WO2013170770A1 - Dérivés d'acétylène ayant une activité antitumorale - Google Patents

Dérivés d'acétylène ayant une activité antitumorale Download PDF

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WO2013170770A1
WO2013170770A1 PCT/CN2013/075738 CN2013075738W WO2013170770A1 WO 2013170770 A1 WO2013170770 A1 WO 2013170770A1 CN 2013075738 W CN2013075738 W CN 2013075738W WO 2013170770 A1 WO2013170770 A1 WO 2013170770A1
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group
alkyl
cycloalkyl
independently selected
ring
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PCT/CN2013/075738
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English (en)
Chinese (zh)
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万惠新
李春丽
石辰
刘海燕
李萍
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上海医药集团股份有限公司
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Publication of WO2013170770A1 publication Critical patent/WO2013170770A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to an ethylene block derivative, particularly an aromatic ring disubstituted ethyl block derivative having antitumor activity, a pharmaceutical composition comprising the same, and the use of the compound and the pharmaceutical composition for treating and/or preventing a tumor.
  • anti-tumor drugs are moving from traditional non-selective single cytotoxic drugs to new mechanisms targeting multiple mechanisms.
  • the development of oncology drugs, research and development of anti-tumor drugs has entered a new era.
  • Molecular targeted therapy of tumors is a therapeutic approach based on the selective killing of tumor cells by chemical or biological means of key protein molecules closely related to tumor growth. It is characterized by specificity, pertinence and effectiveness, and patients are well tolerated, and the side effects are much lower than traditional chemotherapy drugs; when combined, it can enhance the efficacy of traditional radiotherapy and chemotherapy, and reduce postoperative recurrence.
  • Imatinib (trade name: Gleevec) is the first small molecule protein kinase inhibitor to be used in the treatment of chronic myeloid leukemia, and is known as a milestone in molecular targeted therapy for tumors. Subsequently, the US FDA approved the second application of imatinib for the treatment of gastrointestinal stromal tumors. After extensive clinical use worldwide, it has been highly praised by the medical community. On December 23, 2002, it was officially recognized by the US FDA. It was approved as a first-line treatment for chronic myeloid leukemia, and it has been praised by the medical community as "sometimes in recent years.” A major breakthrough "anti-tumor targeted small molecule oral pharmaceutical preparation.
  • Imatinib has been approved for use as a rare disease in countries such as the United States, the European Union, and Japan, and has been approved for use in chronic myeloid leukemia in more than 80 countries around the world, and is also approved for use in many developed and developing countries.
  • Molecular pathology studies revealed that its resistance mechanisms include: 1) Abl kinase mutations, accounting for 35%-45% of patients with overall resistance.
  • Src family members Src, Lyn, and Hck are downstream of BCR-Abl and are activated by Abl to promote cell growth, survival, and differentiation; however, in some tumors resistant to Imatinib, despite BCR-Abl Activity is suppressed, downstream of Src, Lyn and Hck signaling pathways Still in an active state, it shows that compensatory bypass is involved in the development of Imatinib resistance.
  • Other resistance mechanisms include overexpression of BCR-Abl itself and overexpression of drug resistance protein BCRP/ABCG2.
  • Dasatinib is a dual inhibitor of Abl-Src, which was approved by the FDA in June 2006 for the treatment of CML patients who are resistant or intolerant to Imatinib. Due to its completely different structure from Imatinib, Dasatinib binds to the active form of BCR-Abl; its ability to inhibit wild-type BCR-Abl kinase is 325 times that of Imatinib, and its binding site is different from Imatinib, thus it is resistant to Imatinib.
  • the BCR-Abl mutant kinase has a good inhibitory effect except for one site (T315I site). More strikingly, Dasatinib also inhibits the activity of Src, and is therefore still effective against tumors that are imatinib-resistant due to Src overactivation. Clinical trials have shown that Dasatinib has a good effect on many different types of Imatinib-resistant patients. However, Dasatinib has not effectively solved the drug resistance caused by BCR-Abl due to the T315I site mutation. Therefore, it is imperative to develop a third-generation BCR-Abl inhibitor.
  • the role of targeted therapy in the treatment of NSCLC is becoming more and more important.
  • the targeted drugs of epidermal growth factor receptor tyrosine kinase inhibitor represented by erlotinib and gefitinib have achieved certain effects.
  • most studies have shown that patients with clinical remission or even regression of NSCLC develop resistance and even disease progression after a period of maintenance therapy.
  • the EGFR TKI resistance mechanism has become a hot topic in the field of oncology.
  • TK activity of EGFR in cells is activated by binding to ligands including EGF, transforming growth factor alpha, amphiregulin, etc., resulting in the formation of homodimers of EGFRs or heterodimers with other family members, the most common Is HER2.
  • ligands including EGF, transforming growth factor alpha, amphiregulin, etc.
  • TK activation of EGFR leads to autophosphorylation of EGFR intracellular regions, and these phosphorylated residues can serve as docking sites for a variety of adaptor molecules, leading to mitogen-activated protein kinase (MAPK).
  • MAPK mitogen-activated protein kinase
  • PI3K/Akt pathway and activation of signal transducers and transcriptional pathway activators promote cell proliferation, angiogenesis, metastasis and inhibition of apoptosis, thereby increasing the survival, proliferation, invasion and metastasis of tumor cells.
  • TK activation of tumor cell EGFR can be disrupted by a variety of oncogene mechanisms, including increased gene copy number and EGFR protein overexpression caused by EGFR gene mutations. More than 60% of NSCLC patients have overexpressed EGFR in their tumor cells, and these patients have a poor prognosis.
  • Reversible EGFR TKIs have significant anti-tumor efficacy in a subset of NSCLC patients: approximately 10% of European patients and 30% of East Asian patients have clinical remission.
  • EGFR gene sequencing revealed that most tumors that responded to EGFR TKIs treatment contained mutations in the EGFR TK region. Overall, the mutation frequency of EGFR is 5%-20%, depending on the study population. Tumor patients carrying EGFR mutations have a response rate of approximately 75% for erlotinib and gefitinib, suggesting that these mutations can cause malignant transformation of cells. All NSCLCs that initially responded to EGFR TKI treatment developed secondary resistance.
  • gefitinib and erlotinib are currently considered to be limited, mainly due to resistance caused by the second point mutation in the TK region.
  • 50% of patients with secondary drug resistance in EGFR TKI develop a threonine-790 mutation to methionine (T790M) o although EGFR TKIs can achieve significant results in these patients, but compared with those who do not have T790M detected, Patients with T790M had a relatively short progression-free survival (7.7 months vs 16.5 months; P ⁇ 0.001).
  • T790M is a potential mechanism of resistance, and in vitro tests have demonstrated that this mutation significantly inhibits the effects of erlotinib and gefitinib, whereas TK activity remains.
  • introduction of T790M into gefitinib-sensitive tumor cells, activated EGFR mutations or increased EGFR copy number can lead to gefitinib resistance.
  • the mechanism by which T790M causes tumor cells to resist EGFR TKIs remains unclear. It is possible that the T790M mutation causes a change in the topology of the ATP-binding pocket of TK and prevents EGFR TKIs from binding through the steric group phenomenon, thereby secondary resistance.
  • the B-raf gene is a member of the RAF family and encodes a silk/threonine-specific kinase. It is an important transduction factor in the RAS/RAF/MEK/ERK/MAPK pathway and is involved in the regulation of various organisms in cells. Learn about events such as cell growth, differentiation, and apoptosis. Recent studies have shown that BRAF tumor gene mutations can be found in some human malignancies. Most literature reports that the rate of B-raf mutation in colorectal cancer is about 15%, and more than 90% are V600E mutations, and negatively correlated with K-ras mutation. Recent studies have shown that BRAF gene mutations have important predictive and prognostic significance in clinical practice.
  • BRAF ⁇ (;V600E) mutant gene can promote the growth and proliferation of human melanoma cells, which can make tumor cells secrete more MMPs and VEGF, enhance the ability of tumor cells to invade and angiogenesis, and improve their ability to metastasize, suggesting BRAF ( V600E) mutations play an important role in melanoma growth, invasion and metastasis, and gene therapy targeting them can inhibit the growth of experimental melanoma.
  • EGFR inhibitors can also develop resistance through a bypass compensatory mechanism, such as Met or PDGFR gene amplification.
  • Met or PDGFR can bind to ErbB3 compensatoryly, replacing the function of the original EGFR, and activating the downstream PI3K signaling pathway, causing the inhibitor to lose its inhibitory effect on tumor cells. Therefore, the combination of an EGFR inhibitor and a Met or PDGFR inhibitor would be an alternative to clinically overcoming EGFR inhibitor resistance.
  • the representative drugs include the recently marketed multi-targeted kinase inhibitor Vandetanib (trade name: Zactima; AstraZeneca). Vandetanib also targets tyrosine kinases such as EGFR, VEGFR and RET, and was approved by the FDA in 2005 as a therapeutic agent for follicular, medullary, undifferentiated or locally advanced and metastatic papillary thyroid cancer.
  • the object of the present invention is to provide a new class of protein kinase inhibitors.
  • the invention provides a compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof,
  • Ring A is selected from heteroaryl
  • n is the number of substituents Ra on ring A, and m is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably
  • m Ra are each independently selected from halogen, -R 2 , -OH, -SH, -OR 2 , -NH 2 , -NHR 2 , -N(R 2 ) 2 , -NHC(0)R 2 , -NHC (0) OR 2 , -NR 3 C(0)R 2 ;
  • Ring T is a heteroaryl group containing at least one nitrogen atom, wherein M is selected from the group consisting of N atoms, CH and CR, wherein R is selected from the group consisting of halogen, -R 2 , -OR 2 , -CN, -OH, -SH, -COOH, -C(0)-R 2 , -C(0)0-R 2 , -OC(0)-R 2 , -NH 2 , -NHR 2 , -N(R 2 )2, -NHC(0)R 2 , -NR 3 C(0)R 2 ;
  • p is the number of substituents Rt on ring T, and t is 0, 1, 2, 3, 4 or 5, preferably 0 or 1;
  • Each of p Rt is independently selected from the group consisting of halogen, -R 2 , -CN, -COOH, -OH, -SH, -OR 2 , -C(0)-R 2 , -C(0)0-R 2 , OC(0)-R 2 , -S(0) x -R 2 , -NH 2 , -NHR 2 , -N(R 2 ) 2 , -NHC(0)R 2 , -NHC(0)OR 2 , -NR 3 C(0)R 2 , wherein x is 0, 1 or 2;
  • Ring B is an aryl group, preferably a C 6 _ 1Q aryl group, more preferably a phenyl group;
  • n is the number of substituents Rb on ring B, and n is 0, 1, 2, 3, 4 or 5, preferably 1 or 2, more preferably
  • R Rb is independently selected from the group consisting of halogen, -R 2 , -CN, -COOH, -OH, -SH, -OR 2 , -C(0)-R 2 , -C(0)0-R 2 , OC(0)-R 2 , -S(0) x -R 2 , -NH 2 , -NHR 2 , -N(R 2 ) 2 , -NHC(0)R 2 , -NHC(0)OR 2 , -NR 3 C(0)R 2 , where x is 0, 1 or 2; or
  • L is a linking group selected from -C0NR - or -NR CO-, wherein is selected from a H atom, an alkyl group, a cycloalkyl group, a hydroxyalkyl group, an aryl group, a heteroaryl group or a heterocyclic group,
  • Each R 2 , R 3 is independently selected from the group consisting of alkyl, alkenyl, blocked, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each R 2 and R 3 is optionally selected from one or more Halogen, -OH, -R 4 , -OR 4 , -C(0)-R 4 , -C(0)0-R 4 , -OC(0)-R 4 , -NH 2 , -NHR 4 , - a group substituted with N(R 4 )2, -NHC(0)R 4 , -NHC(0)OR 4 , -NR 5 C(0)R 4 ;
  • Each F and R 5 are independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each R 4 , R 5 is optionally selected from one or more selected from the group consisting of -OH, -CN, -NH 2 , alkyl, monoalkylamino, dialkylamino, cycloalkyl, heterocyclyl, alkoxy, light-based, oxy-based, light-based oxy-based, amino-based Base, the second base, the base of the base, the base of the oxycarbonylamino, the base of the ring, the base of the ring, the base of the heterocyclic base, the base of the aryl, the base of the base, the carbonyl of the ring, the oxycarbonyl, the alkane Substituted by a group of an oxycarbonyl heterocyclic group, an (alkoxycarbonyl)(alkyl)amino group, or a (de
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate, a polymorph, a tautomer, a metabolite or a former
  • the drug and a pharmaceutically acceptable carrier.
  • Another aspect of the invention relates to a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvent a compound, a polymorph, a tautomer, a metabolite or a prodrug or a pharmaceutical composition of the invention for inhibiting the activity of a protein kinase.
  • Another aspect of the invention relates to a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof or a medicament of the invention
  • a composition for preventing and/or treating a tumor A composition for preventing and/or treating a tumor.
  • Another aspect of the invention relates to a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof or a medicament of the invention
  • a composition for the preparation of a medicament for inhibiting protein kinase activity Use of a composition for the preparation of a medicament for inhibiting protein kinase activity.
  • Another aspect of the invention relates to a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof or a medicament of the invention
  • a pharmaceutically acceptable salt thereof a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof or a medicament of the invention
  • Use of the composition in the manufacture of a medicament for the treatment and/or prevention of a tumor Use of the composition in the manufacture of a medicament for the treatment and/or prevention of a tumor.
  • a further aspect of the invention relates to a method of modulating protein kinase activity, which comprises the protein kinase and the above compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph thereof , solvate, prodrug or metabolite contact.
  • the regulatory protein kinase activity is inhibition of protein kinase activity. This method can be used in vivo as well as in vitro.
  • Another aspect of the invention relates to a method of inhibiting protein kinase activity in a mammal, particularly a human, comprising administering to a mammal, in particular a human, in need thereof a therapeutically effective amount of a compound of the invention, which is pharmaceutically acceptable Salts, stereoisomers, solvates, polymorphs, tautomers, metabolites or prodrugs thereof or pharmaceutical compositions of the invention.
  • a compound of the invention which is pharmaceutically acceptable Salts, stereoisomers, solvates, polymorphs, tautomers, metabolites or prodrugs thereof or pharmaceutical compositions of the invention.
  • Another aspect of the invention relates to a method of treating and/or preventing a tumor in a mammal, in particular a human, comprising administering to a mammal, in particular a human, in need thereof a therapeutically effective amount of a compound of the invention, pharmaceutically thereof Acceptable salts, stereoisomers, solvates, polymorphs, tautomers, metabolites or prodrugs thereof or pharmaceutical compositions of the invention.
  • the tumor is inhibited by inhibition of a protein kinase.
  • Another aspect of the invention relates to the use of a compound of the invention in combination or in combination with one or more other compounds of the invention or one or more other anti-cancer drugs for the treatment and/or prevention of a tumor.
  • the manufacturer's instructions for use of the kit can be utilized, or the reaction can be carried out and purified according to methods well known in the art or as described in the present invention.
  • the above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification.
  • a group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.
  • a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left.
  • -CH 2 0- is equivalent to -OCH 2 -.
  • d- 6 alkyl refers to an alkyl group as defined below having a total of from 1 to 6 carbon atoms.
  • the total number of carbon atoms in the simplified symbol does not include carbon that may be present in the substituents of the group.
  • halogen means fluoro, chloro, bromo or iodo.
  • Haldroxy means an -OH group.
  • Hydroalkyl means an alkyl group as defined below which is substituted by a hydroxy group (-OH).
  • Neitro means -N0 2 .
  • Amino means -NH 2 .
  • Substituted amino means an amino group substituted by one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkyl Amido, aralkylamino, heteroarylalkylamino.
  • alkyl means consisting solely of carbon and hydrogen atoms, containing no A saturated bond, a linear or branched hydrocarbon chain group having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and bonded to the remainder of the molecule by a single bond.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2 , 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, decyl and decyl.
  • alkoxy refers to a radical of the formula -OR a where R a is alkyl as defined above.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.
  • alkylcarbonyl refers to a -C(O)-R a group, wherein Ra is alkyl as defined above.
  • alkoxycarbonyl refers to a -C(0)0-R a group, wherein Ra is alkyl as defined above.
  • monoalkylamino refers to a radical of the formula -NHR a , wherein is alkyl as defined above.
  • monoalkylamino include, but are not limited to, methylamino, ethylamino, isopropyl Amino group, etc.
  • dialkylamino refers to a radical of the formula -NR a R b wherein each of Ra and R b is independently alkyl as defined above.
  • dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, dipropylamino, methylethylamino, and the like.
  • alkenyl as a group or part of another group means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10) More preferably, 2 to 6) a straight or branched hydrocarbon chain group having a carbon atom and attached to the remainder of the molecule through a single bond, such as, but not limited to, vinyl, propenyl, allyl, butyl- 1-Alkenyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl and the like.
  • block group as a group or part of another group means consisting only of carbon atoms and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having for example 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and a linear or branched hydrocarbon chain bonded to the rest of the molecule by a single bond
  • a group such as, but not limited to, an ethyl group, a propan-1-yl group, a but-1-block group, a pent-1-en-4-yl group, and the like.
  • cycloalkyl as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, which may include condensing A ring system, a bridged ring system or a spiro ring system having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated and may be suitably employed
  • the carbon atom is connected to the rest of the molecule by a single bond.
  • a carbon atom in a cycloalkyl group may be optionally oxidized.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzene And cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctene , fluorenyl, bicyclo [2.2.1] heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl
  • cycloalkyloxy refers to a radical of the formula -OR e , wherein! ⁇ is a cycloalkyl group as defined above.
  • heterocyclyl as a group or part of another group means a stable consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. a 3- to 20-membered non-aromatic cyclic group.
  • a heterocyclic group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include a fused ring system. a bridged ring system or a spiro ring system; the nitrogen, carbon or sulfur atom in the heterocyclic group may be optionally oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated.
  • the heterocyclic group may be bonded to the remainder of the molecule via a carbon atom or a hetero atom and through a single bond.
  • one or more of the rings may be an aryl or heteroaryl group as defined below, provided that The point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • the heterocyclic group is preferably a stable 4 to 11 member comprising from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • Non-aromatic monocyclic, bicyclic, bridged or spiro group More preferably, it is a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heterocyclic groups include but not Limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]decane-7-yl, 2- Oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, azetidinyl, pyranyl , tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinazolidyl, Thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indany
  • heterocyclyloxy refers to a radical of the formula -OR d where is a heterocyclyl radical as defined above.
  • aryl as a group or part of another group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms.
  • an aryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is via The atom on the aromatic ring is bonded to the rest of the molecule through a single bond.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, anthracenyl, 2,3-dihydro-1H-isoindole Base, 2-benzoxazolinone, 2 ⁇ -1,4-benzoxazine-3(4 ⁇ )-keto-7-yl and the like.
  • aralkyl refers to an alkyl group as defined above substituted with an aryl group as defined above.
  • heteroaryl as a group or part of another group means having from 1 to 15 carbon atoms (preferably having from 1 to 10 carbon atoms) and from 1 to 6 selected from nitrogen in the ring. a 5- to 16-membered conjugated ring system of a hetero atom of oxygen and sulfur.
  • a heteroaryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the hetero The aryl group is attached to the remainder of the molecule via a single bond through an atom on the aromatic ring.
  • the nitrogen, carbon or sulfur atom in the heteroaryl group can be optionally oxidized; the nitrogen atom can optionally be quaternized.
  • the heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, or from 1 to 4 selected from 1 to 4 Nitrogen, oxygen and sulfur miscellaneous A stable 5- to 9-member aromatic group.
  • heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, fluorenyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, pyridazinyl, isodecyl, oxazolyl, isoxazolyl , fluorenyl, quinolyl, isoquinolyl, dinaphthyl, naphthyridyl, quinoxalinyl, pteridinyl, oxazolyl, porphyrin, phenanthryl, phenanthroline, acridine Phenyl, phena
  • heteroarylalkyl refers to a fluorenyl group as defined above which is substituted by a heteroaryl group as defined above.
  • optionally or “optionally” means that the subsequently described event or condition may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or condition.
  • optionally substituted aryl means that the aryl group is substituted or unsubstituted, and the description includes both the substituted aryl group and the unsubstituted aryl group.
  • the group when a group is described as "optionally substituted", the group may be optionally substituted at one or more suitable positions with the following groups: alkyl, alkenyl, block , halogen, haloalkyl, haloalkenyl, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, trimethylsilyl, -OR 1() , -C(O) -R 10 -C(O)OR 10 -OC(0)-Rio -N(R 10 ) 2 , -C(O)N(R 10 ) 2 , -N(R 10 )C(O)R u , -N(R 10 )C(O)OR u , -N(R 10 )S(O) t R u (where t is 1 or 2), -S(0) t ORi i (where t is 1 or 2) ), -S(0) t Rii (where t is 0, 1
  • a chemical moiety is generally considered to be a chemical entity that is embedded or attached to a molecule.
  • Stepoisomer means a compound composed of the same atom, bonded by the same bond, but having a different three-dimensional structure.
  • the invention will cover various stereoisomers and mixtures thereof.
  • the compound of the present invention contains an olefinic double bond
  • the compound of the present invention is intended to contain ⁇ - and ⁇ -geometric isomers unless otherwise stated.
  • Tautomer refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention will also be embraced within the scope of the invention.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereomers and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the invention is intended to include all possible isomers, as well as racemic and optically pure forms thereof.
  • the preparation of the compounds of the invention may employ racemates, diastereomers or enantiomers as starting materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as by crystallization and chiral chromatography.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • pharmaceutically acceptable acid addition salt means a salt formed with an inorganic or organic acid which retains the bioavailability of the free base without other side effects.
  • Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate , trifluoroacetate, propionate, hexanoate, octoate, decanoate, ⁇ -monoenoate, glycolate, gluconate, lactate, sebacate, hexane Acid salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, besylate, p-toluenesulfonate , alginate, ascorbate, salicylate, 4-
  • “Pharmaceutically acceptable base addition salt” means a salt formed with an inorganic base or an organic base capable of maintaining the bioavailability of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like.
  • Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines, and basic ion exchange resins.
  • ammonia isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclo Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, hydrazine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin, and the like.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
  • Polymorph refers to a different solid crystalline phase of certain compounds of the invention resulting from the presence of two or more different molecular arrangements in a solid state. Certain compounds of the invention may exist in more than one crystal form, and the invention is intended to include various crystal forms and mixtures thereof.
  • solvate refers to an aggregate comprising one or more molecules of the compound of the invention and one or more solvent molecules.
  • the solvent may be water, and the solvate in this case is a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms.
  • the compounds of the present invention form true solvates, but in some cases, it is also possible to retain only a variable amount of water or a mixture of water and a portion of the indefinite solvent.
  • the compound of the present invention can be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.
  • metabolic refers to a functional group reaction (I phase biotransformation reaction, including oxidation, reduction, hydrolysis, etc.) and binding reaction (phase biotransformation) of a drug after being absorbed by the body and under the action of an enzyme. a compound produced by biotransformation, such as reaction.
  • the invention also includes prodrugs of the above compounds.
  • prodrug means a compound which can be converted into a biologically active compound of the invention under physiological conditions or by solvolysis.
  • prodrug refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention.
  • Prodrugs may be inactive when administered to an individual in need thereof, but are converted in vivo to the active compound of the invention.
  • Prodrugs are typically rapidly converted in vivo to produce the parent compound of the invention, for example by hydrolysis in blood.
  • Prodrug compounds generally provide the advantage of solubility, histocompatibility or sustained release in mammalian organisms.
  • Prodrugs include known amino protecting groups and carboxy protecting groups.
  • pharmaceutical composition refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, thereby facilitating the absorption of the active ingredient and thereby exerting biological activity.
  • pharmaceutically acceptable refers to a substance that does not affect the biological activity or properties of the compounds of the invention. (e.g., carrier or diluent), and relatively non-toxic, i.e., the substance can be administered to an individual without causing undesirable biological reactions or interacting with any of the components contained in the composition in an undesirable manner.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvants, carriers, excipients, glidants, sweeteners approved by the relevant government authorities for acceptable use by humans or domestic animals. , diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsions.
  • subject refers to an individual having a disease or condition, and the like, including mammals and non-mammals.
  • mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (eg, chimpanzees and other mites and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals For example, rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs.
  • non-mammals include, but are not limited to, birds and fish.
  • the mammal is a human.
  • preventing include the possibility of reducing the occurrence or deterioration of a disease or condition by a patient.
  • treatment and other similar synonyms as used herein includes the following meanings:
  • an "effective amount,” “therapeutically effective amount,” or “pharmaceutically effective amount,” as used herein, refers to at least one agent or compound that, after administration, is sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent. The amount. The result can be the reduction and/or alleviation of signs, symptoms or causes, or any other desired changes in the biological system.
  • an "effective amount” for treatment is an amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic.
  • An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.
  • administering refers to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration.
  • parenteral injections including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical administration and rectal administration.
  • the techniques of administration of the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Those discussed in Easton, Pa.
  • the compounds and compositions discussed herein are administered orally.
  • pharmaceutical combination means a medical treatment obtained by mixing or combining more than one active ingredient, It includes both fixed and unfixed combinations of active ingredients.
  • fixed combination refers to the simultaneous administration of at least one of the compounds described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form.
  • unfixed combination refers to the simultaneous administration, combination or sequential administration of at least one of the compounds described herein and at least one synergistic formulation to the patient in the form of separate entities. These are also applied to cocktail therapy, for example the administration of three or more active ingredients.
  • the invention provides a compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof,
  • Ring A is selected from heteroaryl
  • n is the number of substituents Ra on ring A, and m is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably
  • m Ra are each independently selected from halogen, -R 2 , -OH, -SH, -OR 2 , -NH 2 , -NHR 2 , -N(R 2 ) 2 , -NHC(0)R 2 , -NHC (0) OR 2 , -NR 3 C(0)R 2 ;
  • Ring T is a heteroaryl group containing at least one nitrogen atom, wherein M is selected from the group consisting of N atoms, CH and CR, wherein R is selected from the group consisting of halogen, -R 2 , -OR 2 , -CN, -OH, -SH, -COOH, -C(0)-R 2 , -C(0)0-R 2 , -OC(0)-R 2 , -NH 2 , -NHR 2 , -N(R 2 )2, -NHC(0)R 2 , -NR 3 C(0)R 2 ;
  • p is the number of substituents Rt on ring T, and t is 0, 1, 2, 3, 4 or 5, preferably 0 or 1;
  • Each of p Rt is independently selected from the group consisting of halogen, -R 2 , -CN, -COOH, -OH, -SH, -OR 2 , -C(0)-R 2 , -C(0)0-R 2 , OC(0)-R 2 , -S(0) x -R 2 , -NH 2 , -NHR 2 , -N(R 2 ) 2 , -NHC(0)R 2 , -NHC(0)OR 2 , -NR 3 C(0)R 2 , wherein x is 0, 1 or 2;
  • Ring B is an aryl group, preferably a C 6 _ 1Q aryl group, more preferably a phenyl group;
  • n is the number of substituents Rb on ring B, and n is 0, 1, 2, 3, 4 or 5, preferably 1 or 2, more preferably
  • R Rb is independently selected from the group consisting of halogen, -R 2 , -CN, -COOH, -OH, -SH, -OR 2 , -C(0)-R 2 , -C(0)0-R 2 , OC(0)-R 2 , -S(0) x -R 2 , -NH 2 , -NHR 2 , -N(R 2 ) 2 , -NHC(0)R 2 , -NHC(0)OR 2 , -NR 3 C(0)R 2 , where x is 0, 1 or 2; or
  • L is a linking group selected from -C0NR - or -NR CO-, wherein is selected from a H atom, an alkyl group, a cycloalkyl group, a hydroxyalkyl group, an aryl group, a heteroaryl group or a heterocyclic group,
  • Each R 2 , R 3 is independently selected from the group consisting of alkyl, alkenyl, blocked, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each R 2 and R 3 is optionally selected from one or more Halogen, -OH, -R 4 , -OR 4 , -C(0)-R 4 , -C(0)0-R 4 , -OC(0)-R 4 , -NH 2 , -NHR 4 , - a group substituted with N(R 4 )2, -NHC(0)R 4 , -NHC(0)OR 4 , -NR 5 C(0)R 4 ;
  • Each F and R 5 are independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each R 4 , R 5 is optionally selected from one or more selected from the group consisting of -OH, -CN, -NH 2 , alkyl, monoalkylamino, dialkylamino, cycloalkyl, heterocyclyl, alkoxy, light-based, oxy-based, light-based oxy-based, amino-based Base, the second base, the base of the base, the base of the oxycarbonylamino, the base of the ring, the base of the ring, the base of the heterocyclic base, the base of the aryl, the base of the base, the carbonyl of the ring, the oxycarbonyl, the alkane Substituted by a group of an oxycarbonyl heterocyclic group, an (alkoxycarbonyl)(alkyl)amino group, or a (de
  • the invention further relates to a compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof, among them:
  • ethyl group moiety and the L moiety are meta-substituted on ring A, and ring A is a 5- to 12-membered heteroaryl group containing 1 to 5 hetero atoms selected from nitrogen, oxygen and sulfur. .
  • the invention also relates to a compound of formula I, a pharmaceutically acceptable salt thereof, A conformation, solvate, polymorph, tautomer, metabolite or prodrug, wherein:
  • ethyl group moiety and the L moiety are meta-substituted on ring A, and ring A is a 5- to 6-membered heteroaryl group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur. .
  • the invention further relates to a compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof, among them:
  • the ethyl group moiety and the L moiety are meta-substituted on the ring A, and the ring A is a pyridyl group, a furyl group or a thiazolyl group.
  • the invention further relates to a compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof, among them:
  • the ethyl group moiety and the L moiety are meta-substituted on the ring A, and the ring A is a pyridyl group.
  • the invention further relates to a compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof, among them:
  • m Ra are each independently selected from halogen, -R 2 , -OR 2 ; each R 2 is independently selected from alkyl, cycloalkyl, and each R 2 is optionally selected from one or more selected from halogen, -R 4 , a group of -OR 4 , -NHR 4 , -N(R 4 ) 2 is substituted; each F is independently selected from an alkyl group or a cycloalkyl group.
  • the invention also relates to compounds of formula I, pharmaceutically acceptable salts thereof, stereoisomers, solvates, polymorphs, tautomers, metabolites thereof or Medicine, where:
  • m Ra are each independently selected from halogen, -R 2 , -OR 2 ; each R 2 is independently selected from d- 6 alkyl, C 3 -8 cycloalkyl, and each R 2 is optionally one or more Substituted with a group selected from the group consisting of halogen, -F, -OR 4 , -NHR 4 , -N(R 4 ) 2 ; each F is independently selected from the group consisting of d- 6 alkyl, C 3 -8 cycloalkyl.
  • the invention further relates to a compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof, among them:
  • m Ra are each independently selected from the group consisting of alkyl, 3 ⁇ 4 alkyl, alkoxyalkyl.
  • the invention also relates to compounds of formula I, pharmaceutically acceptable salts thereof, stereoisomers, solvates, polymorphs, tautomers, metabolites thereof or Medicine, where:
  • Each of m Ra is independently selected from the group consisting of d- 6 alkyl, halogenated d- 6 alkyl, d- 6 alkoxy d- 6 alkyl.
  • the invention further relates to a compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof, among them:
  • Each of R 2 is independently selected from the group consisting of halogen, —R 2 , —OR 2 , —NHR 2 , —N(R 2 ) 2 , wherein each R 2 is independently selected from alkyl, cycloalkyl, and each R 2 is Optionally substituted with one or more groups selected from the group consisting of halogen, -R 4 , -OR 4 , -NHR 4 , -N(R 4 ) 2 ; each R 4 is independently selected from alkyl, cycloalkyl, heterocycle And each R 4 is optionally substituted by one or more groups selected from the group consisting of alkyl, monoalkylamino, dialkylamino, cycloalkyl, heterocyclyl, alkoxy, alkoxyalkyl ; or
  • heterocyclic group is optionally substituted by one or more alkyl groups, optionally one or more A cycloalkyl group is substituted.
  • the invention also relates to compounds of formula I, pharmaceutically acceptable salts thereof, stereoisomers, solvates, polymorphs, tautomers, metabolites thereof or Medicine, where:
  • Each of R Rb is independently selected from the group consisting of halogen, -R 2 , -OR 2 , -NHR 2 , -N(R 2 ) 2 , wherein each R 2 is independently selected from d- 6 alkyl, C 3 -8 cycloalkyl And each R 2 is optionally substituted with one or more groups selected from the group consisting of halogen, —R 4 , —OR 4 , —NHR 4 , —N(R 4 ) 2 ; each R 4 is independently selected from d 6 alkyl, a C 3 -8 cycloalkyl group, a stable 4- to 11-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, and each F is optionally selected from one or more selected from d- 6 alkyl, mono d_ 6 alkylamino, di-d_ 6 alkylamino, C 3 _ 8 cycloalkyl group, comprising a stable 4-11 y
  • heterocyclic group is optionally substituted by one or more d- 6 alkyl groups, optionally an alkyl group Or a plurality of C 3 -8 cycloalkyl groups.
  • the invention also relates to a compound of formula I, a pharmaceutically acceptable salt thereof, A conformation, solvate, polymorph, tautomer, metabolite or prodrug, wherein:
  • R Rb is independently d- 6 alkyl or C 3 -8 cycloalkyl, and the alkyl or cycloalkyl is optionally one or more selected from -R 4 , -NHR 4 , -N(R 4) 2-substituted group; each independently selected from F d_ 6 alkyl, [3 _ 8 cycloalkyl group, comprising a stable 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur is 4-8 yuan a heterocyclic group, and each R4 is optionally substituted with one or more groups selected from the group consisting of d- 6 alkyl, mono d- 6 alkylamino, di- 6 alkylamino;
  • Two adjacent Rbs together with a carbon atom on the ring B to which they are attached form a 4- to 11-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur; optionally substituted with one or more d_ 6 alkyl substituted, the alkyl group is optionally substituted with one or more C 3 _ 8 cycloalkyl substituted.
  • the present invention is also directed to a compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof , among them:
  • the alkyl group is optionally substituted with one or more C 3 _ 8 cycloalkyl substituted.
  • the invention further relates to a compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof, among them:
  • Two adjacent Rbs together with the carbon atom on the ring B to which they are attached form a 5-membered heterocyclic group containing one nitrogen atom, which is optionally substituted by one or more alkyl groups, the alkane The group is optionally substituted by one or more cycloalkyl groups.
  • the invention further relates to a compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof, among them:
  • M is selected from the group consisting of N atom, CH and B CR, wherein R is selected from alkyl or haloalkyl, preferably d- 6 alkyl or halogenated d- 6 fluorenyl;
  • the ring T is selected from a 5- to 12-membered fused heteroaryl group containing 1 to 5 hetero atoms selected from nitrogen, oxygen and sulfur, wherein at least one of the hetero atoms is a nitrogen atom.
  • the invention further relates to a compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof, among them:
  • Ring T is selected from
  • the invention further relates to a compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof, among them:
  • Each of p Rt is independently selected from halo, -R 2 ; each R 2 is independently selected from alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each R 2 is optionally one or more a group selected from a halogen, an alkyl group;
  • the invention also relates to a compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug, wherein: preferably, p Rt are each independently selected from halogen, -R 2 ; each R 2 is independently selected From a D 6 alkyl group, a C 3 -8 cycloalkyl group, a stable 4- to 8-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, C.
  • An aryl group a stable 5- to 9-membered heteroaryl group containing 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and each R 2 is optionally selected from one or more selected from halogen, d- 6 alkyl Replaced by the group.
  • the invention further relates to a compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof, among them:
  • R is selected from the group consisting of H atom, alkyl group, cycloalkyl group and hydroxyalkyl group, preferably H atom, d- 6 alkyl group, C 3 -8 cycloalkyl group and hydroxy-d- 6 alkyl group; preferably, R is selected from H atom , d 6 alkyl; more preferably, 11 atoms.
  • the invention further relates to a compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof, wherein the compound is selected from:
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate, a polymorph, a tautomer, a metabolite or a former
  • the drug and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and Aerosol.
  • compositions of the present invention can be prepared by methods well known in the pharmaceutical art.
  • a pharmaceutical composition intended for administration by injection can be prepared by combining a compound of the present invention or a pharmaceutically acceptable salt or prodrug thereof with sterilized distilled water to form a solution.
  • Surfactants may be added to promote the formation of a homogeneous solution or suspension.
  • Actual methods of preparing pharmaceutical compositions are known to those skilled in the art, for example see The Science and Practice of Pharmacy (Pharmaceutical Science and Practice), 20 th Edition (Philadelphia College of Pharmacy and Science, 2000).
  • dosage forms suitable for oral administration include capsules, tablets, granules And syrup and the like.
  • the compound of the present invention contained in these preparations may be a solid powder or granule; a solution or suspension in an aqueous or non-aqueous liquid; a water-in-oil or oil-in-water emulsion or the like.
  • the above dosage forms can be prepared from the active compound with one or more carriers or excipients via conventional pharmaceutical methods.
  • non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like.
  • Carriers for liquid preparations include, but are not limited to, water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like.
  • the active compound can form a solution or suspension with the above carriers. The particular mode of administration and dosage form will depend on the physicochemical properties of the compound itself, as well as the severity of the disease being applied.
  • Another aspect of the invention relates to a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof or a medicament of the invention
  • a composition for inhibiting the activity of a protein kinase A composition for inhibiting the activity of a protein kinase.
  • Another aspect of the invention relates to a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof or a medicament of the invention
  • a composition for preventing and/or treating a tumor A composition for preventing and/or treating a tumor.
  • the compound of the present invention a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate, a polymorph, a tautomer, a metabolite or a prodrug thereof can effectively inhibit the growth of various tumor cells, and Bcr-Abl, c-KIT, PDGFR, c-Src, KDR, RET, FYN, FES, AXL, RSK, FER, SYK, HER2, LTK, ZAP70, AG, LYN, LCK, BRAF, BRAFV600E, AblT315I, FGR, Inhibition of HCK, HER4, p38, MINK, MAPK, EphB, YES, BRK, TIE, CSK, MUSK, FGFR, JAK, EphA, IKKB, P70S6K, FLT, EGFR, BTK, ITK, PDGFR, etc.
  • the mutants AblT315I, BRAFV600E, etc.
  • tumor includes but is not limited to: leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, lung adenocarcinoma, breast cancer , prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer and other diseases.
  • Another aspect of the invention relates to a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof or a medicament of the invention
  • a composition for the preparation of a medicament for inhibiting protein kinase activity Use of a composition for the preparation of a medicament for inhibiting protein kinase activity.
  • Another aspect of the invention relates to a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof or a medicament of the invention
  • a pharmaceutically acceptable salt thereof a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof or a medicament of the invention
  • Use of the composition in the manufacture of a medicament for the treatment and/or prevention of a tumor Use of the composition in the manufacture of a medicament for the treatment and/or prevention of a tumor.
  • a further aspect of the invention relates to a method of modulating protein kinase activity, which comprises combining said protein kinase with a compound of the invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polycrystal thereof The form, solvate, prodrug or metabolite or pharmaceutical composition of the invention is contacted.
  • the regulatory protein kinase activity is inhibition of protein kinase activity. This method can be used in vivo as well as in vitro.
  • Another aspect of the invention relates to a method of inhibiting protein kinase activity in a mammal, particularly a human, comprising administering to a mammal, in particular a human, in need thereof a therapeutically effective amount of a compound of the invention, which is pharmaceutically acceptable Salts, stereoisomers, solvates, polymorphs, tautomers, metabolites or prodrugs thereof or pharmaceutical compositions of the invention.
  • a compound of the invention which is pharmaceutically acceptable Salts, stereoisomers, solvates, polymorphs, tautomers, metabolites or prodrugs thereof or pharmaceutical compositions of the invention.
  • Another aspect of the invention relates to a method of treating and/or preventing a tumor in a mammal, in particular a human, comprising administering to a mammal, in particular a human, in need thereof a therapeutically effective amount of a compound of the invention, pharmaceutically thereof An acceptable salt, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof or a medicament of the invention Composition.
  • the tumor is inhibited by inhibition of a protein kinase.
  • a therapeutically effective daily dose is from about 0.001 mg/kg to about 100 mg/kg; a preferred therapeutically effective dose is from about 0.01 mg/kg to about 50 mg/kg; a more preferred therapeutically effective dose is about 1 mg/kg Up to approx. 25 mg/kg
  • the compounds of the invention may be used in combination or in combination with one or more other compounds of the invention or one or more other anti-cancer drugs to treat and/or prevent tumors.
  • Drugs that can be used in combination with the compounds of the invention include, but are not limited to, docetaxel, gemcitabine, cisplatin, carboplatin, Gleevec, temozolomide, doxorubicin, dacarbazine, tro***e, etoposide, soft red And cytarabine and the like.
  • the intermediate compound functional groups may need to be protected by a suitable protecting group.
  • suitable protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, and the like.
  • Suitable protecting groups for amino, mercapto and fluorenyl include t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable mercapto protecting groups include -C(0)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
  • protecting groups are described in detail in Greene, T. W. and P. G. M. Wuts, Protective Groups in Organi Synthesis WQ ⁇ ⁇ EcU Wiley.
  • the protecting group can also be a polymeric resin.
  • the present invention is prepared by -E.
  • Process A comprises the steps of: (1) subjecting mercapto compound A-1 (which is commercially available or prepared by methods known to those skilled in the art) under typical condensation conditions (e.g., condensing agent method, mixed anhydride) Method, activation method, etc.) is condensed with A-2 to give hydrazide A-3; (2) hydrazide hydrazide A-3 is condensed to give intermediate A-4, and the ring can be used in a suitable solvent (such as water, methanol, ethanol).
  • a suitable solvent such as water, methanol, ethanol.
  • Process B comprises the steps of: (1) heating a mercapto compound B-1 (which is commercially available or prepared by methods known to those skilled in the art) with formic acid or formate or orthoformate The ring is intermediate to obtain the intermediate B-2; (2) the intermediate B-2 is subjected to halogenation under various halogenating agents (e.g., Cl 2 , Br 2 , I 2 , NIS, NBS, NCS, IC1, IBr, etc.) Substituting to give intermediate B-3; (3) coupling intermediate B-3 with TMS protected block B under transition metal catalysis to obtain intermediate B-4, the coupling reaction using palladium catalyst (such as Pd ( PPh 3 ) 4 , PdAc 2 , Pd 2 (Dba) 3 Pd(PPh) 3 Cl 2 , etc.), copper salts (such as cuprous chloride, cuprous bromide, cuprous iodide, etc.) and various organic bases or Inorganic bases (such as triethylamine, DI
  • organic or inorganic bases such as triethylamine, DIPEA, potassium carbonate, sodium carbonate, sodium bicarbonate, etc.
  • solvents such as THF, toluene, DMF, etc.
  • temperature such as 20-150 degrees
  • Process C comprises the steps of: (1) heating a mercapto compound C-1 (which is commercially available or prepared by methods known to those skilled in the art) with formic acid or formate or orthoformate The ring is intermediate to obtain intermediate C-2; (2) intermediate C-2 is subjected to various halogenating agents (such as Cl 2 , Br 2 , I 2 , NIS, NBS, NCS, IC1, IBr, etc.) Halogenation reaction to obtain intermediate C-3; (3) coupling intermediate C-4 with TMS protected block B under transition metal catalysis to obtain intermediate C-5, the coupling reaction using palladium catalyst (such as ⁇ ⁇ 1 ⁇ 3 ) 4 , PdAc 2 , Pd 2 (Dba) 3 Pd(PPh) 3 Cl 2 , etc.), copper salts (such as cuprous chloride, cuprous bromide, cuprous iodide, etc.) and various organic bases Or an inorganic base (such as triethylamine, DIPEA, potassium carbonate, sodium carbonate
  • Process D comprises the steps of: (1) rendering an aromatic amine D-1 (which is commercially available or prepared by methods known to those skilled in the art) with various halogenated aldehydes, ketones or corresponding acetals , ketal (such as 2-chloroacetaldehyde, 2-bromoacetaldehyde, 2-chloroacetaldehyde acetal, 2-bromoacetone, 1-bromo-2-butanone, 2-bromo-1-cyclopropylethanone , 3-bromo-1-trifluoromethyl-2-propanone or methyl bromopyruvate, etc.) cyclized under the catalysis of acid (concentrated hydrochloric acid, hydrobromic acid, etc.) or alkali (TEA, sodium carbonate, etc.) (B) intermediate D-2 is subjected to a halogenation reaction under the action of various halogenating agents (such as Cl 2 , Br 2 , I 2 , NIS, NBS, NCS,
  • the method E comprises the following steps: (1) obtaining an aryl b-block intermediate E-1 and an intermediate E-2 by a method of the method AD or other literature methods, wherein La and Lb are an acyl group and an amino group or an amino group and an acyl group, respectively; (2) The target compound I(E) is synthesized by a conventional amide bond condensation method.
  • Trimethylsilyl-propionic acid- ⁇ '-pyridin-2-yl-hydrazide 0.5 g, 2.1 mmol was dissolved in phosphorus oxychloride (5 mL). The mixture was stirred with heating at 60 ° C for 18 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and concentrated under reduced pressure to remove excess phosphorus oxychloride. The residue was dissolved in methylene chloride (50 mL) and neutralized with a saturated sodium hydrogen carbonate solution to give an organic phase. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the concentrate was dissolved in tetrahydrofuran (8 mL), and then a tetrabutylammonium fluoride aqueous solution (a solution of 809 mg of tetrabutylammonium fluoride dissolved in 0.5 mL of water) was added dropwise, and the mixture was stirred at room temperature for 2 hours.
  • the reaction mixture was concentrated under reduced pressure.
  • EtOAc EtOAc m. Purification afforded the intermediate 3-ethylidene-[1,2,4]triazolo[4,3-a]pyridine (yellow solid, 242 mg).
  • 5-morpholine-2-hydroxypyrimidine hydrochloride (3.76 g, 17.3 mmol) and diethyl aniline (5.54 mL, 34.64 mmol) were dissolved in acetonitrile (75 ml), and phosphorus oxychloride (8 mL, 86.6 mmol), then heated to reflux for 3.5 h. After the reaction is completed, it is cooled to room temperature, and the mixture is neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to dryness.
  • -Chloro-pyrimidin-5-yl)-morpholine (yellow solid, 2.26 g).
  • Step 7 6-morpholine-4-yl-3-trimethylsilylethidyl-[1,2,4]triazole [4,3-a]pyrimidine
  • N-methylsilyl-propionic acid N'-(5-morpholine-4-yl-pyrimidin-2-yl)-hydrazide (1.98 g, 6.23 mmol) was dissolved in tetrahydrofuran (40 mL) under nitrogen Triphenylphosphine (1.96 g, 7.47 mmol), azide trimethylsilane (1.07 mL, 8.10 mmol) and diisopropylazodicarboxylate (1.35 mL, 6.85 mmol) were added. This mixture is in the room Stir for 3 h. After the TLC reaction was completed, water was added thereto, and dichloromethane was extracted.
  • Step 8 3-Ethyl -6-morpholine-4-yl-[1,2,4]triazole [4,3-a]pyrimidine
  • 3-Isoimidazo[l,2-a]pyridine (3.6 g, 15 mmol) was dissolved in N,N-dimethylformamide (30 mL), and ethyltrimethylsilane (2.16) was added thereto. mL, 19.5 mmol) and diisopropylethylamine (3.72 mL, 22.5 mmol), and the mixture was bubbled with nitrogen for 5 min and placed in a sealed tube, and then was added tetratriphenylphosphine palladium (867 mg, 0.75 mmol) and Cuprous iodide (214 mg, 1.125 mmol) was heated to 60 Q C under nitrogen for overnight reaction.
  • 6-chloro-imidazole [l,2-a]pyridine 6-chloro-imidazole [l,2-b]pyridazine, imidazole [l,2-b]pyridazine, 1-methyl-1H-imidazole, 1H-carbazole and 1H-pyrazole [3,4-b]pyridine were used as starting materials, and the following intermediates 6 to 9 were synthesized in a similar manner to Intermediate 5.
  • 6-Chloro-3-aminopyridazine (10 g, 77.2 mmol) was dissolved in absolute ethanol (120 mL), and then ethyl bromopyruvate (11.70 mL, 92.6 mmol) was slowly added thereto. The liquid was heated to reflux overnight. After the reaction was completed by TLC, the reaction mixture was cooled to room temperature, and the solvent was evaporated to dryness. The residue was dissolved in saturated aqueous sodium hydrogen carbonate, and extracted with dichloromethane (50 mL ⁇ 3). The residue was dried with EtOAc EtOAc m.
  • Ethyl 6-chloro-imidazole [l,2-b]pyridazine-2-carboxylate 8.2 g, 36 mmol was dissolved in methanol (250 mL), and 10% palladium carbon catalyst was added thereto under nitrogen atmosphere (lg Then, the system was replaced with hydrogen three times and continued to react at room temperature for 2 h. After the TLC detection reaction was completed, the catalyst was removed by filtration, and the filter cake was washed with methanol.
  • Lithium tetrahydrogen aluminum (3.8 g, 100 mmol) was placed in a nitrogen-protected 250 mL three-necked flask, and anhydrous tetrahydrofuran (100 mL) was slowly poured into it under ice cooling, and slowly added to the bubble-free gas.
  • Ethyl imidazo[l,2-b]pyridazine-2-carboxylate (6.4 g, 33.5 mmol) was reacted at room temperature for 4 h.
  • reaction solution was cooled to 0 Q C in an ice bath, and water (3.8 mL) and a 10% sodium hydroxide solution (3.8 mL) were slowly added dropwise thereto, and stirred for half an hour. Filtration under reduced pressure, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford intermediate imid[l,2-b]pyridazin-2-yl-methanol (yellow solid, 2.7 g).
  • Imidazo[l,2-b]pyridazin-2-ylmethanol (270 mg, 1.8 mmol) was dissolved in dichloromethane (20 mL). g, 2.7 mmol) and sodium bicarbonate powder C457 mg, 5.4 mmol), continue to react at room temperature for 2 h. After the TLC detection reaction was completed, a saturated sodium thiosulfate solution (20 mL) was added to the reaction mixture, and after stirring for 10 minutes, the organic phase was separated, and the aqueous phase was extracted with dichloromethane (10 mL ⁇ 3), and the organic phase was combined. Washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated.
  • Methyl 2-methyl- 4-nitro-benzoate (3.0 g, 15 mmol) was dissolved in carbon tetrachloride (50 mL), followed by N-bromosuccinimide (3.0 g, 17 mmol) and benzoyl peroxide (100 mg, 0.4 mmol), and the reaction mixture was refluxed for 10 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and evaporated.
  • the third step 5-amino-2-cyclopropylmethyl-2,3-dihydro-isoindole-1-one
  • the fourth step 4-iodo-pyridine-2-carboxylic acid (2-cyclopropylmethyl-1-oxo-2,3-dihydro-1H-isoindole-5-yl)-amide
  • EtOAc EtOAc m. 5-Bromo-6-methyl-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-nicotinamide (yellow solid, 0.26 g) ), the yield is 65%.
  • Methyl 3-iodo-4-fluoromethylnicotinate (280 mg, 0.95 mmol) was dissolved in methanol (10 mL), 4N sodium hydroxide solution (0.88 mL, 3.5 mmol), and stirred at 75 ° C for 2.5 h . After completion of the reaction, the solvent was evaporated, and the residue was evaporated to m.
  • Step 5 4-fluoromethyl-3-iodo-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-nicotinamide
  • 3-iodo-4-fluoromethylnicotinic acid (225 mg, 0.8 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (180 ⁇ , 1.09 mmol) and 2-(7-azabenzotriazole)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethylurea hexafluorophosphate (610 mg, 1.6 mmol), stir for 5 min and add 3 -Trifluoromethyl-4-(4-methylpiperazinylmethyl)aniline (198 mg, 0.72 mmol). After the reaction, the system was added with water and extracted with ethyl acetate twice.
  • Ethyl 3-iodo-4-hydroxymethylnicotinate (lg, 3.4 mmol) was dissolved in dichloromethane (20 mL), and then was added to Dess-Martin reagent (2.18 g, 5.1 mmol) and solid sodium hydrogen carbonate powder (863) Mg, 10.3 mmol), stir the reaction for 5 h at room temperature. After the reaction was completed, the mixture was evaporated.
  • the third step 3-iodo-4-difluoromethylnicotinic acid
  • Ethyl 3-iodo-4-difluoromethyl nicotinic acid (900 mg, 2.88 mmol) was dissolved in methanol (10 mL), 4N aqueous sodium hydroxide (2.6 mL, 10.4 mmol), and stirred at 75 °C The reaction was 2.5 h. After completion of the reaction, the solvent was evaporated, and the residue was adjusted to pH 3 with 2N hydrochloric acid and ethyl acetate.
  • the fourth step N- ⁇ K4-methylpiperazinyl-1-methyl)-3-trifluoromethylphenyl)-3-iodo-4-difluoromethylnicotinamide
  • Step 2 lp-iodo-4-nitro-benzyl)-4-methyl-piperazine
  • the reduced iron powder (637 mg, 11.37 mmol) was placed in a 25 mL reaction flask, 5 mL water and 0.5 mL glacial acetic acid were added, heated to reflux and stirred for 20 minutes.
  • a solution of 1-(2-cyclopropyl-4-nitro-benzyl)-4-methyl-piperazine (626 mg, 2.27 mmol) in ethanol (1 mL) was added to the reaction mixture and refluxed for 15 minutes. Stop heating.
  • the pH of the system was adjusted to 8 to 9 with a saturated sodium carbonate solution while hot. After the system was cooled to room temperature, the solvent was evaporated under reduced pressure.
  • Step 5 N-[3-Cyclopropyl-4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-6-difluoromethyl-5-iodo-nicotinamide
  • 6-Difluoromethyl-5-iodo-nicotinic acid (74 mg, 0.245 mmol), 3-cyclopropyl-4-(4-methyl-piperazinemethylidenemethyl)-aniline (40 mg, 0.163 Ment) and 2-(7-azabenzotriazole) ⁇ ' ⁇ '-tetramethylurea hexafluorophosphate (94 mg, 0.245 mmol) dissolved in N,N-dimethylformamide ( In 3 mL), N,N-dimethylformamide (42 mg, 0.326 mmol) was slowly added to the system and stirred at room temperature overnight.
  • Ethyl-6-(hydroxymethyl)-5-iodo-pyridine-3-carboxylate (386 mg, 1.25 mmol) was dissolved in dichloromethane (5 mL), pyridine (0.1 mL) Sulfoxide (0.18 mL, 2.5 mmol) was stirred at room temperature for 1 h. After the completion of the TLC reaction, the reaction mixture was washed with water, dried over anhydrous sodium sulfate, and evaporated, evaporated, evaporated, evaporated. , 227 mg).
  • Ethyl-6-(chloromethyl)-5-iodo-pyridine-3-carboxylate (194 mg, 0.593 mmol) was dissolved in methanol (3 mL), and sodium methoxide solution (25% in MeOH, 0.5 mL). The reaction was heated to 75 Q C for 30 min. After the TLC detection reaction, the solvent was evaporated to dryness, and the residue was dissolved in water. The mixture was adjusted to pH 3-4 with 2N aqueous hydrochloric acid, and the solid was precipitated, filtered, washed with a small amount of water, and dried to give 5-iodo-6-methoxy Methyl-nicotinic acid (white solid, 116 mg).
  • Step 3 5-iodo-6-methoxymethyl-N-[4-(4-methyl-piperazinylmethyl)-3-trifluoromethyl-phenyl]-nicotinamide
  • 3-iodo-4-methylnicotinic acid (396 mg) was dissolved in N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (333 L) and 2-(7) -azabenzotriazole)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethylurea hexafluorophosphate (613 mg), stirred for 15 min, then added 4-(tert-butyl-dimethyl-silicon Oxymethyl)-3-trifluoromethyl-phenylamine (410 mg) was stirred at room temperature for 4 h. After the reaction, the system was added with water and extracted with ethyl acetate twice.
  • N- (4-Hydroxymethyl-3-trifluoromethylphenyl)-5-iodo-6-methyl-nicotinamide (90 mg) was dissolved in N,N-dimethylformamide (5 mL) N,N-diisopropylethylamine (73 L) was added, and methanesulfonyl chloride (50 L) was added dropwise under ice-cooling, and stirred at room temperature overnight. Water was added, and the mixture was extracted with EtOAc. EtOAc (EtOAc)
  • Step 5 N-[4-(3-Dimethylamino-pyrrolidin-1-ylmethyl)-3-trifluoromethylphenyl]-5-iodo-6-methyl-nicotinamide
  • N-(4- ⁇ [(2-dimethylamino-ethyl)-methyl-amino]-methyl 3 intermediate was obtained by the same synthesis method as in Example 28 using N-methylhomopiperazine as the starting material. -Trifluoromethylphenyl)-5-iodo-6-methyl-nicotinamide. MS m/z (ESI): 261.2 [M+2].
  • Example 1 6-Methyl-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethylphenyl]-5-[1,2,4] Azole [4,3-a]pyridin-3-ylethylidene-nicotinamide
  • Example 2 to Example 26 was obtained by the same general procedure as in Example 1 using different aryl b-block and halogenated intermediates as starting materials.
  • Example 36 6-Methyl-N-[4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]-5-(6-pyridin-3-yl- Imidazole [l,2-b]pyridazin-3-ylethylidene)-nicotinamide
  • the compounds of the present invention have good inhibitory activities against different kinase mutants such as AblT315I BrafV600E and the like.
  • the inhibitory activity of some of the compounds on AWT315I kinase is shown in the following table (where IC 5 ⁇ 100 nM is represented by the symbol ++++; 100 nM ⁇ IC 50 ⁇ 500 nM is represented by the symbol +++; 500 nM ⁇ IC 50 ⁇ 1000 nM is represented by the symbol ++; IC 5 > 1000 nM is represented by the symbol +).
  • the cell proliferation inhibitory activity test described in the test example is for measuring the proliferation inhibitory activity of the compound of the present invention against a cell line highly expressed such as EGFR Bcr-Abl, and the inhibitory activity of the test compound on cell proliferation is determined by a half inhibitory concentration: IC 5 .
  • the experimental protocol for this type of test is as follows: Select different cells, such as K-562 cells, A431 cells, etc.
  • Cell concentration for example, 25000 cells/ml medium
  • the cells were seeded on a white opaque 384-well culture plate; the cells were then placed in an environment of 37 ° C 5% CO 2 for culture; after 24 hours, culture was performed. A series of concentration gradients were added to the cell culture medium, and 10 concentrations were generally selected. After the cells were returned to the original culture environment for 48 hours, the test compound was determined according to the method of CellTiter-Glo Luminescent Cell Viability Assay.
  • the compound of the present invention has an activity of inhibiting proliferation of K-562 cells, and the results of cell proliferation inhibitory activity of some of the compounds of the examples are shown below (inhibition activity is represented by IC 5 values, wherein IC 5 . ⁇ 50 nM is represented by the symbol ++++ 50 nM ⁇ IC 5 ⁇ 500 nM is represented by the symbol +++; 500 nM ⁇ IC 50 ⁇ 1000 nM is represented by the symbol ++; IC 5 Q > 1000 nM is denoted by the symbol +).
  • Pharmacokinetic test of the compound of the present invention Rat or mouse is used as a test animal, and the plasma or the mouse is administered by the LC/MS/MS method at different times after intragastric administration and intravenous administration of the compound of the example. Drug concentration, the pharmacokinetic behavior of the compounds of the invention in rats or mice was investigated and their pharmacokinetic characteristics were evaluated.
  • test animals were healthy adult male SD rats or mice, provided by Shanghai Xipuerkekai Experimental Animal Co., Ltd.; administration mode and sample collection: intravenous injection into SD rats or mice (3 mg/ Kg, I mg/mL suspension of test compound) and intragastric administration (10 mg/kg, I mg/mL suspension of test compound), before and after administration 2, 5 , 15, 30, 60, 90, 120, 240, 360, 480, 1440 min in the rat or mouse fundus venous plexus to take blood 0.4 mL; take 50 L of plasma samples, respectively, add 200 internal standard acetonitrile solution to precipitate protein, Vortex for 10 min, centrifuge at 6000 g for 10 min; take 200 ⁇ supernatant 6000 g and centrifuge again for 10 min; then take 75 ⁇ supernatant, add gradient initial mobile phase to dilute, centrifuge at 6000 g for 10 min; The clear solution 70 was injected into a 96-well plate at an injection volume of 5 L for LC
  • the compound of the example 2, 3, 9, 13, 22, 27, 34 was stable in the plasma of mice and mice after intravenous administration, and the half-life was 160 min to 300 min; the plasma concentration-time curve after intragastric administration The lower area AUC is 60-200uM.min, the highest blood concentration is greater than 0.5uM, and the relative bioavailability is 20% ⁇ 60%. Therefore, the results indicate that the compound of the present invention has good pharmacokinetic properties in rats or mice.
  • Test Example 4 Pharmacodynamic test in nude mice
  • mice (Shanghai Xipuer-Beikai Experimental Animals Co., Ltd.) were used, weighing 16-18 g, female.
  • the tumor-bearing mice were tested for drug administration. The drug was administered once a day for 5 days, and the drug was stopped for 2 days for a total of 9 days. The tumor volume and body weight were measured daily.
  • Tumor Volume TV
  • RTV relative tumor volume
  • TV t the tumor volume at each measurement
  • relative tumor growth rate T/C (%) T RTV / C RTV Xl00, where T RTV: treatment group RTV, C RTV is negative control group RTV.
  • T/C relative tumor growth rate
  • the compounds of Examples 2, 9, 13, 22, 27, 34, etc. at a dose of 2.5 mg/kg to 10 mg/kg, significantly inhibited the growth of the K562 xenograft tumor nude mice until the regression.
  • the T/C ratio was less than 10%, and the test animals were better tolerated, and the change in body weight was less than 20%; and the compound of Example 2, 9, 13, 22, etc. was administered to the 32DT315I cells at a dose of 15 mg/kg.
  • Tumor model nude mice also have a significant effect of inhibiting growth until regression.
  • the T/C ratio on day 9 of administration is less than 50%, and the survival time of experimental animals can be significantly prolonged.
  • the median survival time is increased from 13 days to 13 days. 15-18 days.
  • some embodiments of the present invention have a good effect of inhibiting the growth of xenografted tumors in nude mice after intragastric administration, and can significantly prolong the survival of the experimental tumor-bearing nude mice.

Abstract

La présente invention concerne un dérivé d'acétylène disubstitué à cycle aromatique ayant la formule générale I, une composition pharmaceutique contenant le composé et des applications du composé et de la composition pharmaceutique pour guérir et/ou prévenir les tumeurs, A, B, T, M, Ra, Rb, Rt, m, n, et p étant définis dans le texte.
PCT/CN2013/075738 2012-05-16 2013-05-16 Dérivés d'acétylène ayant une activité antitumorale WO2013170770A1 (fr)

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WO2015050505A1 (fr) * 2013-10-03 2015-04-09 Agency For Science, Technology And Research Dérivés d'alcynes bicycliques et leurs utilisations
KR20160067873A (ko) * 2013-10-03 2016-06-14 에이전시 포 사이언스, 테크놀로지 앤드 리서치 비사이클릭 알킨 유도체들 및 이의 용도들
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