CN105949178B

CN105949178B - Benzimidazole compound, preparation method, intermediate and application thereof

Info

Publication number: CN105949178B
Application number: CN201610133605.7A
Authority: CN
Inventors: 张锐豪
Original assignee: Siegley Suzhou Biomedical Co Ltd
Current assignee: Siegley (Suzhou) biomedical Co., Ltd
Priority date: 2015-03-09
Filing date: 2016-03-09
Publication date: 2020-05-26
Anticipated expiration: 2036-03-09
Also published as: CN105949178A

Abstract

The invention discloses a benzimidazole compound, a preparation method, an intermediate and application thereof. The invention provides a benzimidazole compound A or a pharmaceutically acceptable salt thereof. The invention also provides application of the compound A or the pharmaceutically acceptable salt thereof in preparing a medicament for treating BRAF kinase and/or RET kinase related diseases. The invention also provides application of the compound A or the medicinal salt thereof in preparing BRAF kinase and/or RET kinase inhibitors. The compound has better effect of inhibiting BRAF and RET kinase.

Description

Benzimidazole compound, preparation method, intermediate and application thereof

Technical Field

The invention relates to a benzimidazole compound, a preparation method, an intermediate and application thereof.

Background

Raf is a multigene family expressing oncogene protein kinases: A-Raf, B-Raf andC-Raf (also known as Raf-1) and subtype variants resulting from differential splicing of mRNA are known (see McCubrey, JA et al 1998 in Leukemia "Leukemia" 12 (12): 1903-. All three Raf kinases are functionally present in certain specific human hematopoietic cells, and their aberrant expression can lead to a abrogation of cytokine dependence. Since C-Raf and A-Raf require additional serine phosphorylation as well as tyrosine phosphorylation in the N region of the kinase domain in order to obtain full activity, there is a difference in the regulatory mechanisms of the three Raf kinases (see Masorl et al, 1999, EMBO J, J. European journal of molecular biologies 18, 2137-S. 2148), and B-Raf has a much higher basal kinase activity than either A-Raf or C-Raf. The three Raf oncogene proteins play a vital role in the transmission process of mitogen signals and anti-apoptosis signals. Recently, it has been shown that B-Raf undergoes frequent mutations in various human cancers (see Wan et al Cell 116, 855-867, 2004), while wild-type C-Raf is often over-activated in different human solid tumors (see Wilhelm et al Drug Discovery Nature Reviews 5, 835-844, 2006). Studies have shown that mutation of B-Raf in skin nevi is a crucial step in melanoma formation (see Pollock et al, Nature Genetics 25: 1-2, 2002). In addition, studies have shown that activating mutations occur in the kinase domain of B-Raf in approximately 66% of malignant melanomas, 12% of colon cancers and 14% of liver cancers (see Dayies et al, Nature 417: 949-954, 2002; Yuen et al, Cancer Research, 2002The disease research 62, 6451-; brose et al, 2002, Cancer Research, 62, 6997-7000). In another aspect, over-activation of C-Raf is common in renal cell carcinoma (50%), hepatocellular carcinoma (100%), ovarian cancer, and the androgenic prostate cancer (see Wilhelm et al, Nature Reviews Drug Discovery review, 5, 835-844, 2006). Detection of mutations in B-Raf and over-activation of C-Raf in various human cancers, definition of wild-type Raf and mutant Raf as tumor antigens, and use of Raf inhibitors

(Sorafenib, BAY43-9006) has attracted a wide range of interest in the scientific community for positive results in clinical trials to evaluate.

Small molecule inhibitors of the Raf/meiosis specific kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway have been investigated for use in anti-cancer therapy (see Thompson et al, 2005, published in Current opinion in Pharmacology, modern opinion of Pharmacology, 5, 1-7; U.S. published application 2003/0216446). Raf kinase inhibitors have been proposed for use in effecting disruption of tumor cell growth and are therefore useful in the treatment of cancers such as histiocytic lymphoma, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer and breast cancer. Raf kinase inhibitors may also be useful in the treatment and/or prevention of disorders associated with neuronal degeneration caused by ischemic events, including cerebral ischemia following cardiac arrest, stroke and multi-infarct dementia, as well as those events occurring after cerebral ischemia, such as those caused by head injury, surgery and/or during labor (nerve trauma).

RET is a neuronal growth factor receptor tyrosine kinase that plays an important role in the formation and survival of skin and intestinal tract afferent receptor cells. RET kinase knockout mice lack enteric neurons and have other nervous system abnormalities, suggesting that functional RET kinase protein products are required for Development (Taraviras, s.et al, Development, 1999, 126: 2785.) studies in patients with congenital megacolon disease show a higher proportion of functional RET mutational deletions than familial and sporadic (butlertiadenn, trans.res, 2013, 162: 1). In addition, RET has also been found to be closely related to irritable bowel syndrome (IBS for short) (Keszthelyi, D., Eur.J. Pain, 2012, 16: 1444; Spiegel, B., et al., am.J. gastroenterol., 2008, 103: 2536).

Similarly, abnormal RET kinase activity is associated with diverse endocrine adenomas (MEN 2A and 2B), familial medullary thyroid tumors (FMTC), thyroid papillary carcinomas (PTC), and congenital megacolon disease (HSCR) (Borello, m., et al, expetpain. the target, 2013, 17: 403). MEN 2A is a cancer syndrome, resulting in dimerization of disulfide bonds by mutation of the extracellular cysteine-rich region of RET, leading to continuous activation of the activity of the tyrosine kinase (Wells Jr, s., et al, j.clin.endocrinol.meta., 2013, 98: 3149). Individuals with such mutations may develop medullary thyroid tumors (MTC), thyroid hyperplasia, and pheochromocytoma. MEN 2B and MEN 2A are similar, but without thyroid hyperplasia, also cause various mucosal ganglions of the lips, tongue and intestinal tract. RET is thought to intervene in tumor initiation by PTC during chromosome recapture (viglititto, g.et al, Oncogene, 1995, 11: 1207). PTC comprises 80% of thyroid tumors.

These facts indicate that the inhibition of RET may be an ideal therapeutic means for treating pain related to irritable bowel syndrome and other gastrointestinal disorders, and for treating tumors associated with sustained RET activation.

The literature (Savithri Ramurthy et al, ACS Med. chem. Lett.2014, 5, 989-992) reports acetamidopyridine compounds

IC for BRAF (V600E)₅₀Less than 50nM (3 nM), but it only has some inhibitory effect on BRAF kinase.

Therefore, there is a need in the art for compounds that inhibit both BRAF and RET kinase with superior efficacy.

Disclosure of Invention

The invention aims to solve the technical problem of providing a benzimidazole compound, a preparation method, an intermediate and an application thereof, wherein the compound has a good effect of inhibiting BRAF and RET kinase.

The invention provides a benzimidazole compound A or a pharmaceutically acceptable salt thereof, which has the following structure:

wherein R is¹、R²And R³Each independently is a hydrogen atom, a cyano group, a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom), C₁～C₆Alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably methyl) or C₁～C₆Alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, or tert-butoxy, preferably methoxy);

R⁴is C₁～C₆Alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably methyl) or "halogen atom-substituted C₁～C₆Alkyl groups of (a); said "halogen atom substituted C₁～C₆The alkyl group of (A) is preferably a halogen atom-substituted C₁～C₄Alkyl groups of (a); said "halogen atom substituted C₁～C₄The halogen atom in the "alkyl group" of (1) is preferably a fluorine atom, a chlorine atom or a bromine atom, and when a plurality of halogen atoms are present, the halogen atoms may be the same or different; said "halogen atom substituted C₁～C₄Alkyl group of (2)' C₁～C₄The alkyl group of (1) "may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; said "halogenC substituted by elemental atoms₁～C₄The alkyl group of (a) is preferably a methyl group substituted with one or more of a fluorine atom, a chlorine atom and a bromine atom or an ethyl group substituted with one or more of a fluorine atom, a chlorine atom and a bromine atom; the "methyl group substituted with a fluorine atom" is preferably a trifluoromethyl group;

R⁵、R⁶、R⁷、R⁸and R⁹Each independently a hydrogen atom, a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom), or "halogen atom-substituted C₁～C₆Alkyl group of (2), "halogen atom substituted C₁～C₆Alkoxy group of ″, C₁～C₆Alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably tert-butyl), C₁～C₆Alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or tert-butoxy, preferably methoxy), C₁～C₆Alkyl mercapto group of (said "C)₁～C₆Alkyl mercapto group of (2)' C₁～C₆The alkyl group of (a) may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; said "C₁～C₆The alkylmercapto group of (1)' is preferably methylmercapto), C₁～C₆Alkylsulfonyl (said "C)₁～C₆Alkylsulfonyl of (1)', C₁～C₆The alkyl group of (a) may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; said "C₁～C₆The alkylsulfonyl group of (1) is preferably a methylsulfonyl group), C₃～C₆A cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl), a phenyl group, a C group having 1 to 2 hetero atoms as oxygen, sulfur or nitrogen atoms₂～C₆The heterocycloalkyl group (e.g., pyranyl, piperidyl or morpholinyl) or the "C having 1 to 3 hetero atoms and being oxygen, sulfur or nitrogen atom₄～C₉Heteroaryl of (e.g. as pyrazole)A phenyl or a quinolyl group); said "halogen atom substituted C₁～C₆The alkyl group of (A) is preferably a halogen atom-substituted C₁～C₄Alkyl groups of (a); said "halogen atom substituted C₁～C₄The halogen atom in the "alkyl group" of (1) is preferably a fluorine atom, a chlorine atom or a bromine atom, and when a plurality of halogen atoms are present, the halogen atoms may be the same or different; said "halogen atom substituted C₁～C₄Alkyl group of (2)' C₁～C₄The alkyl group of (1) "may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; said "halogen atom substituted C₁～C₄The alkyl group of (a) is preferably a methyl group substituted with one or more of a fluorine atom, a chlorine atom and a bromine atom or an ethyl group substituted with one or more of a fluorine atom, a chlorine atom and a bromine atom; the "methyl group substituted with a fluorine atom" is preferably a trifluoromethyl group; said "halogen atom substituted C₁～C₆The alkoxy group of (A) is preferably a halogen atom-substituted C₁～C₄Alkoxy groups of "; said "halogen atom substituted C₁～C₄The halogen atom in the "alkoxy group of (1)" is preferably a fluorine atom, a chlorine atom or a bromine atom, and when a plurality of halogen atoms are present, the halogen atoms may be the same or different; said "halogen atom substituted C₁～C₄Alkoxy group of (2)' C₁～C₄The alkoxy group of (1) "may be methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or tert-butoxy; said "halogen atom substituted C₁～C₄The alkoxy group of (a) is preferably a methoxy group substituted with one or more of a fluorine atom, a chlorine atom and a bromine atom or an ethoxy group substituted with one or more of a fluorine atom, a chlorine atom and a bromine atom; the "methoxy group substituted with a fluorine atom" is preferably a trifluoromethoxy group;

R¹⁰is C₁～C₄Alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably methyl) or C₃～C₆Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, preferably cyclopropyl);

said R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹And R¹⁰Can also be respectively and independently coated with C₁～C₆Alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably methyl), C₁～C₆Alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or tert-butoxy, preferably methoxy), "halogen atom-substituted C₁～C₆And "halogen atom-substituted C₁～C₆Substituted with one or more of "alkoxy", which when substituted with a plurality of substituents may be the same or different; said "halogen atom substituted C₁～C₆The alkyl group of (A) is preferably a halogen atom-substituted C₁～C₄Alkyl groups of (a); said "halogen atom substituted C₁～C₄The halogen atom in the "alkyl group" of (1) is preferably a fluorine atom, a chlorine atom or a bromine atom, and when a plurality of halogen atoms are present, the halogen atoms may be the same or different; said "halogen atom substituted C₁～C₄Alkyl group of (2)' C₁～C₄The alkyl group of (1) "may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; said "halogen atom substituted C₁～C₄The alkyl group of (a) is preferably a methyl group substituted with one or more of a fluorine atom, a chlorine atom and a bromine atom or an ethyl group substituted with one or more of a fluorine atom, a chlorine atom and a bromine atom; the "methyl group substituted with a fluorine atom" is preferably a trifluoromethyl group; said "halogen atom substituted C₁～C₆The alkoxy group of (A) is preferably a halogen atom-substituted C₁～C₄Alkoxy groups of "; said "halogen atom substituted C₁～C₄The halogen atom in the "alkoxy group of (1)" is preferably fluorineAn atom, a chlorine atom or a bromine atom, and when a plurality of halogen atoms are present, the halogen atoms may be the same or different; said "halogen atom substituted C₁～C₄Alkoxy group of (2)' C₁～C₄The alkoxy group of (1) "may be methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or tert-butoxy; said "halogen atom substituted C₁～C₄The alkoxy group of (a) is preferably a methoxy group substituted with one or more of a fluorine atom, a chlorine atom and a bromine atom or an ethoxy group substituted with one or more of a fluorine atom, a chlorine atom and a bromine atom; the "methoxy group substituted with a fluorine atom" is preferably a trifluoromethoxy group.

In the compound A, the R¹Preferably a hydrogen atom, a cyano group, a halogen atom, or C₁～C₆Alkyl group of (1).

In the compound A, the R²Preferably a hydrogen atom or C₁～C₆Alkyl group of (1).

In the compound A, the R³Preferably a hydrogen atom or C₁～C₆Alkyl group of (1).

In the compound A, the R⁴Preferably C₁～C₆Alkyl group of (1).

In the compound A, the R⁵Preferably a hydrogen atom or a halogen atom.

In the compound A, the R⁹Preferably a hydrogen atom or a halogen atom.

In the compound A, the R⁶Preferably a hydrogen atom, a "halogen atom-substituted C₁～C₆Alkyl "or" halogen atom-substituted C₁～C₆An alkoxy group of ".

In the compound A, the R⁸Preferably a hydrogen atom, a "halogen atom-substituted C₁～C₆Alkyl "or" halogen atom-substituted C₁～C₆An alkoxy group of ".

In the compound A, the R⁷Preferably a hydrogen atom, a halogen atom or a "halogen atom-substituted C₁～C₆Alkyl groups of (1).

In the compound A, the R¹⁰Preferably C₁～C₄Alkyl or C₃～C₆Cycloalkyl, more preferably methyl or cyclopropyl.

In said compound A, preferably said R¹、R²And R³At least two of which are hydrogen atoms.

In said compound A, preferably said R⁵And R⁹At least one of which is a hydrogen atom.

In said compound A, preferably said R⁶And R⁸At least one of which is a hydrogen atom.

In said compound A, preferably said R⁵、R⁶、R⁷、R⁸And R⁹At least three of which are hydrogen atoms.

In said compound A, preferably said R⁵、R⁶、R⁷、R⁸And R⁹At least one of which is "halogen atom-substituted C₁～C₆Alkyl "or" halogen atom-substituted C₁～C₆An alkoxy group of ".

For RET kinase, the above-mentioned substituents are further preferably as follows:

In the compound A, the R⁴Preferably C₁～C₆Alkyl group of (1).

In the compound A, the R⁵Preferably a hydrogen atom or a halogen atom.

In the compound A, the R⁹Preferably a hydrogen atom or a halogen atom.

In the compound A, the R⁷Preferably a hydrogen atom, a halogen atom or a "halogen atom-substituted C₁～C₆More preferably a hydrogen atom or a "halogen atom-substituted C₁～C₆Alkyl groups of (1).

In the compound A, the R¹⁰Preferably C₁～C₄Alkyl or C₃～C₆Cycloalkyl, more preferably C₃～C₆Cycloalkyl, most preferably cyclopropyl.

For BRAF (V600E) kinase, the above substituents are further preferably as follows:

in the compound A, the R¹Preferably a hydrogen atom, a cyano group, a halogen atom, or C₁～C₆More preferably a hydrogen atom or a cyano group.

In the compound A, the R⁴Preferably C₁～C₆Alkyl group of (1).

In the compound A, the R⁵Preferably a hydrogen atom or a halogen atom.

In the compound A, the R⁹Preferably a hydrogen atom or a halogen atom.

In the compound A, the R⁶Preferably a hydrogen atom, a "halogen atom-substituted C₁～C₆Alkyl "or" halogen atom-substituted C₁～C₆More preferably a hydrogen atom or a "halogen atom-substituted C₁～C₆Alkyl groups of (1).

In the compound A, the R⁸Preferably a hydrogen atom, a "halogen atom-substituted C₁～C₆Alkyl "or" halogen atom-substituted C₁～C₆More preferably a hydrogen atom or a "halogen atom-substituted C₁～C₆Alkyl groups of (1).

In the compound A, the R⁷Preferably a hydrogen atom, a halogen atom (e.g. chlorine atom) or a "halogen atom-substituted C₁～C₆Alkyl groups of (1).

In the compound A, the R¹⁰Preferably C₃～C₆Cycloalkyl, more preferably cyclopropyl.

For BRAF kinase, the above substituents are further preferably as follows:

in the compound A, the R¹Preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom.

In the compound A, the R³Preferably a hydrogen atom or C₁～C₆More preferably a hydrogen atom.

In the compound A, the R⁴Preferably C₁～C₆Alkyl group of (1).

In the compound A, the R⁵Preferably a hydrogen atom or a halogen atom.

In the compound A, the R⁹Preferably a hydrogen atom or a halogen atom.

In the compound A, the R⁷Preferably a hydrogen atom, a halogen atom or a "halogen atom-substituted C₁～C₆More preferably "C substituted with a halogen atom₁～C₆Alkyl groups of (1).

Preferably, the compound A is any one of the following compounds:

the compound A can exist in all or part of tautomeric forms.

According to the reports in the literature (Paul T.C. Wan (2004), Cell, Vol.116, 855-867), the compounds similar to the compounds for inhibiting BRAF kinase in the present patent generally adopt pyridine ring, and the lone pair of electrons on the nitrogen atom of the pyridine ring of the compounds form a key hydrogen bond with the amide-NH of the hinge region of the kinase in the process of combining with the active pocket of the BRAF kinase. It is also documented (Joule, John A.; Mills, Keith, eds. (2010); Heterocyclic Chemistry (5th ed.). Oxford: Wiley.p.250.Albert, Adrien (1968); Heterocyclic Chemistry, and introduction.London: Athlone Press.pp.437-439), that generally, the greater the electron density of a nitrogen atom on a pyridine ring, i.e., the more basic, the stronger the hydrogen bond formed, the more active the corresponding compound inhibits the enzyme, and conversely, the lower the electron density of the nitrogen atom (e.g., the pyrimidine ring), i.e., the less basic, the weaker the hydrogen bond formed with the enzyme, the weaker the less active the corresponding compound inhibits the kinase.

However, in the present invention, it has been unexpectedly found that although the electron density on the nitrogen atom of the pyrimidine ring formed by substituting nitrogen at a specific position on the pyridine ring is sharply decreased and the basicity is decreased, the obtained compound (i.e. the compound containing pyrimidine ring) not only exhibits better activity for inhibiting BRAF kinase, but also exhibits good activity for inhibiting RET kinase at the same time | RET is different from BRAF, and is a transmembrane Receptor Tyrosine Kinase (RTKs), and unlike other RTKs, the glial cell derived nerve factor family (GFLs) must first combine with GFR α co-receptor to form heterodimeric complex, and then undergo a series of physiological processes to activate RET signaling, and further activate RAS-MAPK and PI3K-AKT signal channels, so that if the compound inhibits RET and BRAF at the same time, the synergistic inhibition effect of the compound on both will make the therapeutic effect better in treating diseases related to the abnormality of the kinase.

The invention also provides a preparation method of the compound A, which comprises the following steps: in an alcohol solvent, in the presence of a desulfurizing agent, carrying out cyclization reaction on a compound B to obtain a compound A;

in the preparation method of the compound a, the alcohol solvent may be an alcohol solvent conventional in the art, and preferably methanol.

In the preparation method of the compound a, the volume mol ratio of the alcohol solvent to the compound B may be a volume mol ratio conventional in the art, preferably 2L/mol to 10L/mol, and more preferably 5L/mol to 8L/mol.

In the preparation method of the compound A, the desulfurizing agent can be a desulfurizing agent conventional in the reaction in the field, and preferably is ferric trichloride, 2-chloro-1-methylpyridine iodide (Mukaiyama reagent), modified Mukaiyama reagent, 2-chloro-1, 3-dimethylimidazole chloride, POCl₃And halogenated alkanes (e.g., methyl iodide).

In the preparation method of the compound a, the molar ratio of the desulfurizing agent to the compound B may be a molar ratio conventional in the art, preferably 0.5 to 1, and more preferably 0.65 to 0.8.

The preparation method of the compound A can also be carried out in the presence of an organic base; the organic base may be any organic base conventional in the art, preferably pyridine; the molar ratio of the organic base to the compound B may be a molar ratio conventionally used in the art, and is preferably 1 to 3, more preferably 1.75 to 2.

In the preparation method of the compound A, the temperature of the cyclization reaction can be a temperature conventional in the field, and is preferably 10-35 ℃.

In the preparation method of the compound a, the progress of the cyclization reaction can be monitored by a monitoring method (e.g. TLC) which is conventional in the art for such cyclization reactions, and generally, when the compound B disappears, the reaction end point is taken as the reaction time, and the reaction time is preferably 1 hour to 24 hours, more preferably 8 hours to 12 hours.

The preparation method of the compound A can also comprise the following steps: performing addition reaction on the compound C and the compound D in an alcohol solvent to obtain a compound B;

in the preparation method of the compound B, the alcohol solvent may be an alcohol solvent conventional in the art, preferably methanol.

In the preparation method of the compound B, the volume mol ratio of the alcohol solvent to the compound C may be a volume mol ratio conventional in the art, preferably 2L/mol to 10L/mol, and more preferably 5L/mol to 8L/mol.

In the preparation method of the compound B, the molar ratio of the compound D to the compound C may be a molar ratio conventional in the art, preferably 1 to 3, and more preferably 1.5 to 2.

In the preparation method of the compound B, the temperature of the addition reaction can be the conventional temperature of the reaction in the field, and is preferably 10-35 ℃.

In the preparation method of the compound B, the progress of the addition reaction can be monitored by a conventional monitoring method (e.g. TLC) of the cyclization reaction in the art, and generally, the end point of the reaction is the disappearance of the compound C, and the reaction time is preferably 1 to 24 hours, more preferably 8 to 12 hours.

The preparation method of the compound A can also comprise the following steps: in an organic solvent, carrying out reduction reaction on the compound E in the presence of saturated ammonium chloride aqueous solution and zinc to obtain a compound C; the organic solvent is an alcohol solvent and/or an ether solvent;

in the preparation method of the compound C, the organic solvent is preferably an organic solvent in which the volume ratio of the alcohol solvent to the ether solvent is 5-8; the alcohol solvent can be alcohol solvent which is conventional in the field, preferably ethanol; the ethereal solvent may be one conventional in the art, and is preferably tetrahydrofuran.

In the preparation method of the compound C, the volume mol ratio of the organic solvent to the compound E can be the volume mol ratio conventional in the art, preferably 2L/mol to 10L/mol, and more preferably 5L/mol to 8L/mol.

In the preparation method of the compound C, the volume molar ratio of the saturated aqueous solution of ammonium chloride to the compound E can be the volume molar ratio conventional in the art, and is preferably 2L/mol to 10L/mol, more preferably 4L/mol to 8L/mol.

In the preparation method of the compound C, the molar ratio of the zinc to the compound E may be a molar ratio conventional in the art, preferably 1 to 50, and more preferably 20 to 25.

In the preparation method of the compound C, the temperature of the reduction reaction may be a temperature conventional in the art, and is preferably 10 to 35 ℃.

In the preparation method of the compound C, the progress of the reduction reaction can be monitored by a conventional monitoring method (e.g. TLC) in the art for such reduction reaction, and generally, the end point of the reaction is the disappearance of the compound E, and the reaction time is preferably 1 hour to 10 hours, more preferably 3 hours to 5 hours.

The preparation method of the compound A can also comprise the following steps: carrying out substitution reaction on a compound F and a compound G in a polar aprotic solvent in the presence of an inorganic base to obtain a compound E;

in the preparation method of the compound E, the polar aprotic solvent can be a polar aprotic solvent which is conventional in the art, and is preferably N, N-dimethylformamide.

In the preparation method of the compound E, the volume molar ratio of the polar aprotic solvent to the compound F can be a volume molar ratio which is conventional in the art, and is preferably 1L/mol to 10L/mol, more preferably 1.5L/mol to 5L/mol.

In the preparation method of the compound E, the inorganic base can be an inorganic base conventional in the art, and preferably potassium carbonate.

In the preparation method of the compound E, the molar ratio of the inorganic base to the compound F may be a molar ratio conventional in the art, preferably 1 to 3, and more preferably 1.5 to 2.

In the preparation method of the compound E, the molar ratio of the compound G to the compound F can be a molar ratio conventional in the art, preferably 1 to 3, and more preferably 1.2 to 2.

In the preparation method of the compound E, the temperature of the substitution reaction can be a temperature conventional in the art, and is preferably 50 ℃ to 130 ℃, and more preferably 100 ℃ to 110 ℃.

In the preparation method of the compound E, the progress of the substitution reaction can be monitored by a conventional monitoring method (e.g. TLC) for the substitution reaction in the art, and generally, when the compound F disappears, the reaction end point is used, and the reaction time is preferably 1 hour to 10 hours, more preferably 3 hours to 5 hours.

The invention also provides a compound B, the structure of which is shown as follows:

wherein R is¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹And R¹⁰Are each independently as described above.

Preferably the following compounds:

the invention also provides a compound C, the structure of which is shown as follows:

wherein R is¹、R²、R³、R⁴And R¹⁰Are each independently as described above. Preferably the following compounds:

the invention also provides a compound E, the structure of which is shown as follows:

the invention also provides a compound G, the structure of which is shown as follows:

wherein R is¹、R²、R³And R⁴Are each independently as defined above, but said compound G is not

Preferably any one of the following compounds:

the invention also provides the application of the compound A or the pharmaceutically acceptable salt thereof in preparing a medicament for treating BRAF kinase and/or RET kinase related diseases; the BRAF kinase can be conventional BRAF kinase in the field, preferably wild-type BRAF kinase or mutant BRAF kinase; the mutant BRAF kinase can be a conventional mutant BRAF kinase in the field, and preferably is BRAF (V600E). The 'diseases related to BRAF kinase and/or RET kinase' can be treated by inhibiting BRAF kinase and/or RET kinase. The "BRAF kinase and/or RET kinase related diseases" can be cancer or Irritable Bowel Syndrome (IBS); the cancer is preferably one or more of breast cancer, intestinal cancer, prostate cancer, lung cancer, liver cancer, pancreatic cancer, stomach cancer, melanoma, medullary thyroid cancer, parathyroid cancer and pheochromocytoma.

The invention also provides the application of the compound A or the pharmaceutically acceptable salt thereof in preparing BRAF kinase and/or RET kinase inhibitors; the BRAF kinase can be conventional BRAF kinase in the field, preferably wild-type BRAF kinase or mutant BRAF kinase; the mutant BRAF kinase can be a conventional mutant BRAF kinase in the field, and preferably is BRAF (V600E).

The invention also provides a pharmaceutical composition comprising the compound a or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; preferably, the dose of compound a is a therapeutically effective amount.

The pharmaceutical compositions may be administered orally, for example in the form of tablets, coated tablets, dragees, hard or soft capsules, solutions, emulsions or suspensions; rectal administration is also possible, for example in the form of suppositories; parenteral administration, for example in the form of injections, is also possible.

The pharmaceutical compositions may be prepared by methods known in the art, for example, by conventional mixing, encapsulating, dissolving, granulating, emulsifying, encapsulating, dragee-making, or lyophilizing processes.

Pharmaceutically acceptable carriers for tablets, coated tablets, dragees and hard gelatine capsules include one or more of lactose, maize starch or derivatives thereof, talc, stearic acid or salts thereof. Pharmaceutically acceptable carriers for preparing soft capsules include one or more of vegetable oils, waxes and fatty oils; depending on the nature of the active ingredient, pharmaceutically acceptable carriers are generally not required in the case of soft capsules. Pharmaceutically acceptable carriers for the preparation of solutions or syrups are one or more of water, polyols, sucrose, invert sugar and glucose. Pharmaceutically acceptable carriers for injections include one or more of water, alcohols, polyols, glycerol, vegetable oils, phosphoric acid and surfactants. Pharmaceutically acceptable carriers for suppositories include one or more of natural or hardened oils, waxes, fatty oils and semi-solid polyols.

The pharmaceutically acceptable carrier may also include one or more of preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents or antioxidants.

The pharmaceutically acceptable carrier may also comprise other therapeutically valuable substances, for example an additional active ingredient other than compound a or a pharmaceutically acceptable salt thereof.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

In the present invention, "pharmaceutically acceptable salts" refer to conventional acid addition salts or base addition salts which retain the biological effectiveness and properties of compound a and which are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Examples of acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, maleic acid, lactic acid, fumaric acid, and the like. Examples of base addition salts include salts derived from ammonium, potassium, sodium and quaternary ammonium hydroxides, such as tetramethylammonium hydroxide. Chemical modification of a pharmaceutical compound (i.e., drug) into a salt is a technique well known to pharmaceutical chemists to achieve improved physical and chemical stability, hygroscopicity, flowability, and solubility of the compound.

As used herein, "pharmaceutically acceptable" in a "pharmaceutically acceptable carrier" means that it is pharmaceutically acceptable and substantially non-toxic to the subject to which the particular compound is administered.

In the present invention, "room temperature" means 10 ℃ to 35 ℃.

The positive progress effects of the invention are as follows: the compounds of the present invention have a superior effect of inhibiting BRAF and RET kinases.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

EXAMPLE 1 preparation of Compound F

To a reaction flask was added 4-amino-6-chloropyrimidine (6g, 46.5mmol), tetrahydrofuran (75mL), pyridine (9.0 mL). Cyclopropylcarbonyl chloride (5.3g, 50.7mmol) was added dropwise at room temperature. After the dropping is finished for 10 minutes, the reaction solution is heated to 60 ℃ and is reacted for 3 hours under the condition of heat preservation. After the reaction solution was cooled, it was diluted with water (100mL), extracted twice with ethyl acetate, and the organic phases were combined, washed with 1N hydrochloric acid and saturated brine and dried. After concentration, N- (6-chloropyrimidin-4-yl) cyclopropylcarboxamide (pale yellow solid, 4.2g, 45.8%) was obtained by beating with N-hexane. (MS: [ M +1] 198.0).

1H-NMR(CDCl3)：δ8.66(s，1H)；8.59(s，1H)；8.26(s，1H)；1.61(m，1H)；1.17(m，2H)；1.01(m，2H).

EXAMPLE 2 preparation of Compound G1

The first step is as follows: 4- (4-methoxybenzyl) hydroxy-2-nitroaniline

A500 mL reaction flask was charged with 4-amino-3-nitrophenol (30.8g, 0.2mol) and N-methylpyrrolidone (300 mL). Potassium tert-butoxide (24.7g, 0.22mol) was added in portions under ice-cooling, and after stirring for 30 minutes, 4-methoxybenzyl chloride (32.8g, 0.21mol) was added dropwise and reacted at room temperature for 3 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried, after spin-drying, the solid was slurried with methyl tert-butyl ether to give the title compound as a red-brown solid (29 g, 50%). (MS: [ M +1] 275.1).

1H-NMR(CDCl3)：δ7.65(d，1H)；7.34-7.44(m，5H)；7.14(dd，1H)；6.77(d，1H)；5.90(s，2H)；5.03(s，2H)；1.61(s，3H).

The second step is that: 4- (4-methoxybenzyl) oxy-N-methyl-2-nitroaniline

A250 mL reaction flask was charged with 4- (4-methoxybenzyl) hydroxy-2-nitroaniline (6.6g, 24mmol) and dimethylformamide (120 mL). Sodium hydride (1.15g, 29mmol) was added portionwise at zero degrees, and after stirring for 30 minutes, iodomethane (3.25g, 23mmol) was further added dropwise, and the reaction was carried out at room temperature for 2 hours. The reaction was poured into ice water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried to give the title compound (tan solid, 7.4g, 106% crude was used directly in the next step). (MS: [ M +1]289.1)

The third step: 4-methylamino-3-nitrophenol

4- (4-methoxybenzyl) oxy N-methyl-2-nitroaniline (7g, 24mmol), dichloromethane (35mL) and trifluoroacetic acid (35mL) were charged into a 100mL reaction flask, and reacted at room temperature for 6 hours, followed by concentration of the reaction mixture to obtain a reddish brown liquid (7.6 g). Silica gel column chromatography (eluent EA/PE is 10% -20%) to obtain the target product (2.7g, 66%) (MS: [ M +1] 169.1).

1H-NMR(DMSO-d6)：δ8.22(m，1H)；7.63(s，1H)；7.54(dd，1H)；7.17(d，1H)；5.31(s，1H)；3.02(d，3H).

EXAMPLE 3 preparation of Compound G2

The first step is as follows: ethyl (4-fluoro-2-methylphenyl) carbonate

A1000 mL reaction flask was charged with 2-methyl 4-fluorophenol (43g, 340mmol) and tetrahydrofuran (600 mL). It was cooled to 0 ℃ and potassium tert-butoxide (45.9g, 410mmol) was added portionwise. After the addition was complete, the reaction was stirred for 10 minutes, and ethyl chloroformate (40.5g, 375mmol) was added dropwise over 5 minutes. After the reaction solution was further stirred for 30 minutes, it was poured into water, the pH was adjusted to acidity with 1N hydrochloric acid, extracted with methyl t-butyl ether, and the organic phase was washed with water, washed with saturated brine and dried. After concentration, the title compound was obtained (yellow oil, 68 g).

The second step is that: ethyl (4-fluoro-2-methyl-5-nitrophenyl) carbonate

A1000 mL reaction flask was charged with sulfuric acid (500mL) and ethyl (4-fluoro-2-methylphenyl) carbonate (68g, 340 mol). Potassium nitrate (34.7g, 0.34mol) was added in portions under an ice bath. After 1 hour at room temperature, the reaction mixture was poured into 500mL of ice water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried, followed by spin-drying, and column chromatography on silica gel (eluent: ethyl acetate/petroleum ether: 0-10%) to give the title compound (reddish brown solid, 50.8g, 62%).

1H-NMR(CDCl3)：δ7.92(d，1H)；7.18(d，1H)；4.36(q，2H)；2.33(s，3H)；1.41(t，3H).

The third step: 2-methyl-4-methylamino-5-nitrophenol

A500 mL reaction flask was charged with ethyl (4-fluoro-2-methyl-5-nitrophenyl) carbonate (15g, 61mmol) and a solution of methylamine in ethanol (250 mL). The reaction was carried out at room temperature for 4 hours. The reaction was spin dried to give the title compound (tan solid, 12.7g, crude for next step). (MS: [ M +1]183.1)

1H-NMR(DMSO-d6)：δ8.18(d，1H)；7.49(s，1H)；6.95(s，1H)；5.39(s，1H)；3.01(d，3H)，2.28(d，3H).

EXAMPLE 4 preparation of Compound G3

Compound G3 was prepared according to the synthetic route of example 3,

(MS：[M+1]183.1)

EXAMPLE 5 preparation of Compound G4

Compound G4 was prepared according to the synthetic route of example 3,

(MS：[M+1]183.1)

EXAMPLE 6 preparation of Compound G5

The first step is as follows: n- (3-fluoro-4-methoxyphenyl) acetamide

A500 mL reaction flask was charged with 3-fluoro-4-methoxyaniline (30g, 0.21mol) and dichloromethane (100 mL). After cooling in an ice bath to 5 ℃ or lower, acetic anhydride (22mL, 0.23mol) was slowly added dropwise thereto, and the internal temperature of the reaction mixture was controlled to 30 ℃ or lower, thereby completing the addition over about 1 hour. After the ice bath was removed and the reaction mixture was stirred at room temperature for 5 hours, n-hexane (300mL) was added to the reaction mixture, and a large amount of solid was precipitated. After stirring for 1 hour, filtration was performed, and the filter cake was washed with n-hexane and dried under vacuum at 30 degrees to give the title compound (off-white solid powder, 28g, 72%). (MS: [ M +1] 184.1).

The second step is that: n- (5-fluoro-4-methoxy-2-nitrophenyl) acetamide

To a 250mL reaction flask were added concentrated sulfuric acid (50mL) followed by N- (3-fluoro-4-methoxyphenyl) acetamide (15g, 82 mmol). The mixture was cooled to 5 ℃ or lower in an ice bath, and nitric acid (13mL, 190mmol) was slowly added dropwise. After the completion of the dropping, the reaction solution was stirred for 1 hour. The reaction solution was then poured into ice water (250g) and stirred to precipitate a large amount of solid. After stirring for 1 hour, filtration was carried out and the filter cake was washed neutral with copious amounts of water and dried under vacuum at 40 ℃ to give the title compound as a yellow solid powder (15.9 g, 85%). (MS: [ M +1] 229.1).

The third step: 5-fluoro-4-methoxy-2-nitroaniline

A500 mL reaction flask was charged with N- (5-fluoro-4-methoxy-2-nitrophenyl) acetamide (15g, 66mmol), ethanol (40mL), water (100mL), and concentrated hydrochloric acid (100 mL). After heating and refluxing for 2 hours, the reaction solution was cooled to gradually precipitate a solid. Standing overnight, filtering, washing the filter cake with a little ethanol, and vacuum drying at 40 deg.C to obtain the target product (red solid powder, 5.3g, 43%) (MS: [ M +1] 187.0).

The fourth step: 5-fluoro-4-methoxy-N-methyl-2-nitroaniline

A250 mL reaction flask was charged with 5-fluoro-4-methoxy-2-nitroaniline (5.3g, 28mmol) and dimethylformamide (100 mL). After cooling in an ice bath to 5 ℃ or lower, sodium hydride (2.72g, 66mmol) was added in portions, and after stirring for 30 minutes, methyl iodide (4.34g, 31mmol) was further added dropwise. After the reaction was carried out at room temperature for 2 hours by removing the ice bath, the reaction mixture was poured into ice water, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure to give the title compound (red brown solid powder, 5.4g, 95% crude product was used directly in the next step). (MS: [ M +1]201.1)

The fifth step: 2-fluoro-4-methylamino-5-nitrophenol

A250 mL reaction flask was charged with 5-fluoro-4-methoxy-N-methyl-2-nitroaniline (5g, 25mmol) and dichloromethane (100 mL). Cooling to-60 ℃, slowly dropwise adding a boron tribromide (31g, 125mmol) dichloromethane solution (50mL), controlling the temperature of the reaction solution to-20 ℃, and keeping the temperature for reaction for 16 hours. Water (200mL) was slowly added dropwise to the reaction mixture, the reaction was quenched, the reaction mixture was allowed to stand for separation, the organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure to give a reddish brown oil (6 g). And (3) performing silica gel column chromatography separation (eluent EA/PE is 10% -30%) to obtain a target product (red solid powder 1.6g, 35%) (MS: M +1 187.1).

1H-NMR(DMSO-d6)：δ8.20(d，1H)；7.65(d，1H)；7.08(m，1H)；5.84(s，1H)；3.01(d，3H).

EXAMPLE 7 preparation of Compound G6

The first step is as follows: 1-bromo-5-fluoro-2- (4-methoxybenzyl) -4-nitrobenzene

A250 mL reaction flask was charged with 2-bromo-4-fluoro-5-nitrophenol (10g, 42mmol) and N-methylpyrrolidone (80 mL). After cooling to 5 ℃ or lower in an ice bath, potassium tert-butoxide (5.7g, 51mmol) was added in portions, and after stirring for 30 minutes, 4-methoxybenzyl chloride (7.2g, 46mol) was added dropwise and reacted at room temperature for 3 hours. The reaction solution was then poured into ice water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried, after which the solid was slurried with methyl tert-butyl ether to give the title compound as a pale yellow solid powder (10.3 g, 68%). (MS: [ M +1] 356.0).

The second step is that: 5-bromo-4- (4-methoxybenzyl) -N-methyl-2-nitroaniline

A500 mL reaction flask was charged with 1-bromo-5-fluoro-2- (4-methoxybenzyl) -4-nitrobenzene (10g, 28mmol) and methylamine in ethanol (120 mL). After 4 hours of reaction at room temperature, the reaction mixture was rotary-distilled under reduced pressure to remove the solvent to give a red oil, which was subjected to column chromatography on silica gel (eluent ethyl acetate/petroleum ether ═ 0% to 20%) to give the title compound (reddish brown solid, 6.9g, 67%). (MS: [ M +1]367.0)

The third step: 2- (4-methoxybenzyl) -5-methylamino-4-nitrobenzonitrile

In a 100mL reaction flask were added 5-bromo-4- (4-methoxybenzyl) -N-methyl-2-nitroaniline (6.5g, 18mmol), cuprous cyanide (3.24g, 36mmol) and N-methylpyrrolidinone (40mL) in that order. Heating to 150 ℃, and keeping the temperature for reaction for 6 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (150mL) was added thereto, followed by stirring for 30 minutes and filtration. The filtrate was washed twice with water, once with saturated brine, dried over anhydrous sodium sulfate, and rotary-evaporated under reduced pressure to remove the solvent to give the title compound (reddish brown solid, 4.1g, crude product used directly in the next step). (MS: [ M +1]314.1)

The fourth step: 2-hydroxy-5-methylamino-4-nitrobenzonitrile

2-hydroxy-5-methylamino-4-nitrobenzonitrile (4g, 13mmol), dichloromethane (20mL) and trifluoroacetic acid (20mL) were added sequentially to a 100mL reaction flask under ice-bath conditions. After 4 hours of reaction at room temperature, the reaction mixture was rotary-distilled under reduced pressure to remove the solvent, to obtain a reddish brown liquid (5 g). Silica gel column chromatography (eluent ethyl acetate/petroleum ether is 10% -30%) to obtain target product (red solid powder 1.4g, 56%) (MS: [ M +1] 194.1).

1H-NMR(DMSO-d6)：δ8.15(d，1H)；7.78(s，1H)；7.21(s，1H)；5.37(s，1H)；3.03(d，3H).

EXAMPLE 7 preparation of Compound A1

Synthesis of N- (6- ((1-methyl-2- ((4- (trifluoromethyl) phenyl) amine) -1H-benzimidazol-5-yl) hydroxy) pyrimidin-4-yl) cyclopropylcarboxamide

The first step is as follows: n- (6- (4- (methylamino) -3-nitrophenol) pyrimidin-4-yl) cyclopropylcarboxamide

A50 mL reaction flask was charged with 4-methylamino-3-nitrophenol (2.7g, 16mmol), potassium carbonate (2.8g, 20mmol), and dimethylformamide (20 mL). N- (6-Chloropyrimidin-4-yl) cyclopropylcarboxamide (2.6g, 13mmol) was added with stirring at room temperature. The reaction solution is heated to 110 ℃ and is reacted for 12 hours under the condition of heat preservation. After the reaction solution was cooled, the reaction solution was poured into ice water to precipitate a solid, which was stirred for 3 hours and then filtered. After drying the filter cake and slurrying with methyl tert-butyl ether, the desired product was obtained (yellow solid, 4g, 92%). (MS: [ M +1]330.1)

1H-NMR(DMSO-d6)：δ11.31(s，1H)；8.5(s，1H)；8.25(m，1H)；7.87(d，1H)；7.57(s，1H)；7.50(dd，1H)；7.07(d，1H)；2.99(d，3H)；2.04(m，1H)；0.85-0.88(m，4H).

The second step is that: n- (6- (3-amino-4- (methylamino) phenol) pyrimidin-4-yl) cyclopropylcarboxamide

A250 mL reaction flask was charged with N- (6- (4- (methylamino) -3-nitrophenol) pyrimidin-4-yl) cyclopropylcarboxamide (4g, 12mmol), ethanol (50mL), tetrahydrofuran (10mL) and saturated ammonium chloride solution (50 mL). Zinc powder (15.8g, 240mmol) was added portionwise with stirring at room temperature. The reaction was stirred for 3 hours and was complete. The reaction solution was filtered, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, dried over sodium sulfate, filtered and dried to obtain the desired product (off-white solid, 3.5g, 96%). (MS: [ M +1]300.1)

The third step and the fourth step: n- (6- ((1-methyl-2- ((4- (trifluoromethyl) phenyl) amine) -1H-benzimidazol-5-yl) hydroxy) pyrimidin-4-yl) cyclopropylcarboxamide

A50 mL reaction flask was charged with N- (6- (3-amino-4- (methylamino) phenol) pyrimidin-4-yl) cyclopropylcarboxamide (600mg, 2mmol) and methanol (10 mL). 1-isothiocyanate-4- (trifluoromethyl) benzene (603mg, 3mmol) was added dropwise with stirring at room temperature. After the reaction was stirred at room temperature for 12 hours, pyridine (553mg, 3.5mmol) and ferric trichloride (702mg, 1.3mmol) were further added, and the reaction was stirred at room temperature for 12 hours. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, dried over sodium sulfate, filtered and dried. Silica gel column chromatography (eluent ethyl acetate/petroleum ether 50% -80%) to obtain the target product (light brown solid powder, 330mg, 35%). (MS: [ M +1]469.1)

1H-NMR(DMSO-d6)：δ11.23(s，1H)；9.48(s，1H)；8.52(s，1H)；8.08(d，2H)；7.69(d，2H)；7.44(s，1H)；7.42(d，1H)；7.26(d，1H)；6.93(dd，1H)；3.79(s，3H)；2.00(m，1H)；0.78-0.83(m，4H).

EXAMPLE 8 preparation of Compounds A2-A31

Compounds A2-A31 (see Table 1) were prepared using the synthetic route of example 7.

TABLE 1

Effects of the embodiment

The compound of the invention has the inhibitory activity to RET kinase, and the experimental steps are as follows:

1. buffer solution preparation: RET 1-fold kinase buffer: 50mM HEPES, pH 7.5, 0.0015% Brij-35, 10mM MgCl₂，2mM DTT。

2. The compound was prepared in 100% DMSO at a gradient concentration, diluted 10-fold with the 1-fold kinase buffer described above to prepare an intermediate diluted compound containing 10% DMSO, 5ul of the intermediate diluted compound was added to a 384-well plate, and the final DMSO concentration in the reaction system was 2%.

3. RET kinase was released to optimal concentration with 1-fold kinase buffer. Add 10ul of kinase solution to 384 well plates and incubate with compound for a certain time.

4. Adding FAM-labeled polypeptide and ATP into 1-fold kinase buffer solution to prepare an optimal RET substrate solution: the reaction was started by adding 10ul of substrate solution to a 384 well plate and allowed to react at 28 ℃ for a certain period of time.

5. Preparing a stop solution: 100mM HEPES, pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent #3, 50mM EDTA. The reaction was stopped by adding 25. mu.l of stop solution, and the rate of conversion was read in a Caliper Reader and calculated as the inhibition rate.

The inhibitory activity of the compound of the invention on BRAF and BRAF (V600E) kinase comprises the following steps:

1. buffer solution preparation: BRAF or BRAF (V600E) 1-fold kinase buffer: 50mM HEPES, pH 7.5, 0.01%, Brij-35, 10mM MgCl2, 1mM EGTA.

2. The compound was prepared in 100% DMSO at a gradient concentration, diluted 25-fold with the 1-fold kinase buffer described above to prepare an intermediate diluted compound containing 4% DMSO, and 2.5ul of the intermediate diluted compound was added to a 384-well plate, and the final DMSO concentration in the reaction system was 1%.

3. BRAF or BRAF (V600E) kinase was made at optimal concentration with 1 fold kinase buffer. Add 5ul of kinase solution to 384 well plates and incubate with compound for a period of time.

4. The BRAF or BRAF (V600E) substrate is diluted with 1 time of kinase buffer solution to be prepared into the optimal concentration, and the final concentration of the substrate solution is Fluorescein-MAP2K10.2 mu M; BRAF ATP concentration 0.1. mu.M; BRAF (V600E) ATP concentration 1.5. mu.M. The reaction was started by adding 2.5ul of substrate solution to a 384 well plate and allowed to react at 28 ℃ for a certain period of time.

5. Preparing a stop solution: antibody 2nM, EDTA 10 mM. Adding 10ul of stop solution into a 384-well plate to stop reaction, uniformly mixing, standing at normal temperature for 30 minutes, detecting the result, copying the data of luminescence reading from an Envision program, and converting into the inhibition percentage.

The biological activities of the compounds A1-A31 of the present invention were measured by the above tests, and the results of the activity inhibition of RET, BRAF and BRAF (V600E) enzymes by the compounds are shown in Table 2, wherein ND indicates no test, and "A" indicates IC₅₀Values less than or equal to 50nM, "B" denotes IC₅₀A value greater than 50nM but less than or equal to 500nM, "C" denotes IC₅₀A value greater than 500nM but less than or equal to 1000nM, D representing IC₅₀Values greater than 1000 nM.

TABLE 2 in vitro Activity test results (IC) of Compound A₅₀，nM)

Claims

1. A benzimidazole compound A or a pharmaceutically acceptable salt thereof, which has the following structure:

wherein R is¹、R²And R³Each independently is a hydrogen atom, a cyano group, a halogen atom or C₁～C₆Alkyl groups of (a);

R⁴is C₁～C₆Alkyl or "halogen atom-substituted C₁～C₆Alkyl groups of (a);

R⁵、R⁶、R⁷、R⁸and R⁹Each independently is a hydrogen atom, a halogen atom, a "halogen atom-substituted C₁～C₆Alkyl group of (2), "halogen atom substituted C₁～C₆Alkoxy group of ″, C₁～C₆Alkyl of (C)₁～C₆Alkoxy radical, C₁～C₆Alkyl mercapto or C₃～C₆Cycloalkyl groups of (a);

R¹⁰is C₁～C₄Alkyl or C₃～C₆A cycloalkyl group.

2. The benzimidazole compound a or a pharmaceutically acceptable salt thereof according to claim 1, wherein when R is above¹、R²And R³When each is independently a halogen atom, the halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom;

and/or, when said R is¹、R²And R³Each independently is C₁～C₆When there is an alkyl group, said C₁～C₆Alkyl of (a) is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl;

and/or, when said R is⁴Is C₁～C₆When there is an alkyl group, said C₁～C₆Alkyl of (a) is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl;

and/or, when said R is⁴Is "halogen atomSub-substituted C₁～C₆When said "alkyl group" is substituted with a halogen atom, said "halogen atom-substituted C₁～C₆Alkyl of (A) is "halogen atom-substituted C₁～C₄Alkyl groups of (a);

and/or, when said R is⁵、R⁶、R⁷、R⁸And R⁹When each is independently a halogen atom, the halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom;

and/or, when said R is⁵、R⁶、R⁷、R⁸And R⁹Each independently being "halogen atom-substituted C₁～C₆When said "alkyl group" is substituted with a halogen atom, said "halogen atom-substituted C₁～C₆Alkyl of (A) is "halogen atom-substituted C₁～C₄Alkyl groups of (a);

and/or, when said R is⁵、R⁶、R⁷、R⁸And R⁹Each independently being "halogen atom-substituted C₁～C₆When said "alkoxy group" is substituted with a halogen atom, said "halogen atom-substituted C₁～C₆Alkoxy of (A) is "halogen atom-substituted C₁～C₄Alkoxy groups of ";

and/or, when said R is⁵、R⁶、R⁷、R⁸And R⁹Each independently is C₁～C₆When there is an alkyl group, said C₁～C₆Alkyl of (a) is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl;

and/or, when said R is⁵、R⁶、R⁷、R⁸And R⁹Each independently is C₁～C₆At alkoxy, said C₁～C₆Alkoxy is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or tert-butoxy;

and/or, when said R is⁵、R⁶、R⁷、R⁸And R⁹Each independently is C₁～C₆Alkyl mercapto of (2), saidC of (A)₁～C₆In the alkyl mercapto group of (1), said C₁～C₆Alkyl of (a) is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl;

and/or, when said R is⁵、R⁶、R⁷、R⁸And R⁹Each independently is C₃～C₆In the case of a cycloalkyl group of (A), said C₃～C₆The cycloalkyl group of (a) is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

and/or, when said R is¹⁰Is C₁～C₄When there is an alkyl group, said C₁～C₄Alkyl of (a) is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl;

and/or, when said R is¹⁰Is C₃～C₆When there is a cycloalkyl group, said C₃～C₆Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

3. The benzimidazole compound a or a pharmaceutically acceptable salt thereof according to claim 2, wherein when R is above⁴Is "halogen atom substituted C₁～C₄When said "alkyl group" is substituted with a halogen atom, said "halogen atom-substituted C₁～C₄In the "alkyl group", the halogen atom is a fluorine atom, a chlorine atom or a bromine atom, and when a plurality of halogen atoms are present, the halogen atoms are the same or different;

and/or, when said R is⁴Is "halogen atom substituted C₁～C₄When said "alkyl group" is substituted with a halogen atom, said "halogen atom-substituted C₁～C₄In the alkyl group of (1), "C" mentioned₁～C₄Alkyl of (a) is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl;

and/or, when said R is⁵、R⁶、R⁷、R⁸And R⁹Each independently being "halogen atom-substituted C₁～C₄When said "alkyl group" is substituted with a halogen atom, said "halogen atom-substituted C₁～C₄In the "alkyl group", the halogen atom is a fluorine atom, a chlorine atom or a bromine atom, and when a plurality of halogen atoms are present, the halogen atoms are the same or different;

and/or, when said R is⁵、R⁶、R⁷、R⁸And R⁹Each independently being "halogen atom-substituted C₁～C₄When said "alkyl group" is substituted with a halogen atom, said "halogen atom-substituted C₁～C₄In the alkyl group of (1), "C" mentioned₁～C₄Alkyl of (a) is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl;

and/or, when said R is⁵、R⁶、R⁷、R⁸And R⁹Each independently being "halogen atom-substituted C₁～C₄When said "alkoxy group" is substituted with a halogen atom, said "halogen atom-substituted C₁～C₄The "alkoxy group" of (a), wherein the halogen atom is a fluorine atom, a chlorine atom or a bromine atom, and when a plurality of halogen atoms are present, the halogen atoms are the same or different;

and/or, when said R is⁵、R⁶、R⁷、R⁸And R⁹Each independently being "halogen atom-substituted C₁～C₄When said "alkoxy group" is substituted with a halogen atom, said "halogen atom-substituted C₁～C₄In the alkoxy group of (1), "C" is mentioned₁～C₄Alkoxy of (a) is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or tert-butoxy;

and/or, when said R is⁵、R⁶、R⁷、R⁸And R⁹Each independently is C₁～C₆Alkyl mercapto of (A), said C₁～C₆The alkylmercapto group of (a) is methylmercapto.

4. The benzimidazole compound A or a pharmaceutically acceptable salt thereof according to claim 3, wherein R is R⁴Is "halogen atom substituted C₁～C₄When said "alkyl group" is substituted with a halogen atom, said "halogen atom-substituted C₁～C₄The alkyl group of (1) is trifluoromethyl;

and/or, when said R is⁵、R⁶、R⁷、R⁸And R⁹Each independently being "halogen atom-substituted C₁～C₄When said "alkyl group" is substituted with a halogen atom, said "halogen atom-substituted C₁～C₄The "alkyl group of (a) is a" methyl group substituted with one or more of a fluorine atom, a chlorine atom and a bromine atom ";

and/or, when said R is⁵、R⁶、R⁷、R⁸And R⁹Each independently being "halogen atom-substituted C₁～C₄When said "alkoxy group" is substituted with a halogen atom, said "halogen atom-substituted C₁～C₄The "alkoxy group of (b) is" a methoxy group substituted with one or more of a fluorine atom, a chlorine atom and a bromine atom ".

5. The benzimidazole compound A or a pharmaceutically acceptable salt thereof according to claim 4, wherein R is R⁵、R⁶、R⁷、R⁸And R⁹When each is independently "methyl substituted with a fluorine atom", said "methyl substituted with a fluorine atom" is trifluoromethyl;

and/or, when said R is⁵、R⁶、R⁷、R⁸And R⁹When each is independently a "methoxy group substituted with a fluorine atom", the "methoxy group substituted with a fluorine atom" is a trifluoromethoxy group.

6. The benzimidazole compound a or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is¹Is a hydrogen atom, a cyano group, a halogen atom, or C₁～C₆Alkyl groups of (a);

and/or, said R²Is a hydrogen atom or C₁～C₆Alkyl groups of (a);

and/or, said R³Is a hydrogen atom or C₁～C₆Alkyl groups of (a);

and/or, said R⁴Is C₁～C₆Alkyl groups of (a);

and/or, said R⁵Is a hydrogen atom or a halogen atom;

and/or, said R⁹Is a hydrogen atom or a halogen atom;

and/or, said R⁶Is a hydrogen atom, a "halogen atom-substituted C₁～C₆Alkyl "or" halogen atom-substituted C₁～C₆Alkoxy groups of ";

and/or, said R⁸Is a hydrogen atom, a "halogen atom-substituted C₁～C₆Alkyl "or" halogen atom-substituted C₁～C₆Alkoxy groups of ";

and/or, said R⁷Is a hydrogen atom, a halogen atom or a "halogen atom-substituted C₁～C₆Alkyl groups of (a);

and/or, said R¹⁰Is C₁～C₄Alkyl or C₃～C₆A cycloalkyl group;

and/or, said R¹、R²And R³At least two of which are hydrogen atoms;

and/or, said R⁵And R⁹At least one of which is a hydrogen atom;

and/or, said R⁶And R⁸At least one of which is a hydrogen atom;

and/or, said R⁵、R⁶、R⁷、R⁸And R⁹At least three of which are hydrogen atoms;

and/or, said R⁵、R⁶、R⁷、R⁸And R⁹At least one of which is "halogen atom-substituted C₁～C₆Alkyl "or" halogen atom-substituted C₁～C₆An alkoxy group of ".

7. The benzimidazole compound a or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound a is any one of the following compounds:

8. a process according to any one of claims 1 to 7 for the preparation of compound A, comprising the following steps: in an alcohol solvent, in the presence of a desulfurizing agent, carrying out cyclization reaction on a compound B to obtain a compound A;

9. a compound of formula B, having the structure:

wherein, R is¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹And R¹⁰Are each independently as defined in any one of claims 1 to 7.

10. The use of a compound a or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7 in the manufacture of a medicament for the treatment of a BRAF kinase and/or RET kinase associated disease.

11. The use of a compound a or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7 in the manufacture of a BRAF kinase and/or RET kinase inhibitor.

12. A pharmaceutical composition comprising compound a or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, and a pharmaceutically acceptable carrier.