) and potassium carbonate were added (79.60 g, 0.58 mol), heated to 95°C, and stirred for 16 hours. The reaction solution was cooled to room temperature, 1 L of ethyl acetate was added, filtered, the filtrate was washed with water (750 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 1-(2,2- Diethoxyethoxy)-2,3-difluorobenzene 1b (80 g, colorless oil), yield: 84.4%.

second step

6,7-Difluorobenzofuran

Dissolve 1-(2,2-diethoxyethoxy)-2,3-difluorobenzene 1b (80 g, 0.33 mol) in 800 mL of toluene, add polyphosphoric acid (154 g, 0.46 mol), and heat to The reaction was stirred at 100°C for 6 hours. The reaction solution was cooled to room temperature, poured into 1 L of water, and the layers were separated. The aqueous phase was extracted with ethyl acetate (500 mL×3). The organic phases were combined, washed with saturated sodium chloride (750 mL×1) solution, and washed with anhydrous sodium sulfate. Dry, filter, concentrate the filtrate under reduced pressure, and purify the resulting residue by silica gel column chromatography with eluent system B to give the title product 6,7-difluorobenzofuran 1c (8.90 g, colorless oil) in yield 17.8%.

third step

6,7-Difluoro-2,3-dihydrobenzofuran

6,7-Difluorobenzofuran 1c (8.60 g, 55.80 mmol) was dissolved in 100 mL of ethyl acetate, 10% palladium on carbon (1 g) was added, hydrogen was replaced three times, and the reaction was stirred for 16 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the title product 6,7-difluoro-2,3-dihydrobenzofuran 1d (6.90 g, colorless oil) in a yield of 79.3%.

the fourth step

6,7-Difluoro-2,3-dihydrobenzofuran-5-carbaldehyde

6,7-Difluoro-2,3-dihydrobenzofuran 1d (6.90 g, 44.20 mmol) was dissolved in 100 mL of dichloromethane, cooled to 0 °C in an ice-water bath, and titanium tetrachloride (13.40 g, 70.40 mmol) was added. mmol), stirred for 5 minutes, slowly added 1,1-dichloromethyl ether (7.60 g, 66.30 mmol) dropwise, the dropwise addition was completed, warmed to room temperature and stirred for 12 hours. 100 mL of ice water was added, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product 6,7-difluoro- 2,3-Dihydrobenzofuran-5-carbaldehyde 1e (6.80 g, pale yellow solid), 83.6% yield.

the fifth step

6,7-Difluoro-2,3-dihydrobenzofuran-5-carboxylic acid

6,7-Difluoro-2,3-dihydrobenzofuran-5-carbaldehyde 1e (6.50 g, 35.30 mmol) was dissolved in 300 mL of a mixed solution of tert-butanol and water (V/V=3:1), Isopentenene (22 g, 0.32 mol), sodium dihydrogen phosphate (24.80 g, 0.16 mol) and sodium chlorite (6.40 g, 70.60 mmol) were added sequentially, and the reaction was stirred for 16 hours. 200 mL of water was added, extracted with ethyl acetate (250 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 6,7-difluoro-2,3-dihydrobenzene and furan-5-carboxylic acid 1f (7 g, white solid), 99.1% yield.

Step 6

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxylic acid

6,7-Difluoro-2,3-dihydrobenzofuran-5-carboxylic acid 1f (7 g, 35 mmol), 2-fluoro-4-iodoaniline (9.10 g, 38.50 mmol), lithium amide (3.25 g , 0.14 mol) and 50 mL of tetrahydrofuran were added to the reaction flask, and the reaction was carried out at 95° C. for 75 minutes by microwave. The reaction solution was cooled to room temperature, poured into 300 mL of water, 4M hydrochloric acid was added dropwise to adjust pH<7, extracted with ethyl acetate (250 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, The resulting residue was purified by silica gel column chromatography with eluent system D to give the title product 7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran- 5-Carboxylic acid 1 g (8 g, brown solid), 54.8% yield.

Step 7

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-5-carboxylic acid

1 g (310 mg, 0.74 mmol) of 7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxylic acid was dissolved in 30 mL of toluene, and added 2,3-Dichloro-5,6-dicyano-p-benzoquinone (253 mg, 1.11 mmol) was heated to 105°C, and the reaction was stirred for 2 hours. The reaction solution was cooled to room temperature, 60 mL of water was added, extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and thin-layer chromatography was performed with developing solvent system B The resulting residue was purified to give the title product 7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-5-carboxylic acid 1h (80 mg, brown solid), yield: 25.9%.

MS m/z(ESI): 415.8[M+1]

Step 8

(R)-N-((2,2-Dimethyl-1,3-dioxol-4-yl)methoxy)-7-fluoro-6-((2-fluoro-4 -iodophenyl)amino)benzofuran-5-carboxamide

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-5-carboxylic acid 1h (40 mg, 0.10 mmol) was dissolved in 10 mL N,N-dimethylformamide, Add (R)-O-((2,2-dimethyl-1,3-dioxol-4-yl)methyl)hydroxylamine 1i (16 mg, 0.11 mmol, using the well-known method "Tetrahedron" Letters, 2006, 47(43), 7607-7609 "prepared), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (55 mg, 0.14 mmol) and N,N-diisopropylethylamine (40 mg, 0.30 mmol), and the reaction was stirred for 2 hours. 20 mL of water was added, extracted with ethyl acetate (20 mL×1), the organic phase was washed successively with water (20 mL×1) and saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, The resulting residue was purified by thin layer chromatography with developing solvent system B to give the title product (R)-N-((2,2-dimethyl-1,3-dioxol-4-yl) Methoxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-5-carboxamide 1j (30 mg, yellow solid), yield: 60.0%.

MS m/z(ESI): 544.9[M+1]

Step 9

(R)-N-(2,3-Dihydroxypropoxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-5-carboxamide

(R)-N-((2,2-dimethyl-1,3-dioxol-4-yl)methoxy)-7-fluoro-6-((2-fluoro- 4-Iodophenyl)amino)benzofuran-5-carboxamide 1j (30 mg, 0.06 mmol) was dissolved in 5 mL of methanol, 1 mL of 1M hydrochloric acid was added, and the reaction was stirred for 3 hours. 20 mL of water was added, extracted with ethyl acetate (20 mL×1), the organic phase was washed successively with water (20 mL×1) and saturated sodium chloride solution (20 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, The resulting residue was purified by thin layer chromatography with developing solvent system B to give the title product (R)-N-(2,3-dihydroxypropoxy)-7-fluoro-6-((2-fluoro-4- Iodophenyl)amino)benzofuran-5-carboxamide 1 (8 mg, white solid), yield: 28.6%.

MS m/z(ESI): 505.2[M+1]

¹ H NMR (400MHz, CD ₃ OD) δ 7.97(s, 1H), 7.90(d, 1H), 7.42(dd, 1H), 7.27(dd, 1H), 7.00-6.99(m, 1H), 6.47 -6.43 (m, 1H), 4.03-3.98 (m, 2H), 3.86-3.83 (m, 2H), 3.58-3.52 (m, 2H).

Example 2

N-((1,3-Dihydroxypropan-2-yl)oxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-5-carboxamide

first step

N-((2,2-Dimethyl-1,3-dioxan-5-yl)oxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzo Furan-5-carboxamide

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-5-carboxylic acid 1h (62 mg, 0.15 mmol) was dissolved in 2 mL of N,N-dimethylformamide, Add O-(2,2-dimethyl-1,3-dioxan-5-yl)hydroxylamine 2a (33 mg, 0.22 mmol, prepared by the known method "Patent WO2003062191A1"), 2-(7- Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (85 mg, 0.22 mmol) and N,N-diisopropylethylamine (58 mg, 0.45 mmol) , and the reaction was stirred for 16 hours. 40 mL of water was added, extracted with ethyl acetate (35 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography with developing solvent system B to obtain the title Product N-((2,2-Dimethyl-1,3-dioxan-5-yl)oxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzene and furan-5-carboxamide 2b (28 mg, brown oil), yield: 34.3%.

MS m/z(ESI): 545.1[M+1]

second step

N-((1,3-Dihydroxypropan-2-yl)oxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-5-carboxamide

N-((2,2-Dimethyl-1,3-dioxan-5-yl)oxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzene And furan-5-carboxamide 2b (28 mg, 0.05 mmol) was dissolved in 5 mL of methanol, 1 mL of 1M hydrochloric acid was added, and the reaction was stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title product N-((1,3-dihydroxypropan-2-yl)oxy)-7-fluoro-6 -((2-Fluoro-4-iodophenyl)amino)benzofuran-5-carboxamide 2 (6 mg, pale yellow solid), 23.1% yield.

MS m/z(ESI): 505.3[M+1]

¹ H NMR (400MHz, DMSO-d ₆ )δ7.94(d,1H), 7.74(s,1H), 7.45-7.42(m,1H), 7.29(d,1H), 7.02(t,1H), 6.47-6.43(m, 1H), 3.84(t, 1H), 3.66(d, 4H)

Example 3

7-Fluoro-6-((2-Fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzofuran-5-carboxamide

first step

7-Fluoro-6-((2-Fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzofuran-5-carboxamide

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-5-carboxylic acid 1h (32 mg, 0.08 mmol) was dissolved in 2 mL of N,N-dimethylformamide, Add O-(2-(vinyloxy)ethyl)hydroxylamine (purchased from Shaoyuan Chemical Technology, 9mg, 0.09mmol), 2-(7-azobenzotriazole)-N,N,N', N'-tetramethylurea hexafluorophosphate (44 mg, 0.12 mmol) and N,N-diisopropylethylamine (30 mg, 0.23 mmol), and the reaction was stirred for 4 hours. 30 mL of water was added, extracted with ethyl acetate (30 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to obtain The title product 7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzofuran-5-carboxamide 3a (20 mg, like white solid), yield: 51.9%.

MS m/z(ESI): 501.0[M+1]

second step

7-Fluoro-6-((2-Fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzofuran-5-carboxamide

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzofuran-5-carboxamide 3a (20 mg, 0.04 mmol ) was dissolved in 2 mL of methanol, 1 mL of 1M hydrochloric acid was added, and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title product 7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-N-(2 -Hydroxyethoxy)benzofuran-5-carboxamide 3 (6 mg, off-white solid), 31.6% yield.

MS m/z(ESI): 475.2[M+1]

¹ H NMR (400MHz, CD ₃ OD) δ 7.83(d, 1H), 7.68(s, 1H), 7.37(dd, 1H), 7.25(d, 1H), 6.93(t, 1H), 6.46-6.40 (m, 1H), 3.94(t, 2H), 3.69(t, 2H)

Example 4

7-Fluoro-6-((2-Fluoro-4-iodophenyl)amino)-N-(3-hydroxypropoxy)benzofuran-5-carboxamide

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-5-carboxylic acid 1h (62 mg, 0.15 mmol) was dissolved in 2 mL of N,N-dimethylformamide, Add 3-(aminooxy)propan-1-ol hydrochloride 4a (33 mg, 0.22 mmol, prepared by the known method "Patent WO2011020861A1"), 2-(7-azobenzotriazole)- N,N,N',N'-tetramethylurea hexafluorophosphate (85 mg, 0.23 mmol) and N,N-diisopropylethylamine (58 mg, 0.45 mmol), and the reaction was stirred for 4 hours. 25 mL of water was added, extracted with ethyl acetate (30 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography with developing solvent system A to obtain the title Product 7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-N-(3-hydroxypropoxy)benzofuran-5-carboxamide 4 (18 mg, white solid), yield : 24.7%.

MS m/z(ESI): 488.9[M+1]

¹ H NMR (400MHz, CD ₃ OD) δ 7.90-7.88 (m, 2H), 7.45-7.40 (m, 1H), 7.30-7.28 (m, 1H), 7.00-6.98 (m, 1H), 6.50- 6.45(m,1H), 3.97(t,1H), 3.69(t,1H), 3.33-3.31(m,4H), 1.86-1.83(m,1H), 1.63-1.59(m,1H).

Example 5

(S)-N-(2,3-Dihydroxypropoxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-5-carboxamide

first step

(S)-N-((2,2-Dimethyl-1,3-dioxol-4-yl)methoxy)-7-fluoro-6-((2-fluoro-4 -iodophenyl)amino)benzofuran-5-carboxamide

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-5-carboxylic acid 1h (42 mg, 0.10 mmol) was dissolved in 2 mL of N,N-dimethylformamide, Add (S)-O-((2,2-dimethyl-1,3-dioxol-4-yl)methyl)hydroxylamine 5a (18 mg, 0.12 mmol, using the well-known method "Patent" WO2003062189A1"), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (57mg, 0.15mmol) and N,N- Diisopropylethylamine (39 mg, 0.30 mmol) and the reaction was stirred for 16 hours. Add 30 mL of water, extract with ethyl acetate (30 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained residue is purified by thin layer chromatography with developing solvent system B to obtain the title Product (S)-N-((2,2-Dimethyl-1,3-dioxol-4-yl)methoxy)-7-fluoro-6-((2-fluoro- 4-Iodophenyl)amino)benzofuran-5-carboxamide 5b (23 mg, colorless oil), yield: 42.3%.

MS m/z(ESI): 545.1[M+1]

second step

(S)-N-(2,3-Dihydroxypropoxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-5-carboxamide

(S)-N-((2,2-dimethyl-1,3-dioxol-4-yl)methoxy)-7-fluoro-6-((2-fluoro- 4-Iodophenyl)amino)benzofuran-5-carboxamide 5b (23 mg, 0.04 mmol) was dissolved in 5 mL of methanol, 1 mL of 1M hydrochloric acid was added, and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title product (S)-N-(2,3-dihydroxypropoxy)-7-fluoro-6-( (2-Fluoro-4-iodophenyl)amino)benzofuran-5-carboxamide 5 (3 mg, white solid), yield: 14.3%.

MS m/z(ESI): 504.8[M+1]

¹ H NMR (400MHz, CD ₃ OD) δ 7.97(s, 1H), 7.90(d, 1H), 7.42(dd, 1H), 7.27(dd, 1H), 7.00-6.99(m, 1H), 6.47 -6.43 (m, 1H), 4.03-3.98 (m, 2H), 3.86-3.83 (m, 2H), 3.58-3.52 (m, 2H).

Example 6

7-Fluoro-6-((2-Fluoro-4-iodophenyl)amino)-N-((1-hydroxy-2-methylpropan-2-yl)oxy)benzofuran-5-carboxamide

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-5-carboxylic acid 1h (42 mg, 0.10 mmol) was dissolved in 2 mL of N,N-dimethylformamide, Add 2-(aminooxy)-2-methylpropan-1-ol hydrochloride 6a (21 mg, 0.15 mmol, prepared by the known method "Patent US20120238599A1"), 2-(7-azobenzo triazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (57 mg, 0.15 mmol) and N,N-diisopropylethylamine (39 mg, 0.30 mmol), stirring reaction 6 Hour. Add 30 mL of water, extract with ethyl acetate (30 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained residue is purified by thin layer chromatography with developing solvent system A to obtain the title Product 7-Fluoro-6-((2-Fluoro-4-iodophenyl)amino)-N-((1-hydroxy-2-methylpropan-2-yl)oxy)benzofuran-5-methyl Amide 6 (15 mg, off-white solid), yield: 29.5%.

MS m/z(ESI): 503.0[M+1]

¹ H NMR (400MHz, CDCl ₃ )δ9.42(s,1H), 7.97(s,1H), 7.75(s,1H), 7.42(d,1H), 6.90-6.89(m,1H), 6.83( s, 1H), 6.40-6.36 (m, 1H), 4.56-4.54 (m, 1H), 3.30-3.28 (m, 2H), 1.20 (s, 6H).

Example 7

6-((2-Fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-2,3-dihydrobenzofuran-5-carboxamide

first step

6-Fluoro-2,3-dihydrobenzofuran-5-carboxylic acid

6-Fluoro-2,3-dihydrobenzofuran-5-carbaldehyde 7a (300 mg, 1.81 mmol, prepared by the well-known method "Patent WO2012019430A1") was dissolved in 24 mL of tert-butanol and water (V/ V=3:1) in the mixed solution, add isopentene (1.14g, 16.27mmol) and sodium dihydrogen phosphate (1.27g, 8.15mmol), add sodium chlorite (0.41g, 3.62mmol) in batches, The reaction was stirred at room temperature for 4 hours. 20 mL of water was added, extracted with ethyl acetate (150 mL×1), the organic phase was washed with saturated sodium chloride solution (100 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 6-fluoro- 2,3-Dihydrobenzofuran-5-carboxylic acid 7b (300 mg, yellow solid), 91.2% yield.

second step

6-((2-Fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxylic acid

6-Fluoro-2,3-dihydrobenzofuran-5-carboxylic acid 7b (100 mg, 0.55 mmol), 2-fluoro-4-iodoaniline (156 mg, 0.66 mmol), bis(trimethylsilyl) Lithium amide (459 mg, 2.75 mmol) and 2 mL of tetrahydrofuran were added to the reaction flask, and the reaction was carried out at 120° C. in a microwave for 1 hour. The reaction solution was cooled to room temperature, poured into 30 mL of ice water, 1M hydrochloric acid was added dropwise to adjust the pH to 1, extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , the resulting residue was purified by thin layer chromatography with developing solvent system B to give the title product 6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxylic acid 7c (20 mg, brown oil), 9.1% yield.

MS m/z(ESI): 400.0[M+1]

third step

6-((2-Fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)-2,3-dihydrobenzofuran-5-carboxamide

6-((2-Fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxylic acid 7c (20 mg, 0.05 mmol) was dissolved in 2 mL of dichloromethane at 0 °C 1-Hydroxybenzotriazole (10 mg, 0.08 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14 mg, 0.08 mmol) were added, and the reaction was stirred at room temperature 2 hours. 2 mL of a solution of O-(2-(vinyloxy)ethyl)hydroxylamine (12 mg, 0.12 mmol) and N,N-diisopropylethylamine (14 mg, 0.12 mmol) in dichloromethane was added and the reaction was stirred for 36 hours. The reaction solution was concentrated under reduced pressure, 2 mL of N,N-dimethylformamide and O-(2-(vinyloxy)ethyl)hydroxylamine (6 mg, 0.06 mmol) were added, and the reaction was stirred for 48 hours. 5 mL of saturated sodium chloride solution and 20 mL of ethyl acetate were added, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography with developing solvent system B to obtain the title product. 6-((2-Fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)-2,3-dihydrobenzofuran-5-carboxamide 7d (5 mg, white solid), yield: 20.6%.

MS m/z(ESI): 483.1[M-1]

the fourth step

6-((2-Fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-2,3-dihydrobenzofuran-5-carboxamide

6-((2-Fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)-2,3-dihydrobenzofuran-5-carboxamide 7d (5 mg , 0.01 mmol) was dissolved in 1 mL of ethanol, 0.1 mL of 1 M hydrochloric acid was added at 0 °C, and the reaction was stirred at room temperature for 2 hours. Add saturated sodium bicarbonate solution at 0 °C to adjust the pH to 7, extract with ethyl acetate (20 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified with Reagent System B to give the title product 6-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-2,3-dihydrobenzofuran-5 - Formamide 7 (3 mg, white solid), 57.1% yield.

MS m/z(ESI): 459.3[M+1]

¹ H NMR (400MHz, CDCl ₃ ) δ 9.23(s,1H), 8.64(s,1H), 7.47-7.44(m,1H), 7.40-7.37(m,1H), 7.12-7.07(m,1H) ),6.56(s,1H),4.61(t,2H),4.06-4.04(m,2H),3.78-3.76(m,2H),3.65-3.64(m,1H),3.15(t,2H).

Example 8

7-Fluoro-6-((2-Fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-2,3-dihydrobenzofuran-5-carboxamide

first step

7-Fluoro-6-((2-Fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)-2,3-dihydrobenzofuran-5-carboxamide

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxylic acid 1 g (42 mg, 0.10 mmol) was dissolved in 3 mL of N,N- In dimethylformamide, O-(2-(vinyloxy)ethyl)hydroxylamine (13mg, 0.12mmol), 2-(7-azobenzotriazole)-N,N,N', N'-tetramethylurea hexafluorophosphate (57 mg, 0.15 mmol) and N,N-diisopropylethylamine (33 mg, 0.25 mmol), and the reaction was stirred for 5 hours. 30 mL of water was added, extracted with ethyl acetate (30 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (40 mL×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and silica gel column chromatography was used The resulting residue was purified with eluent system B to give the title product 7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)- 2,3-Dihydrobenzofuran-5-carboxamide 8a (45 mg, brown solid), yield: 89.0%.

MS m/z(ESI): 501.0[M-1]

second step

7-Fluoro-6-((2-Fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-2,3-dihydrobenzofuran-5-carboxamide

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)-2,3-dihydrobenzofuran-5-methyl Amide 8a (45 mg, 0.09 mmol) was dissolved in 3 mL of methanol, 1 mL of 1 M hydrochloric acid was added, and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-N-(2 -Hydroxyethoxy)-2,3-dihydrobenzofuran-5-carboxamide 8 (30 mg, white solid), 70.3% yield.

MS m/z(ESI): 477.2[M+1]

¹ H NMR (400MHz, CDCl ₃ ) δ 7.48(s, 1H), 7.42(d, 1H), 7.28(s, 1H), 6.46-6.43(m, 1H), 4.79(t, 2H), 3.97- 3.94 (m, 2H), 3.78-3.70 (m, 2H), 3.31 (t, 2H).

Example 9

7-Chloro-6-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-2,3-dihydrobenzofuran-5-carboxamide

first step

7-Chloro-6-fluoro-2,3-dihydrobenzofuran-5-carboxylic acid

6-Fluoro-2,3-dihydrobenzofuran-5-carboxylic acid 7b (346 mg, 1.90 mmol) was dissolved in 7 mL of N,N-dimethylformamide, and N-chlorosuccinimide was added (355 mg, 2.66 mmol), the temperature was raised to 60°C and the reaction was stirred for 16 hours. 120 mL of ethyl acetate was added, washed with saturated sodium chloride solution (100 mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title Product 7-chloro-6-fluoro-2,3-dihydrobenzofuran-5-carboxylic acid 9a (30 mg, yellow solid) in 7.3% yield.

second step

7-Chloro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxylic acid

7-Chloro-6-fluoro-2,3-dihydrobenzofuran-5-carboxylic acid 9a (30 mg, 0.14 mmol), 2-fluoro-4-iodoaniline (39 mg, 0.17 mmol), lithium amide (14 mg) , 0.55 mmol) and 4 mL of tetrahydrofuran were added to the reaction flask, and the reaction was carried out at 100 °C in a microwave for 1 hour. The reaction solution was cooled to room temperature, 30 mL of water was added, 1M hydrochloric acid was added dropwise to adjust pH<7, extracted with ethyl acetate (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, using The resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 7-chloro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5 - Carboxylic acid 9b (18 mg, brown solid), 30.0% yield.

third step

7-Chloro-6-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)-2,3-dihydrobenzofuran-5-carboxamide

7-Chloro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxylic acid 9b (18 mg, 0.04 mmol) was dissolved in 2 mL of N,N- In dimethylformamide, O-(2-(vinyloxy)ethyl)hydroxylamine (5mg, 0.05mmol), 2-(7-azobenzotriazole)-N,N,N', N'-tetramethylurea hexafluorophosphate (23 mg, 0.06 mmol) and N,N-diisopropylethylamine (16 mg, 0.12 mmol), and the reaction was stirred for 3 hours. 30 mL of water was added, extracted with ethyl acetate (30 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (40 mL×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and silica gel column chromatography was used The resulting residue was purified with eluent system B to give the title product 7-chloro-6-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)- 2,3-Dihydrobenzofuran-5-carboxamide 9c (8 mg, brown solid), yield: 37.2%.

the fourth step

7-Chloro-6-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-2,3-dihydrobenzofuran-5-carboxamide

7-Chloro-6-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)-2,3-dihydrobenzofuran-5-methyl Amide 9c (8 mg, 0.02 mmol) was dissolved in 2 mL of methanol, 1 mL of 1 M hydrochloric acid was added, and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title product 7-chloro-6-((2-fluoro-4-iodophenyl)amino)-N-(2 -Hydroxyethoxy)-2,3-dihydrobenzofuran-5-carboxamide 9 (4 mg, brown solid), 51.3% yield.

MS m/z(ESI): 493.4[M+1]

¹ H NMR (400MHz, CDCl ₃ )δ10.12(br,1H), 7.82(s,1H), 7.43(d,1H), 6.42-6.40(m,1H), 6.28-6.24(m,1H), 4.80(t, 2H), 3.86-3.84(m, 2H), 3.61-3.59(m, 2H), 3.37(t, 2H).

Example 10

(S)-N-(2,3-Dihydroxypropyl)-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxamide

6-((2-Fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxylic acid 7c (40 mg, 0.10 mmol) was dissolved in 3 mL of N,N-dimethylmethane In the amide, add (S)-3-amino-1,2-propanediol (11mg, 0.12mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl urea hexafluorophosphate (57 mg, 0.15 mmol) and N,N-diisopropylethylamine (32 mg, 0.25 mmol), and the reaction was stirred for 3 hours. 30 mL of water was added, extracted with ethyl acetate (30 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (25 mL×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and thin-layer chromatography was performed. The resulting residue was purified with developing solvent system A to give the title product (S)-N-(2,3-dihydroxypropyl)-6-((2-fluoro-4-iodophenyl)amino)-2,3 - Dihydrobenzofuran-5-carboxamide 10 (25 mg, light red solid), yield: 52.8%.

MS m/z(ESI): 471.0[M-1]

¹ H NMR (400MHz, CDCl ₃ ) δ 9.59(s, 1H), 7.44(dd, 1H), 7.36(dd, 1H), 7.33(s, 1H), 7.12(t, 1H), 6.61(s, 1H), 6.55-6.52(m, 1H), 4.58(t, 2H), 3.89-3.87(m, 1H), 3.68-3.53(m, 4H), 3.15(t, 2H)

Example 11

(R)-N-(2,3-Dihydroxypropyl)-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxamide

6-((2-Fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxylic acid 7c (40 mg, 0.10 mmol) was dissolved in 3 mL of N,N-dimethylmethane In the amide, add (R)-3-amino-1,2-propanediol (11mg, 0.12mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl urea hexafluorophosphate (57 mg, 0.15 mmol) and N,N-diisopropylethylamine (32 mg, 0.25 mmol), and the reaction was stirred for 4 hours. 30 mL of water was added, extracted with ethyl acetate (25 mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (25 mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and thin layer chromatography was performed. The resulting residue was purified with developing solvent system A to give the title product (R)-N-(2,3-dihydroxypropyl)-6-((2-fluoro-4-iodophenyl)amino)-2,3 - Dihydrobenzofuran-5-carboxamide 11 (15 mg, tan solid), yield: 31.7%.

MS m/z(ESI): 473.3[M+1]

¹ H NMR (400MHz, CDCl ₃ ) δ 9.59(s,1H), 7.43(dd,1H), 7.37(dd,1H), 7.33(s,1H), 7.12(t,1H), 6.61(s, 1H), 6.57-6.54 (m, 1H), 4.61 (t, 2H), 3.90-3.85 (m, 1H), 3.65-3.56 (m, 4H), 3.14 (t, 2H).

Example 12

(S)-N-(2,3-Dihydroxypropyl)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5- formamide

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxylic acid 1 g (42 mg, 0.10 mmol) was dissolved in 3 mL of N,N-dihydrobenzofuran In methylformamide, add (S)-3-amino-1,2-propanediol (11mg, 0.12mmol), 2-(7-azobenzotriazole)-N,N,N',N' - Tetramethylurea hexafluorophosphate (57 mg, 0.15 mmol) and N,N-diisopropylethylamine (33 mg, 0.25 mmol), and the reaction was stirred for 3 hours. Add 30 mL of water, extract with ethyl acetate (30 mL × 2), combine the organic phases, wash with saturated sodium chloride solution (25 mL × 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified with eluent system A to give the title product (S)-N-(2,3-dihydroxypropyl)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino )-2,3-dihydrobenzofuran-5-carboxamide 12 (30 mg, white solid), yield: 60.8%.

MS m/z(ESI): 491.2[M+1]

¹ H NMR (400MHz, CDCl ₃ ) δ 9.59(s,1H), 7.43(dd,1H), 7.37(dd,1H), 7.33(s,1H), 7.12(t,1H), 6.61(s, 1H), 6.57-6.54 (m, 1H), 4.61 (t, 2H), 3.90-3.85 (m, 1H), 3.65-3.56 (m, 4H), 3.14 (t, 2H).

Example 13

(R)-N-(2,3-Dihydroxypropoxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5 -Formamide

first step

(R)-N-((2,2-Dimethyl-1,3-dioxol-4-yl)methoxy)-7-fluoro-6-((2-fluoro-4 -Iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxamide

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxylic acid 1 g (17 mg, 0.04 mmol) was dissolved in 1 mL of N,N- In dimethylformamide, (R)-O-((2,2-dimethyl-1,3-dioxol-4-yl)methyl)hydroxylamine 1i (8 mg, 0.05 mmol) was added ), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (23mg, 0.06mmol) and N,N-difluorophosphate (23mg, 0.06mmol) were added at 0°C Isopropylethylamine (13 mg, 0.10 mmol), warmed to room temperature and stirred the reaction for 2 hours. Add 30 mL of water, extract with ethyl acetate (25 mL × 2), combine the organic phases, wash with saturated sodium chloride solution (30 mL × 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified with developing solvent system B to give the title product (R)-N-((2,2-dimethyl-1,3-dioxol-4-yl)methoxy)- 7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxamide 13a (10 mg, white solid), yield: 45.4%.

MS m/z(ESI): 547.1[M+1]

second step

(R)-N-(2,3-Dihydroxypropoxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5 -Formamide

(R)-N-((2,2-dimethyl-1,3-dioxol-4-yl)methoxy)-7-fluoro-6-((2-fluoro- 4-Iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxamide 13a (10 mg, 0.02 mmol) was dissolved in 2 mL of ethanol, 2 mL of 1M hydrochloric acid was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title product (R)-N-(2,3-dihydroxypropoxy)-7-fluoro-6-( (2-Fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxamide 13 (3 mg, brown solid), yield: 32.4%.

MS m/z(ESI): 507.2[M+1]

¹ H NMR (400MHz, CD ₃ OD) δ 7.43 (dd, 1H), 7.33-7.32 (m, 1H), 7.30 (s, 1H), 6.53-6.47 (m, 1H), 4.77 (t, 2H) , 3.98-3.96(m, 1H), 3.88-3.84(m, 2H), 3.59-3.56(m, 2H), 3.36(m, 1H), 3.36(t, 2H).

Example 14

(S)-N-(2,3-Dihydroxypropoxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5 -Formamide

first step

(S)-N-((2,2-Dimethyl-1,3-dioxol-4-yl)methoxy)-7-fluoro-6-((2-fluoro-4 -Iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxamide

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxylic acid 1 g (40 mg, 0.10 mmol) was dissolved in 1 mL of N,N- In dimethylformamide, (S)-O-((2,2-dimethyl-1,3-dioxol-4-yl)methyl)hydroxylamine 5a (17 mg, 0.12 mmol) was added ), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (55mg, 0.14mmol) and N,N-difluorophosphate (55mg, 0.14mmol) were added at 0°C Isopropylethylamine (31 mg, 0.24 mmol), warmed to room temperature and stirred the reaction for 4 hours. Add 30 mL of water, extract with ethyl acetate (30 mL × 1), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Product (S)-N-((2,2-Dimethyl-1,3-dioxol-4-yl)methoxy)-7-fluoro-6-((2-fluoro- 4-Iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxamide 14a (35 mg, white solid), yield: 67.3%.

MS m/z(ESI): 546.9[M+1]

second step

(S)-N-(2,3-Dihydroxypropoxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5 -Formamide

(S)-N-((2,2-dimethyl-1,3-dioxol-4-yl)methoxy)-7-fluoro-6-((2-fluoro- 4-Iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxamide 14a (35 mg, 0.06 mmol) was dissolved in 2 mL of ethanol, 1 mL of 1M hydrochloric acid was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title product (S)-N-(2,3-dihydroxypropoxy)-7-fluoro-6-( (2-Fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxamide 14 (13 mg, pale yellow solid), yield: 40.6%. MS m/z(ESI): 507.2[M+1]

¹ H NMR (400MHz, CDCl ₃ ) δ 7.48(s, 1H), 7.42(dd, 1H), 7.28-7.26(m, 1H), 7.18(s, 1H), 6.40-6.40(m, 1H), 4.78(t, 2H), 3.92-3.85(m, 3H), 3.73-3.71(m, 2H), 3.69-3.59(m, 1H), 3.28(t, 2H).

Example 15

N-((1,3-Dihydroxypropan-2-yl)oxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran -5-Carboxamide

first step

N-((2,2-Dimethyl-1,3-dioxan-5-yl)oxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-2 ,3-Dihydrobenzofuran-5-carboxamide

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxylic acid 1 g (42 mg, 0.10 mmol) was dissolved in 2 mL of N,N- In dimethylformamide, O-(2,2-dimethyl-1,3-dioxan-5-yl)hydroxylamine 2a (16 mg, 0.11 mmol), 2-(7-azobenzotrioxide) were added azole)-N,N,N',N'-tetramethylurea hexafluorophosphate (57mg, 0.15mmol) and N,N-diisopropylethylamine (39mg, 0.30mmol), the reaction was stirred for 3 hours . Add 30 mL of water, extract with ethyl acetate (30 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained residue is purified by thin layer chromatography with developing solvent system B to obtain the title Product N-((2,2-Dimethyl-1,3-dioxan-5-yl)oxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)- 2,3-Dihydrobenzofuran-5-carboxamide 15a (19 mg, off-white solid), yield: 34.5%.

MS m/z(ESI): 544.9[M-1]

second step

N-((1,3-Dihydroxypropan-2-yl)oxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran -5-Carboxamide

N-((2,2-dimethyl-1,3-dioxan-5-yl)oxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)- 2,3-Dihydrobenzofuran-5-carboxamide 15a (19 mg, 0.03 mmol) was dissolved in 2 mL of methanol, 1 mL of 1 M hydrochloric acid was added, and the reaction was stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title product N-((1,3-dihydroxypropan-2-yl)oxy)-7-fluoro-6 -((2-Fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxamide 15 (4 mg, brown solid), 23.5% yield.

¹ H NMR (400MHz, CDCl ₃ ) δ 7.50(d,1H), 7.44-7.38(m,1H), 7.29-7.26(m,1H), 6.43-6.38(m,1H), 4.78(t,2H) ), 3.89-3.82 (m, 1H), 3.70-3.64 (m, 4H), 3.30 (t, 2H).

Example 16

N-(Cyclopropylmethoxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxamide

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxylic acid 1 g (42 mg, 0.10 mmol) was dissolved in 2 mL of N,N- In dimethylformamide, O-(cyclopropylmethyl)hydroxylamine 16a (26mg, 0.30mmol, prepared by the known method "Patent WO2012074999A1"), 2-(7-azobenzotriazole) -N,N,N',N'-tetramethylurea hexafluorophosphate (57 mg, 0.15 mmol) and N,N-diisopropylethylamine (39 mg, 0.30 mmol), and the reaction was stirred for 4 hours. Add 30 mL of water, extract with ethyl acetate (30 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained residue is purified by thin layer chromatography with developing solvent system B to obtain the title Product N-(cyclopropylmethoxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxamide 16 (13 mg, light brown solid), yield: 26.5%.

MS m/z(ESI): 487.3[M+1]

¹ H NMR (400MHz, CDCl ₃ ) δ 9.06(s, 1H), 7.56(s, 1H), 7.40-7.37(m, 2H), 6.48-6.44(m, 1H), 4.77(t, 2H), 3.73 (d, 2H), 2.89 (t, 2H), 1.12-1.09 (m, 1H), 0.58-0.55 (m, 2H), 0.30-0.27 (m, 2H).

Example 17

(R)-(7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-yl)(4-hydroxyisoxazole-2- base) ketone

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxylic acid 1 g (42 mg, 0.10 mmol) was dissolved in 2 mL of N,N- In dimethylformamide, (R)-isoxazol-4-ol hydrochloride 17a (15 mg, 0.12 mmol, prepared by a known method "Tetrahedron Letters, 2006, 47(43), 7635-7639" was added to obtained), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (57mg, 0.15mmol) and N,N-diisopropyl Ethylamine (39 mg, 0.30 mmol), and the reaction was stirred for 4 hours. Add 30 mL of water, extract with ethyl acetate (30 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Product (R)-(7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-yl)(4-hydroxyisoxazole-2 -yl)methanone 17 (10 mg, light brown solid), yield: 20.4%.

MS m/z(ESI): 489.2[M+1]

¹ H NMR (400MHz, CD ₃ OD) δ 7.38(d, 1H), 7.29-7.26(m, 2H), 6.50-6.45(m, 1H), 4.78-4.71(m, 3H), 3.95-3.88( m, 3H), 3.69 (d, 1H), 3.30 (t, 2H).

Example 18

(S)-(7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-yl)(4-hydroxyisoxazole-2- base) ketone

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxylic acid 1 g (42 mg, 0.10 mmol) was dissolved in 2 mL of N,N- In dimethylformamide, (S)-isoxazol-4-ol hydrochloride 18a (15 mg, 0.12 mmol, prepared by a known method "Tetrahedron Letters, 2006, 47(43), 7635-7639" was added to obtained), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (57mg, 0.15mmol) and N,N-diisopropyl Ethylamine (39 mg, 0.30 mmol), and the reaction was stirred for 6 hours. Add 35 mL of water, extract with ethyl acetate (30 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue obtained by thin-layer chromatography using the developing solvent system A to obtain the title product (S)-(7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-yl)(4-hydroxyisoxazole-2- yl)methanone 18 (19 mg, off-white solid), yield: 38.8%.

MS m/z(ESI): 489.3[M+1]

¹ H NMR (400MHz, CD ₃ OD) δ 7.38 (d, 1H), 7.29-7.25 (m, 2H), 6.50-6.45 (m, 1H), 4.77-4.71 (m, 3H), 3.95-3.87 ( m, 3H), 3.69 (d, 1H), 3.29 (t, 2H).

Example 19

1-(2,3-Dihydroxypropyl)-N-(7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-yl ) cyclopropane-1-sulfonamide

first step

6,7-Difluoro-5-nitro-2,3-dihydrobenzofuran

6,7-Difluoro-2,3-dihydrobenzofuran 1d (350 mg, 2.24 mmol) was dissolved in 5 mL of concentrated sulfuric acid at 0°C, sodium nitrate (200 mg, 2.35 mmol) was added, and the mixture was stirred for 1 hour. 20 mL of ice water and 20 mL of ethyl acetate were added, the layers were separated, the organic phase was washed with water (20 mL×2) and saturated sodium chloride solution (20 mL×2) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title Product 6,7-difluoro-5-nitro-2,3-dihydrobenzofuran 19a (450 mg, red solid) in 100% yield.

second step

7-Fluoro-N-(2-Fluoro-4-iodophenyl)-5-nitro-2,3-dihydrobenzofuran-6-amine

6,7-Difluoro-5-nitro-2,3-dihydrobenzofuran 19a (450 mg, 2.24 mmol) and 2-fluoro-4-iodoaniline (640 mg, 2.70 mmol) were dissolved in 5 mL of dimethyl To the sulfoxide, cesium carbonate (1.10 g, 3.38 mmol) was added, and the reaction was stirred at 90° C. for 2 hours. 30 mL of water and 30 mL of ethyl acetate were added, and the layers were separated. The organic phase was washed with water (20 mL×1) and saturated sodium chloride solution (20 mL×2) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title. Product 7-fluoro-N-(2-fluoro-4-iodophenyl)-5-nitro-2,3-dihydrobenzofuran-6-amine 19b (0.94 g, yellow solid), proceed directly to next step reaction.

third step

7-Fluoro-N ⁶ -(2-Fluoro-4-iodophenyl)-2,3-dihydrobenzofuran-5,6-diamine

7-Fluoro-N-(2-fluoro-4-iodophenyl)-5-nitro-2,3-dihydrobenzofuran-6-amine 19b (0.94 g, 2.25 mmol) and stannous chloride Dihydrate (1.52 g, 6.75 mmol) was dissolved in 5 mL of diethyl ether, 2 mL of concentrated hydrochloric acid was added, and the mixture was stirred at 60° C. for 2 hours. The reaction solution was cooled to room temperature, 1M sodium hydroxide solution was added dropwise to adjust the pH to 7, 30 mL of water and 30 mL of ethyl acetate were added, the layers were separated, and the organic phase was followed by water (30 mL × 1) and saturated sodium chloride solution (30 mL × 2 ), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 7-fluoro-N ⁶ -(2-fluoro-4-iodo) Phenyl)-2,3-dihydrobenzofuran-5,6-diamine 19c (0.30 g, white powder), 34.5% yield.

MS m/z(ESI): 389.0[M+1]

the fourth step

1-Allyl-N-(7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-yl)cyclopropane-1-sulfonamide

7-Fluoro- ^N6- (2-fluoro-4-iodophenyl)-2,3-dihydrobenzofuran-5,6-diamine 19c (75 mg, 0.19 mmol) and 1-allyl ring Propane-1-sulfonyl chloride 19d (75 mg, 0.42 mmol, prepared by the known method "Patent US20120136030A1") was dissolved in 2 mL of pyridine, 4-dimethylaminopyridine (2 mg, 0.02 mmol) was added, and the reaction was stirred for 16 hours. The reaction solution was poured into 20 mL of ice water, extracted with ethyl acetate (20 mL × 1), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system B , to give the title product 1-allyl-N-(7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-yl)cyclopropane -1-Sulfanilamide 19e (60 mg, yellow oil), yield: 58.3%.

the fifth step

1-(2,3-Dihydroxypropyl)-N-(7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-yl ) cyclopropane-1-sulfonamide

1-Allyl-N-(7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-yl)cyclopropane-1- Sulfanilamide 19e (30 mg, 0.06 mmol) was dissolved in 2 mL of tetrahydrofuran, 40 μL of 4% osmium tetroxide solution was added dropwise, 4-methylmorpholine nitrogen oxide (7 mg, 0.06 mmol) was added, and the reaction was stirred for 16 hours. 20 mL of saturated sodium chloride solution was added, extracted with ethyl acetate (60 mL × 1), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography with developing solvent system B, The title product 1-(2,3-dihydroxypropyl)-N-(7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran- 5-yl)cyclopropane-1-sulfonamide 19 (10 mg, brown solid), yield: 31.3%.

MS m/z(ESI): 567.3[M+1]

¹ H NMR (400MHz, CDCl ₃ )δ8.02(s,1H), 7.40-7.38(m,1H), 7.25-7.23(m,1H), 6.26-6.23(m,1H), 6.04(s,1H) ), 4.72(t, 2H), 3.92-3.90(m, 1H), 3.57-3.54(m, 1H), 3.44-3.41(m, 1H), 3.30(t, 2H), 2.10-2.05(m, 2H) ), 0.91-0.84 (m, 4H).

Example 20

5-(6-((2-Fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-yl)-1,3,4-oxadiazol-2-amine

first step

2-(6-((2-Fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carbonyl)carbazate tert-butyl ester

6-((2-Fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxylic acid 7c (100 mg, 0.25 mmol) was dissolved in 2 mL of N,N-dimethylmethane To the amide, tert-butylcarbazate (70 mg, 0.53 mmol) and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (195 mg, 0.38 mmol) were added, and the reaction was stirred for 2 hours. 20 mL of water and 20 mL of ethyl acetate were added, the layers were separated, the organic phase was washed with water (20 mL×1) and saturated sodium chloride solution (20 mL×2) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product tert-Butyl 2-(6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carbonyl)carbazate 20a (80 mg, yellow oil), yielded Rate: 66.7%.

MS m/z(ESI): 512.0[M-1]

second step

6-((2-Fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carbohydrazide

Dissolve tert-butyl 2-(6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carbonyl)carbazate 20a (80 mg, 0.16 mmol) in In 5 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the reaction was stirred for 3 hours. 20 mL of water and 20 mL of ethyl acetate were added, and the layers were separated. The organic phase was washed with water (20 mL×1) and saturated sodium chloride solution (20 mL×2) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by developing solvent system A to give the title product 6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carbohydrazide 20b (30 mg , black solid), 45.4% yield.

MS m/z(ESI): 414.0[M+1]

third step

5-(6-((2-Fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-yl)-1,3,4-oxadiazol-2-amine

6-((2-Fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carbohydrazide 20b (30 mg, 0.07 mmol) was dissolved in 5 mL of dioxane, followed by Cyanogen bromide (10 mg, 0.09 mmol), sodium bicarbonate (7 mg, 0.08 mmol) and 5 mL of water were added, and the reaction was stirred at 60° C. for 1 hour. 10 mL of water and 10 mL of ethyl acetate were added, and the layers were separated. The organic phase was washed with water (20 mL×1) and saturated sodium chloride solution (20 mL×2) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography with developing solvent system A to give the title product 5-(6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-yl)- 1,3,4-Oxadiazol-2-amine 20 (15 mg, white solid), 47.2% yield.

MS m/z(ESI): 439.0[M+1]

¹ H NMR (400MHz, CDCl ₃ ) δ 9.16(s, 1H), 7.52(s, 1H), 7.48(d, 1H), 7.41(d, 1H), 7.21(t, 1H), 6.58(s, 1H), 4.97(s, 2H), 4.62(t, 2H), 3.20-3.16(m, 2H).

Example 21

5-(7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-yl)-1,3,4-oxadiazole-2 -amine

first step

2-(7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carbonyl)carbazate tert-butyl ester

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carboxylic acid 1 g (150 mg, 0.36 mmol) was dissolved in 3 mL of N,N- In dimethylformamide, tert-butylcarbazate (57mg, 0.43mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylureahexa Fluorophosphate (205 mg, 0.54 mmol) and N,N-diisopropylethylamine (139 mg, 1.08 mmol), and the reaction was stirred for 3 hours. 40 mL of ethyl acetate was added, washed with saturated sodium chloride solution (40 mL×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to obtain the title Product tert-butyl 2-(7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carbonyl)carbazate 21a (168 mg, brown solid), yield: 87.9%.

MS m/z(ESI): 529.9[M-1]

second step

7-Fluoro-6-((2-Fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carbohydrazide

2-(7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carbonyl)carbazate tert-butyl ester 21a (168 mg, 0.32 mmol) was dissolved in 5 mL of methanol, 1 mL of saturated hydrochloric acid methanol solution was added, and the mixture was stirred at room temperature for 2 hours to stop the reaction. The reaction solution was concentrated under reduced pressure to obtain crude 7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carbohydrazide 21b (140 mg, white solid), which was directly used in the next reaction.

third step

5-(7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-yl)-1,3,4-oxadiazole-2 -amine

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carbohydrazide 21b (140 mg, 0.32 mmol) was dissolved in 8 mL of dioxane To the mixed solution of ring and water (V/V=1:1), cyanogen bromide (37 mg, 0.36 mmol) and sodium bicarbonate (7 mg, 0.36 mmol) were sequentially added, and the reaction was stirred at 60° C. for 1 hour. 40 mL of water was added, extracted with ethyl acetate (40 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to obtain The title product 5-(7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-yl)-1,3,4-oxadiazole -2-amine 21 (60 mg, white solid), 40.5% yield.

MS m/z(ESI): 457.1[M+1]

Example 22

2-((5-(7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-benzodihydrofuran-5-yl)-1,3,4-oxa oxadiazol-2-yl)amino)ethanol

first step

5-(7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-benzodihydrofuran-5-yl)-1,3,4-oxadiazole-2 (3H)-keto

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-dihydrobenzofuran-5-carbohydrazide 21b (120 mg, 0.26 mmol) was dissolved in 5 mL of N,N -In dimethylformamide, N,N'-carbonyldiimidazole (243 mg, 1.50 mmol) and N,N-diisopropylethylamine (483 mg, 3.75 mmol) were added, and the reaction was stirred at room temperature for 16 hours. Add 30 mL of water, use ethyl acetate (30 mL×2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the resulting residue by silica gel column chromatography with eluent system B to give the title product 5-( 7-Fluoro-6-((2-Fluoro-4-iodophenyl)amino)-2,3-benzodihydrofuran-5-yl)-1,3,4-oxadiazole-2(3H) - Ketone 22a (120 mg, tan solid), yield: 35.1%.

MS m/z(ESI): 455.9[M-1]

second step

2-(7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-benzodihydrofuran-5-carbonyl)-N-(2-hydroxyethyl)semicarbazide

5-(7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-benzodihydrofuran-5-yl)-1,3,4-oxadiazole- 2(3H)-ketone 22a (120 mg, 0.26 mmol) and 2-hydroxyethylamine (48 mg, 0.78 mmol) were dissolved in 10 mL of ethanol, and the temperature was raised to 100 °C and stirred for 16 hours to stop the reaction. The reaction solution was concentrated under reduced pressure to obtain the crude title product 2-(7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-chromodihydrofuran-5-carbonyl)- N-(2-hydroxyethyl)semicarbazide 22b (129 mg, tan solid) was used directly in the next reaction.

MS m/z(ESI): 519.1[M+1]

third step

2-((5-(7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-benzodihydrofuran-5-yl)-1,3,4-oxa oxadiazol-2-yl)amino)ethanol

The crude product 2-(7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-2,3-chromodihydrofuran-5-carbonyl)-N-(2-hydroxyethyl) ) semicarbazide 22b (129 mg, 0.25 mmol) was dissolved in 30 mL of dichloromethane, followed by adding triphenylphosphine (98 mg, 0.37 mmol), triethylamine (51 mg, 0.50 mmol) and carbon tetrachloride (154 mg, 1.00 mmol) ), heated to reflux for 6 hours to stop the reaction. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to give the title product 2-((5-(7-fluoro-6-((2-fluoro-4-iodophenyl) Amino)-2,3-benzodihydrofuran-5-yl)-1,3,4-oxadiazol-2-yl)amino)ethanol 22 (13 mg, brown-red solid), 10.0% yield.

MS m/z(ESI): 501.2[M+1]

¹ H NMR (400MHz, CD ₃ OD) δ 7.96(s, 1H), 7.45(s, 1H), 7.40(d, 1H), 7.30(d, 1H), 6.58-6.55(m, 1H), 4.75 (t, 2H), 3.72 (t, 2H), 3.41 (t, 2H), 3.32 (t, 2H).

Example 23

6-((4-Bromo-2-chlorophenyl)amino)-N-(2-hydroxyethoxy)-2,3-dihydrobenzofuran-5-carboxamide

first step

6-((4-Bromo-2-chlorophenyl)amino)-2,3-chromodihydrofuran-5-carboxylic acid

6-Fluoro-2,3-dihydrobenzofuran-5-carboxylic acid 7b (50 mg, 0.27 mmol), 4-bromo-2-chloroaniline (68 mg, 0.33 mmol), lithium amide (34 mg, 1.38 mmol) Put it into a reaction flask, replace it with nitrogen three times, add 1 mL of tetrahydrofuran, and react in a microwave at 80° C. for 1 hour. The reaction solution was cooled to room temperature, poured into 40 mL of ice water, 1M hydrochloric acid was added dropwise to adjust the pH to 1-2, extracted with ethyl acetate (40 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced was concentrated under pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system B to give the title product, 6-((4-bromo-2-chlorophenyl)amino)-2,3-chromodihydrofuran-5- Carboxylic acid 23a (20 mg, yellow solid), 19.8% yield.

MS m/z(ESI): 367.9[M+1]

second step

6-((4-Bromo-2-chlorophenyl)amino)-N-(2-(vinyloxy)ethoxy)-2,3-chromodihydrofuran-5-carboxamide

6-((4-Bromo-2-chlorophenyl)amino)-2,3-benzodihydrofuran-5-carboxylic acid 23a (20 mg, 0.05 mmol), 1-hydroxybenzotriazole (11 mg, 0.08 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (16 mg, 0.08 mmol) were dissolved in 1 mL of N,N-dimethylformamide at 0°C After stirring for 20 minutes, O-(2-(vinyloxy)ethyl)hydroxylamine (11 mg, 0.11 mmol) and triethylamine (13 mg, 0.13 mmol) were added, the mixture was naturally raised to room temperature, and the reaction was stirred for 12 hours to stop the reaction. 3 mL of saturated sodium chloride solution was added, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product 6-((4-bromo-2 -Chlorophenyl)amino)-N-(2-(vinyloxy)ethoxy)-2,3-benzodihydrofuran-5-carboxamide 23b (19 mg, yellow solid), used directly in the next step reaction.

MS m/z(ESI): 451.0[M-1]

third step

6-((4-Bromo-2-chlorophenyl)amino)-N-(2-hydroxyethoxy)-2,3-dihydrobenzofuran-5-carboxamide

6-((4-Bromo-2-chlorophenyl)amino)-N-(2-(vinyloxy)ethoxy)-2,3-benzodihydrofuran-5-carboxamide 23b (19 mg , 0.04 mmol) was dissolved in 1 mL of ethanol, 0.2 mL of 1M hydrochloric acid was added at 0 °C, and it was naturally raised to room temperature, and the reaction was stirred for 2 hours. 2 mL of saturated sodium bicarbonate was added at 0°C, extracted with ethyl acetate (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by thin layer chromatography with developing solvent system B The resulting residue gave the title product 6-((4-bromo-2-chlorophenyl)amino)-N-(2-hydroxyethoxy)-2,3-dihydrobenzofuran-5-carboxamide 23 (5 mg, white solid), 29.6% yield. MS m/z(ESI): 427.1[M+1]

¹ H NMR (400MHz, CDCl ₃ )δ9.31(s,1H), 8.72(s,1H), 7.56(s,1H), 7.30(d,1H), 7.26(s,1H), 6.65(s, 1H), 4.62 (t, 3H), 4.06-4.04 (m, 2H), 3.78-3.77 (m, 2H), 3.15 (t, 3H).

Example 24

8-Fluoro-7-((2-Fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)chroman-6-carboxamide

first step

7,8-Difluorochroman-6-carbaldehyde

7,8-Difluorochroman 24a (190 mg, 1.12 mmol, prepared by the well-known method "Patent WO2009068152") was dissolved in 10 mL of dichloromethane, cooled to 0°C in an ice-water bath, and tetrachloromethane was added. Titanium oxide (338 mg, 1.79 mmol) was stirred for 5 minutes, 1,1-dichloromethyl ether (192 mg, 1.67 mmol) was slowly added dropwise, the dropwise addition was completed, and the mixture was warmed to room temperature and stirred for 12 hours. The reaction was quenched by adding 20 mL of ice water, extracted with dichloromethane (25 mL×2), the organic phase was collected, washed with saturated sodium chloride solution (30 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, The crude title product 7,8-difluorochroman-6-carbaldehyde 24b (230 mg, yellow oil) was obtained and used directly in the next reaction.

second step

7,8-Difluorochroman-6-carboxylic acid

The crude 7,8-difluorochroman-6-carbaldehyde 24b (230 mg, 1.12 mmol) was dissolved in 12 mL of a mixed solution of tert-butanol and water (V/V=3:1), followed by adding isopentane alkene (705 mg, 10.08 mmol), sodium dihydrogen phosphate (786 mg, 5.04 mmol) and sodium chlorite (202 mg, 2.24 mmol), and the reaction was stirred for 4 hours. 30 mL of water was added, extracted with ethyl acetate (25 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 7 ,8-Difluorochroman-6-carboxylic acid 24c (220 mg, yellow solid) in 88.7% yield.

third step

8-Fluoro-7-((2-Fluoro-4-iodophenyl)amino)chroman-6-carboxylic acid

7,8-Difluorochroman-6-carboxylic acid 24c (220 mg, 1.03 mmol), 2-fluoro-4-iodoaniline (268 mg, 1.13 mmol), lithium amide (64 mg, 2.56 mmol) and 4 mL of tetrahydrofuran was added to the reaction flask, and the reaction was microwaved at 90°C for 80 minutes. The reaction solution was cooled to room temperature, 50 mL of ethyl acetate was added, the solution was washed successively with 1M hydrochloric acid (20 mL×1) and saturated sodium chloride solution (40 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, The resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 8-fluoro-7-((2-fluoro-4-iodophenyl)amino)chroman-6-carboxylic acid 24d (250 mg, brown solid), 58.0% yield.

MS m/z(ESI): 430.0[M-1]

the fourth step

8-Fluoro-7-((2-Fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)chroman-6-carboxamide

8-Fluoro-7-((2-fluoro-4-iodophenyl)amino)chroman-6-carboxylic acid 24d (50 mg, 0.116 mmol) and O-(2-(vinyloxy) Ethyl)hydroxylamine (14 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (37 mg, 0.29 mmol) and 2-(7- Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (66 mg, 0.17 mmol), warmed to room temperature and stirred for 12 hours. 30 mL of water was added, extracted with ethyl acetate (25 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system B to obtain the title Product 8-fluoro-7-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)chroman-6-carboxamide 24e (35 mg , white solid), yield: 58.3%.

MS m/z(ESI): 515.1[M-1]

the fifth step

8-Fluoro-7-((2-Fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)chroman-6-carboxamide

8-Fluoro-7-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)chroman-6-carboxamide 24e (35 mg , 0.07 mmol) was dissolved in 2 mL of methanol, 1 mL of 1 M hydrochloric acid was added, and the reaction was stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title product 8-fluoro-7-((2-fluoro-4-iodophenyl)amino)-N-(2- Hydroxyethoxy)chroman-6-carboxamide 24 (10 mg, white solid), 30.3% yield.

MS m/z(ESI): 491.2[M+1]

¹ H NMR (400MHz, CDCl ₃ )δ9.72(brs,1H), 7.42-7.39(m,2H), 7.26-7.24(s,1H), 6.86(br,1H), 6.41-6.36(m,1H) ), 4.37-4.31(m, 2H), 3.93-3.91(m, 2H), 3.67-3.65(m, 2H), 2.83-2.81(m, 2H), 2.08-2.04(m, 2H).

Example 25

(R)-N-(2,3-Dihydroxypropoxy)-8-fluoro-7-((2-fluoro-4-iodophenyl)amino)chroman-6-carboxamide

first step

(R)-N-((2,2-Dimethyl-1,3-dioxol-4-yl)methoxy)-8-fluoro-7-((2-fluoro-4 -Iodophenyl)amino)chroman-6-carboxamide

8-Fluoro-7-((2-fluoro-4-iodophenyl)amino)chroman-6-carboxylic acid 24d (50 mg, 0.12 mmol) and (R)-O-((2, 2-Dimethyl-1,3-dioxol-4-yl)methyl)hydroxylamine 1i (16 mg, 0.11 mmol) was dissolved in 3 mL of N,N-dimethylformamide, and N,N-dimethylformamide was added. N-diisopropylethylamine (37 mg, 0.29 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (66 mg, 0.17 mmol), and the reaction was stirred for 12 hours. 20 mL of water was added, extracted with ethyl acetate (30 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product (R)-N-((2,2-dimethyl-1 ,3-dioxol-4-yl)methoxy)-8-fluoro-7-((2-fluoro-4-iodophenyl)amino)chroman-6-methyl Amide 25a (45 mg, brown oil) was used directly in the next reaction.

MS m/z(ESI): 561.1[M+1]

second step

(R)-N-(2,3-Dihydroxypropoxy)-8-fluoro-7-((2-fluoro-4-iodophenyl)amino)chroman-6-carboxamide

The crude (R)-N-((2,2-dimethyl-1,3-dioxol-4-yl)methoxy)-8-fluoro-7-((2-fluoro -4-iodophenyl)amino)chroman-6-carboxamide 25a (30 mg, 0.06 mmol) was dissolved in 3 mL of methanol, 2 mL of 1M hydrochloric acid was added, and the reaction was stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title product (R)-N-(2,3-dihydroxypropoxy)-8-fluoro-7-(( 2-Fluoro-4-iodophenyl)amino)chroman-6-carboxamide 25 (8 mg, white solid), yield: 28.6%.

MS m/z(ESI): 521.2[M+1]

¹ H NMR (400MHz, CDCl ₃ )δ9.87(br,1H), 7.45-7.41(m,2H), 7.27-7.26(m,1H), 6.71(brs,1H), 6.36-6.41(m,1H) ), 4.34-4.31(m, 2H), 3.89-3.68(m, 5H), 3.59-3.65(m, 1H), 3.53(m, 1H), 2.86-2.83(m, 2H), 2.09-2.06(m , 2H).

Example 26

(R)-N-(2,3-Dihydroxypropoxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzo[d][1,3]m-bis Oxole-5-carboxamide

first step

4,5-Difluorobenzo[d][1,3]dioxole

3,4-Difluoro-1,2-benzenediol 26a (900 mg, 6.16 mmol, prepared by a known method "FEMS Microbiology Letters, 1999, 181(1), 73-82"), dibromomethane ( 1.60 g, 9.24 mmol) and cesium carbonate (3.01 g, 9.24 mmol) were dissolved in 10 mL of N,N-dimethylformamide, heated to 110° C., and the reaction was stirred for 2 hours. The reaction solution was cooled to room temperature, 50 mL of ethyl acetate was added, filtered, the filtrate was washed with water (50 mL×1), the aqueous phase was extracted with ethyl acetate (50 mL×1), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 4,5-difluorobenzo[d][1,3]dioxol 26b (280 mg , pale yellow oil), yield: 28.7%.

second step

6,7-Difluorobenzo[d][1,3]dioxol-5-carbaldehyde

4,5-Difluorobenzo[d][1,3]dioxol 26b (280 mg, 1.77 mmol) was dissolved in 10 mL of dichloromethane, and titanium tetrachloride (535 mg, 1.77 mmol) was added at 0°C. 2.83 mmol), stirred for 5 minutes, added 1,1-dichloromethyl ether (305 mg, 2.65 mmol), warmed to room temperature and stirred the reaction for 12 hours. The reaction was quenched by adding 30 g of ice water, extracted with dichloromethane (30 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B. The residue gave the title product 6,7-difluorobenzo[d][1,3]dioxol-5-carbaldehyde 26c (140 mg, white solid), yield: 42.5%.

third step

6,7-Difluorobenzo[d][1,3]dioxol-5-carboxylic acid

6,7-Difluorobenzo[d][1,3]dioxol-5-carbaldehyde 26c (140 mg, 0.75 mmol) was dissolved in 5 mL of tert-butanol and water (V/V=3:1 ), 2-methyl-2-butene (472mg, 6.75mmol), sodium dihydrogen phosphate (526mg, 3.38mmol) and sodium chlorite (135mg, 1.50mmol) were added successively, and the reaction was stirred for 4 hours . 20 mL of water was added, 1M hydrochloric acid solution was added dropwise to adjust pH<7, extracted with ethyl acetate (30 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to obtain the title product 6,7- Difluorobenzo[d][1,3]dioxole-5-carboxylic acid 26d (150 mg, white solid) in 98.6% yield.

the fourth step

7-Fluoro-6-((2-Fluoro-4-iodophenyl)amino)benzo[d][1,3]dioxol-5-carboxylic acid

6,7-Difluorobenzo[d][1,3]dioxol-5-carboxylic acid 26d (150 mg, 0.25 mmol), 2-fluoro-4-iodoaniline (64 mg, 0.27 mmol) ) and lithium amide (16 mg, 0.62 mmol) were added to the reaction flask, 6 mL of tetrahydrofuran was added, nitrogen was replaced three times, and the reaction was carried out at 90° C. for 75 minutes by microwave. LC-MS showed that the reaction did not proceed, additional lithium amide (16 mg, 0.62 mmol) was added, and the reaction was microwaved at 100° C. for 1.5 hours. The reaction solution was cooled to room temperature, 30 mL of water was added, 1M hydrochloric acid was added dropwise to adjust pH<7, extracted with ethyl acetate (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, using The resulting residue was purified by silica gel column chromatography with eluent system B to give the title product, 7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzo[d][1,3]metabis Oxole-5-carboxylic acid 26e (61 mg, brown solid), 19.6% yield.

the fifth step

(R)-N-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)-7-fluoro-6-((2-fluoro-4-iodobenzene yl)amino)benzo[d][1,3]dioxol-5-carboxamide

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)benzo[d][1,3]dioxol-5-carboxylic acid 26e (30 mg, 0.07 mmol) and (R)-O-((2,2-dimethyl-1,3-dioxol-4-yl)methyl)hydroxylamine 1i (12 mg, 0.08 mmol) was dissolved in 2 mL of N,N -In dimethylformamide, add N,N-diisopropylethylamine (28mg, 0.22mmol) and 2-(7-azobenzotriazole)-N,N,N',N'- Tetramethylurea hexafluorophosphate (41 mg, 0.11 mmol) and the reaction was stirred for 4 hours. 30 mL of water was added, extracted with ethyl acetate (30 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to obtain The title product (R)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-7-fluoro-6-((2-fluoro-4- Iodophenyl)amino)benzo[d][1,3]dioxol-5-carboxamide 26f (45 mg, brown oil), yield: 51.2%.

MS m/z(ESI): 549.0[M+1]

Step 6

(R)-N-(2,3-Dihydroxypropoxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzo[d][1,3]m-bis Oxole-5-carboxamide

(R)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-7-fluoro-6-((2-fluoro-4-iodo Phenyl)amino)benzo[d][1,3]dioxol-5-carboxamide 26f (20 mg, 0.04 mmol) was dissolved in 2 mL of methanol, 1 mL of 1M hydrochloric acid was added, and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to obtain 30 mg of a crude product, which was purified by thin layer chromatography with developing solvent system A to obtain the title product (R)-N-( 2,3-Dihydroxypropoxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzo[d][1,3]dioxol-5 - Formamide 26 (4 mg, brown solid), yield: 22.2%.

MS m/z(ESI): 509.0[M+1]

¹ H NMR (400MHz, CD ₃ OD) δ 7.40(d, 1H), 7.28(d, 1H), 6.96(s, 1H), 6.43-6.38(m, 1H), 6.14(s, 2H), 3.92 -3.90(m, 1H), 3.83-3.79(m, 2H), 3.57-3.53(m, 2H).

Example 27

7-Fluoro-6-((2-Fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,3]dioxol-5 -Formamide

first step

7-Fluoro-6-((2-Fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d][1,3]dioxane Pentene-5-carboxamide

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)benzo[d][1,3]dioxol-5-carboxylic acid 26e (100 mg, 0.24 mmol) , O-(2-(vinyloxy)ethyl)hydroxylamine (26mg, 0.26mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea Hexafluorophosphate (140 mg, 0.36 mmol) was dissolved in 5 mL of N,N-dimethylformamide, N,N-diisopropylethylamine (93 mg, 0.72 mmol) was added, and the reaction was stirred at room temperature for 3 hours. 20 mL of water was added, extracted with ethyl acetate (20 mL×1), the organic phase was washed with water (20 mL×1) and saturated sodium chloride solution (20 mL×2) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , the resulting residue was purified by thin layer chromatography with developing solvent system B to give the title product 7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy) Ethoxy)benzo[d][1,3]dioxol-5-carboxamide 27a (80 mg, black solid), yield: 66.7%.

MS m/z(ESI): 502.9[M-1]

second step

7-Fluoro-6-((2-Fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,3]dioxol-5 -Formamide

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d][1,3]dioxa Cyclopentene-5-carboxamide 27a (80 mg, 0.07 mmol) was dissolved in 10 mL of methanol, 5 mL of 1M hydrochloric acid was added, and the reaction was stirred for 3 hours. 20 mL of water was added to the reaction solution, filtered, and the filter cake was washed with water (20 mL×1) and ethyl acetate (20 mL×2), and dried to obtain the title product 7-fluoro-6-((2-fluoro-4-iodobenzene) yl)amino)-N-(2-hydroxyethoxy)benzo[d][1,3]dioxol-5-carboxamide 27 (25 mg, white solid) in 78.1% yield. MS m/z(ESI): 479.2[M+1]

¹ H NMR (400MHz, CD ₃ OD) δ 11.7(s, 1H), 8.21(s, 1H), 7.53-7.50(m, 1H), 7.30-7.28(m, 1H), 7.03(s, 1H) , 6.42-6.40(m, 1H), 6.21(s, 2H), 4.71(t, 1H), 3.80(t, 2H), 3.53-3.51(m, 2H).

Example 28

(R)-(7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)benzo[d][1,3]dioxol-5-yl)(2- (Hydroxymethyl)pyrrolidin-1-yl)methanone

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)benzo[d][1,3]dioxol-5-carboxylic acid 26e (50 mg, 0.12 mmol) , D-prolinol (13mg, 0.13mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (70mg, 0.18mmol) ) and N,N-diisopropylethylamine (46 mg, 0.36 mmol) were dissolved in 10 mL of N,N-dimethylformamide, and the reaction was stirred for 3 hours. 20 mL of water was added, extracted with ethyl acetate (20 mL×1), the organic phase was washed with water (20 mL×1) and saturated sodium chloride solution (20 mL×2) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , the resulting residue was purified by thin layer chromatography with developing solvent system B to give the title product (R)-(7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzo[d][ 1,3]dioxol-5-yl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone 28 (10 mg, black solid), yield: 16.7%.

MS m/z(ESI): 503.2[M+1]

¹ H NMR (400MHz, CDCl ₃ )δ7.37-7.35(m,1H), 7.27-7.25(m,1H), 6.70(s,1H), 6.49-6.45(m,1H), 6.33(brs,1H) ), 6.10(s, 2H), 4.22-4.15(m, 2H), 3.72-3.69(m, 1H), 3.53-3.51(m, 1H), 3.49-3.38(m, 2H), 2.25-2.06(m , 2H), 1.82-1.78 (m, 2H).

Example 29

(R)-(7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)benzo[d][1,3]dioxol-5-yl)(4- Hydroxyisoxazol-2-yl)methanone

first step

(R)-(7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)benzo[d][1,3]dioxol-5-yl)(4- Hydroxyisoxazol-2-yl)methanone

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)benzo[d][1,3]dioxol-5-carboxylic acid 26e (50 mg, 0.12 mmol) , (R)-isoxazol-4-ol hydrochloride 17a (17mg, 0.13mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (70 mg, 0.18 mmol) and N,N-diisopropylethylamine (50 mg, 0.36 mmol) were dissolved in 10 mL of N,N-dimethylformamide, and the reaction was stirred at room temperature for 3 hours. 20 mL of water was added, extracted with ethyl acetate (20 mL×1), the organic phase was washed with water (20 mL×1) and saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, The resulting residue was purified by thin layer chromatography with developing solvent system B to give the title product (R)-(7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzo[d][1 ,3]dioxol-5-yl)(4-hydroxyisoxazol-2-yl)methanone 29 (20 mg, pink solid), yield: 33.3%.

MS m/z(ESI): 491.2[M+1]

¹ H NMR (400MHz, DMSO-d ₆ )δ7.55(s,1H), 7.48-7.45(m,1H), 7.27-7.25(m,1H), 6.37-6.35(m,1H), 6.21(s) , 2H), 5.58 (d, 1H), 4.61 (brs, 1H), 3.81-3.73 (m, 3H), 3.46 (d, 1H).

Example 30

(7-Fluoro-6-((2-Fluoro-4-iodophenyl)amino)benzo[d][1,3]dioxol-5-yl)(4-methylpiperazine -1-yl)methanone

first step

(7-Fluoro-6-((2-Fluoro-4-iodophenyl)amino)benzo[d][1,3]dioxol-5-yl)(4-methylpiperazine -1-yl)methanone

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)benzo[d][1,3]dioxol-5-carboxylic acid 26e (100 mg, 0.24 mmol) , N-methylpiperazine (26mg, 0.26mmol) was dissolved in 10mL N,N-dimethylformamide, and 2-(7-azobenzotriazole)-N,N,N',N was added. '-Tetramethylurea hexafluorophosphate (140 mg, 0.36 mmol) and N,N-diisopropylethylamine (93 mg, 0.72 mmol), and the reaction was stirred for 3 hours. 20 mL of water was added, extracted with ethyl acetate (20 mL×1), the organic phase was washed with water (20 mL×1) and saturated sodium chloride solution (20 mL×2) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , the resulting residue was purified by thin layer chromatography with developing solvent system B to give the title product (7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzo[d][1,3] m-dioxol-5-yl)(4-methylpiperazin-1-yl)methanone 30 (10 mg, pink solid), yield: 8.3%.

MS m/z(ESI): 500.2[M-1]

¹ H NMR (400MHz, CDCl ₃ ) δ 7.37-7.34(m,1H), 7.25-7.22(m,1H), 6.61(s,1H), 6.44-6.39(m,1H), 6.10(s,2H) ), 6.03-5.97 (m, 1H), 3.62-3.34 (m, 8H), 2.23 (s, 3H).

Example 31

(7-Fluoro-6-((2-Fluoro-4-iodophenyl)amino)benzo[d][1,3]dioxol-5-yl)(5-methyl-1H -imidazol-2-yl)methanone

first step

7-Fluoro-6-((2-Fluoro-4-iodophenyl)amino)benzo[d][1,3]dioxol-5-acid chloride

7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)benzo[d][1,3]dioxol-5-carboxylic acid 26e (50 mg, 0.12 mmol) It was dissolved in 3 mL of toluene, thionyl chloride (19 mg, 0.14 mmol) and 1 drop of N,N-dimethylformamide were added dropwise, the temperature was raised to 60° C., and the reaction was carried out for 2 hours. Distillation under reduced pressure gave the crude title product 7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzo[d][1,3]dioxol-5-acid chloride 31a (55 mg, black solid), used directly in the next step.

second step

(7-Fluoro-6-((2-Fluoro-4-iodophenyl)amino)benzo[d][1,3]dioxol-5-yl)(5-methyl-1 -((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanone

5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole 31b (25 mg, 0.12 mmol, was prepared by the known method "Journal of Organic Chemistry, 1986, 51" (10), prepared from 1891-4") was dissolved in 2 mL of tetrahydrofuran, n-butyllithium (0.1 mL, 0.15 mmol) was added dropwise at -78 °C, the reaction was stirred for 20 minutes, and 1 mL of crude 7-fluoro-6- A solution of ((2-fluoro-4-iodophenyl)amino)benzo[d][1,3]dioxol-5-acid chloride 31a (55 mg, 0.12 mmol) in tetrahydrofuran, warmed to room temperature, Stir for 20 minutes. The reaction was quenched by adding 5 mL of water, extracted with ethyl acetate (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography with developing solvent system B , to give the title product (7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzo[d][1,3]dioxol-5-yl)(5- Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanone 31c (5 mg, yellow oil), yield: 7.2%.

MS m/z(ESI): 614.2[M+1]

third step

(7-Fluoro-6-((2-Fluoro-4-iodophenyl)amino)benzo[d][1,3]dioxol-5-yl)(5-methyl-1H -imidazol-2-yl)methanone

(7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzo[d][1,3]dioxol-5-yl)(5-methyl- 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanone 31c (5 mg, 0.01 mmol) was dissolved in 2 mL of ethanol, 2 mL of 4M hydrochloric acid was added, and heated To 60°C, the reaction was stirred for 3 hours. 5 mL of water was added to the reaction solution, and sodium bicarbonate solution was added dropwise to adjust the pH to 9-10, extracted with ethyl acetate (20 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified with developing solvent system B to give the title product (7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzo[d][1,3]dioxolane Alken-5-yl)(5-methyl-1H-imidazol-2-yl)methanone 31 (1.2 mg, yellow solid), 30.7% yield.

MS m/z(ESI): 484.0[M+1]

Test case:

Biological evaluation

Test Example 1. Determination of MEK Kinase Activity by Compounds of the Invention

In vitro MEK kinase activity was tested by the following method.

MEK kinase used in this experiment: MEK 1 (Recombinant Human Protein, Invitrogen, Cat. No. PV3093).

Kit used: Z'-LYTE ^™ Kinase Assay Kit-Ser/Thr 03Peptide (Invitrogen, Cat. No. PV3176).

The in vitro cell experiments described below can determine the proliferation inhibitory activity of the test compounds on MEK kinase. The test compounds are dissolved in dimethyl sulfoxide according to the concentration required by the experiment, and the compound DMSO solution is prepared. The concentrations are: 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.125 μM, 1.5625 μM, 0.78125 μM, 0.390625 μM, 0.1953125 μM, 0.09765625 μM, and 0.048828125 μM. Prepare 1× Buffer A (Invitrogen, Cat. No. PV3189); dilute ATP with 1× Buffer A to obtain a 400 μM ATP solution, mix an appropriate amount of Z'-LYTE ^™ Ser/Thr 03Peptide (Invitrogen, Cat. No. PV3200), MEK kinase (MEK1) enzyme and 1 × Buffer A mixed; appropriate amount of Z'-LYTE ^™ Ser/Thr 03phosphoPeptide substrate (Invitrogen, product number PV3215) and 1 × Buffer A were prepared into a mixed solution for use, and the test compound DMSO solution was prepared with 1 × buffer to make 4% DMSO Compound solution, add 2.5μL of test compound DMSO solution to the reaction well, use 1×Buffer A, 2.5μL of 400μM ATP solution and 5μL of enzyme and substrate mixture to form a 10μL reaction system, after incubation at 37°C for 4 hours, follow Reagent A: Buffer B = 1:1024 to prepare the mixture, add 5 μL of the mixture of Reagent A (Invitrogen, Catalog No. PV3295) and Buffer B (Invitrogen, Catalog No. P3127) to the reaction wells, incubate at 25°C for 60 min, and use a NovoStar microplate reader to read the fluorescence , excitation wavelength: 400nm, emission wavelength: 445nm and 520nm.

Activity of the compound of the present invention: The biochemical inhibitory activity of the compound of the present invention against MEK kinase (MEK 1) was determined by the above test, and the measured IC ₅₀ values are shown in Table 1.

Table 1 Inhibitory activity of the compounds of the present invention on MEK kinase (MEK 1)

Example number Mek1 1 1.01 2 3.48 3 1.74 4 29.76 5 5.66 6 7.62 7 62.82 8 5.67 9 21.47 13 6.96 14 6.01 15 11.65 16 83.69 26 13.86 27 82.86

Conclusion: The compound of the present invention has obvious inhibitory effect on MEK 1 kinase activity.

Test Example 2. Assay for Inhibitory Proliferation of the Compounds of the Invention on MEK2 Kinase

In vitro MEK2 kinase activity was tested by the following method.

MEK kinases used in this experiment:

MAP2K2 (MEK2) Recombinant Human Protein (Invitrogen, Catalog No. PV3615)

MAPK1 (ERK2) Recombinant Human Protein (Invitrogen, Catalog No. PV3314)

Kit used in this experiment: Z'-LYTE ^™ Kinase Assay Kit-Ser/Thr 03Peptide (Invitrogen, Cat. No. PV3176).

The in vitro cell experiments described below can determine the proliferation inhibitory activity of the test compounds on MEK kinase. The test compounds are dissolved in dimethyl sulfoxide according to the concentration required by the experiment, and the compound DMSO solution is prepared. The concentrations are: 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.125 μM, 1.5625 μM, 0.78125 μM, 0.390625 μM, 0.1953125 μM, 0.09765625 μM, and 0.048828125 μM. Prepare 1× Buffer A (Invitrogen, Cat. No. PV3189); dilute ATP with 1× Buffer A to obtain a 400 μM ATP solution, mix an appropriate amount of Z'-LYTE ^™ Ser/Thr 03Peptide (Invitrogen, Cat. No. PV3200), MEK kinase (MEK2) enzyme, ( ERK2) enzyme was mixed with 1× Buffer A; an appropriate amount of Z’-LYTE ^™ Ser/Thr 03phosphoPeptide substrate (Invitrogen, product number PV3215) and 1× Buffer A were prepared into a mixed solution for use, and the test compound DMSO solution was prepared with 1× buffer solution 4% DMSO compound solution, add 2.5 μL 4% DMSO compound buffer solution, 2.5 μL 400 μM ATP solution and 5 μL enzyme and substrate mixture to the reaction well to form a 10 μL reaction system, after incubation at 25°C for 1.5 hours, Prepare the mixed solution according to Reagent A:Buffer B=1:1024, add 5 μL of the mixture of Reagent A (Invitrogen, Cat. No. PV3295) and Buffer B (Invitrogen, Cat. No. P3127) to the reaction well, incubate at 25°C for 60 min, use NovoStar enzyme The standard instrument reads fluorescence, excitation wavelength: 400nm, emission wavelength: 445nm and 520nm.

The MEK kinase (MEK 2) biochemical inhibitory activity of the compounds of the present invention was determined by the above test, and the IC ₅₀ values measured are shown in Table 2.

Table 2 Inhibitory activity of the compounds of the present invention on MEK kinase (MEK 2)

Example IC₅₀/(nM) 1 93.20 2 218.1 3 135.1 8 403.9 26 555.4

Conclusion: The compounds of the present invention have obvious inhibitory effect on MEK 2 kinase activity.

Test Example 3. Proliferation inhibition assay of the compounds of the present invention on Colo205

Source of cell line used in this experiment: Colo205 (Cell Bank of Chinese Academy of Sciences, product number TCHu102).

The in vitro cell assay described below can measure the proliferation inhibitory activity of the test compound on human colon cancer cell lines, and its activity can be expressed as an _IC50 value. The general scheme of this type of experiment is as follows: first, the cell line to be tested (purchased from the cell bank of the Chinese Academy of Sciences) is inoculated on a 96-well culture plate with a suitable cell concentration of 4000 cells/mL medium, and then the cells are incubated in a carbon dioxide incubator at 37°C. Incubate, let them grow overnight, change the medium to medium with a series of concentration gradients (10000nM, 1000nM, 100nM, 10nM, 1nM, 0.1nM) test compound solutions, put the culture plate back into the incubator, and continue Cultivate for 72 hours. After 72 hours, CCK8 (Cell Counting Kit-8, item number: CK04, purchased from Tongren Chemical) method can be used to test the activity of the compounds for inhibiting cell proliferation. _IC50 values can be calculated from the inhibition of cells by a test compound at a series of different concentrations.

The biological activity of the compounds of the present invention is obtained from the above analysis, and the calculated IC ₅₀ values are as follows in Table 3:

Table 3 The proliferation inhibitory activity of the compounds of the present invention on Colo205 cells

Example number Colo205 1 0.20 2 4.72 3 1.52 4 76.48 5 6.24 6 12.03 8 9.93 9 38.35 13 7.17 14 90.10 15 14.33 26 99.06

Conclusion: The preferred compounds of the present invention all have significant proliferation inhibitory activity on Colo205 cells.

Test Example 4. Assay for Inhibitory Proliferation of HCT116 Cells by Compounds of the Invention

The in vitro cell assay described below can measure the proliferation inhibitory activity of the test compound on human non-small cell lung cancer cells and human colon cancer cells, and the activity can be expressed by IC ₅₀ value.

Cell line used in this experiment: HCT116 (Cell Bank of Chinese Academy of Sciences, Cat. No. TCHu 99)

The general scheme of this type of experiment is as follows: first, the cell line to be tested is seeded on a 384-well cell culture plate at a suitable cell concentration of 1000 cells/well, and then the cells are cultured in a 37°C, 5% carbon dioxide incubator, and let them After growing overnight, the medium was replaced with a medium containing a series of concentration gradients (1000nM, 250nM, 62.50nM, 15.63nM, 3.91nM, 0.98nM, 0.24nM, 0.06nM, 0.015nM, 0.004nM) test compound solutions, Put the plate back into the incubator and incubate for 72 hours. After 72 hours, CCK8 (Cell Counting Kit-8, Cat. No.: CK04, purchased from Tongren Chemical) method can be used to test compounds for inhibiting cell proliferation activity. _IC50 values can be calculated from the inhibition of cells by a test compound at a series of different concentrations.

The biological activity of the compounds of the present invention is obtained from the above analysis, and the calculated IC ₅₀ values are as follows in Table 4:

Table 4 Proliferation inhibitory activity of the compounds of the present invention on HCT116 cells

Example IC₅₀/(nM) 1 1 2 12.38 8 106.50

Conclusion: The preferred compounds of the present invention all have obvious proliferation inhibitory activity on HCT116 cells.

Test Example 5. Assay for Inhibitory Proliferation of the Compounds of the Present Invention on Human Non-Small Cell Lung Cancer Cell A549

The in vitro cell assay described below can measure the proliferation inhibitory activity of the test compound on human non-small cell lung cancer cell A549, and its activity can be expressed as an _IC50 value.

Cell line: A549 (Cell Bank of Chinese Academy of Sciences, Cat. No. TCHu150)

Kit used: Cell Counting Kit-8 (CCK8, Cat. No.: CK04, purchased from Tongren Chemical)

The general scheme of this type of experiment is as follows: first, the cell line to be tested is seeded on a 384-well cell culture plate at a suitable cell concentration of 1000 cells/well, and then the cells are cultured in a 37°C, 5% carbon dioxide incubator, and let them After growing overnight, the medium was replaced with a medium containing a series of concentration gradients (1000nM, 250nM, 62.50nM, 15.63nM, 3.91nM, 0.98nM, 0.24nM, 0.06nM, 0.015nM, 0.004nM) test compound solutions, Put the plate back into the incubator and incubate for 72 hours. After 72 hours, CCK8 (Cell Counting Kit-8, Cat. No.: CK04, purchased from Tongren Chemical) method can be used to test compounds for inhibiting cell proliferation activity. _IC50 values can be calculated from the inhibition of cells by a test compound at a series of different concentrations.

The biological activity of the compounds of the present invention is obtained from the above analysis, and the calculated IC ₅₀ values are as follows in Table 4:

Table 5 Proliferation inhibitory activity of the compounds of the present invention on A549 cells

Example IC₅₀/(nM) 1 184.10 2 47.24 8 486.6

Conclusion: The preferred compounds of the present invention all have obvious proliferation inhibitory activity on A549 cells.

Pharmacokinetic evaluation

Test Example 6, Pharmacokinetic testing of the compounds of Example 1, Example 2 and Example 3 of the present invention

1. Abstract

Using SD rats as the test animals, the LC/MS/MS method was used to determine the drug concentrations in the plasma at different times after the rats were given the compounds of Example 1, Example 2 and Example 3 by gavage. The pharmacokinetic behavior of the compounds of the present invention in rats was studied, and their pharmacokinetic characteristics were evaluated.

2. Test plan

2.1 Test drug

Example 1, Example 2 and Example 3

2.2 Experimental animals

Twelve healthy adult SD rats were divided into 3 groups, 4 rats in each group, half male and half male, purchased from Shanghai Sipple-Bikai Laboratory Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2008-0016.

2.3 Drug preparation

Weigh an appropriate amount of sample, add 40 μL of Tween 80, add 0.5% CMC-Na, and sonicate to prepare a 1 mg/mL suspension.

2.4 Administration

12 SD rats were divided into 3 groups, 4 rats in each group, half male and half male, and were administered by gavage respectively after an overnight fast, the dose was 10 mg/kg, and the administration volume was 10 mL/kg.

3. Operation

Before administration and 0.5, 1, 2, 4, 6, 8, 11, and 24 hours after administration, 0.1 mL of blood was collected from the orbit, placed in a heparinized test tube, centrifuged at 3500 rpm for 10 minutes, separated from plasma, and stored at -20°C . Eat 2 hours after dosing.

LC/MS/MS method was used to determine the content of the test compound in the plasma of rats after intragastric administration. The linear range of the analytical method was 1.00-2000 ng/mL, and the lower limit of quantification was 1.00 ng/mL; the plasma samples were analyzed after pretreatment with precipitated proteins.

4. Pharmacokinetic parameter results

The pharmacokinetic parameters of the compounds of the present invention are as follows in Table 6:

Conclusion: The compound of the present invention has good pharmacokinetic absorption and has obvious pharmacokinetic absorption effect.

Claims (17)

1. a kind of logical formula (I) compound represented or its officinal salt:

Wherein:

For singly-bound or double bond；

P is selected from O, CR⁶Or-CR⁶R⁷-；

R¹、R²、R³Or R⁴It is each independently selected from hydrogen atom or halogen；

R⁵For-C (O) NR⁹R¹⁰；

R⁶Or R⁷It is each independently selected from hydrogen atom；

R⁹For hydrogen atom；

R¹⁰For C_1-6Alkoxy, wherein the C_1-6Alkoxy is optionally further selected from hydroxyl or C by one or more_3-6Cycloalkanes Replaced the substituent group of base；

N is 0.

2. logical formula (I) compound represented according to claim 1 or its officinal salt, to change shown in logical formula (II) Close object or its officinal salt:

Wherein:P, R¹~R³And R⁵Definition as described in the appended claim 1.

3. logical formula (I) compound represented according to claim 1 or its officinal salt, wherein R¹For halogen.

4. logical formula (I) compound represented according to claim 1 or its officinal salt, wherein R²Or R³For halogen.

5. logical formula (I) compound represented according to claim 1 or its officinal salt, wherein R⁴For hydrogen atom.

6. logical formula (I) compound represented according to claim 1 or its officinal salt, wherein R⁹For hydrogen atom；R¹⁰For C_1-6Alkoxy, wherein the C_1-6Alkoxy is optionally further replaced by one or two hydroxyls or by a C_3-6Cycloalkanes Replaced base.

7. compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from:

8. a kind of general formula (IA) compound represented or its officinal salt:

Wherein:

PG is-C (O) R^d；

R^dSelected from hydroxyl or halogen；And

N, P, R¹~R⁴Definition as described in the appended claim 1.

9. general formula (IA) compound represented according to claim 8 or its officinal salt, wherein the compound is selected from:

10. a kind of method for preparing compound or pharmaceutically acceptable salt thereof according to claim 1, this method comprises:

General formula (IA) compound and compound G or its reactant salt obtain logical formula (I) compound；

Wherein:

PG is-C (O) R^d, compound G is aminated compounds；

R^dSelected from hydroxyl；And

N, P, R¹~R⁵Definition as described in the appended claim 1.

11. a kind of pharmaceutical composition, described pharmaceutical composition contains any one institute according to claim 1~7 of therapeutically effective amount The compound or pharmaceutically acceptable salt thereof stated and one or more pharmaceutically acceptable carriers.

12. described in any item compound or pharmaceutically acceptable salt thereofs or according to claim 11 according to claim 1~7 Purposes of the pharmaceutical composition in the drug that preparation inhibits MEK.

13. purposes according to claim 12, to treat inflammatory conditions, autoimmune disease, cardiovascular disease in preparation Disease, proliferative diseases drug in purposes.

14. purposes according to claim 12 is the purposes in the drug of preparation treating cancer, wherein the cancer Selected from melanoma, brain tumor, the cancer of the esophagus, gastric cancer, liver cancer, cancer of pancreas, colorectal cancer, lung cancer, kidney, breast cancer, oophoroma, Prostate cancer, cutaneum carcinoma, neuroblastoma, sarcoma, osteoma, orchioncus, uterine cancer, H/N tumors, Huppert's disease, Malignant lymphoma, leukaemia, thyroid tumors, tumor of ureter, tumor of bladder, gallbladder cancer, cholangiocarcinoma, chorioepithelioma or Pediatric tumors.

15. purposes according to claim 12 is the purposes in the drug of preparation treating cancer, wherein the cancer Selected from osteosarcoma or seminoma.

16. purposes according to claim 12 is the purposes in the drug of preparation treating cancer, wherein the cancer Selected from osteochondroma, colorectal cancer or lung cancer.

17. purposes according to claim 14, wherein the drug further joins with another or a variety of anticancer agents Close application.