CN108794484B - [1,2,4] triazolo [4,3-a ] pyrazine derivative, pharmaceutical composition, preparation method and application thereof - Google Patents

[1,2,4] triazolo [4,3-a ] pyrazine derivative, pharmaceutical composition, preparation method and application thereof Download PDF

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CN108794484B
CN108794484B CN201810404445.4A CN201810404445A CN108794484B CN 108794484 B CN108794484 B CN 108794484B CN 201810404445 A CN201810404445 A CN 201810404445A CN 108794484 B CN108794484 B CN 108794484B
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enyl
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王加维
田从凡
王霞
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Beijing Shiantai Medicine Technology Development Co ltd
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    • 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
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Abstract

The invention discloses [1,2,4]]Triazolo [4,3-a]Pyrazine derivatives, pharmaceutical compositions, methods of preparation and uses thereof. The compound is selected from a compound shown in the following formula A, a stereoisomer, a racemate, a tautomer, an isotopic marker, a nitrogen oxide, a solvate or a pharmaceutically acceptable salt thereof. The compound has good TRK kinase inhibitory activity, is suitable for medicine and has clinical application value. In addition, the compound has simple synthesis steps, so the compound has good economic utilization value.

Description

[1,2,4] triazolo [4,3-a ] pyrazine derivative, pharmaceutical composition, preparation method and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a [1,2,4] triazolo [4,3-a ] pyrazine derivative, a pharmaceutical composition, a preparation method and an application thereof.
Background
Chromosomal rearrangements containing the ROS1 gene in the glioblastoma cell line U118MG were found to produce the ROS1 fusion gene (Genes Chromosomes Cancer,37,58-71 (2003)). The fusion between FIG and ROS1 causes structural alterations that constitutively activate ROS1 kinase activity, and the FIG-ROS1 fusion protein has cellular transformation activity or tumorigenic activity mediated by activation of the ROS1 signaling pathway involving STAT3, ERK, and SHP2 (proc. nat1.acad. sci. usa,100, 916-. Large scale screening of patient samples using FISH (fluorescence in situ hybridization) has identified fusion genes of the ROS1 gene with SDC, CD74, EZR, SLC34a2, LRIG3 or TPM 3. In addition, analysis of patient samples indicated that the ROS1 gene is highly expressed in brain tumors (Cancer res.,69,2180-2184 (2009)).
ROS1 are activated in tumors expressing ROS1 fusion genes, such as non-small Cell lung cancer, cholangiocarcinoma or brain cancer (Cell,131,1190-1203(2007), PLoS One,6(1), e15640 (2011)). Thus, drugs that inhibit ROS1 kinase activity can block the downstream ROS1 pathway, namely STAT3, ERK, SHP2, thereby preventing tumor growth and survival. ROS1 kinase has been reported as a potential target for the treatment of cancer, for example crizotinib (j. crin. oncol.2011.39.4197(2012)), TAE684(PLoS One,6(1), e15640(2011)), pyrazole derivatives (bioorg.med.chem.lett.,19,4720-4723(2009)) and aminopyrazine derivatives (WO 2012/005299). The neurotrophin tyrosine kinase receptor, also known as tropomyosin-related kinase (Trk), is a soluble growth factor-activated high affinity receptor for Neurotrophins (NTs). The NTRK receptor family has 3 members: NTRK1 (also known as TrkA), NTRK2 (also known as TrkB), NTRK3 (also known as TrkC). NT includes the following proteins: nerve Growth Factor (NGF) activating NTRK1, brain-derived neurotrophic factor (BDNF) and NT-4/5 activating NTRK2 and NT3 activating NTRK 3. Each NTRK receptor contains an extracellular domain (ligand binding site), a transmembrane domain, and an intracellular domain (containing a kinase domain). Each kinase catalyzes autophosphorylation upon binding to a ligand and then activates downstream signaling pathways.
Normally, NTRK is widely expressed in nerve continence, plays an important role in the maintenance and survival of these cells, and plays an important role in the development and function of the nervous system (Current Opinion in Neurobiology,11, 272-. A large number of recent literature reports that overexpression, activation, amplification, fusion gene formation or mutation of NTRK is associated with neuroblastoma (Pediatr Blood Cancer,59, 226-.
Selective NTRK tyrosine kinase inhibitors have been reported, including CEP-751, CEP-701(cancer research,59, 2395-2341(1999)), indolocarbazole compounds (WO01/14380), oxindole compounds (WO2/20479, WO02/20513), pyrazolyl fused ring compounds (Japanese patent laid-open No. 15-231687), isothiazole compounds (bioorg. Med. chem. Lett.,16,3444-3448(2006)), and other types of compounds (WO2005/049033, WO2005/103010, WO2006/082392, WO2006/087530, WO 2006087538). Imidazopyridazine backbone compounds (WO2007/013673, WO2007/025540, WO2007/147646, WO2008/052734, WO 2012/125667).
Therefore, the research and development of new high-efficiency low-toxicity and drug-resistance drugs with TRK kinase inhibitory activity have great social significance.
Disclosure of Invention
In order to improve the above problems, the present invention provides a compound represented by the following formula a, a stereoisomer, a racemate, a tautomer, an isotopic label, a nitrogen oxide, a solvate, or a pharmaceutically acceptable salt thereof,
Figure BDA0001646518070000021
G1is selected from
Figure BDA0001646518070000022
Wherein R is1Selected from H, unsubstituted or optionally substituted by one or more RaSubstituted of the following groups: c3-20Cycloalkyl, 3-20 membered heterocyclyl, C6-20Aryl, 5-20 membered heteroaryl;
x is selected from CRbWherein R isbSelected from H, ═ O, unsubstituted or optionally substituted with one or more RcSubstituted of the following groups: c1-40Alkyl or C1-40An alkoxy group;
G2、G4identical or different, independently of one another, from H, unsubstituted or optionally substituted by one or more RdSubstituted of the following groups: c1-40Alkyl radical, C2-40Alkenyl radical, C2-40Alkynyl, C1-40Alkoxy radical, C3-20Cycloalkyl, 3-20 membered heterocyclyl, C6-20Aryl, 5-20 membered heteroaryl;
G3is selected from
Figure BDA0001646518070000031
Wherein R is2、R3Identical or different, independently of one another, from H, unsubstituted or optionally substituted by one or more ReSubstituted of the following groups: c3-20Cycloalkyl, 3-20 membered heterocyclyl, C6-20Aryl radical, 5-a 20 membered heteroaryl;
or, R2、R3Together with the nitrogen atom to which they are attached form a group selected from unsubstituted or optionally substituted by one or more ReSubstituted ring systems of: 3-20 membered heterocyclyl, 5-20 membered heteroaryl;
each Ra、Rc、RdIdentical or different, independently of one another, from the group-F, -Cl, -Br, -I, or from the following groups: c1-40Alkyl radical, C1-40An alkoxy group;
Reis selected from-NH2-F, -Cl, -Br, -I, -OH, -SH, -CN, - (O), unsubstituted or optionally substituted by one or more RfSubstituted of the following groups: -NH-S (O)2-C1-40Alkyl, -S (O)2-C1-40Alkyl, -NH-C1-40Alkyl, di- (C)1-40Alkyl) amino, -C (O) -C1-40Alkyl radical, C1-40Alkyl radical, C1-40Alkoxy radical, C3-20Cycloalkyl, 3-20 membered heterocyclyl;
Rfis selected from-NH2、-F、-Cl、-Br、-I、-OH、-SH、-CN、＝O、C1-40Alkyl radical, C2-40Alkenyl radical, C2-40Alkynyl, C3-20Cycloalkyl, 3-20 membered heterocyclyl, C6-20Aryl, 5-20 membered heteroaryl;
a bond connecting the substitution sites.
According to an exemplary embodiment of the invention, G1In R1Selected from C, unsubstituted or optionally substituted by one or more of the following groups6-20Aryl or 5-20 membered heteroaryl: -F, -Cl, -Br, -I, C1-12Alkyl radical, C1-12An alkoxy group;
for example, G1In R1Selected from the following groups, unsubstituted or optionally substituted with one or more-F, -Cl, -Br, methoxy or ethoxy: phenyl, pyridyl;
according to an exemplary embodiment of the invention, G1Wherein X is selected from CH2、C＝O、-NH2-OH, or the following groups optionally substituted by one or more-F, -Cl, -Br: -C (C)1-12Alkyl radical)2、-CH-C1-12Alkyl, -CH-C1-12Alkoxy, or-NH-C1-12An alkyl group;
for example, G1Selected from the following groups:
Figure BDA0001646518070000041
wherein,
Figure BDA0001646518070000042
and (b) represents a bond linking the substitution sites.
According to an exemplary embodiment of the invention, G2、G4Identical or different, independently of one another, from H, unsubstituted or optionally substituted by one or more C1-12Alkyl-substituted the following groups: c1-12Alkyl radical, C1-12An alkoxy group.
According to an exemplary embodiment of the invention, G3In R2、R3Identical or different, independently of one another, from H, C which is unsubstituted or optionally substituted by one or more3-20Cycloalkyl, 3-20 membered heterocyclyl, C6-20Aryl, 5-20 membered heteroaryl: -NH2、-F、-Cl、-Br、-I、-OH、-SH、-CN、＝O、-NH-S(O)2-C1-12Alkyl, -S (O)2-C1-12Alkyl, -S (O)2-NH2、 -NH-C1-12Alkyl, di- (C)1-12Alkyl) amino, -C (O) -C1-12Alkyl, -C (O) -NH2、C1-12Alkyl radical, C1-12Alkoxy, 3-20 membered heterocyclyl;
or, R2、R3Together with the nitrogen atom to which they are attached form a 3-20 membered heterocyclyl group selected from unsubstituted or optionally substituted with one or more of the following: -NH2、-F、-Cl、-Br、-I、-OH、-SH、-CN、＝O、-C(O)-NH2、C1-12Alkyl radical, C1-12An alkoxy group;
for example, G3Selected from the following groups:
Figure BDA0001646518070000051
wherein,
Figure BDA0001646518070000052
is a bond connecting the substitution sites.
According to an exemplary embodiment, the compound of formula a is selected from the group including, but not limited to, the following compounds:
Figure BDA0001646518070000053
Figure BDA0001646518070000061
Figure BDA0001646518070000071
Figure BDA0001646518070000081
the invention also provides a pharmaceutical composition, which comprises one, two or more of a therapeutically effective amount of a compound shown as the formula A, a stereoisomer, a racemate, a tautomer, an isotope label, a nitrogen oxide, a solvate or a pharmaceutically acceptable salt thereof.
According to an embodiment of the present invention, the pharmaceutical composition further optionally comprises pharmaceutically acceptable excipients thereof, such as carriers, excipients; the auxiliary materials are selected from one, two or more of the following materials: disintegrants, glidants, lubricants, diluents or fillers, binders, colorants.
The present invention also provides a method for treating a disease by inhibiting TRK kinase activity comprising administering to a patient in need of such treatment and/or prevention a therapeutically effective amount of one, two or more of a compound represented by formula a, a stereoisomer, a racemate, a tautomer, an isotopic label, a nitric oxide, a solvate, or a pharmaceutically acceptable salt thereof.
According to an embodiment of the invention, the disease is selected from breast cancer, skin cancer, bladder cancer, ovarian cancer, stomach cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, rectal cancer, esophageal cancer, tongue cancer, kidney cancer, renal parenchymal cancer, cervical cancer, uterine corpus cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, astrocytic cancer, meningioma, hodgkin's lymphoma, non-hodgkin's lymphoma, acute lymphatic leukemia, chronic lymphatic leukemia, acute myeloid leukemia, chronic myeloid leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, bronchial cancer, multiple myeloma, basal cell tumor, seminoma, rhabdomyosarcoma, chondrosarcoma, myosarcoma, or fibrosarcoma.
The invention also provides application of one, two or more of the compound shown in the formula A, the stereoisomer, racemate, tautomer, isotopic marker, nitrogen oxide, solvate or pharmaceutically acceptable salt thereof in preparing medicines.
According to an embodiment of the present invention, the medicament achieves the purpose of treating diseases by inhibiting TRK kinase activity; the disease is selected from breast cancer, skin cancer, bladder cancer, ovarian cancer, stomach cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, rectal cancer, esophageal cancer, tongue cancer, kidney cancer, renal parenchymal cancer, cervical cancer, uterine corpus cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, astrocytic cancer, meningioma, hodgkin's lymphoma, non-hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, bronchial cancer, multiple myeloma, basal cell tumor, seminoma, rhabdomyosarcoma, chondrosarcoma, myosarcoma, or fibrosarcoma.
The present invention also provides a process for the preparation of a compound of formula a, comprising:
(1) synthesis of intermediate III
Figure BDA0001646518070000091
Reacting the compound I with the compound II to obtain a compound III;
(2) synthesis of intermediate V
Figure BDA0001646518070000092
Reacting the compound III obtained in the step (1) with a compound IV to obtain a compound V;
(3) synthesis of intermediate VI
Figure BDA0001646518070000093
Reacting the compound V obtained in the step (2) to obtain a compound VI;
(4) synthesis of Compounds of formula A
Figure BDA0001646518070000101
Reacting the compound VI obtained in the step (3) with a compound VII to obtain a compound shown in a formula A;
wherein G is1、G2、G3、G4、R1、R2、R3And X is as defined above.
According to the production method of the present invention, in the step (1),
the reaction is carried out at a temperature of 20 ℃ to 100 ℃;
the reaction is carried out in the presence of a base; the base is one or two or more selected from triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide;
the reaction is carried out in a solvent; the solvent is one or two or more of alcohol solvent, ether solvent and aromatic solvent; for example, one, two or more selected from ethanol, isopropanol, dioxane, tetrahydrofuran, and toluene.
According to the production method of the present invention, in the step (2),
the reaction is carried out at a temperature of 20 ℃ to 100 ℃;
the reaction is carried out in the presence of a catalyst; the catalyst is selected from PdCl2(PPh3)2、Pd(PPh3)4、Pd2(dba)3、 Pd(OAc)2、Pd(dppf)2Cl2One, two or more of;
the reaction is carried out in the presence of a ligand; the ligand is selected from one, two or more of 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (SPhos) and 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene (XantPhos);
the reaction is carried out in the presence of a base; the alkali is one or two or more of cesium carbonate, sodium tert-butoxide, potassium phosphate and sodium acetate.
According to the production method of the present invention, in the step (3),
the reaction is carried out at a temperature of 20 ℃ to 100 ℃;
the reaction is carried out in the presence of a base; the alkali is selected from one, two or more of lithium hydroxide, sodium hydroxide and potassium hydroxide.
According to the production method of the present invention, in the step (4),
the reaction is carried out at a temperature of 20 ℃ to 100 ℃;
the reaction is carried out in the presence of a base; the base is selected from one, two or more of triethylamine, diisopropylethylamine, N-methylmorpholine and DMAP;
the reaction is carried out in the presence of a condensing agent; the condensing agent is selected from one, two or more of EDCI, HATU, BopCl and DCC.
Advantageous effects
The compound has good TRK kinase inhibitory activity, is suitable for medicine and has clinical application value. In addition, the compound has simple synthesis steps, so the compound has good economic utilization value.
Definition and description of terms
Unless otherwise indicated, the definitions of groups and terms described in the specification and claims of the present application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. The definitions of the groups and the structures of the compounds in such combinations and after the combination are within the scope of the present specification.
The term "C1-40Alkyl is understood to preferably mean a straight-chain or branched, saturated monovalent hydrocarbon radical having from 1 to 40 carbon atoms, preferably C1-10An alkyl group. "C1-10Alkyl "is understood to preferably mean a straight-chain or branched, saturated monovalent hydrocarbon radical having 1,2, 3,4, 5,6, 7, 8, 9 or 10 carbon atoms. The alkyl group is, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a 2-methylbutyl group, a 1-ethylpropyl group, a 1, 2-dimethylpropyl group, a neopentyl group, a 1, 1-dimethylpropyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-ethylbutyl group, a 1-ethylbutyl group, a 3, 3-dimethylbutyl group, a2, 2-dimethylbutyl group, a 1, 1-dimethylbutyl group, a2, 3-dimethylbutyl group, a 1, 3-dimethylbutyl group or a 1, 2-dimethylbutyl group. In particular, the radicals have 1,2, 3,4, 5,6 carbon atoms ("C)1-6Alkyl groups) such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, more particularly groups having 1,2 or 3 carbon atoms ("C)1-3Alkyl groups) such as methyl, ethyl, n-propyl or isopropyl.
The term "C2-40Alkenyl "is understood to preferably mean a straight-chain or branched monovalent hydrocarbon radical comprising one or more double bonds and having from 2 to 40 carbon atoms, preferably" C2-10Alkenyl ". "C2-10Alkenyl "is understood to preferably mean a straight-chain or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2,3, 4,5, 6,7, 8, 9 or 10 double bondsCarbon atoms, especially 2 or 3 carbon atoms (' C)2-3Alkenyl "), it being understood that in the case where the alkenyl group comprises more than one double bond, the double bonds may be separated from each other or conjugated. The alkenyl group is, for example, vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, (E) -but-2-enyl, (Z) -but-2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, pent-4-enyl, (E) -pent-3-enyl, (Z) -pent-3-enyl, (E) -pent-2-enyl, (Z) -pent-2-enyl, (E) -pent-1-enyl, (Z) -pent-1-enyl, hex-5-enyl, (E) -hex-4-enyl, (Z) -hex-4-enyl, m-n-2-enyl, m-n-1-enyl, m-n-E-4-enyl, m-n-2-, (E) -hex-3-enyl, (Z) -hex-3-enyl, (E) -hex-2-enyl, (Z) -hex-2-enyl, (E) -hex-1-enyl, (Z) -hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E) -1-methylprop-1-enyl, (Z) -1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E) -2-methylbut-2-enyl, (Z) -2-methylbut-2-enyl, (E) -1-methylbut-2-enyl, (Z) -1-methylbut-2-enyl, (E) -3-methylbut-1-enyl, (Z) -3-methylbut-1-enyl, (E) -2-methylbut-1-enyl, (Z) -2-methylbut-1-enyl, (E) -1-methylbut-1-enyl, (Z) -1-methylbut-1-enyl, 1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl group and 1-isopropylvinyl group.
The term "C2-40Alkynyl "is understood to mean a straight-chain or branched monovalent hydrocarbon radical comprising one or more triple bonds and having from 2 to 40 carbon atoms, preferably" C2-C10Alkynyl ". The term "C2-C10Alkynyl "is understood as preferably meaning a straight-chain or branched, monovalent hydrocarbon radical which contains one or more triple bonds and has 2,3, 4,5, 6,7, 8, 9 or 10 carbon atoms, in particular 2 or 3 carbon atoms (" C2-C3-alkynyl "). The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynylA group, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 3-methylbut-1-ynyl, 2-ethylbut-3-ynyl, 3-methylbut-2-ynyl, 3-ethylbut-, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2-dimethylbut-3-ynyl, 1-dimethylbut-2-ynyl or 3, 3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.
The term "C3-20Cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 20 carbon atoms, preferably "C3-10Cycloalkyl groups ". The term "C3-10Cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3,4, 5,6, 7, 8, 9 or 10 carbon atoms. Said C is3-10Cycloalkyl groups may be monocyclic hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic hydrocarbon groups such as decalin rings.
The term "3-20 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring comprising 1-5 heteroatoms independently selected from N, O and S, preferably "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring comprising 1-5, preferably 1-3 heteroatoms selected from N, O and S. The heterocyclic group may be attached to the rest of the molecule through any of the carbon atoms or nitrogen atom (if present). In particular, the heterocyclic group may include, but is not limited to: 4-membered rings such as azetidinyl, oxetanyl; 5-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclyl group may be bicyclic, for example but not limited to a 5,5 membered ring, such as a hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl ring, or a 5,6 membered bicyclic ring, such as a hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl ring. The nitrogen atom containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, 2, 5-dihydro-1H-pyrrolyl, 4H- [1,3,4] thiadiazinyl, 4, 5-dihydrooxazolyl, or 4H- [1,4] thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. According to the invention, the heterocyclic radical is non-aromatic.
The term "C6-20Aryl "is understood to preferably mean a mono-, bi-or tricyclic hydrocarbon ring having a monovalent or partially aromatic character with 6 to 20 carbon atoms, preferably" C6-14Aryl ". The term "C6-14Aryl "is to be understood as preferably meaning a mono-, bi-or tricyclic hydrocarbon ring having a monovalent or partially aromatic character with 6,7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (" C6-14Aryl group "), in particular a ring having 6 carbon atoms (" C6Aryl "), such as phenyl; or biphenyl, or is a ring having 9 carbon atoms ("C9Aryl), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C10Aryl radicals), such as tetralinyl, dihydronaphthyl or naphthyl, or rings having 13 carbon atoms ("C13Aryl radicals), such as the fluorenyl radical, or a ring having 14 carbon atoms ("C)14Aryl), such as anthracenyl.
The term "5-20 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: having 5 to 20 ring atoms and comprising 1 to 5 heteroatoms independently selected from N, O and S, such as "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: which has 5,6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and which comprises 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S and, in addition, can be benzo-fused in each case. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and their benzo derivatives, such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, and the like; or azocinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.
Unless otherwise indicated, heterocyclyl, heteroaryl or heteroarylene include all possible isomeric forms thereof, e.g., positional isomers thereof. Thus, for some illustrative, non-limiting examples, pyridyl or pyridinylene includes pyridin-2-yl, pyridinylene-2-yl, pyridin-3-yl, pyridinylene-3-yl, pyridin-4-yl, and pyridinylene-4-yl; thienyl or thienylene includes thien-2-yl, thien-3-yl and thien-3-yl.
The target compound may be isolated according to known methods, for example by extraction, filtration or column chromatography.
Depending on their molecular structure, the compounds of the invention may be chiral and may therefore exist in various enantiomeric forms. These compounds may thus be present in racemic or optically active form. The compounds of the invention or intermediates thereof may be separated into enantiomeric compounds by chemical or physical methods well known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from mixtures by reaction with optically active resolving agents. Examples of suitable resolving agents are optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g. N-benzoylproline or N-benzenesulfonylproline) or various optically active camphorsulphonic acids. The chromatographic enantiomeric resolution can also advantageously be carried out with the aid of optically active resolving agents, such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chirally derivatized methacrylate polymers, which are immobilized on silica gel. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane/isopropanol/acetonitrile.
Pharmaceutically acceptable salts may be acid addition salts of the compounds of the invention having sufficient basicity, for example having a nitrogen atom in the chain or ring, for example with the following inorganic acids: for example hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or hydrogen sulfates, or acid addition salts with organic acids such as: such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, Mandelic acid, ascorbic acid, glucoheptylic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid.
Since the compound of the present invention may exist at a plurality of salt-forming sites, the "pharmaceutically acceptable salt" includes not only the salt formed at1 salt-forming site among the compounds of the present invention but also the salt formed at 2,3 or all of the salt-forming sites among them. For this purpose, the molar ratio of the "pharmaceutically acceptable salt" of the compound of formula (I) to the cation of the acid (anion) or base required for salt formation may vary within wide limits, and may be, for example, 4:1 to 1:4, such as 3:1, 2:1, 1:2, 1:3, etc.
According to the present invention, the pharmaceutically acceptable anion includes anions selected from the group consisting of those generated by ionization of inorganic or organic acids. The "inorganic acid" includes, but is not limited to, hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, or nitric acid. The "organic acid" includes, but is not limited to, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, maleic, Fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid.
The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule. The compounds of the invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; whereas in phenol the enol type predominates. The present invention encompasses all tautomeric forms of the compounds.
The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound of the present invention sufficient to effect the intended use, including but not limited to the treatment of a disease as defined below. The therapeutically effective amount may vary depending on the following factors: the intended application (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition and the mode of administration, etc., can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on the following factors: the particular compound selected, the dosage regimen to be followed, whether to administer it in combination with other compounds, the timing of administration, the tissue to be administered and the physical delivery system carried.
The term "adjuvant" refers to a pharmaceutically acceptable inert ingredient. Examples of types of excipients include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients enhance the handling characteristics of the pharmaceutical formulation, i.e., make the formulation more amenable to direct compression by increasing flowability and/or cohesiveness. Examples of typical pharmaceutically acceptable carriers suitable for use in the above formulations are: sugars such as lactose, sucrose, mannitol, and sorbitol; starches, such as corn starch, tapioca starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates, such as magnesium stearate and calcium stearate; stearic acid; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; nonionic, cationic and anionic surfactants; a glycol polymer; fatty alcohols; and grain hydrolyzed solids and other nontoxic compatible excipients commonly used in pharmaceutical formulations, such as fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, colorants, and the like.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
Example 1
Preparation of (R) -6- (2- (2,5-2, 5-difluorophenyl) pyrrolidin-1-yl) -N- (4- (methylsulfonylamino) phenyl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxamide
Figure BDA0001646518070000161
The first step is as follows:
dissolving the compound 1a (14.5g,100mmol) and the compound 1b (12.3g,100mmol) in a mixed solvent of toluene (100ml) and pyridine (20ml), heating to 100 ℃, stirring for 6 hours, detecting the reaction by TLC, adding diluted hydrochloric acid to quench the reaction after the reaction is finished, drying an organic layer, filtering, concentrating, and carrying out column chromatography to obtain 18.7g of yellow oily matter with the yield of 88.0%. The second step is that:
compound 1c (18.5g,87.0mmol) obtained in the first step, compound 1d (15.9g,87.0mmol), cesium carbonate (42.0g,130.5mmol), Pd (dba)2(2.6g,4.4mmol) and 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (2.6g,4.4mmol) are dissolved in DMF (100ml), the temperature is raised to 100 ℃, the mixture is stirred and reacted for 12 hours, the reaction is detected by TLC, after the reaction is finished, the reaction solution is poured into water (100ml), ethyl acetate (200mlx2) is extracted, organic phases are combined and dried, filtered, concentrated and separated by column chromatography to obtain 20.2g of off-white solid, and the yield is 64.6%.
The third step:
dissolving the compound 1e (20.0g,55.7mmol) obtained in the second step in ethanol (100ml) and purified water (50ml), adding sodium hydroxide (6.7g,167.0mmol) at room temperature, stirring for 12 hours, detecting by TLC, removing ethanol under reduced pressure after the reaction is finished, adding ethyl acetate (200ml), adjusting pH to 5-6 with diluted hydrochloric acid, drying the organic layer, filtering, concentrating, and separating by column chromatography to obtain off-white solid 15.3g with yield 79.7%.
The fourth step:
dissolving the compound 1f (1.0g,3.0mmol) obtained in the third step, 1g (558mgg,3.0mmol) and DIPEA (580mg,4.5mmol) in DMF (20ml), adding HATU (1.7g,4.5mmol) at room temperature, stirring for 4 hours, detecting by TLC, adding water (20ml) after the reaction is finished, quenching the reaction, extracting with ethyl acetate (100mlx2), combining organic layers, drying the organic layers, filtering, concentrating, and performing column chromatography to obtain 0.7g of off-white solid with the yield of 45.5%. MS-ESI: M/z 514.5[ M +1 ].
Example 2
Preparation of (S) -6- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) -N- (4- (dimethylamino) phenyl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxamide
Prepared by the method of reference example 1, MS-ESI: M/z 464.5[ M +1 ].
Figure BDA0001646518070000171
Example 3
Preparation of (R) -6- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) -N- (4-aminosulfonylphenyl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxamide
Prepared by the method of reference example 1, MS-ESI: M/z 500.5[ M +1 ].
Figure BDA0001646518070000172
Example 4
Preparation of (R) -N- (4-carbamoylphenyl) -6- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxamide
Prepared by the method of reference example 1, MS-ESI: M/z 464.5[ M +1 ].
Figure BDA0001646518070000173
Example 5
Preparation of (R) -6- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) -N- (4- (2-hydroxypropan-2-yl) phenyl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxamide
Prepared by the method of reference example 1, MS-ESI: M/z 479.5[ M +1 ].
Figure BDA0001646518070000181
Example 6
Preparation of (R) -6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -N- (4- (methylsulfonylamino) phenyl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxamide
Referring to the procedure of example 1, MS-ESI: M/z 527.2[ M +1 ].
Figure BDA0001646518070000182
Example 7
Preparation of (R) -N- (4- (dimethylamino) phenyl) -6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxamide
Referring to the procedure of example 1, MS-ESI: M/z 477.2[ M +1 ].
Figure BDA0001646518070000183
Example 8
Preparation of (R) -6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -N- (4-aminosulfonylphenyl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxamide
Referring to the procedure of example 1, MS-ESI: M/z 513.1[ M +1 ].
Figure BDA0001646518070000184
Example 9
Preparation of (R) -N- (4-aminocarbonylphenyl) -6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxamide
Referring to the procedure of example 1, MS-ESI: M/z 477.2[ M +1 ].
Figure BDA0001646518070000191
Example 10
Preparation of (R) -6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -N- (4- (2-hydroxypentan-2-yl) phenyl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxamide
Referring to the procedure of example 1, MS-ESI: M/z 492.2[ M +1 ].
Figure BDA0001646518070000192
Example 11
Preparation of (R) -6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -N- (4-methoxyphenyl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxamide
Referring to the procedure of example 1, MS-ESI: M/z 464.2[ M +1 ].
Figure BDA0001646518070000193
Example 12
Preparation of (R) -N- (benzo [ d ] [1,3] dioxolan-5-yl) -6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxamide
Referring to the procedure of example 1, MS-ESI: M/z 478.2[ M +1 ].
Figure BDA0001646518070000201
Example 13
Preparation of (R) -N- (4-cyanophenyl) -6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxamide
Referring to the procedure of example 1, MS-ESI: M/z 459.2[ M +1 ].
Figure BDA0001646518070000202
Example 14
Preparation of (R) -6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -N- (2-methoxypyridin-4-yl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxamide
Referring to the procedure of example 1, MS-ESI: M/z 465.2[ M +1 ].
Figure BDA0001646518070000203
Example 15
Preparation of (R) -6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -N- (pyrimidin-2-yl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxamide
Referring to the procedure of example 1, MS-ESI: M/z 436.2[ M +1 ].
Figure BDA0001646518070000204
Example 16
Preparation of (R) - (6- (2- (6-fluoropyridin-2-yl) pyrrolidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) (morpholinyl) methylketone
Referring to the procedure of example 1, MS-ESI: M/z 398.2[ M +1 ].
Figure BDA0001646518070000211
Example 17
Preparation of (R) - (6- (2- (6-fluoropyridin-2-yl) pyrrolidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) (piperazin-1-yl) methylketone
Referring to the procedure of example 1, MS-ESI: M/z: 397.2[ M +1 ].
Figure BDA0001646518070000212
Example 18
Preparation of (3, 5-dimethylpiperidin-1-yl) (6- ((R) -2- (6-fluoropyridin-2-yl) pyrrolidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) methylketone
Referring to the procedure of example 1, MS-ESI: M/z 425.2[ M +1 ].
Figure BDA0001646518070000213
Example 19
Preparation of (R) - (6- (2- (6-fluoropyridin-2-yl) pyrrolidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) (4-methylpiperidin-1-yl) methylketone
Referring to the procedure of example 1, MS-ESI: M/z 411.2[ M +1 ].
Figure BDA0001646518070000214
Example 20
Preparation of (R) -1- (6- (2- (6-fluoropyridin-2-yl) pyrrolidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carbonyl) piperidin-4-one
Referring to the procedure of example 1, MS-ESI: M/z 410.2[ M +1 ].
Figure BDA0001646518070000221
Example 21
Preparation of (R) -6- (2- (2-fluoro-5-methoxyphenyl) pyrrolidin-1-yl) -N- (4- (methylsulfonylamino) phenyl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxamide
Referring to the procedure of example 1, MS-ESI: M/z 426.2[ M +1 ].
Figure BDA0001646518070000222
Example 22
Preparation of (R) -N- (4- (dimethylamino) phenyl) -6- (2- (2-fluoro-5-methoxyphenyl) pyrrolidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxamide
Referring to the procedure of example 1, MS-ESI: M/z 476.2[ M +1 ].
Figure BDA0001646518070000223
Example 23
Preparation of (R) -6- (2- (2-fluoro-5-methoxyphenyl) pyrrolidin-1-yl) -N- (4-aminosulfonylphenyl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxamide
Referring to the procedure of example 1, MS-ESI: M/z is 512.1[ M +1 ].
Figure BDA0001646518070000231
Example 24
Preparation of (R) -N- (4-aminocarbonylphenyl) -6- (2- (2-fluoro-5-methoxyphenyl) pyrrolidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxamide
Referring to the procedure of example 1, MS-ESI: M/z 476.2[ M +1 ].
Figure BDA0001646518070000232
Example 25
Preparation of (R) -6- (2- (2-fluoro-5-methoxyphenyl) pyrrolidin-1-yl) -N- (4- (2-hydroxypropan-2-yl) phenyl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxamide
Referring to the procedure of example 1, MS-ESI: M/z 491.2[ M +1 ].
Figure BDA0001646518070000233
Example 26
Preparation of (R) -6- (2- (5-chloro-2-fluorophenyl) pyrrolidin-1-yl) -N- (4- (methylsulfonylamino) phenyl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxamide
Referring to the procedure of example 1, MS-ESI: M/z 530.1[ M +1 ].
Figure BDA0001646518070000241
Example 27
Preparation of (R) -6- (2- (5-chloro-2-fluorophenyl) pyrrolidin-1-yl) -N- (4- (dimethylamino) phenyl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxamide
Referring to the procedure of example 1, MS-ESI: M/z 480.2[ M +1 ].
Figure BDA0001646518070000242
Example 28
Preparation of (R) -6- (2- (5-chloro-2-fluorophenyl) pyrrolidin-1-yl) -N- (4-aminosulfonylphenyl) - [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxamide
Referring to the procedure of example 1, MS-ESI: M/z 516.1[ M +1 ].
Figure BDA0001646518070000243
EXAMPLE 29 determination of biological Activity
Determination of biological Activity
TrkA ELISA assay
TrkA kinase activity was assessed using an enzyme-linked immunosorbent assay in the presence of the inhibitor. Immulon 4HBX384 well microtiter plates were coated with 0.025mg/ml poly (Glu, Ala, Tyr; 6:3:1) solution and each concentration of test compound, 2.5nM TrkA (histidine-tagged recombinant human TrkA fine structure) and 500. mu.M ATP were incubated in the coated plates at ambient temperature for 25 minutes with shaking. The assay buffer was composed of 25mM MOPS pH7.5, 0.005% (V/V) Triton X-100 and 5mM MgCl2And (4) forming. The reaction mixture was removed from the plate by washing with PBS containing 0.1% (V/V) Tween 20. Phosphorylation reaction products were detected using a 0.2 μ g/mL phosphotyrosine specific monoclonal antibody coupled to horseradish peroxidase in combination with a TMB peroxidase enzyme system. After addition of 1M phosphoric acid, the color of the chromogenic substance became stronger quantitatively by the absorbance at 450 nm. Calculating IC using parametric logarithmic curve fitting50The value is obtained.
The results indicate that the IC for TrkA is that of the compounds of examples 1-2850Values between 10nM and 10. mu.M, where IC of the compounds of examples 5, 9, 13, 1750Values between 15nM and 20nM, and IC for the compounds of examples 27 and 2850The value is higher than 5. mu.M.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (6)

1. The following compounds:
Figure FDA0002289778870000011
Figure FDA0002289778870000021
Figure FDA0002289778870000031
2. a pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1; the pharmaceutical composition achieves the purpose of treating diseases by inhibiting the activity of TRK kinase.
3. The pharmaceutical composition of claim 2, wherein the composition comprises a pharmaceutically acceptable excipient thereof;
the auxiliary materials are selected from one, two or more of the following materials: disintegrants, glidants, lubricants, diluents or fillers, binders, colorants.
4. Use of one or more of the compounds of claim 1 in the manufacture of a medicament;
the medicine achieves the purpose of treating diseases by inhibiting the activity of TRK kinase.
5. The use of claim 4, wherein the disease is selected from breast cancer, skin cancer, bladder cancer, ovarian cancer, stomach cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, rectal cancer, esophageal cancer, tongue cancer, kidney cancer, renal parenchymal cancer, cervical cancer, uterine body cancer, endometrial cancer, testicular cancer, astrocytic cancer, meningioma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, bronchial cancer, multiple myeloma, basal cell tumor, seminoma, chondrosarcoma, myosarcoma, or fibrosarcoma.
6. A process for preparing a compound of claim 1 comprising:
(1) synthesis of intermediate III
Figure FDA0002289778870000041
Reacting the compound I with the compound II to obtain a compound III;
(2) synthesis of intermediate V
Figure FDA0002289778870000042
Reacting the compound III obtained in the step (1) with a compound IV to obtain a compound V;
(3) synthesis of intermediate VI
Figure FDA0002289778870000043
Reacting the compound V obtained in the step (2) to obtain a compound VI;
(4) synthesis of Compounds of formula A
Figure FDA0002289778870000051
Reacting the compound VI obtained in the step (3) with a compound VII to obtain a compound shown in a formula A;
wherein G is1、G2、G3、G4、R1、R2、R3X has the meaning indicated in claim 1.
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